Introduction to Biological Psychology

🧭 Overview

🧠 One-sentence thesis

Biological psychology investigates how physical processes in the brain and nervous system generate our minds, behavior, and sense of self, and this field has evolved from ancient debates about mind-body relationships to modern materialist approaches that use sophisticated techniques to study neural mechanisms underlying behavior.

📌 Key points (3–5)

• Historical shift: Understanding moved from heart-centered (Aristotle) to brain-centered (Hippocrates, Galen) explanations, and from dualism (Descartes) to materialism (contemporary view that mind arises from physical brain processes).
• Methodological evolution: Techniques progressed from crude permanent lesions to modern methods that can record and temporarily modulate specific neural populations while observing behavior.
• Behavioral vs. cognitive approaches: Mid-20th century behaviorists (Watson, Skinner) rejected internal mental states, but evidence like sensory preconditioning forced recognition that learning involves internal cognitive structures.
• Common confusion: Behaviorally silent learning shows that learning ≠ immediate behavior change; animals can form associations (e.g., light-tone pairing) that only affect behavior later, proving internal representations exist.
• Tinbergen's four questions: Biological psychology asks about proximate causes (mechanisms and development within a lifetime) and ultimate causes (evolutionary history and adaptive function).

🏛️ Historical foundations of mind-brain understanding

❤️ Heart vs. brain debate in ancient Greece

• Aristotle's view (~350 BCE): The heart was the seat of mind and thought; the brain merely cooled blood.
• Why this seemed plausible: In threatening situations, people consciously feel heart changes (racing pulse) but not brain activity changes.
• Linguistic legacy: Heart-centered thinking persists in language—"heartfelt" apologies, heart emojis for love, Shakespeare's "false heart."

Modern research shows a grain of truth: pressure receptors in arteries activate with each heartbeat and can influence how the brain processes threat-related stimuli.

🧠 Brain-centered view emerges

• Hippocrates and Plato (4th century BCE): Argued the brain connects physically via nerves to sense organs and muscles, making it the likely seat of mind.
• Galen (2nd century CE):
  • Treated gladiator injuries; observed that head trauma causes immediate unconsciousness.
  • Performed experiments: cutting the laryngeal nerve stopped vocalization, proving specific nerve functions.
  • Rejected lungs as thought center; saw them as bellows driving air through the larynx.

🌍 Islamic Golden Age contributions

• Ibn Sina (Avicenna, 980 CE):
  • Refined Galen's ideas with detailed stroke descriptions.
  • Correctly identified strokes as caused by blockages or bursts in brain blood circulation.
  • Used pulse rate changes to identify emotionally significant people when treating "love disorder" (similar to severe depression).
  • Documented opium's pain-relief properties and serious side effects (breathing suppression, addiction).

Don't confuse: These early scholars lacked modern neuroscience but made crucial observations linking brain damage to specific behavioral changes.

🔄 Descartes and the dualism problem

🤔 Cartesian dualism

• René Descartes (1637): Discourse on Method argued for mind-body separation.
• Famous conclusion: "Cogito, ergo sum" (I think, therefore I am)—the only certainty is that conscious awareness proves one's existence.

Dualism: The philosophical position that mind and body are fundamentally different kinds of entities.

⚙️ Attempted mechanism for interaction

• Descartes' proposal (De homine, 1633):
  • Mind and body interact through the pineal gland (the only unpaired brain structure).
  • "Animal spirits" (fluids in brain ventricles) move to muscles via a pneumatic mechanism.
  • The pineal acts as a valve between mind and brain.
• Reality: The pineal gland is an endocrine gland regulating sleep patterns, not a mind-body interface.

🔥 Reflex mechanisms

• Descartes described simple reflexes (e.g., withdrawing a foot from fire) as occurring via the spinal cord without involving the pineal gland.
• Though many details were wrong, Descartes was a materialist about the body—he viewed it as a mechanism.

Example: His drawing shows fire stimulating the foot, pulling a "thread" that opens a pore, allowing animal spirits to flow and activate muscles for withdrawal—like pulling a cord to ring a bell.

⚡ From fluid to electrical mechanisms

🔋 Discovery of electrical nerve conduction

• Stephen Hales (1733): First suggested nerve transmission might be electrical, not fluid-based (controversial at the time).
• Luigi Galvani (1791):
  • Demonstrated electrical stimulation of a frog's sciatic nerve produces muscle contractions.
  • Announced he had shown "the electric nature of animal spirits."
• Hermann von Helmholtz (1850s):
  • Measured nerve conduction speed in frog: ~30 meters/second.
  • Disproved earlier speculation that nerve impulses traveled at or faster than light speed.

🧩 Brain localization debates

• Franz Gall & Johann Spurzheim (early 1800s):
  • Proposed different cognitive functions localize to specific cortical areas.
  • Created phrenology: examining skull shape to assess individual abilities.
  • Initially popular but later discredited.
  • The two had a spectacular falling-out over plagiarism accusations.

🗣️ Evidence for localization

• Paul Broca (1860s): Correlated language loss with damage to specific brain areas (only visible through post-death dissection).
• Cerebral lateralization: Broca noted language loss almost always involved left cortex lesions, often with right-side limb weakness.
  • Marc Dax made similar observations in the 1830s but published posthumously in 1865.
  • Once thought uniquely human, lateralization is now known to be widespread in vertebrates with ancient evolutionary origins.

Don't confuse: Early lesion studies showed an area was necessary for a function but couldn't prove it was the only important area. Modern fMRI reveals multiple active areas during tasks.

🐀 Behaviorism and the positivist revolution

📊 Positivist foundations

• Auguste Compte: Argued social sciences should adopt physical science methods—rely solely on empirical observation, not introspection.
• Application to psychology: Record observable behavior in laboratory or field; avoid unobservable mental states.

🔬 Watson's radical behaviorism

John Watson (1913): "Psychology, as the behaviorist views it, is a purely objective, experimental branch of natural science which needs introspection as little as do the sciences of chemistry and physics."

• Emphasized simple stimulus-response relationships.
• Resisted considering complex cognitive processes (risked returning to mind-body dualism).

Little Albert experiment (1920):

• Conditioned 9-month-old Albert B. to fear a white rat.
• Method: Paired rat presentation with loud, unexpected sound (hammer hitting steel bar).
• Result: After several pairings, Albert cried when shown the rat; fear generalized to rabbits.
• Ethical note: Would not be approved under modern psychological ethics codes.

Element	Role in conditioning
White rat (initially neutral)	Conditioned stimulus
Loud sound (naturally aversive)	Unconditioned stimulus
Fear response	Conditioned response

🧪 Pavlovian conditioning origins

• Ivan Pavlov: Nobel Prize-winning Russian physiologist.
• Used dogs; measured salivation to meat presentation.
• Paired ticking metronome (not a bell, as commonly stated) with meat.
• Eventually metronome alone elicited salivation.
• Historical note: The phenomenon was already known; Magendie described similar observations in humans in 1836.

🚫 Skinner's extreme position

Burrhus Skinner (The Behaviour of Organisms, 1938): Argued cognitive or physiological explanations are unnecessary.

"The simplest contingencies involve at least three terms—stimulus, response, and reinforcer... when all relevant variables are thus taken into account, there is no need to appeal to an inner apparatus, whether mental, physiological, or conceptual."

Donald Hebb's counter-argument (The Organisation of Behavior, 1949):

• Wrote "in profound disagreement" with Skinner's program.
• Argued for close relationship between psychology and physiology.
• Proposed learning involves convergence of information about two events on a single nerve cell, strengthening connections.
• Remembered as: "Cells that fire together, wire together" (Carla Schatz's mnemonic).
• Led to modern understanding of long-term potentiation (LTP) as a model for learning and memory mechanisms.

Don't confuse: Behaviorism rejected internal states entirely; cognitive approaches recognize internal representations are necessary to explain behavior.

🦆 European ethology and field studies

🐦 Lorenz and Tinbergen's approach

• Konrad Lorenz & Nikolaas Tinbergen: Emphasized detailed study of animal behavior, often in field settings rather than laboratories.

Imprinting experiment (Lorenz):

• Divided newly-hatched greylag geese into two groups.
• One group exposed to mother goose, other to Lorenz himself.
• After several days, mixed goslings together.
• Result: When Lorenz and mother walked in different directions, goslings divided based on original exposure.

Imprinting: Learning that occurs early in life but continues to influence behavior into adulthood (now used more broadly than original bird-specific definition).

🔍 Tinbergen's field experiments

• Began career in Holland studying how insects use landmarks to locate burrows.
• Held as hostage during WWII; survived and moved to Oxford in late 1940s.
• Like Watson and Skinner, interested in explaining behavior in its own terms rather than exploring underlying brain mechanisms (positivist approach).

On animal emotions (The Study of Instinct, 1951):

"Because subjective phenomena cannot be observed objectively in animals, it is idle to claim or deny their existence."

🧠 The cognitive revolution in animal learning

🔄 Sensory preconditioning reveals hidden learning

Tony Dickinson (Contemporary Animal Learning Theory, 1980): Used sensory preconditioning to demonstrate behaviorally silent learning.

Standard Pavlovian procedure:

1. Rats trained to press bar for sweetened food pellets.
2. Light paired with mild foot shock (several pairings).
3. Test: Light alone → rats freeze and pause bar-pressing briefly.

Sensory preconditioning modification:

1. Pre-exposure phase: Light paired with tone (nothing happens; rats ignore it; no behavior change).
2. Conditioning phase: Light paired with shock (as above).
3. Test: Tone alone → rats freeze and pause, despite never experiencing tone-shock pairing.

Phase	Standard procedure	Sensory preconditioning
Pre-exposure	None	Light + Tone (no consequence)
Conditioning	Light + Shock	Light + Shock
Test stimulus	Light	Tone
Result	Freezing	Freezing (despite no tone-shock pairing)

💡 Implications for cognitive structures

Dickinson's conclusion:

"Sensory preconditioning is but one of many examples of behaviourally silent learning... Something must change during learning and I shall argue that this change is best characterised as a modification of some internal structure."

• Learning does not require overt behavioral change.
• Internal cognitive structures must exist to store associations.
• In 1980, Dickinson questioned whether we could identify the neurophysiological substrate; by the 2020s, modern techniques can identify specific neuronal ensembles supporting learning.

Modern example (Koya et al., 2020):

• Mice learned clicks predict sucrose availability.
• Genetically modified mice allowed researchers to make activated neurons glow green.
• Small, stable groups of neurons ("neuronal ensembles") activated consistently across days.
• Disrupting these cells' activity impaired learned approach behavior.

Don't confuse: Absence of immediate behavior change ≠ absence of learning. Internal representations can form without observable responses.

🐵 Primate cognition and social complexity

🌳 Field studies reveal cognitive sophistication

Jane Goodall (early 1960s):

• Studied chimpanzees at Gombe Stream, Tanzania.
• Gathered evidence of rich social/emotional lives and tool use.
• Revolutionized primate behavior studies.
• Controversially gave chimpanzees names rather than numbers (colleagues wanted "objective" numbering).

Alison Jolly (1960s):

• Studied lemur behavior in Madagascar.
• Argued major driver of primate cognitive evolution was complex demands of living in long-lasting social groups.

🗣️ Social knowledge in baboon calls

Cheney & Seyfarth study: Female chacma baboons use "reconciliatory grunts" after aggressive encounters to signal peaceful conclusion.

Playback experiment:

• Played grunt to female who had just groomed another female → behaved as if call directed at someone else.
• Played grunt to female who had recently fought with that same female → behaved as if call directed at her.

Interpretation: Baboons interpret calls based on prior knowledge of social relationships and recent interactions—evidence of sophisticated social cognition.

🐘 Broader implications

• Field studies of other long-lived mammals (elephants, dolphins) suggest complex social networks and sophisticated cognitive abilities.
• Social complexity may drive cognitive evolution across multiple mammal lineages.

🎯 Tinbergen's four questions framework

📋 Two levels of causation

Proximate causes (within individual's lifetime):

1. Mechanisms: Underlying causes of behavior changes (brain mechanisms, hormonal changes).
2. Development: How behavior changes as individual matures.

Ultimate causes (evolutionary timescale): 3. Phylogeny: Evolutionary relationships between behavior patterns in different species. 4. Adaptive function: Advantages of particular behaviors in natural selection context.

🐦 Example: Why do male chaffinches sing in spring?

Causes and mechanisms (proximate):

• Day length increases in spring.
• Testosterone secretion increases (demonstrated experimentally in canaries by Nottebohm).
• Testosterone produces bill darkening and singing behavior.
• Brain changes occur: new neurons form in song-related areas (surprising discovery—challenged consensus that mature vertebrate brains never add neurons).

Development (proximate):

• Chaffinch song has species-typical structure: several short trills followed by characteristic terminal flourish.
• Song is recognizable but has unexpected individual complexity.
• (Excerpt ends before completing developmental explanation.)

Don't confuse: Proximate questions ask "how does it work now?" while ultimate questions ask "why did this evolve?" Both are valid and complementary approaches.

🔬 Contemporary materialist consensus

🧩 Two key features of modern biological psychology

1. Universal materialism: Almost all contemporary psychologists and neuroscientists accept that behavior complexity, including consciousness, results from physical mechanisms in the nervous system.

2. Legitimacy of subjective phenomena: After mid-20th century hiatus, emotion and consciousness are no longer "off limits" for scientific study.

🎯 Modern challenge

Understanding how the nervous system:

• Builds internal representations of the external world
• Uses these representations
• Attaches emotional weight to them

Historical trajectory: From ancient heart-brain debates → Cartesian dualism → behaviorist rejection of internal states → cognitive revolution recognizing internal representations → modern neuroscience identifying specific neural mechanisms.

🧭 Overview

🧠 One-sentence thesis

The nervous system is organized as an input-computation-output system that detects information from the world and body, processes it through interconnected structures, and generates behavioral and physiological responses to enable survival and interaction with the environment.

📌 Key points (3–5)

• Computer analogy: The nervous system works like a computer—taking inputs (sensory information), performing computations (integrating and processing), and generating outputs (motor commands and physiological changes).
• Two-part division: The nervous system splits into the central nervous system (CNS: brain and spinal cord) and peripheral nervous system (PNS: nerves connecting CNS to the body).
• PNS subdivisions: The PNS divides into somatic (voluntary interactions with external world) and autonomic (involuntary regulation of internal organs) systems.
• Common confusion: Dorsal/ventral terminology—in the brain these mean top/bottom, but in the spinal cord they mean back/front, because humans walk upright and the brain is angled relative to the spine.
• Symmetry principle: The nervous system is symmetrical around the midline, with left and right halves mirroring each other structurally (though some functions are lateralized).

🖥️ The nervous system as a computer

🖥️ Input-computation-output framework

The nervous system is the network of neurons and supporting cells (glia) that detect something, transmit that information, integrate it with other information, and send instructions to other parts of the body.

• Every part of the nervous system performs the same basic job: input → computation → output.
• Whole-system example: Detect a lion (visual input) → compute that running is needed → generate leg muscle contractions (motor output).
• Single-neuron example: Receive information about light on retina in different locations → integrate to detect a vertical line → output that information to the next neuron.
• The "program" run by each cell or structure is determined by how it connects to other cells and the biological rules governing those connections.

🔗 How connections determine function

• The computation performed depends on connectivity patterns between neurons and structures.
• These connections can change over time, allowing learning and adaptation.
• Don't confuse: The nervous system doesn't just relay information in one direction—outputs often feed back to structures that provided inputs, forming loops.

🗂️ Major divisions of the nervous system

🗂️ Central vs peripheral

Division	Components	Role
Central Nervous System (CNS)	Brain and spinal cord	Computes what to do with information; sends outputs
Peripheral Nervous System (PNS)	Cranial and spinal nerves	Provides input to CNS; carries outputs to body

• The PNS connects the CNS with the rest of the body.
• Symmetry around the midline is a general organizing principle.

🦾 Somatic nervous system (voluntary control)

The somatic nervous system deals with interactions with the external environment: sensing the outside world via sensory neurons and sending signals via motor neurons to control skeletal muscles.

• Voluntary behaviors: Hearing your name called, interpreting it, turning toward the sound.
• Involuntary reflexes: Automatic responses without conscious control.
• Simplest reflex example: Muscle stretch reflex—sensory neurons detect muscle stretch → activate motor neurons in spinal cord → contract the same muscle to counter the stretch (e.g., maintaining posture when leaning, or preventing dropping a heavy load).
• Important: Even simple reflexes involve the CNS—the synapse between sensory and motor neurons occurs in the spinal cord.
• No somatic neurons exist entirely in the PNS: sensory neurons synapse first in the CNS; motor neuron cell bodies are in the CNS with axons extending out.

🫀 Autonomic nervous system (involuntary control)

The autonomic nervous system mediates interactions with the body's internal environment, for example regulating heart rate.

• These are broadly involuntary reflexes, though the brain can modulate them (e.g., people can train themselves to control heart rate).
• Sensory neurons provide information about internal organs to the CNS.
• Motor neurons affect internal organs, often by modulating smooth muscle tone (e.g., changing blood vessel diameter).

Three subdivisions:

Division	Location	Function	Key features
Enteric	Embedded in gastrointestinal wall	Regulates gut motility and hormone secretion	~500 million neurons; can function without brain input
Sympathetic	Thoracic/lumbar spinal cord	"Fight-and-flight" responses	Increases heart rate, blood flow to brain/heart/muscles; uses noradrenaline
Parasympathetic	Cranial nerves and sacral spinal cord	"Rest-and-digest" responses	Decreases heart rate, directs blood to gut; uses acetylcholine

⚖️ Balance, not binary switching

• Don't confuse: The body doesn't switch completely between sympathetic and parasympathetic—it's about the balance of activity between the two at any moment.
• This balance is not uniform across the body; different organs can be independently regulated (e.g., heart rate vs bladder control).

🔬 Neurotransmitter patterns

• Preganglionic neurons (both divisions): use acetylcholine.
• Sympathetic postganglionic: use noradrenaline (norepinephrine in US).
• Parasympathetic postganglionic: use acetylcholine.
• Sympathetic neurons synapse in ganglia near the spinal cord or in abdominal ganglia.
• Parasympathetic neurons synapse in ganglia very close to target organs, so preganglionic neurons are much longer.
• The vagus nerve carries the vast majority of parasympathetic fibers, innervating most thoracic and abdominal organs.

🧭 Navigating the CNS: compass directions

🧭 Directional terminology

The CNS uses multiple terms to describe locations and orientations:

Human brain	Spinal cord	Meaning
Anterior / Rostral	Anterior / Rostral	Front / toward nose
Posterior / Caudal	Posterior / Caudal	Back / toward tail
Superior / Dorsal	Superior / Dorsal	Top / toward back
Inferior / Ventral	Inferior / Ventral	Bottom / toward stomach

• Why the confusion? Humans walk upright, so the brain is angled relative to the spinal cord.
• In most animals (e.g., mice), the brain continues straight from the spinal cord, so dorsal brain aligns with the animal's back.
• In humans, the top of the head points differently than the back, creating terminology overlap.
• Medial: closer to the midline.
• Lateral: closer to the side.

🔪 Anatomical slices

Three standard ways to slice through the brain to see inside:

• Sagittal: side-to-side slices (midline sagittal shows left-right symmetry).
• Coronal: front-to-back slices.
• Horizontal/Transverse: top-to-bottom slices.

🦴 The spinal cord

🦴 Segmental organization

• Divided into segments, each connecting to a pair of sensory and motor nerves.
• From head to tail: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral segments.
• Carries somatosensory information up to the brain and motor information down to muscles.

🎨 Grey and white matter organization

Grey matter: neuronal cell bodies and short-range connections. White matter: myelinated and unmyelinated axons forming connections to other regions.

• Structure: Grey matter surrounds a central canal (containing cerebrospinal fluid); white matter surrounds the grey matter.
• Grey matter horns:
  • Dorsal horn: sensory information.
  • Lateral horn: sympathetic motor neurons.
  • Ventral horn: motor information.
• White matter tracts (organized pathways):
  • Dorsal column: axons from somatosensory neurons (cell bodies in dorsal root ganglia).
  • Lateral corticospinal tract: axons from motor neurons in cerebral cortex controlling voluntary limb movement.

🚪 Entry and exit points

• Sensory afferents: enter through the dorsal root; cell bodies form the dorsal root ganglion just outside the spinal cord.
• Motor neurons: exit through the ventral root; synapse at neuromuscular junctions on skeletal muscle, releasing acetylcholine to initiate contraction.
• Dermatome: region of skin innervated by sensory fibers from a given spinal nerve.
• Myotome: muscles contacted by motor fibers from a single nerve.

🧠 The brain: three major parts

🧠 Overall structure

The brain comprises:

1. Brainstem (continuous with spinal cord)
2. Cerebellum (posterior to brainstem)
3. Forebrain (largest, most anterior/superior)

🌉 The brainstem

🌉 White matter highways

• Much of the brainstem volume is white matter tracts carrying information up to the brain or down to the spinal cord, and to/from cranial nerves.
• Pyramids (in medulla): prominent bundles carrying descending motor axons to spinal cord.
• Pons (Latin for "bridge"): wide transverse fibers connecting brainstem to cerebellum.

🎯 Grey matter nuclei

Clusters of neuronal cell bodies nestled within the white matter tracts:

Sensory and motor nuclei:

• Cranial nerve nuclei: contain cell bodies projecting into or receiving from cranial nerves.
• Dorsal column nuclei: where many touch neurons from the spinal cord make their first connections.

Neuromodulatory nuclei: These produce chemicals released over large forebrain regions, regulating arousal, attention, mood, movement, motivation, and memory:

• Dopamine: ventral tegmental area and substantia nigra pars compacta (midbrain).
• Serotonin: Raphe nuclei (medulla to midbrain).
• Noradrenaline: locus coeruleus (midbrain) and medial reticular zone (pons).
• Acetylcholine: pedunculopontine nucleus (pons) and basal forebrain.

Regulatory nuclei:

• Particularly in the medulla, these regulate life-sustaining functions: breathing, heart rate, swallowing, consciousness.
• Brainstem damage can be life-threatening (e.g., from brain swelling compressing the brainstem against the skull).

🎹 The cerebellum

🎹 Structure and location

The cerebellum, or "little brain," lies inferior to the occipital and temporal lobes and posterior to the pons.

• Has a distinct laminar (layered) structure with clear connectivity patterns.
• Highly folded structure resembling a seahorse (hippocampus) or ram's horn (Cornu ammonis).

🔬 Cellular organization

Three main layers:

1. Granule cell layer: contains ~50 billion granule cells (¾ of all brain neurons), densely packed small neurons.
2. Molecular layer: contains parallel fibers (axons of granule cells arranged in parallel).
3. Purkinje cell layer: output cells with highly branched, flat dendritic trees.

Information flow:

• Input: Mossy fibers from pons (carrying cortical information) → synapse onto granule cells.
• Processing: Granule cell axons rise vertically, split into T-shape, form parallel fibers → synapse onto Purkinje cells.
• Additional input: Climbing fibers from medulla (carrying motor information) → synapse onto Purkinje cells.
• Output: Purkinje cells → deep cerebellar nuclei → thalamus → cerebral cortex.

⚙️ Functions

• Best understood: Bringing together diverse sensory information to guide motor behaviors—important for balance and motor learning (e.g., learning to ride a bicycle, playing piano).
• Broader roles: Functional imaging shows involvement in language comprehension, autobiographical memory, and attention.
• The highly organized circuitry has allowed neuroscientists detailed insights into how the cerebellum performs its functions.

🏛️ The forebrain

🏛️ Major components

• Diencephalon: thalamus and hypothalamus.
• Cerebrum: two cerebral hemispheres containing:
  • Cerebral cortex (outer layer).
  • Subcortical structures (hippocampus, basal ganglia, amygdala).
• Corpus callosum: very large white matter tract connecting the two hemispheres.

🔄 Diencephalon: thalamus and hypothalamus

🔄 Thalamus: the information hub

The thalamus is an information hub, relaying ascending and descending information from widespread brain areas.

• Organized into functionally specialized nuclei processing specific information types.
• Example—visual processing: Dorsal lateral geniculate nucleus receives visual information from optic nerve → projects to primary visual cortex.
• Example—auditory processing: Medial geniculate nucleus receives auditory information from inferior colliculus → projects to auditory cortex.

Thalamocortical loops:

• Not just one-direction relay—nuclei also receive descending information from cortex, forming circuits.
• These loops exist for sensory processing, higher-order areas, and motor areas.
• Memory example: Anterior thalamus receives information from hippocampus, mammillary bodies, and cerebral cortex → projects to cingulate cortex.
• Motor/motivation example: Loops incorporating striatum and basal ganglia nuclei (via ventrolateral, mediodorsal, anterior thalamic nuclei).
• Don't confuse: The nervous system's input-computation-output is not simply one direction—outputs often feed back to input structures, creating loops.

🌡️ Hypothalamus: homeostasis and more

• Located below the thalamus, above the pituitary gland.
• Contains ~22 nuclei, highly connected to brainstem, amygdala, and hippocampus.

Functions:

• Regulation of homeostatic processes: eating, drinking, temperature, circadian rhythms.
• Emotion and memory processing.
• Sexual behavior (some nuclei are sexually dimorphic—structurally/functionally different in males vs females).
• Motivated behaviors: defensive freezing, flight behaviors.

How it effects changes:

1. Projections via brainstem to autonomic nervous system.
2. Regulating hormone release via connections with adjacent pituitary gland.

🧩 Cerebral cortex

🧩 Structure and folding

The cerebral cortex is the outermost layer of the forebrain, richly folded in humans to maximize surface area.

• Folds form characteristic sulci (grooves) and gyri (ridges).
• Largest folds separate the cortex into 4 lobes: frontal, temporal, parietal, occipital.

📚 Six-layered organization (neocortex)

Most cerebral cortex is neocortex with 6 layers of neurons:

• Layer 1: Very few cell bodies; mostly dendrite tips and axons.
• Layers 2 & 3: Neurons that receive/send projections to nearby cortical regions.
• Layer 4: Receives ascending inputs from thalamus (thick in sensory cortices).
• Layers 5 & 6: Send descending projections to other brain areas (thick in motor regions).

Columnar organization:

• More vertical than horizontal connectivity.
• Neurons in the same vertical "column" have the same response properties (activated by the same stimulus type).

🗺️ Brodmann areas and functional specialization

Cytoarchitecture: the organization of cell layers across the cortex.

• In 1909, Korbinian Brodmann divided the cortex into 52 areas based on cellular organization (now called Brodmann areas).
• Different cellular organization indicates different circuitry and information processing.
• Many Brodmann areas correspond to functional specializations:
  • Area 17: primary visual cortex.
  • Area 4: primary motor cortex.

Three functional categories:

1. Sensory: Primary sensory cortices receive information first; secondary areas do further processing.
2. Motor: Primary motor cortex sends axons to spinal cord for voluntary movement; secondary/premotor areas project to primary motor cortex to select/coordinate movements.
3. Associative: Process multimodal information (e.g., auditory + visual); important for language, spatial processing, abstract thinking, planning, memory.

🗺️ Topographic organization

• Somatotopic: Adjacent skin parts represented by adjacent somatosensory cortex regions.
• Retinotopic: Adjacent retina regions represented by adjacent primary visual cortex regions.
• Further subdivision into columns processing different stimulus features (e.g., visual orientation).

↔️ Lateralization of function

While most brain areas are structurally symmetrical, some functions are lateralized:

1. Sensory processing: Generally occurs in the opposite hemisphere from where input is received (e.g., left somatosensory cortex processes right body stimuli).
2. Visual processing streams:
   • Left hemisphere lesions: deficits in perceiving fine details.
   • Right hemisphere lesions: impaired perception of wider field/"big picture."
3. Language: Production and comprehension typically localized to left hemisphere (especially in right-handed people).

🕸️ Connectivity patterns

• Most common projection target: other cortical neurons.
• 80% of intracortical projections: to neurons in the same area.
• Most connections between areas: to nearby areas.
• Only 5%: long-range connections to distant cortical regions or transcallosal (across corpus callosum between hemispheres).
• These connections form large-scale brain networks contributing to perceptual and cognitive functions.

⚙️ Basal ganglia

⚙️ Components and location

The basal ganglia are a group of subcortical nuclei (beneath the cerebral cortex).

Components:

• Dorsal striatum: caudate nucleus + putamen.
• Ventral striatum (nucleus accumbens).
• External and internal globus pallidus.
• Subthalamic nucleus (in diencephalon).
• Substantia nigra (in midbrain).

🔁 Cortico-basal ganglia-thalamo-cortical loops

Information flow: Widespread cerebral cortex → basal ganglia → thalamus → back to cerebral cortex.

Functions:

• Selecting motor actions (starting and stopping behaviors).
• Motivated behavior (selecting actions based on likely good/bad outcomes).
• Include excitatory and inhibitory pathways; balance is important for inhibiting or initiating motor outputs.

🏥 Clinical relevance

Disruptions cause imbalance between facilitatory and inhibitory effects, seen in:

• Neurological conditions: Parkinson's disease, Huntington's disease.
• Psychiatric conditions: schizophrenia, Tourette's syndrome, obsessive-compulsive disorder, addiction.

🐚 Hippocampus

🐚 Structure and location

The hippocampus is an important structure involved in episodic memory, spatial processing, and contextual learning.

• Has a distinctly different laminar structure from cerebral cortex (allocortex with fewer layers).
• Formed of two interlinked U-shaped folds: dentate gyrus and hippocampus "proper."
• Curved into elegant 3D shape like a seahorse (hippocampus) or ram's horn (Cornu ammonis).
• Subfields named CA1, CA2, CA3 (Cornu ammonis regions).

🔬 Well-characterized circuitry

Input pathway: Entorhinal cortex → perforant path → granule cells in dentate gyrus → mossy fibers → CA3.

Internal processing:

• CA3 pyramidal neurons send Schaffer collaterals (axon branches) to CA2 and CA1.
• CA3 also sends recurrent collaterals—axon branches that synapse back onto CA3 cells.

Output pathways:

• Most outputs via subiculum to cortical/subcortical regions.
• Fornix connects hippocampus (via CA3) to mammillary bodies of diencephalon.

🧠 Functions and learning

Changes in connection strength during learning are thought to support:

• Pattern completion: Remembering more of an event/stimulus when exposed to only part of it.
• Pattern separation: Remembering events/stimuli as distinct from each other.

🏥 Clinical significance

• Damage effects: Memory deficits; occurs early in Alzheimer's disease.
• Selective damage: Can occur when brain is deprived of oxygen (e.g., during birth) → amnesia.
• Epilepsy: Recurrent collateral connectivity (excitatory neurons exciting themselves) makes hippocampus a common focus of epileptic activity and seizures.

🌰 Amygdala

🌰 Structure and location

• Named for its almond shape.
• Sits adjacent to hippocampus beneath cerebral cortex within temporal lobe.
• Made up of different nuclei: basolateral, corticomedial, centromedial.

🎭 Functions

The amygdala is important for processing of emotions and for the impact of emotions on learning; particularly involved in fear learning.

Inputs:

• Wide regions of sensory and prefrontal cortex.
• Hippocampus.
• Visceral information from brainstem nuclei.
• This allows integration of body state with contextual information.

Outputs:

• Cerebral cortex (particularly prefrontal and cingulate).
• Hippocampus.
• Ventral striatum.
• Thalamus.
• Hypothalamus.

⚡ Producing emotional responses

Example—fear response: When a stimulus associated with punishment appears:

• Alter hormone release via hypothalamus.
• Trigger freezing behaviors.
• Activate sympathetic nervous system via brainstem.

🏥 Lesion effects

People with amygdala lesions display:

• Reduction in emotional behavior.
• Placidness or "flatness of affect."
• Reduced learning about emotional or frightening stimuli/situations.

💧 Non-neuronal brain structures

💧 Ventricles and cerebrospinal fluid (CSF)

Within the brain and spinal cord are a series of connected spaces containing cerebrospinal fluid.

Structure:

• Central canal of spinal cord extends into brainstem.
• Expands at pons level to form fourth ventricle.
• Cerebral aqueduct (narrow channel) connects to third ventricle (at diencephalon level).
• Two narrow channels connect to large lateral ventricles (extending into cerebrum).

CSF production:

• Made by ependymal cells lining ventricles in the choroid plexus.
• These cells surround capillaries and filter blood to produce CSF.
• CSF is similar to blood plasma (mostly water with ions and glucose) but has less protein.

CSF flow and function:

• Flows from fourth ventricle into subarachnoid space (between meninges covering the brain).
• Circulates the brain, then drains into veins in dural sinuses.
• Functions: Shock absorber (cushions brain during head impacts); clears metabolic waste from brain into blood.

🛡️ Meninges (three protective layers)

From innermost to outermost:

1. Pia: Delicate membrane directly covering brain and spinal cord.
2. Arachnoid: Web-like membrane above the pia; subarachnoid space (fluid-filled) lies between pia and arachnoid.
3. Dura: Tough outer membrane supporting large blood vessels draining cerebral blood toward heart.

🩸 Vasculature: the brain's blood supply

🩸 Energy demands

• Brain is 2% of body mass but uses 20% of energy when resting.
• Relies on constant supply of oxygen and glucose.
• Loss of consciousness occurs within 10 seconds if blood flow is disrupted.

🔄 Circle of Willis and arterial supply

• Four arteries feed the brain, forming the circle of Willis.
• This circle ensures that reduced flow to one artery can be compensated by redistribution from others.
• Major arteries branch off to perfuse different brain regions.
• These branch into smaller arteries, arterioles, then dense capillary networks.

🕸️ Capillary density

• 1 to 2 meters of capillaries in every cubic millimeter of brain tissue.
• Capillaries are <10 microns in diameter, taking up only ~2% of brain volume.
• In cerebral cortex, each neuron is only 10-20 microns from its nearest capillary.
• This dense network supplies oxygen and glucose very close to active neurons.

🎛️ Blood flow regulation

• Smooth muscle cells/pericytes in vessel walls can dilate or constrict to regulate blood flow.
• Active neurons and astrocytes produce molecules that dilate local arterioles and capillaries.
• Blood flow increases to active regions, usually supplying more oxygen than needed.
• Blood oxygen levels increase in active regions → BOLD signal (blood oxygen level dependent) detectable by MRI, used as surrogate for neuronal activity in experiments.

🚧 Blood-brain barrier (BBB)

A specialized feature of the brain's vascular system that protects the brain from circulating toxins or immune cells.

• Endothelial cells lining brain blood vessels are very tightly joined.
• Express relatively few transporter proteins.
• Harder for molecules and cells to access brain from blood.

🏥 Vascular disorders

Stroke (ischemic or hemorrhage):

• Reduction in blood supply due to blockage or leakage in blood vessels.
• Reduces oxygen to brain region fed by lesioned vessel.
• Damages neurons in that region → corresponding functional deficits.

Alzheimer's disease:

• Decrease in brain blood flow many years before symptoms develop.
• Possible links: decreased ability to clear toxic proteins, increased BBB permeability, chronic lack of oxygen supply.

🧭 Overview

🧠 One-sentence thesis

The nervous system comprises neurons that perform signaling and information processing, glia that provide diverse support functions, and vascular cells that regulate energy supply and the blood-brain barrier—all tightly packed together to enable detection, integration, and behavioral output.

📌 Key points (3–5)

• Neurons have soma, dendrites (input), and axon (output); they integrate inputs and generate action potentials to communicate via neurotransmitters at synapses.
• Five glial types (astrocytes, oligodendrocytes, Schwann cells, microglia, ependymal cells) support neurons by controlling the extracellular environment, insulating axons, combating damage, and producing CSF.
• Vascular cells (endothelial cells, smooth muscle, pericytes) form the blood-brain barrier and regulate blood flow to match neuronal activity.
• Common confusion: Neurons are often shown with space between them in diagrams, but in reality all cell processes are tightly intertwined and fill nearly all available space.
• Morphology matters: neuron shape, size, dendritic spine density, and connection patterns determine how each neuron performs computations.

🧬 Neuron structure and function

🧬 Basic neuron anatomy

Neuron: the cell that performs signaling and information processing in the nervous system.

• Every neuron has three core components:
  • Soma (cell body): contains the nucleus.
  • Dendrites: branching processes that receive most inputs from other cells.
  • Axon: thin process that carries the output signal (action potential) to other cells.
• The axon initial segment (top of the axon) is where the neuron "decides" whether inputs are strong enough to trigger an action potential.
• The axon terminal releases neurotransmitter into the synapse (tiny gap between cells) to pass the signal to the next cell.

🔄 Input-computation-output cycle

• Neurons mirror the brain's overall function at the cellular level:
  1. Input: dendrites and dendritic tree receive signals.
  2. Computation: inputs are integrated across dendrites and soma.
  3. Output: if strong enough, an action potential travels down the axon to the terminal.
• Example: A neuron receiving many weak inputs may not fire, but the same neuron receiving fewer strong inputs might fire—this is the "decision" process.

🌳 Neuron morphology affects computation

Neuron type	Structure	Functional implication
Multipolar	Branched dendritic tree + single axon	Most common; can integrate many inputs
Bipolar	Single dendrite + single axon (opposite ends of soma)	Common in sensory neurons (e.g., retina)
Pseudounipolar	Single process (axon) that receives at one end, releases at the other	Simplified input-output pathway

• Why shape matters: The number and location of inputs change how summation happens.
• Example: Cerebellar Purkinje cells receive many synapses from climbing fibers (strong connection) but only one synapse per granule cell (weak connection)—so a single climbing fiber has much more influence.

🌿 Dendritic spines and gating

• Some dendrites have small protrusions called dendritic spines.
• Synapses can form on the spine or on the spine neck.
• This arrangement allows some inputs to "gate" (control) the effect of other inputs, adding computational flexibility.
• Don't confuse: Smooth dendrites vs. spiny dendrites—spines enable more complex input interactions.

🧩 Classifying neurons

🧩 By morphology (multipolar subtypes)

• Pyramidal cells: pyramidal soma, long apical dendrite pointing up, tufty basal dendrites, axon with collaterals.
• Purkinje cells (cerebellum): round soma, flat highly branched dendritic tree, single long axon.
• Granule cells: small soma, simple dendritic tree, axon that splits in two.
• Chandelier cells: highly branched axon forming "candle-like" connections with many axon initial segments.

⚡ By effect: excitatory vs. inhibitory

Excitatory neurons: make the target cell more likely to fire an action potential.
Inhibitory neurons: make the target cell less likely to fire.

• Pyramidal cells and granule cells are excitatory.
• Purkinje cells and chandelier cells are inhibitory.

🧪 By neurotransmitter

• Glutamatergic neurons release glutamate (excitatory).
• GABAergic neurons release GABA (inhibitory).
• Dopaminergic neurons release dopamine (effect depends on target cell's receptors).
• The excerpt notes broad overlap: glutamate → excitatory, GABA → inhibitory, but dopamine can have varied effects.

🔗 By connectivity

• Principal neurons: project long distances to different brain regions (often excitatory, but not always—e.g., Purkinje cells are inhibitory principal cells).
• Interneurons: project locally; the term is commonly used only for inhibitory interneurons (e.g., chandelier cells).
• Don't confuse: The term "interneuron" is not consistently applied to all local cells; excitatory local cells are usually described by location and morphology (e.g., "Layer 5 pyramidal cell") rather than called interneurons.

🛡️ Glial cells: the support network

🛡️ Five main glial types

The excerpt identifies five glial cell types, each with specialized roles:

Glial type	Location	Key roles
Astrocytes	CNS	Encircle synapses, remove neurotransmitter, regulate ions, release ATP/lactate/glucose, communicate with blood vessels, form glia limitans
Oligodendrocytes	CNS	Wrap myelin around axons (multiple processes per cell) to speed conduction
Schwann cells	PNS	Wrap myelin around axons (one process per cell)
Microglia	CNS	Brain's resident immune cell; survey for damage, remove debris, regulate synapses and blood vessels
Ependymal cells	Ventricle lining	Produce cerebrospinal fluid (CSF)

⭐ Astrocytes: star-shaped multitaskers

Astrocyte: glial cell with star-like morphology and many fine processes.

• Each human astrocyte can contact up to 2 million synapses.
• Functions include:
  • Physical support for neuronal connections.
  • Removing neurotransmitter from synapses to "reset" them after transmission.
  • Regulating extracellular ion levels.
  • Releasing substances (ATP, lactate, glucose) to modulate neuronal activity and provide metabolic support.
• End feet: specialized astrocyte processes that wrap around blood vessels (part of the blood-brain barrier) and the brain surface (forming the glia limitans).
• Astrocytes regulate local blood flow and take up glucose from blood.
• In response to damage or infection, astrocytes become "activated" and can form scar tissue—helpful short-term, but problematic if prolonged (can block new neuronal connections).

🧵 Oligodendrocytes and Schwann cells: insulation specialists

Myelin: fatty substance wrapped around axons to insulate them and speed up action potential conduction.

• Oligodendrocytes (CNS): send multiple myelinating processes to nearby axons.
• Schwann cells (PNS): each has one myelinating process.
• Both provide metabolic support by releasing and taking up molecules around axons.
• Example: In multiple sclerosis, the immune system attacks oligodendrocytes, causing demyelination → impaired signaling → neurological problems depending on which axons are affected.

🦠 Microglia: the brain's immune sentinels

• Small cells with constantly extending and retracting processes that survey the brain.
• When they detect damage or infection, they activate, migrate to the site, form a barrier, and remove debris.
• Increasingly recognized to regulate normal brain function (synaptic transmission, blood vessel signaling), not just respond to damage.
• Don't confuse short-term vs. long-term activation: Acute microglial responses are beneficial, but chronic activation (e.g., in Alzheimer's or after stroke) can be harmful.

💧 Ependymal cells: CSF producers

• Line the ventricles (cavities within the brain).
• Produce cerebrospinal fluid (CSF).

🩸 Vascular cells: energy supply and barrier control

🩸 Three main vascular cell types

The brain's dense vascular network is built from:

Cell type	Location	Key roles
Endothelial cells	Vessel wall (next to blood)	Form tight junctions (blood-brain barrier), regulate molecule/cell entry, control blood flow
Smooth muscle cells	Larger vessels (arteries, arterioles)	Contract/dilate to change vessel diameter and blood flow
Pericytes	Smaller vessels (capillaries)	Wrap around vessels, contract/dilate, stabilize new vessels, control BBB

🚧 The blood-brain barrier (BBB)

Blood-brain barrier (BBB): tight junctions between endothelial cells and pericytes that restrict molecule and cell entry into the brain.

• Endothelial cells in the brain are very tightly joined and express few transporter proteins.
• This makes it harder for molecules and immune cells to access the brain from the blood, protecting the brain from circulating toxins.
• Endothelial cells regulate entry by:
  • Expressing specific transporter proteins for certain small molecules.
  • Expressing adhesion proteins that allow immune cells to crawl between or through endothelial cells when needed.

🔄 Blood flow regulation

• Endothelial cells respond to signals from blood or brain to produce molecules that contract or dilate smooth muscle cells or pericytes.
• Smooth muscle cells (ring-shaped) and pericytes (distinct body with extending processes) can also respond directly to signals from neurons and astrocytes.
• This allows blood flow to match changes in neuronal activity—active brain regions get more blood.
• Example: When a brain region becomes active, local signals cause vessels to dilate → increased blood flow → more oxygen and glucose delivered.

🩺 Vascular dysfunction in disease

• Ischemic or hemorrhage stroke: blockage or leakage in blood vessels → reduced oxygen → neuron damage → functional deficits.
• Alzheimer's disease: decreased brain blood flow many years before symptoms; possible links include reduced clearance of toxic proteins, increased BBB permeability, or chronic oxygen lack.

🧱 The brain is densely packed

🧱 No empty space

• Diagrams often show cells with lots of space between them, but this is misleading.
• In reality, different cells' processes are closely intertwined and crammed together, taking up almost all available space.
• Evidence: 3D reconstructions from electron micrographs show structures filling the space.

🔬 Electron microscopy and reconstruction

• Sequential slices of very small tissue bits are imaged with an electron microscope.
• Structures are labeled and traced in each image, then assembled into a 3D reconstruction.
• This reveals in superb detail how structures connect (e.g., which dendrites an axon contacts).
• Limitation: Tracking every process in even a small volume is computationally expensive—not yet possible for a whole cortical column or brain region.

📋 Key takeaways summary

📋 Neurons

• All have soma, axon, dendrites but vary in shape, size, and neurotransmitter.
• This diversity enables different computations.

📋 Glia (5 types)

• Astrocytes, oligodendrocytes, Schwann cells, microglia: control extracellular environment, provide support, insulate axons, detect/combat damage, contact blood vessels.
• Ependymal cells: produce CSF.

📋 Vascular cells

• Endothelial cells, smooth muscle cells, pericytes: form dense blood vessel network, control energy supply, regulate what crosses between blood and brain tissue (BBB).

📋 Spatial organization

• All these cells and their processes are tightly packed, filling nearly all available space in the brain.

🧭 Overview

🧠 One-sentence thesis

Neurons control their membrane potential by opening and closing ion channels that allow ions to flow down electrochemical gradients, while the sodium-potassium pump uses energy to maintain the concentration gradients that make electrical signalling possible.

📌 Key points (3–5)

• Equilibrium potentials: Each ion has an equilibrium potential (calculated by the Nernst equation) determined by its concentration gradient and charge; K⁺ is negative (-80 mV), Na⁺ is positive (+62 mV), and Cl⁻ is negative (-65 mV).
• Resting membrane potential: The resting potential (~-70 mV) is close to but not equal to E_K because the membrane is mostly permeable to K⁺ (via leak channels) but also slightly permeable to Na⁺, pulling it toward E_Na.
• Membrane potential control: Cells change membrane potential by opening/closing ion channels to alter permeability to different ions, not by changing concentration gradients.
• Common confusion: Ion flow down gradients requires no energy, but maintaining the gradients requires ATP via the Na⁺/K⁺ ATPase pump.
• Energy cost: The Na⁺/K⁺ ATPase consumes over half the brain's energy (and over 10% of the whole body's energy) to maintain ion gradients.

🧮 Equilibrium potentials and the Nernst equation

🧮 How equilibrium potentials are calculated

The excerpt explains that equilibrium potentials arise from the Nernst equation, which relates concentration gradients and ion charge to the voltage at which an ion is at equilibrium.

• The equation uses the natural logarithm (ln) of the concentration ratio ([ion]_out / [ion]_in).
• The sign of the equilibrium potential depends on:
  • Whether the ion is more concentrated inside or outside (determines if the log is positive or negative).
  • The charge of the ion (multiplies the log result).

⚡ Potassium (K⁺): E_K = -80 mV

• K⁺ is more concentrated inside the cell than outside, so ([K⁺]_out / [K⁺]_in) < 1.
• The natural log of a number less than 1 is negative.
• K⁺ has a charge of +1, so the equilibrium potential is negative.

⚡ Sodium (Na⁺): E_Na = +62 mV

• Na⁺ is more concentrated outside the cell than inside, so ([Na⁺]_out / [Na⁺]_in) > 1.
• The natural log of a number greater than 1 is positive.
• Na⁺ has a charge of +1, so the equilibrium potential is positive.

⚡ Chloride (Cl⁻): E_Cl = -65 mV

• Cl⁻ is more concentrated outside the cell than inside, so ([Cl⁻]_out / [Cl⁻]_in) > 1.
• The natural log of a number greater than 1 is positive.
• Cl⁻ has a charge of -1, so multiplying by the charge makes the equilibrium potential negative.

Don't confuse: The equilibrium potential is not the resting membrane potential; it is the voltage at which one specific ion would be at equilibrium.

🔋 The resting membrane potential

🔋 Why resting potential is not equal to E_K

The excerpt states that at rest, potassium leak channels are open, which drives the resting membrane potential toward E_K (-80 mV). However, the resting potential is around -70 mV, not -80 mV.

• Reason: A small number of sodium channels are also open at rest, making the membrane slightly permeable to Na⁺.
• This small Na⁺ permeability pulls the resting potential slightly away from E_K toward E_Na (+62 mV).
• The resting potential is closest to E_K because the membrane is most permeable to K⁺, but it is a bit more positive than E_K due to the small Na⁺ permeability.

🔋 How membrane potential is set at any moment

At any point during neuronal signalling or at rest, the membrane potential is set by the electrochemical gradients to different ions and the relative permeability of the membrane to these ions.

• Cells control membrane potential by opening and closing ion channels, which changes permeability to different ions.
• Ions then flow down their electrochemical gradients into or out of the cell.
• Example: When sodium channels open, Na⁺ permeability increases, Na⁺ enters the cell, and the membrane potential moves toward E_Na (becomes more positive). When sodium channels close, the membrane becomes more permeable to K⁺ again, and the potential returns toward the resting level.

🔋 The Goldman-Hodgkin-Katz equation

The Goldman-Hodgkin-Katz (GHK) equation calculates the membrane potential (E_m) from:

• The permeabilities of the membrane to K⁺, Na⁺, and Cl⁻ (pK, pNa, pCl).
• The concentration gradients of these ions.
• The membrane potential is weighted toward the equilibrium potential of the ion with the greatest permeability at that moment.

Note: The Cl⁻ concentration gradient is expressed in reverse compared to K⁺ and Na⁺ to account for its opposite (negative) charge.

🔄 The sodium-potassium ATPase pump

🔄 Why the pump is necessary

• During rest and signalling, ions flow through ion channels down their electrochemical gradients (no energy required).
• The membrane potential is controlled by changing permeability, not by changing concentration gradients.
• Very few ions need to flow to change membrane potential, so concentrations do not change much in the short term.
• However, because the membrane potential does not sit at the equilibrium potential for any ion, there is a net K⁺ flux out of the cell and a net Na⁺ flux into the cell, even at rest.
• Over the longer term, these fluxes would dissipate the concentration gradients if not corrected.

🔄 How the pump works

The sodium-potassium pump, or the Na⁺/K⁺ ATPase, is a protein that sits in the plasma membrane and pumps sodium out of the cell and potassium back into the cell.

• Pumping occurs against the ions' electrochemical gradients, so it requires energy in the form of ATP.
• The pump removes a phosphate group from ATP (forming ADP), releasing energy that changes the pump's shape.
• For every ATP molecule used, the pump moves 3 Na⁺ ions out of the cell and 2 K⁺ ions into the cell.

⚡ The pump is electrogenic

• Because 3 Na⁺ ions are removed for every 2 K⁺ ions brought in, the pump causes a net export of positive charge.
• This contributes a little to the negative resting membrane potential.
• However, the strongest effect of the Na⁺/K⁺ ATPase on resting potential is maintaining the potassium electrochemical gradient, so that E_K is maintained.

💰 Energy cost of the pump

• The Na⁺/K⁺ ATPase is always at work because there are ion fluxes even at rest.
• Its activity increases when neurons are signalling and more ions need to be pumped back.
• Maintaining ion concentration gradients is so important that the Na⁺/K⁺ ATPase is the single most energy-consuming process in the brain, consuming over half of all the energy it uses.
• The brain uses 20% of the body's energy at rest, despite being only 2% of body mass.
• Therefore, the Na⁺/K⁺ ATPase alone uses over 10% of the energy used by the whole body.

Don't confuse: Ion flow through channels (down gradients) is passive and requires no energy; pumping ions back (against gradients) requires ATP.

🧠 Action potentials: generation and propagation

🧠 What an action potential is

An action potential is a brief electrical signal that is conducted from the axon hillock (where the neuron's soma joins the axon) along the axon to the axon terminals.

• It is a rapid, localised change in membrane voltage.
• The membrane transiently shifts from the negative resting potential to a positive membrane potential (depolarisation).
• The membrane then rapidly repolarises (becomes negative again) and hyperpolarises (becomes even more negative) before returning to resting potential.
• This entire voltage change occurs in less than 5 ms.
• The transient voltage change spreads like a wave down the axon at 1–100 m/s.

⚡ Voltage-gated sodium channels cause the upstroke

• The upstroke (rapid depolarisation) is caused by voltage-gated sodium channels that open at a threshold of -55 mV.
• When the membrane depolarises to -55 mV, these channels start to open.
• Na⁺ floods into the cell, depolarising the membrane further and opening even more sodium channels.
• This feedforward activation makes the action potential an all-or-nothing event: if threshold is reached, an action potential fires; if not, it does not fire.
• The action potential is always the same size and is not graded by the size of the incoming depolarisation.

⚡ Voltage-gated potassium channels cause the downstroke

• Voltage-gated sodium channels rapidly inactivate (close), stopping Na⁺ influx.
• Voltage-gated potassium channels activate at the same threshold as sodium channels but more slowly, or at a more positive voltage (around +30 mV).
• When potassium channels open, K⁺ leaves the cell, causing the membrane to hyperpolarise (the falling phase).

⚡ Afterhyperpolarisation

• Many voltage-gated potassium channels switch off slowly after the membrane potential falls below their threshold.
• After the membrane repolarises to resting potential, some voltage-gated potassium channels are still open (in addition to leak channels).
• The membrane is now more permeable to K⁺ than at rest, so the membrane potential hyperpolarises below resting potential, closer to E_K.
• As the voltage-gated potassium channels close, permeability returns to normal and the membrane potential returns to resting.

🚫 Refractory periods

• Voltage-gated sodium channels have an inactivation gate on the intracellular side that swings shut during the rising phase, blocking the pore and stopping Na⁺ flux.
• Even when the membrane falls below threshold (closing the voltage-sensitive gate), the inactivation gates are still closed.
• Absolute refractory period: The time when sodium channels are inactivated and firing another action potential is impossible.
• Relative refractory period: Sodium channels' inactivation gates start to reopen during the falling phase, but voltage-gated potassium channels are still open. A stronger stimulus is needed to fire another action potential.
• Stronger stimuli can produce faster firing rates by intruding into the relative refractory period.

🏃 Action potential propagation

• Action potentials are initiated at the axon's initial segment near the soma.
• In an unmyelinated axon, positive charge (Na⁺) that enters during the upstroke spreads to adjacent membrane, depolarising it and opening voltage-gated sodium channels there.
• A wave of depolarisation and repolarisation spreads down the axon to the axon terminals.
• Sodium channel inactivation prevents upstream spread: the upstream membrane is in the absolute refractory period, so the action potential can only spread downstream.

🏃 Increasing conduction speed

Increasing axon diameter:

• Reduces resistance to current flow within the axon.
• Allows depolarisation to passively spread further down the axon.
• More rapidly activates action potential firing in downstream membrane.

Myelination:

• Layers of myelin (from oligodendrocytes in CNS or Schwann cells in PNS) insulate the axon membrane.
• Myelinated membrane has low permeability and high resistance to current flow, so current spreads further inside the axon without leaking out.
• Myelin decreases membrane capacitance (the amount of charge stored at the membrane) by increasing the distance between intracellular and extracellular fluids.
• Lowered capacitance allows current to spread further and faster.
• Depolarisation rapidly spreads passively along myelinated axon segments but needs periodic boosting.
• Nodes of Ranvier: Gaps in the myelin sheath packed with ion channels. When nodes depolarise, voltage-gated sodium channels open, triggering a new action potential that passively spreads to the next node.
• Saltatory conduction: The action potential rapidly jumps between nodes (from Latin 'saltare' – 'to jump').

Axon type	Conduction speed	Example
Small, unmyelinated	0.5–2 m/s	Slow conduction
Large, myelinated	Up to 100 m/s	Sensory neurons carrying spatial information

Don't confuse: Myelination speeds conduction and also makes action potentials more energy-efficient, because fewer ions flow to depolarise myelinated membrane, so less ATP is needed to pump ions back.

💡 Energy use by action potentials

• Ion flow through voltage-gated channels during the action potential occurs down electrochemical gradients, so it does not itself use energy.
• Very few ions flow during an action potential, so concentration gradients do not change significantly in the short term.
• Over the longer term, ions need to be pumped back to maintain concentration gradients and resting potential, using ATP via the Na⁺/K⁺ ATPase.
• Myelination makes action potential firing more energy efficient because fewer ions need to flow, so less ATP is needed.

🔗 Synaptic transmission: communication between neurons

🔗 Overview of synaptic transmission

• Neurons signal electrically within a cell (via action potentials) but chemically between cells (via neurotransmitters).
• Presynaptic neuron: The neuron sending the signal.
• Postsynaptic neuron: The neuron receiving the signal.
• Synaptic cleft: The tiny gap between the two neurons.

🔗 Steps of synaptic transmission

1. An action potential arrives at the axon terminal (presynaptic terminal), depolarising it.
2. Depolarisation opens voltage-gated calcium channels (threshold ~-10 mV). Ca²⁺ enters the cell down its electrochemical gradient (higher outside: 1.5–2 mM vs. inside: 0.05–0.1 mM).
3. Ca²⁺ binds to a protein called synaptotagmin.
4. Synaptic vesicles (membrane 'bags' packed with neurotransmitter) are docked at the active zone by SNARE proteins. When Ca²⁺ binds synaptotagmin, vesicle and plasma membranes fuse, releasing neurotransmitter into the synaptic cleft.
5. Neurotransmitter diffuses across the narrow synaptic cleft to the postsynaptic cell.
6. Neurotransmitter binds to receptors on the postsynaptic membrane (usually on a dendrite). Many receptors are ligand-gated ion channels that open when the neurotransmitter (ligand) binds. Ions flow through, producing a voltage change in the postsynaptic cell.
7. To terminate signalling, neurotransmitter is removed from the synaptic cleft by transporters on neurons or astrocytes, which take up neurotransmitter for breakdown, recycling, or repackaging. Some neurotransmitters are broken down by proteins in the synaptic cleft.

➕ Excitatory synapses

Excitatory synapses make the postsynaptic neuron more likely to fire an action potential by producing a depolarisation, moving it toward the threshold potential for opening voltage-gated sodium channels.

Glutamate:

• The main excitatory neurotransmitter in the brain.
• Main receptors: AMPA and NMDA receptors.

AMPA receptors:

• Ligand-gated ion channels permeable to both Na⁺ and K⁺.
• Main effect is Na⁺ influx, so the membrane depolarises toward threshold.
• This depolarising change is called an excitatory postsynaptic potential (EPSP) and lasts several (>10) milliseconds.

NMDA receptors:

• Ligand-gated ion channels permeable to Ca²⁺, Na⁺, and K⁺.
• Also voltage-dependent: blocked by Mg²⁺ unless the membrane is depolarised.
• Slower to open and close than AMPA receptors.
• Do not contribute much to the EPSP but play an important role in altering synaptic strength.

Metabotropic glutamate receptors:

• Also known as G-protein coupled receptors.
• Bind glutamate but do not directly open an ion channel.
• Trigger intracellular signalling pathways that alter other ion channels.
• Have slower effects than ionotropic receptors (like AMPA and NMDA).

➕ Summation of EPSPs

• Usually a single EPSP from one synapse is not enough to reach threshold for firing an action potential.
• Multiple synaptic inputs need to be summed together.
• Temporal summation: If the presynaptic neuron fires many action potentials in a short time, inputs into a single synapse add together to form a larger EPSP.
• Spatial summation: If different excitatory synapses are active at the same time, their EPSPs add together to generate a larger EPSP.
• Both temporal and spatial summation integrate inputs onto a postsynaptic cell to determine whether it fires an action potential.

➖ Inhibitory synapses

Inhibitory synapses make the postsynaptic neuron less likely to fire an action potential, by hyperpolarising the membrane or by preventing it from depolarising by holding the membrane below that needed to activate sodium channels.

GABA (gamma aminobutyric acid):

• The main inhibitory neurotransmitter in the brain.
• Main receptors: GABA_A and GABA_B receptors.

GABA_A receptors:

• Ligand-gated ion channels permeable to Cl⁻.
• When GABA binds, Cl⁻ enters the cell.
• E_Cl = -65 mV, so opening GABA_A channels tends to keep the membrane potential near -65 mV.
• Because -65 mV is below the threshold for sodium channel activation, this inhibits action potential firing.
• Depending on the membrane voltage when channels open, the membrane might slightly hyperpolarise or depolarise, but in each case the effect is inhibitory (an inhibitory postsynaptic potential or IPSP) because it holds the membrane away from threshold.
• Example: If the membrane is at -75 mV, opening GABA_A channels will depolarise it slightly to -65 mV, but the open channels prevent further depolarisation to threshold. If the membrane is at -60 mV, opening GABA_A channels will hyperpolarise it to -65 mV. In both cases, the neuron is less likely to reach threshold.

GABA_B receptors:

• Metabotropic receptors linked to activation of potassium channels, increasing K⁺ permeability.
• Their activation shifts the membrane potential toward E_K.

Don't confuse: An IPSP can involve a small depolarisation (if the membrane is more negative than E_Cl), but it is still inhibitory because it prevents the membrane from reaching threshold.

🧭 Overview

🧠 One-sentence thesis

Neurons integrate both excitatory and inhibitory synaptic inputs through spatial and temporal summation to determine whether to fire an action potential, with this computational process shaped by cell morphology, synapse location, and the diversity of neurotransmitter systems.

📌 Key points (3–5)

• Inhibitory synapses use neurotransmitters like GABA to prevent action potentials by keeping the membrane potential below threshold, either through hyperpolarization or by preventing depolarization.
• Synaptic integration combines all excitatory (EPSPs) and inhibitory (IPSPs) inputs through temporal and spatial summation to decide whether the neuron fires.
• Location matters: synapse position on the neuron (distal dendrites vs soma vs axon) dramatically affects how much influence that input has on firing decisions.
• Common confusion: inhibitory signals don't always hyperpolarize—GABA_A receptors can slightly depolarize a cell if it's already very negative, but they still inhibit by holding the membrane away from threshold.
• Plasticity enables learning: the ability to modify synaptic strength, location, and properties forms the basis of learning, memory, and perception.

🚫 Inhibitory synapses and mechanisms

🚫 How inhibition works

Inhibitory post-synaptic potential (IPSP): a membrane potential change that makes the neuron less likely to fire an action potential by holding the membrane potential away from threshold.

• Inhibitory synapses don't simply "turn off" neurons; they make firing less likely by manipulating membrane voltage.
• Two main strategies: hyperpolarize the membrane (make it more negative) or prevent it from reaching threshold even if it depolarizes slightly.

🧪 GABA_A receptors: chloride channels

• What they are: ligand-gated ion channels permeable to Cl⁻ ions when GABA binds.
• How they inhibit: opening these channels tends to keep membrane potential near -65 mV (the chloride equilibrium potential, E_Cl).
• Why -65 mV matters: this voltage is below the threshold needed to activate sodium channels and fire an action potential.

The counterintuitive case:

• If the neuron is at -75 mV when GABA_A receptors open, the membrane actually depolarizes slightly toward -65 mV.
• This is still inhibitory because the open channels prevent further depolarization beyond -65 mV to reach threshold.
• If the membrane is at -60 mV, opening GABA_A channels hyperpolarizes it back to -65 mV.
• In both cases, the neuron is held away from firing threshold.

⚡ GABA_B receptors: potassium-mediated hyperpolarization

• What they are: metabotropic receptors linked to potassium channel activation.
• How they work: increase K⁺ permeability, shifting membrane potential toward E_K (-80 mV), which hyperpolarizes the cell.
• Key difference from GABA_A: these IPSPs are slower because they require intracellular signaling cascades rather than direct ion channel opening.

🧮 Synaptic integration and computation

🧮 How neurons decide to fire

• Postsynaptic cells use temporal summation (multiple inputs arriving close in time) and spatial summation (inputs from different locations) to integrate all synaptic inputs.
• If the net effect depolarizes the axon initial segment above threshold, the cell fires an action potential.
• This integration process is the basis of neuronal computation—how neurons process information to generate thoughts and feelings.

📍 Location determines influence

The position of a synapse on the neuron dramatically affects its impact:

Synapse location	Effect on firing decision	Why
Distal dendrites (far from soma)	Smaller effect	Signal degrades over distance traveled
Soma	Moderate to strong effect	Closer to axon initial segment
Axon initial segment	Strongest effect	Direct influence on action potential generation

🚧 Inhibitory gating

• What it is: inhibitory synapses positioned between excitatory synapses and the soma can block EPSPs from reaching the soma.
• Example: an excitatory input on a distal dendrite can be "gated" by an inhibitory synapse closer to the soma on the same dendrite, preventing the EPSP from influencing the firing decision.

🔧 Factors affecting signal spread

Several properties determine how well EPSPs and IPSPs travel along dendrites:

• Ion channel density: fewer channels mean less charge leakage, so signals travel farther.
• Cell size: smaller cells have lower capacitance, allowing signals to spread farther with less loss.
• Voltage-gated channels in dendrites: these can boost signals from distal dendrites, compensating for distance.
• Cell morphology: highly branched cells lose more charge at membranes.

🧠 Computational flexibility through plasticity

Plasticity: the ability to modify synaptic properties based on the cell's activity.

• Many factors can be modified: synapse location, synapse strength, cell shape, ion channel number and location.
• This plasticity allows neurons to alter how different synaptic connections contribute to firing decisions.
• Why it matters: plasticity enables associations to form and break between neurons, forming the basis of learning and memory and shaping perception.

🔌 Gap junctions: electrical synapses

🔌 Direct electrical connections

Gap junctions: direct electrical connections between neurons formed by pairs of hemichannels made of connexin proteins.

• Unlike chemical synapses, gap junctions allow direct electrical communication between cells.
• They are relatively non-selective, allowing both cations and anions through, plus small molecules like ATP.

⚙️ Properties and distribution

• Usually open, though their opening can be regulated.
• Allow electrical signals to spread through connected cells.
• Where they're found:
  • More common during development
  • Rare between excitatory cells in mature nervous systems
  • Most common between certain inhibitory interneurons in brain and retina
  • Common between glia such as astrocytes

🧪 Neurotransmitter diversity

🧪 Beyond glutamate and GABA

While glutamate is the main excitatory neurotransmitter and GABA the main inhibitory neurotransmitter in the brain, many other neurotransmitters exist, categorized by chemical structure:

Category	Examples	Key features
Amino acids	Glutamate, GABA, glycine	Glycine is the major inhibitory transmitter in brainstem and spinal cord
Monoamines	Noradrenaline, dopamine, serotonin	Originate in specific midbrain/brainstem nuclei; project widely; modulate reward, attention, alertness
Peptides	Endorphins, enkephalins, dynorphins, oxytocin, somatostatin	Natural opioid peptides activate same receptors as morphine/heroin; often co-released with GABA or serotonin
Purines	ATP, adenosine	ATP is the cell's main energy currency
Acetylcholine	—	Structurally unique; excitatory in peripheral nervous system (including neuromuscular junction); regulates alertness, memory, attention in brain

🔬 Monoamines: widespread modulators

• Specific populations of monoaminergic neurons originate in specific midbrain and brainstem nuclei.
• Send projections to widespread brain regions.
• Modulate processes such as reward, attention, and alertness.
• Noradrenaline also serves as an excitatory transmitter in the peripheral nervous system.

💊 Peptide neurotransmitters and opioids

• Naturally occurring opioid peptides (endorphins, enkephalins, dynorphins) activate the same receptors as opiate drugs like morphine and heroin.
• Peptide neurotransmitters are often co-released at synapses with other transmitters like GABA or serotonin.
• This co-release adds another layer of complexity to synaptic signaling.

🧭 Overview

🧠 One-sentence thesis

Drugs must navigate complex barriers and metabolic processes to reach the brain, where they interact with receptors in specific ways that determine their therapeutic effects and side effects.

📌 Key points (3–5)

• Drug distribution challenges: Drugs spread through the bloodstream but face barriers (like the blood-brain barrier) and can be trapped in inactive sites (depot binding), making brain delivery difficult.
• Lipid solubility and ionization control membrane crossing: Drugs cross membranes via passive diffusion; their ability depends on being lipid-soluble and non-ionized, leading to phenomena like ion trapping.
• Metabolism inactivates and transforms drugs: Liver enzymes and other mechanisms break down drugs, sometimes creating active metabolites; individual variation (sex, age, genetics, tolerance) affects metabolism rates.
• Pharmacodynamics: agonists vs antagonists: Agonists bind receptors and trigger effects; antagonists block receptors without triggering effects; dose-response curves reveal potency (ED₅₀) and efficacy (maximum effect).
• Common confusion—competitive vs non-competitive antagonists: Competitive antagonists can be overcome by increasing agonist dose (shift ED₅₀ right, same max); non-competitive antagonists cannot be fully overcome (shift right and reduce max effect).

🚚 Drug distribution and barriers

🚚 How drugs spread through the body

• After entering the bloodstream, drugs distribute throughout the body via circulation.
• Distribution is not instantaneous or uniform—drugs may be delayed or sequestered.
• Depot binding: drugs can become trapped in inactive sites (e.g., fat stores) where no receptors exist; these stores slowly release the drug or its metabolites, prolonging effects.
• Example: A lipid-soluble drug accumulates in fat tissue and is gradually released over time, extending its action even after administration stops.

🧱 The blood-brain barrier (BBB)

Blood-brain barrier (BBB): a selective barrier that drugs must cross to reach the brain.

• Only lipid-soluble drugs can easily pass through the BBB.
• Why lipid solubility matters: The BBB is made of tightly packed cells with lipid membranes; non-lipid-soluble drugs cannot diffuse through.
• Example: Heroin is more lipid-soluble than morphine, so it crosses the BBB faster, acts more quickly, and may contribute to its higher addictive potential.
• Challenge for psychopharmacology: Delivering drugs to the brain is difficult; drugs act on peripheral tissues first, causing unwanted side effects before reaching the brain.

💧 Membrane crossing: lipid solubility and ionization

• Drugs usually lack helper proteins to cross membranes, so they rely on passive diffusion down their concentration gradient.
• Lipid bilayer structure: Body membranes are made of lipids, so drugs must be lipid-soluble to pass through.
• Ionization reduces lipid solubility: When a drug becomes ionized (charged), it becomes less lipid-soluble and struggles to cross membranes.

Drug type	Less ionized in...	Example
Weak acids	Acidic solutions	Aspirin in stomach (pH 2.0)
Weak bases	Basic solutions	(Not detailed in excerpt)

🔒 Ion trapping

Ion trapping: a situation where a drug becomes highly ionized in a compartment and cannot easily leave because it is no longer lipid-soluble.

• Example: Aspirin (a weak acid) is non-ionized in the acidic stomach (pH 2.0), so it crosses the stomach lining into the bloodstream. Blood is slightly basic (pH 7.4), so aspirin becomes ionized and is "trapped" in the blood vessel—it cannot easily cross back out.
• How to overcome ion trapping: Concentration gradients can drive the drug to move from high-concentration compartments to low-concentration ones, even if ionized.
• Don't confuse: Ion trapping is not permanent; it just makes crossing membranes harder unless concentration differences are large enough.

🔥 Metabolism and excretion

🔥 How the body inactivates drugs

• First-pass metabolism: Drugs taken orally pass through the liver before reaching systemic circulation; liver enzymes (microsomal enzymes) break them down.
• Biotransformation: The liver metabolizes drugs to make them more ionized, reducing lipid solubility and preventing them from crossing the BBB.
• Excretion routes: Metabolized drugs are primarily excreted via the kidneys (urine), but also through bile, feces, breath, sweat, and saliva.

🧪 Active metabolites

• Some drugs are metabolized into molecules that are also biologically active.
• Example: Heroin is metabolized into morphine in the brain; both have similar effects.
• Opposing effects possible: Some metabolites have opposite effects to the parent drug.
• Example: Alcohol is metabolized into acetaldehyde (via alcohol dehydrogenase), which makes people feel sick. Acetaldehyde is then metabolized into acetic acid (via aldehyde dehydrogenase). Disulfiram blocks aldehyde dehydrogenase, causing acetaldehyde to accumulate and produce unpleasant effects, theoretically discouraging drinking (though compliance is often poor).

🧬 Individual variation in metabolism

Factor	Effect on metabolism	Example
Sex	Women may have lower gastric alcohol dehydrogenase	More alcohol enters bloodstream for same dose
Chronic use	Enzyme induction increases metabolism	Chronic drinkers have higher alcohol dehydrogenase; need more alcohol for same effect (tolerance)
Age	Older individuals have reduced liver function	Exaggerated alcohol effects in older people
Genetics	Polymorphisms affect enzyme levels	Some lack aldehyde dehydrogenase; acetaldehyde accumulates, causing unpleasant effects

• Enzyme induction: Repeated drug use increases expression of drug-metabolizing enzymes, leading to tolerance (more drug needed for same effect).

💊 Pharmacodynamics: how drugs act at receptors

💊 What pharmacodynamics studies

Pharmacodynamics: the study of the effect a drug has once it reaches its target in the body.

• While pharmacokinetics explains how a drug gets to the brain, pharmacodynamics describes what the drug does there.
• Drugs can interact with many types of molecules (not just receptors) to affect brain function.
• Example: Nicotine binds to nicotinic acetylcholine receptors (ionotropic receptors that normally bind acetylcholine).

🔑 Receptors and ligands

Receptor: a molecule that a drug (or endogenous ligand) binds to, initiating a biological effect.

• Receptors are often proteins in cell membranes, but can also be in the cytoplasm.
• Autoreceptors: receptors on pre-synaptic terminals that help self-regulate neurotransmitter release (e.g., dopamine D3 receptor).
• "Dirty" drugs: Most drugs bind to multiple receptor types to varying degrees, causing side effects.
• Example: Second-generation antipsychotic medications bind many receptor types, leading to significant individual variation in tolerability.

🔓 Agonists: the "lock-and-key" mechanism

Agonist: a drug that binds to a receptor and initiates a biological effect.

• Agonists work like a key turning a lock—they activate the receptor.
• Weak binding: Drugs bind receptors weakly and can rapidly dissociate, so acute effects are reversible.
• Why reversibility matters: When the drug leaves, the endogenous ligand can bind again.

📈 Dose-response curves and drug potency

📈 The law of mass action

Law of mass action: a drug reaches its maximal effect when all receptors are occupied.

• Increasing the dose increases the probability of binding to receptors, up to a limit.
• Dose-response curve: S-shaped curve with log(dose) on x-axis and measured response on y-axis.
• ED₁₀₀: Effective dose 100—the dose at which the drug occupies all receptors and produces maximum effect.
• ED₅₀: Effective dose 50—the dose producing half the maximal effect, or the dose producing an effect in 50% of the population; a measure of potency.

📊 Therapeutic index and safety

• Drugs have multiple effects; each receptor type may have a different ED₅₀.
• TD₅₀: Toxic dose 50—the dose producing a toxic effect (e.g., sedation) in 50% of subjects.
• LD₅₀: Lethal dose 50—the dose that kills 50% of subjects.

Therapeutic index (TI): margin of safety = TD₅₀ / ED₅₀ (or LD₅₀ / ED₅₀).

• A higher therapeutic index means a safer drug (larger gap between effective and toxic doses).

⚖️ Efficacy vs potency

Term	Definition	What it tells us
Efficacy	Maximum effect a drug can produce	How well the drug works at its best
Potency	How much drug is needed to produce an effect	How much is needed (lower ED₅₀ = more potent)

• Example: Hydromorphine, morphine, and codeine all relieve pain (similar efficacy), but codeine requires a higher dose (less potent, higher ED₅₀).
• Example: Aspirin is both less potent and less efficacious than morphine for pain relief—it requires higher doses and cannot fully eliminate pain.
• Why differences exist: Pharmacokinetics (e.g., BBB crossing), receptor affinity (how long the drug stays bound), and different mechanisms (morphine binds opioid receptors; aspirin inactivates cyclooxygenase enzyme).

🚫 Antagonists: blocking receptor effects

🚫 What antagonists do

Antagonist: a drug that binds to a receptor and counteracts the effect of an agonist or endogenous ligand.

• Antagonists have no intrinsic activity—they do not trigger a biological response on their own.
• Think of an antagonist as a key that fits the lock but does not turn.
• Effectiveness is measured by how antagonists shift agonist dose-response curves.

🥊 Competitive antagonists

Competitive antagonist: binds to the same receptor site as an agonist, competing for binding.

• Effect on dose-response curve: Shifts the agonist's ED₅₀ to the right (more agonist needed).
• Can be overcome: Increasing the agonist dose can outcompete the antagonist; theoretically, the same ED₁₀₀ can be reached.
• Don't confuse: Competitive antagonists do not reduce the maximum possible effect, only require more agonist to reach it.

🛡️ Non-competitive antagonists

Non-competitive antagonist: binds to a different receptor site than the agonist, making receptors unavailable.

• Effect on dose-response curve: Shifts ED₅₀ to the right and reduces ED₁₀₀ (lowers maximum effect).
• Cannot be overcome: Increasing agonist dose cannot fully restore the effect because the antagonist does not compete for the same site.
• Example: (Not specified in excerpt, but mechanism is clear.)

⏳ Irreversible antagonists

• Most antagonists form weak, temporary bonds (reversible).
• Irreversible antagonists: Form long-lasting bonds with receptors.
• Example: Alpha-bungarotoxin (from banded krait venom) blocks acetylcholine receptors at neuromuscular junctions, causing paralysis, respiratory failure, and death.
• Hypothetical recovery: If the body synthesizes new receptors and the antagonist is eliminated, function can be restored.

🔀 Other types of agonists

🔀 Indirect agonists (allosteric modulators)

Indirect agonist: binds to a different receptor site than the full agonist or endogenous ligand, enhancing their effects.

• Example: Benzodiazepines bind to GABA_A receptors and enhance the channel's conductance when GABA is also attached.

⚖️ Partial agonists

Partial agonist: binds to the same receptor site as a full agonist but has low efficacy.

• Produces a smaller maximum response than a full agonist.
• When both are present: The partial agonist competes for binding sites and antagonizes the full agonist (because it is less effective).
• Can be overcome: Increasing the full agonist dose allows it to outcompete the partial agonist.
• Also called mixed agonist-antagonist drugs.

🔻 Inverse agonists

Inverse agonist: reduces spontaneous receptor activity, even when no ligand is bound.

• Some receptors have endogenous activity without ligands; inverse agonists reduce this.
• Dose-response curve: Descending (opposite of agonists).
• Example: Beta-carboline alkaloids bind to GABA_A receptors at the same site as benzodiazepines but have opposite effects—they increase anxiety (sometimes called "anti-benzodiazepines").
• Don't confuse: Competitive antagonists at GABA_A receptors do not affect receptor function on their own; they only block other drugs' effects.

🔁 Effects of repeated drug use

🔁 Tolerance

Tolerance: a decrease in drug effects with repeated administration at the same dose.

• More drug is needed to achieve the same effect.
• Example: Repeated amphetamine use can cause tolerance to euphoria-inducing effects.

🔁 Sensitization (reverse-tolerance)

Sensitization: an increase in drug effects with repeated administration.

• Less drug is needed to achieve the same effect.
• Example: Repeated amphetamine use can cause sensitization to psychomotor or psychosis-associated effects (while tolerance develops to euphoria).
• Mixed effects: Some drug responses undergo tolerance while others are sensitized.

🔁 Cross-tolerance

Cross-tolerance: tolerance to one drug reduces the effects of another drug targeting similar receptors.

• Example: Alcohol drinkers may be less affected by benzodiazepines because both depend on GABA transmission and GABA receptor expression.

🔁 Mechanisms

• Tolerance: Can result from enzyme induction (increased metabolism), receptor downregulation, or other adaptive changes.
• Sensitization: May involve increased neurotransmitter release (e.g., amphetamine increases dopamine levels across administrations).

🧭 Overview

🧠 One-sentence thesis

Touch sensitivity varies across the body because of differences in receptor density and receptive field size, and touch information travels from skin receptors through the spinal cord to the brain where it serves both discriminatory and affective (social bonding) functions.

📌 Key points (3–5)

• Receptor adaptation: Touch receptors are classified as fast-adapting (stop responding quickly to constant stimuli) or slow-adapting (continue responding), allowing the sensory system to signal change rather than waste energy on constant, unchanging information.
• Two-point discrimination and sensitivity: Body regions differ in sensitivity because of receptor density and receptive field size—small, distinct receptive fields (e.g., fingertips) allow detection of two close points as separate, while large or overlapping fields (e.g., upper arm) cause them to be perceived as one.
• Transduction mechanism: Touch stimuli are converted into neural signals (receptor potentials) when mechanical force opens ion channels in receptors like Pacinian corpuscles, causing sodium influx and depolarization that can trigger action potentials.
• Pathway to the brain: Touch information enters the spinal cord via the dorsal root, ascends in the dorsal column to the dorsal column nuclei, crosses to the opposite side in the medial lemniscus, synapses in the thalamus (VPL), and reaches the primary somatosensory cortex (S1), which is topographically organized as a "homunculus."
• Affective vs discriminatory touch: Touch serves not only to identify objects (discriminatory) but also plays a critical role in social bonding and emotional functioning (affective touch), with early nurturing tactile experiences influencing later social and emotional development.

🧬 Touch receptor types and adaptation

🧬 Four main receptor types

The excerpt describes four types of sensory receptor cells for touch, each with distinct locations and functions:

Receptor	Location	Activating stimulus
Meissner's corpuscles	Superficial	Light touch and vibration
Merkel's discs	Superficial	Light touch and pressure
Pacinian corpuscles	Deep	Heavy pressure and vibration
Ruffini's endings	Deep	Skin stretch

• These receptors are modified neurons embedded in the skin.
• Their location (superficial vs deep) and structure determine what kind of mechanical stimulus they respond to.

⏱️ Fast vs slow adaptation

Fast adapting receptors: stop responding very quickly to a constant stimulus.
Slow adapting receptors: continue to respond, albeit at a lesser level, to constant stimuli.

• Why adaptation matters: Sensory systems signal change rather than constant, unchanging information, avoiding wasted energy.
• Key survival information comes from changing stimuli, not static ones.
• Example: When you first put on a watch, you feel it; after a few minutes, you no longer notice it (fast adaptation).
• Don't confuse: Adaptation is not "getting used to" pain or ignoring a stimulus—it's a receptor-level property that determines how long the receptor continues to fire in response to a steady stimulus.

📏 Sensitivity and two-point discrimination

📏 Why some body parts are more sensitive

• Receptive field: the skin area where a touch will be detected by a single receptor cell.
• High sensitivity arises from:
  • High density of receptors
  • Small, distinct receptive fields
• Low sensitivity arises from:
  • Low density of receptors
  • Large or overlapping receptive fields

🔬 Two-point discrimination threshold

Two-point discrimination threshold: the minimum separation at which two points touched on the skin at the same time are felt as two different points rather than one.

• The excerpt provides typical threshold values (in millimeters):
  • Index finger: 2 mm (very sensitive)
  • Palm of hand: 13 mm
  • Forehead: 18 mm
  • Upper arm: 47 mm (less sensitive)
  • Thigh: 46 mm (less sensitive)
• How it works: When two points are close together and fall within the same receptive field, they activate the same receptor and are perceived as a single stimulus. When they fall in different receptive fields, they activate different receptors and are perceived as two separate points.
• Example: On your fingertip, two points 2 mm apart will activate different receptors, so you feel two distinct touches. On your upper arm, the same 2 mm separation falls within one large receptive field, so you feel only one touch.

⚡ Transduction: from touch to nerve impulse

⚡ What transduction is

Transduction: the process whereby a sensory stimulus is converted into an electrical signal in the form of a membrane potential.

• Transduction is common across all sensory systems, but the mechanism varies by stimulus and receptor type.
• Much of what we know about touch transduction comes from studies of Pacinian corpuscles (often in cats, which closely resemble humans).

🧅 Structure and mechanism of Pacinian corpuscles

• Structure: Multiple layers (like an onion skin) surrounding a sensory nerve ending with an unmyelinated tip in the center.
• Mechano-sensitive ion channels: Channels in the membrane of the unmyelinated tip that open and close depending on mechanical force.
• How transduction occurs:
  1. Force is applied to the skin.
  2. The layered corpuscle acts as a mechanical filter, transmitting strain to the unmyelinated tip.
  3. The force causes mechano-sensitive ion channels to open.
  4. Sodium ions (Na⁺) flow into the cell (down their electrical and chemical gradients—from the positively-charged, high-concentration extracellular space into the negatively-charged, low-concentration cell interior).
  5. The influx of positive sodium ions depolarizes the cell (makes the inside less negative).

🔋 Receptor potential and action potentials

Receptor potential: a change in membrane potential within a sensory receptor cell caused by the presence of a sensory stimulus.

• The receptor potential is similar to a post-synaptic potential: it degrades rapidly.
• If sufficient depolarization occurs at the point where the unmyelinated tip meets the first myelinated region, an action potential is triggered.
• Stimulus intensity encoding:
  • As stimulus intensity increases, the receptor potential gets larger (ion channels remain open longer, allowing greater sodium influx).
  • Action potentials are all-or-nothing signals (cannot change in size).
  • A larger receptor potential means a greater frequency of action potentials, not larger action potentials.
• Example: A light touch causes a small receptor potential and a few action potentials per second; a firm press causes a larger receptor potential and many action potentials per second.
• Don't confuse: The receptor potential (graded, local) with the action potential (all-or-nothing, long-distance).

🛤️ Pathways to the brain

🛤️ Dorsal root ganglion and spinal cord entry

• Sensory receptor cell structure: These neurons have a bifurcating (splitting) axon:
  • One part travels from the sensory nerve ending in the skin to the cell body in the dorsal root ganglion.
  • The other part continues from the cell body into the spinal cord.
• Dorsal root ganglion: A cluster of sensory neuron cell bodies located just outside the spinal cord at every segment (cervical, thoracic, lumbar, sacral).
• Which ganglion receives information depends on where in the body the touch originated.
• Example: The thumb sends information into the C6 spinal nerve.
• Face exception: Touch information from the face enters the central nervous system via the trigeminal system at the brainstem, not the spinal cord.

🧭 Dorsal column/medial lemniscal pathway

Dorsal column/medial lemniscal pathway: the main pathway for touch information to reach the brain.

The pathway involves three neurons (first, second, and third order):

1. First order neuron (the sensory receptor cell):

   • Axons enter the spinal cord via the dorsal root.
   • They ascend directly up the spinal cord on the same side of the midline.
   • They synapse in the dorsal column nuclei (DCN) in the medulla.

2. Second order neuron:

   • Originates in the DCN.
   • Axons travel in the medial lemniscus to the thalamus.
   • They synapse in the ventral posterior lateral thalamic nucleus (VPL).

3. Third order neuron:

   • Originates in the VPL.
   • Carries the signal to the primary somatosensory cortex (S1) in the parietal lobe.

• Key detail: The pathway crosses to the contralateral (opposite) side in the medial lemniscus, after leaving the DCN.

🗺️ Somatosensory homunculus

Somatosensory homunculus ("little man"): a topographically organized map of the body in the primary somatosensory cortex (S1), where areas of the body are represented in proportion to the input they receive.

• First proposed in 1937 by neurosurgeon Wilder Penfield, based on electrical stimulation of the cortical surface during epilepsy surgery in conscious patients.
• Patients could report what they felt when different cortical regions were stimulated.
• Limitations: Exact stimulation patterns and intensity were not recorded, so the representation may not be entirely accurate.
• Despite potential inaccuracies, the homunculus concept has persisted and continues to inspire research.
• Motor homunculus: A matching map on the motor cortex; connectivity between the sensory and motor homunculi is critical for fine motor control (e.g., impaired connectivity is linked to poor fine motor control in autism spectrum disorder).

🌐 Beyond S1

• Touch processing does not stop at S1.
• Signals continue to:
  • Secondary somatosensory cortex (S2) in the parietal cortex
  • Insular cortex (nestled deep within the folds between parietal and temporal lobes)
• An extensive cortical network is involved in processing touch information.

🤲 Perception of touch: discriminatory and affective

🤲 Active vs passive touch

• Active touch: Requires intentional movement of the fingers over the object (e.g., running fabric between your fingers to assess smoothness, thickness, weight).
• Passive touch: The object is pressed against the fingers without intentional movement.

Research findings:

• Early research suggested active touch may be more informative for determining object shape.
• Later work (controlling for pressure) showed little difference, or even an advantage for passive touch.
• Primary somatosensory cortex shows greater activation under active touch conditions, possibly because of input from the motor cortex as the fingers move.
• Proprioception's role: Active touch activates both touch receptors in the skin and proprioceptive receptors (which detect body position). Some researchers propose that these inputs converge in the brain, causing greater excitation; others suggest they compete rather than combine.
• Don't confuse: Active touch with "better" touch—the evidence is mixed, and the difference may depend on the task and the role of proprioception.

💞 Affective touch and social bonding

Discriminatory touch: Touch used to perceive and identify objects in the environment.
Affective touch: Touch that conveys emotional and social information, playing a critical role in social bonding.

• Much physical contact is with other people, not inanimate objects.
• Affective touch begins in infancy: parent-infant touch is a key part of nurturing.
• Mechanisms: The relationship between early tactile nurturing and later social/emotional functioning is thought to be mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis (which underpins stress responses) and hormones like oxytocin.

🐭 Evidence from animal studies

• Research in rodents: Greater nurturing behavior (licking, grooming, huddling, playing) results in greater density of connections in the somatosensory cortex of offspring.
• This demonstrates a direct link between early tactile experience and brain development.

👶 Evidence from human studies

• Ethical constraint: It would be unethical to experimentally divide human infants into high and low nurturing conditions.
• Care-leavers study: Researchers compared care-leavers (who likely experienced reduced tactile nurturing due to neglect/abuse) with non-care-leavers in the UK.
• Finding: Care-leavers were less sensitive to the affective components of touch.
• Other factors: Levels of empathy and loneliness can also affect how people perceive affective touch.
• Autism Spectrum Disorder: Individuals with ASD have impaired responses to interpersonal touch.

🔑 Key implications

• Affective touch is not just "nice to have"—it is critical for social and emotional functioning.
• Early adversity in the form of lack of nurturing tactile stimulation can have long-lasting impacts on touch perception and social bonding.
• Altered perception of affective touch is related to empathy, loneliness, and certain diagnoses.

🧠 Key concepts summary

🧠 Transduction and encoding

• Transduction: Mechanical force → ion channel opening → sodium influx → depolarization (receptor potential) → action potential.
• Intensity encoding: Larger stimuli → larger receptor potentials → higher frequency of action potentials (not larger action potentials).

🧠 Pathway summary

• Skin → dorsal root ganglion (first order neuron) → dorsal column → DCN in medulla (synapse with second order neuron) → medial lemniscus (crosses to opposite side) → VPL in thalamus (synapse with third order neuron) → S1 in parietal cortex → S2 and insular cortex.

🧠 Sensitivity and representation

• Sensitivity depends on receptor density and receptive field size.
• The body is topographically mapped onto S1 as a homunculus, with representation proportional to input (not body size).

🧠 Two functions of touch

• Discriminatory: Identifying objects, their size, weight, texture, stiffness, etc.
• Affective: Social bonding, emotional regulation, and nurturing, with long-term impacts on development and well-being.

🧭 Overview

🧠 One-sentence thesis

Pain is not simply a direct signal from injury to brain but a complex, modulated experience that encompasses physical damage (nociceptive), nerve damage (neuropathic), and psychological factors (psychogenic), all subject to control by both spinal and brain mechanisms.

📌 Key points (3–5)

• Three types of pain: nociceptive (from actual tissue damage), neuropathic (from damage to pain pathways themselves), and psychogenic (from psychological factors without physical injury).
• Pain pathways can be interrupted: both at the spinal cord level (Gate Control Theory via touch input) and by descending signals from the brain (PAG and other structures).
• Common confusion: pain location vs. injury location—referred pain occurs when visceral injury is perceived as somatic pain elsewhere; phantom limb pain occurs when pain is felt in a missing body part.
• Treatment varies by type and duration: acute pain often responds to medication, while chronic pain typically requires multifaceted approaches including drugs, stimulation techniques, surgery, and psychological therapy.
• Pain serves survival: hyperalgesia and allodynia after injury promote rest and recovery, but pain can also be suppressed when survival depends on mobility (e.g., battlefield injuries).

🔬 Nociception and detection mechanisms

🔬 What nociceptors detect

Nociceptor: a modified neuron in the skin (and throughout the body) responsible for detecting tissue damage; takes the form of free nerve endings without specialized structures.

• Nociceptors detect three main categories of noxious stimuli:
  • Mechanical: intense pressure (pinching, crushing) via mechano-nociceptors
  • Chemical: substances released from damaged cells (potassium, hydrogen ions, bradykinin, prostaglandins) plus immune response chemicals (histamine, serotonin, ATP)
  • Thermal: extreme temperatures (>45°C or <5°C) via heat-sensing channels

⚡ Transduction mechanisms

• Mechanical transduction: mechano-sensitive ion channels open, allowing sodium influx → depolarizing receptor potential (similar to touch receptors)
• Chemical transduction: when cells rupture, intracellular contents (especially potassium) spill into extracellular space; some chemicals directly activate nociceptors (potassium, bradykinin), others sensitize them (prostaglandins)
• Thermal transduction: heat-sensing channels open, allowing both sodium and calcium into the nociceptor → depolarization
• If receptor potential is large enough → action potential is triggered → signal transmitted to CNS

📍 Distribution and special cases

• Nociceptors are found throughout the body except inside bones and in the brain (explaining why brain surgery can be performed on awake patients)
• Somatic pain: from muscles, skin, or joints (common)
• Visceral pain: from internal organs like heart, lungs, bladder (rare)
• The rarity of visceral pain contributes to referred pain phenomenon

Example: Heart attack pain perceived in left arm and shoulder because visceral and somatic signals converge on the same spinal neuron; the brain interprets the ambiguous signal based on what it most expects (shoulder injury more common than heart injury).

🔄 Sensitivity changes after injury

• Hyperalgesia: increased sensitivity to painful stimuli following injury
  • Evolutionary benefit: promotes rest and recovery (part of "sickness behaviour")
• Allodynia: nociceptors become sensitive to normally non-noxious stimuli (e.g., gentle touch becomes painful)
• Don't confuse: hyperalgesia = more pain from painful stimuli; allodynia = pain from non-painful stimuli

🛤️ Pain pathways to the brain

🛤️ Two routes from spinal cord

Route 1: Spinal reflex arc

• Nociceptor → interneuron → motor neuron (all within spinal cord)
• Responsible for pain withdrawal reflex (e.g., pulling hand from hot surface)
• Works below conscious awareness for fast response
• Does not travel to brain

Route 2: Spinothalamic tract (conscious pain)

• Nociceptor terminates in superficial spinal cord layers
• Synapses with lamina I neurons (transmission cells)
• Second-order neuron crosses midline immediately and ascends to thalamus
• Targets two thalamic nuclei:
  • Ventroposterior lateral (VPL) → secondary somatosensory cortex
  • Central laminar nucleus → insula and cingulate cortex
• Only this pathway produces conscious pain perception

🔀 Key anatomical difference

Pathway	Crosses midline	Side of ascent
Touch (from previous section)	In brainstem	Ipsilateral in spinal cord
Pain (spinothalamic)	In spinal cord	Contralateral in spinal cord

Clinical significance: Brown-Séquard Syndrome occurs when one side of spinal cord is severed → loss of touch sensation on same side as injury, loss of pain sensation on opposite side.

Don't confuse: the crossing point differs between touch and pain pathways, creating this unusual dissociation.

🚪 Gate Control Theory

🚪 The spinal gate mechanism

Gate Control Theory (Melzack & Wall, 1965): proposes a gating mechanism in the spinal cord that can prevent pain signals from reaching the brain when activated by touch input.

The circuitry involves three key neurons:

1. Nociceptor (pain input)
2. Touch receptor neuron
3. Lamina II interneuron (the "gate")
4. Lamina I transmission cell (sends signal to brain)

🔓 How the gate opens (pain perceived)

When only nociceptor is activated:

• Nociceptor excites transmission cell directly (+)
• Nociceptor inhibits lamina II interneuron (-)
• Inhibiting the interneuron removes its normal inhibition of transmission cell (disinhibition)
• Result: transmission cell is highly excited → pain signal reaches brain

🔒 How the gate closes (pain reduced)

When touch receptor is also activated:

• Touch receptor excites the inhibitory lamina II interneuron (+)
• Lamina II interneuron inhibits transmission cell (-)
• Result: transmission cell activity is suppressed → less pain signal reaches brain

Example: When you bump your elbow, you instinctively rub the site—this activates touch receptors that close the gate and reduce pain perception. Caregivers "rubbing it better" for children uses this same mechanism.

🧪 Evidence status

• Supporting evidence: lamina II interneurons contain GABA (inhibitory neurotransmitter)
• Contradicting evidence: nociceptors only form excitatory synapses (theory proposes they inhibit lamina II)
• Despite mixed evidence, the theory has been highly influential in pain research

🧠 Descending control from the brain

🧠 Periaqueductal grey (PAG) pathway

• PAG (also called central grey) in brainstem is activated by spinothalamic tract activity
• Electrical stimulation of PAG produces powerful analgesic (pain-relieving) effect
• Site where endogenous opioids act

Mechanism:

• PAG connects to locus coeruleus (noradrenergic neurons) and raphe nuclei (serotoninergic neurons)
• These structures send signals down to spinal cord
• Target: lamina II interneurons → suppress lamina I transmission cells
• Result: reduced activity in spinothalamic tract → less pain perception

🔁 Negative feedback loop

1. Noxious stimulus → excites spinothalamic tract
2. Spinothalamic activity → activates PAG
3. PAG → sends signal down to spinal cord
4. Spinal signal → interrupts/silences incoming nociceptor signals

Evolutionary benefit: allows continued function during survival-critical situations (battlefield injuries, escaping danger).

🎯 Attentional analgesia

• Occurs when attention is directed away from painful stimulus
• Common in medical/dental settings: posters on ceiling, music, conversation as distraction

Neural pathways (Oliva et al., 2022):

• Anterior cingulate cortex (ACC) → locus coeruleus → spinal cord
• ACC → PAG → medulla → spinal cord
• Both pathways work in parallel

Example: During vaccination, the nurse chats with you to engage your attention elsewhere; during dental work, you focus on a ceiling poster—both reduce pain perception through descending control.

🧩 Beyond physical damage

🧩 Neuropathic pain

Neuropathic pain: pain arising from damage to the nociceptors and pathways that carry pain information, not from damage to the body location where pain is felt.

Example: Thalamic syndrome

• Caused by thalamic damage (e.g., from stroke)
• Produces intense burning or crushing pain from any skin contact at specific body location
• No actual damage to that body location—damage is to the thalamus itself

Don't confuse: nociceptive pain = damage at the site where pain is felt; neuropathic pain = damage to pain pathways, not the perceived site.

💔 Psychogenic pain

Psychogenic pain: pain attributed to psychological factors without physical injury to body or nerves.

Sources of psychogenic pain:

• Relationship breakdown or bereavement ("heartache")
• Social exclusion and rejection (Social Pain Theory)
• Loss of desirable interpersonal relationships

🧪 Brain overlap evidence

Research using fMRI (Eisenberger et al., 2003):

• Participants played virtual ball game while brain scanned
• When excluded from game → anterior cingulate cortex (ACC) more active
• ACC activity correlated with self-reported distress
• Same ACC region activated by physical pain

Further evidence: paracetamol (physical pain reliever) decreases both ACC activity and perceived social pain (De Wall et al., 2010).

Implication: social/psychological pain and physical pain share neural substrates, supporting the idea that "heartache" is neurologically real.

💊 Treatment approaches

💊 Acute vs. chronic pain considerations

Pain type	Duration	Treatment approach
Acute	Short-term (e.g., cut, broken bone)	Often drug treatment alone
Chronic	>3 months	Multifaceted approach needed

Consequences of untreated chronic pain: altered mood, mental health disorders, cognitive impairments, sleep disruption, reduced quality of life.

💊 Drug treatments by site of action

1. At sensory nerve ending:

• NSAIDs (e.g., ibuprofen)
• Block sensitization of nociceptors by prostaglandins
• Long-term use risk: stomach problems

2. On nociceptor axon:

• Local anaesthetics (e.g., lidocaine)
• Block sodium channels → prevent depolarization and action potentials

3. In spinal cord:

• Opioids, gabapentin, ketamine
• Act through various mechanisms
• Long-term opioid use risk: addiction

4. In brain:

• Opioids (thalamus, sensory cortex)
• Antidepressants
• May not stop pain but reduce its impact by altering mood

⚡ Stimulation techniques

TENS (Transcutaneous Electrical Nerve Stimulation):

• Low-voltage electrical stimulation to pain site
• Thought to activate touch receptors → close spinal gate (Gate Control Theory)
• Mixed effectiveness:
  • Labour pain: little difference vs. control (1671 women studied)
  • Period pain: significant relief vs. sham TENS (260 individuals)
  • Knee osteoarthritis: effective at reducing pain and improving walking

🔪 Surgical approaches (extreme cases only)

Used for intractable pain in terminal cancer (up to 90% of patients):

Cordotomy:

• Cut spinothalamic tract on one side of spinal cord
• Only reduces contralateral pain (pain crosses midline immediately on entering spinal cord)
• Suitable for unilateral pain

Myelotomy:

• Cut at middle of spinal cord where spinothalamic neurons cross
• Targets bilateral pain

🧠 Multifaceted chronic pain management

Pain management clinics provide:

• Team approach: pain consultants, physiotherapists, psychologists, occupational therapists
• Patient-centered and active participation
• Education about pain
• Cognitive behavioral therapy
• Minimal analgesic requirements as goal

👻 Phantom limb pain

Phantom limb pain: ongoing painful sensations appearing to come from a body part that is no longer there.

• Occurs in up to 80% of amputees
• Also occurs after mastectomy (up to 80% of patients)
• Name is misleading—not limited to limbs
• Likely caused by changes in nervous system wiring after amputation
• Very difficult to treat despite 38+ different therapies tested

Mirror therapy (novel approach):

• Patient positions mirror between intact and missing limb
• Looks at reflection of intact limb → creates visual representation of missing limb
• Moves intact limb while watching reflection
• Can create perception of regaining control over missing limb
• May relieve cramped/clenched sensations in phantom limb
• Evidence for effectiveness still insufficient

🎭 Placebo effect in pain treatment

Placebo effect: individual gains benefit without receiving real treatment.

Possible mechanisms:

1. Conditioned behavior: learned association between pain relief and taking tablet/receiving treatment → conditioned response even with inert substance
2. Expectation: expecting to get better after seeing doctor → experience pain relief from expectation

Both mechanisms are plausible given descending pain control pathways from brain (top-down modulation).

Don't confuse placebo effect with:

• Natural recovery over time (natural trajectory of condition)
• Hawthorne effect: behavior changes simply from being observed in study (e.g., trial participants may exercise more regularly, leading to pain relief independent of treatment)

Clinical trial implications: Need careful design with appropriate control groups (e.g., real TENS, sham TENS, and waiting-list control) to distinguish true treatment effects from placebo and Hawthorne effects.

🧭 Overview

🧠 One-sentence thesis

The visual system transforms light into neural signals through a complex process involving refraction by the eye's optical structures, phototransduction in retinal photoreceptors, and hierarchical processing through multiple brain pathways to create our perception of color, motion, and depth.

📌 Key points (3–5)

• Light as stimulus: Vision detects electromagnetic radiation in the visible spectrum (380-780 nm), which behaves as both wave and particle (photons).
• Eye optics before transduction: Light must be refracted by the cornea and lens to focus on the retina before any neural processing begins—refractive errors (myopia, hyperopia) occur when this focusing fails.
• Two photoreceptor types: Rods (sensitive, low-acuity, night vision, peripheral) vs. cones (less sensitive, high-acuity, color vision, concentrated in fovea).
• Unique transduction mechanism: Unlike other senses, light causes hyperpolarization (not depolarization) by closing ion channels and reducing glutamate release—this minimizes background noise.
• Common confusion: The retina has a layered structure with photoreceptors at the back (furthest from incoming light), and visual information travels through bipolar cells before reaching ganglion cells that form the optic nerve.

🌈 The nature of light

🌊 Wave-particle duality

Light: electromagnetic radiation that behaves as both transverse waves and discrete particles (photons).

• The visible spectrum spans 380-780 nm wavelength (violet to red).
• Historically debated: Newton argued particles, Hooke argued waves; Einstein resolved it by showing light exhibits both properties depending on the experiment.
• The photoelectric effect (electrons ejected from metal by high-energy light) was key evidence for the particle nature—only high-frequency (short-wavelength) light has enough energy per photon to eject electrons.

👁️ What we can detect

• Human vision operates across a huge luminance range: 10⁻⁶ to 10⁸ candela per meter squared (cd m⁻²).
• Example: dim night sky at the low end, direct sunlight at the high end; a typical computer screen is 50-300 cd m⁻².
• Different wavelengths correspond to different perceived colors (violet = 380 nm, red = 780 nm).

🔍 Eye anatomy and focusing

🪟 The dioptric apparatus

Dioptric apparatus: the structures (cornea, lens, and others) that refract light to bring it to a focal point on the retina.

• Cornea: provides most of the eye's refractive power but is fixed (cannot adjust).
• Lens: can change shape (fatter or flatter) by contraction of ciliary muscles to adjust focus for objects at different distances.
• The goal: light waves must converge to a focal point on the retinal surface for a clear image.

🩺 Refractive errors

Three common types affect 2.2 billion people worldwide:

Condition	Problem	Focal point location	Correction needed
Myopia (short-sightedness)	Too much refractive power	In front of retina	Diverging lens to reduce power
Hyperopia (long-sightedness)	Too little refractive power	Behind retina	Converging lens to increase power
Presbyopia (age-related)	Lens hardens, loses flexibility	Variable	Bifocal/varifocal lenses

• Don't confuse: These are optical problems (before transduction), not neural problems—they can often be corrected with glasses or contact lenses.

🎯 Retinal structure

• The retina has a layered cellular organization.
• Photoreceptors are in the deepest layer (furthest from incoming light).
• Light must pass through other retinal layers before reaching photoreceptors—this seems counterintuitive but is how the human eye is structured.

📸 Photoreceptors and transduction

🕯️ Rods vs. cones comparison

Feature	Rods	Cones
Number	~20× more than cones	Fewer overall
Location	Peripheral retina	Concentrated in fovea (central retina)
Sensitivity	High (work in dim light)	Lower (need brighter light)
Vision type	Scotopic (night vision)	Photopic (day vision)
Acuity	Low (grouped connections)	High (one-to-one connections)
Color	One type (peak ~498 nm, blue-green)	Three types (S, M, L wavelengths)

• Why rods have lower acuity: Multiple rods connect to the same bipolar cell, so the brain cannot tell exactly which rod was activated—this creates larger receptive fields.
• Why cones provide high acuity: One-to-one connections create very small receptive fields, allowing precise localization.

🎨 Three cone types

• Short-wave (S), Medium-wave (M), Long-wave (L) cones—sometimes called blue, green, and red.
• Each has different spectral sensitivity (different peak wavelengths).
• Their overlapping sensitivities allow color discrimination.
• Example: A 540 nm light would activate both M and L cones because it falls within both their sensitivity ranges.

⚡ The transduction cascade

Phototransduction: the process by which light energy is converted into electrical signals in photoreceptors.

The process involves multiple steps (described here for rods with rhodopsin; analogous in cones):

1. Photon absorption: Light energy hits rhodopsin, causing 11-cis-retinal to change shape to all-trans-retinal—this "activates" rhodopsin.

2. G-protein activation: Activated rhodopsin interacts with transducin (a G-protein), causing it to release GDP and bind GTP instead.

3. Subunit dissociation: The GTP-bound α subunit separates from the β and γ subunits.

4. Enzyme activation: The α-GTP complex activates phosphodiesterase (PDE).

5. Channel closure: PDE breaks down cGMP, which normally keeps ion channels open; when cGMP decreases, sodium and calcium channels close.

🌙 The "dark current" and hyperpolarization

• Unique feature: In darkness, photoreceptors have a steady inward flow of positive ions (the "dark current")—they are partially depolarized at rest.
• Light response: Light causes channels to close, stopping the dark current, which hyperpolarizes the cell.
• Why this design?: Minimizes background noise—small random fluctuations in channel opening don't matter when there's a steady baseline current; only a large coordinated closure (from light) produces a clear signal.
• Don't confuse: This is opposite to other senses where stimulus causes depolarization; here stimulus causes hyperpolarization.

🔄 Bipolar cells: ON and OFF types

• Photoreceptors release less glutamate when light is present (due to hyperpolarization).
• OFF bipolar cells: Decrease firing when glutamate decreases (straightforward excitatory response).
• ON bipolar cells: Increase firing when glutamate decreases—this happens because they express mGluR6 receptors that close cation channels when active; less glutamate means less mGluR6 activation, so channels open and the cell depolarizes.
• This creates parallel pathways for detecting light onset (ON) and offset (OFF).

🧠 Visual pathways to the brain

🛤️ From eye to cortex

The cortical route (main conscious vision pathway):

1. Optic nerve: Axons of retinal ganglion cells leave through the blind spot.

2. Optic chiasm: Where the two optic nerves meet; information is reorganized so left visual field (from both eyes) goes to right brain, and right visual field goes to left brain.

3. Lateral geniculate nucleus (LGN): First stop in the thalamus; has six layers (three per eye) with retinotopic mapping (adjacent neurons receive information from adjacent retinal regions).

4. Primary visual cortex (V1): In the occipital lobe; also called striate cortex; information enters at layer IV with different LGN layers projecting to different sublayers.

🏛️ Cortical organization

• Orientation columns: Groups of neurons that respond preferentially to lines at specific angles (e.g., 45° from vertical).
• Ocular dominance columns: Groups that respond preferentially to one eye or the other.
• Hypercolumns: Theoretical units containing all orientations and both eyes' representations for each part of the visual field.
• Over 30 cortical regions receive visual information beyond V1.

🔀 Dorsal and ventral streams

After V1, visual processing splits into two major pathways:

Stream	Regions	Function	Nickname
Ventral	V1 → V2 → V4 → inferior temporal	Object identity	"What" pathway
Dorsal	V1 → V2 → V3 → V5 → parietal	Location and visually-guided movement	"Where" pathway

• Similar to the auditory system's division into what and where pathways.

🎯 Subcortical pathway: superior colliculus

• Located in the midbrain (above the inferior colliculus).
• Involved in localization and motion coding.
• Implicated in blindsight: a phenomenon where people with damaged visual cortex report being unable to see but can still detect, localize, or discriminate stimuli at better-than-chance levels.
• Blindsight Type 1: Can guess stimulus features without awareness.
• Blindsight Type 2: Can detect change but don't perceive what changed.
• This demonstrates that subcortical pathways can support some visual processing without conscious awareness.

🎨 Perceiving color, motion, and depth

🌈 Color processing

Trichromacy: the presence of three types of cones with different spectral sensitivities.

• Evolutionary advantage: Helps identify ripe fruits and suitable foods (red-green discrimination especially important for detecting high-energy foods).

Opponent processing theory: Cone outputs are organized into three channels:

1. Red-green channel: Receives opposing inputs from L and M cones.
2. Luminance channel: Receives matching (additive) inputs from L and M cones.
3. Blue-yellow channel: Receives excitatory input from S cones and inhibitory input from the luminance channel.

• Cells following this pattern found in LGN and V1.
• V4: Contains neurons responding to a full range of colors (not just the four opponent colors).
• V8: Combines color information with memory.

🎭 Color constancy

Color constancy: the phenomenon where we perceive object colors as stable despite changes in overall illumination.

• Example: Tree leaves appear the same green in bright sunshine and overcast conditions, even though the actual light reaching your eye differs.
• The brain compensates by taking into account the average color across the entire visual scene.

🏃 Motion detection

• Some V1 cells respond to specific orientations; others respond to specific movement directions.
• V5 (MT): Critical for motion detection; receives input from both V1 and superior colliculus.
• V5a (MST): Adjacent to V5; contains neurons responding to complex motion patterns including spiral motion.

📐 Depth perception

The retinal image is two-dimensional, but we perceive a three-dimensional world using depth cues:

Monocular cues (work with one eye):

• Interposition: Objects that obscure others are closer.
• Linear perspective: Parallel lines converge with distance.
• Size constancy: Smaller objects are likely farther away (not just smaller).
• Height in field: Objects near the horizon are farther; those at the bottom are nearest.

Binocular cues (require both eyes):

• Binocular disparity: Slightly different images from left and right eyes provide depth information.

Don't confuse: Depth perception requires integrating multiple cues—no single cue is sufficient on its own.

🩺 Visual impairment and blindness

👓 Refractive errors

• Leading cause of visual impairment worldwide (2.2 billion affected).
• 800 million have impairment that could be addressed with glasses/contact lenses.
• Do not typically cause blindness—these are correctable optical problems.

🌫️ Cataracts

Cataracts: cloudy patches that develop in the lens, blocking light transmission to the retina.

• Leading cause of blindness worldwide (51% of cases).
• Risk factors: aging (most common over 60), eye disease, trauma, systemic disease (e.g., diabetes).
• Associated with cognitive decline and increased depression in age-related cases.
• Treatment: Surgical lens replacement with synthetic lens (routine 30-minute procedure under local anesthetic in high-income countries; often inaccessible in low- and middle-income countries).

💧 Glaucoma

Glaucoma: increased pressure within the eye due to poor fluid drainage, leading to optic nerve damage.

• Second leading cause of blindness (8% of cases).
• Develops gradually over time; more common in older people.
• Treatment: Eye drops, laser treatment, or surgery to reduce intraocular pressure—but damage may be irreversible.
• Associated with poorer quality of life.

🎯 Age-related macular degeneration (AMD)

AMD: deterioration of the macular region of the retina, causing blurred central vision while peripheral vision remains intact.

• Third leading cause of blindness (5% of cases).
• Risk factors: aging, smoking, sunlight exposure.
• Causes complete blindness in only a small percentage (peripheral vision remains).
• Still associated with reduced quality of life, anxiety, and depression.

Two types:

Type	Mechanism	Frequency	Treatment
Dry AMD	Cellular waste buildup causes blood vessel deterioration and photoreceptor death	~90% of AMD cases	None available
Wet AMD	New weak blood vessels form and leak	~10% (progression from dry)	Regular eye injections to reduce vessel growth; photodynamic therapy (laser)

🌍 Global impact

• All three major causes of blindness are age-related.
• All significantly impact quality of life and mental health.
• Access to treatment varies widely: routine in high-income countries, often inaccessible in low- and middle-income countries.
• Don't confuse: Refractive errors are the most common impairment but not a major cause of blindness; cataracts are the leading cause of actual blindness.

🧭 Overview

🧠 One-sentence thesis

Hearing is a critical distal sense that enables us to navigate the world and communicate, relying on complex mechanisms from sound wave detection in the cochlea through ascending and descending brain pathways to create perception of frequency, intensity, and location.

📌 Key points (3–5)

• Sound as a distal sense: Unlike touch and pain (proximal senses), hearing detects stimuli not in direct contact with the body—sound waves travel through air from a distant source.
• Three-part ear structure: The outer ear funnels sound, the middle ear amplifies it to overcome the air-to-fluid barrier, and the inner ear (cochlea) transduces sound via specialized hair cells.
• Dual coding mechanisms: Frequency is coded by both place (location along the cochlea) and temporal (firing timing) mechanisms; intensity is coded by firing rate and number of neurons.
• Common confusion—hair cells vs neurons: Hair cells are not modified neurons and cannot produce action potentials themselves; they release glutamate onto cochlear nerve neurons, which then fire.
• Hearing loss categories: Conductive (outer/middle ear damage), cochlear, and retrocochlear (nerve/brain damage); each has different impacts on threshold and discrimination, with significant social and educational consequences.

🌊 The sound stimulus and its characteristics

🌊 What sound waves are

Sound wave: a longitudinal wave produced from fluctuations in air pressure by vibration of objects, creating regions of compression (particles closer) and rarefraction (particles further apart).

• The vibrating object does not touch the body directly.
• This makes hearing a distal sense, contrasted with touch and pain (proximal senses where the stimulus contacts the body).

📏 Three key wave characteristics

Characteristic	What it measures	Perceptual correlate	Range/notes
Frequency	Time for one full cycle; measured in Hertz (Hz)	Pitch	Humans hear 20–20,000 Hz; low <500 Hz (waves, elephants), high (whistling, nails on chalkboard)
Amplitude	Amount of air pressure fluctuation; measured in pascals (Pa), converted to decibels (dB)	Loudness	Humans hear 0–140 dB; normal conversation ~60 dB SPL; above 140 dB is harmful
Phase	Relationship between different waves (in phase = peaks align; out of phase = different stages)	(Relative property)	Used for comparing waves, not absolute

• dB SPL = sound pressure level referenced to the lowest intensity a young person can hear at 1000 Hz.
• Pure waves (e.g., tuning fork) have a single frequency; natural sounds contain multiple frequencies combined, creating complex waveforms.
• Real environments have multiple moving sound sources, making detection and perception complex.

🦻 Structure and function of the ear

🦻 Three-part division

The ear has three functional sections:

1. Outer ear: gathers and funnels sound; protective features.
2. Middle ear: amplifies the signal to prepare it for the fluid-filled inner ear; protective function.
3. Inner ear: contains sensory receptor cells (hair cells) where transduction occurs.

👂 Outer ear

• Pinna (auricle): the visible part; static in humans (unlike most species).
• Functions:
  • Funnels sound inward.
  • Ridges help localize sound sources.
  • Protection: ear wax provides water-resistant, antibacterial, antifungal coating; tiny hairs prevent entry of particles/insects.

🔊 Middle ear: overcoming the air-to-fluid barrier

• Sits behind the tympanic membrane (ear drum).
• Contains three tiny bones (ossicles) in an air-filled chamber.
• Why amplification is needed: When sound moves from air to water (or fluid), most is reflected back (~99.99% lost); only ~0.01% transmits into water.
  • Example: sounds become very quiet and muffled when your ear is underwater.
• The ossicles create a lever between the tympanic membrane and the cochlea, plus changes in contact area, resulting in a 20-fold increase in pressure as the sound wave enters the fluid-filled cochlea.
• Middle ear reflex: triggered by sounds >70 dB SPL; muscles lock the ossicles in place, preventing signal transmission and protecting the inner ear from loud sounds.

🐌 Inner ear: the cochlea and transduction

🐌 Cochlear structure

• The cochlea is a tiny tube coiled like a snail.
• Sound enters via the oval window.
• The tube is divided into three chambers (scalae) by membranes:
  • Scala media sits between the basilar membrane (below) and Reissner's membrane (above).
  • Contains the organ of Corti, which houses the sensory cells.

🎯 Inner hair cells: the transducers

Hair cells: sensory receptor cells for hearing, named for hair-like stereocilia protruding from the apical end.

• Apical end: stereocilia project into endolymph (fluid with very high potassium concentration—opposite of typical extracellular space).
• Basal end: sits in perilymph; contains synaptic vesicles and calcium-gated channels.
• Not neurons: Hair cells lack axons and cannot produce action potentials themselves.

⚡ Transduction mechanism

1. Sound wave → fluid movement in cochlea → basilar membrane moves.
2. Stereocilia bend.
3. Mechano-sensitive ion channels in stereocilia tips open.
4. Potassium floods in (from the high-K⁺ endolymph) → depolarization = auditory receptor potential.
5. Depolarization opens calcium channels → glutamate release from basal end.
6. Glutamate binds to AMPA receptors on cochlear nerve neurons.
7. If sufficient glutamate binds, an action potential is produced in the cochlear nerve, sending the signal to the brain.

Don't confuse: Unlike somatosensory receptor cells (which are modified neurons), hair cells are not neurons and rely on synaptic transmission to cochlear nerve neurons to generate action potentials.

🧠 Auditory pathways to and from the brain

🧠 Ascending pathway: cochlea to cortex

The pathway is complex, passing through multiple brainstem and midbrain structures before reaching the cortex:

1. Cochlear nerve → enters brainstem.
2. Cochlear nuclear complex (brainstem) → receives input from ipsilateral ear only.
3. Trapezoid body → crosses to the other side.
4. Superior olive (brainstem) → first structure to receive input from both ears.
5. Lateral lemniscus → ascends.
6. Inferior colliculus (midbrain).
7. Medial geniculate nucleus (thalamus).
8. Primary auditory cortex (temporal lobe).

🛤️ Beyond primary auditory cortex: two streams

After the primary auditory cortex, information divides into two pathways:

Stream	Direction	Structures	Function
Ventral "what" pathway	Down and forward	Superior temporal region, ventrolateral prefrontal cortex	Auditory object recognition; modulated by emotion
Dorsal "where" pathway	Up and forward	Posterodorsal cortex (parietal lobe), dorsolateral prefrontal cortex	Sound localization; modulated by spatial attention

🔽 Descending pathways

• The auditory cortex sends projections down to every structure in the ascending pathway: medial geniculate nucleus, inferior colliculus, superior olive, cochlear nuclear complex.
• The superior olive also connects directly to inner and outer hair cells.
• Functions: protection from loud noises, learning about relevant sounds, adjusting responses for sleep/wake cycles, effects of attention.

Don't confuse: Ascending pathways carry sensory information up to the cortex; descending pathways allow higher brain regions to modulate lower structures, similar to pain pathways.

🎵 Perceiving sound features: frequency, intensity, and location

🎵 Frequency coding: place and temporal mechanisms

🗺️ Place code

Place code: different frequencies are detected at different locations within the cochlea; the brain deduces frequency by knowing where transduction occurred.

• Basal end of cochlea → high frequency sounds.
• Apical end → low frequency sounds.
• Mechanism: Different frequencies cause different displacement patterns of the basilar membrane; only hair cells at the peak displacement location respond.
• Each hair cell has a characteristic frequency to which it responds.

⏱️ Temporal code

Temporal code: the timing of action potentials in the cochlear nerve directly reflects the frequency of the incoming sound wave (phase-locked firing).

• Research shows a relationship between sound wave frequency and cochlear nerve firing.
• Problem: Neurons can fire up to ~1000 Hz, but humans hear up to 20,000 Hz.
• Solution—volley principle: Groups of neurons work together; each fires in turn, so the combined output mimics the stimulus frequency even though individual neurons cannot fire that fast.

🔀 Combined coding

• Temporal code operates at very low frequencies (<50 Hz).
• Place code operates at higher frequencies (>3,000 Hz).
• Both mechanisms code intermediate frequencies.
• Once encoded in the cochlea, frequency information is preserved throughout the auditory pathway.

Perceptual correlate: Frequency → pitch (high frequency = high pitch).

🔊 Intensity coding: firing rate and neuron number

🔊 Two proposed mechanisms

1. Firing rate in the auditory nerve:

   • More intense sound → larger amplitude wave → stereocilia held open longer → more potassium influx → larger receptor potential → more glutamate release → higher firing rate in cochlear nerve neurons.
   • (Action potentials are all-or-none, so intensity is coded by frequency of firing, not size.)

2. Number of neurons firing:

   • Normally, only hair cells at the characteristic frequency location are activated.
   • More intense sounds → sufficient displacement to activate hair cells on either side of the peak → more cochlear nerve neurons fire.

⚠️ Ambiguity and overlap

• Common confusion: Increased firing rate could indicate either higher frequency or greater intensity.
• The signal can be ambiguous; perception of loudness (the perceptual correlate of intensity) is significantly affected by frequency.
• Resolution: Combination of multiple coding mechanisms + small head movements that change intensity help disambiguate.

📍 Sound localization: interaural cues

📍 Where localization coding begins

• Localization requires comparing input from both ears.
• Cannot happen in the cochlea (each cochlea receives input from one ear only).
• First occurs in the superior olive (brainstem), which receives input from both cochlear nuclear complexes.

🕰️ Medial superior olive: interaural time delay

• Sound travels at 348 m/s; average distance between ears is 20 cm.
• A sound from directly to the right reaches the right ear 0.6 ms before the left ear.
• Neurons in the medial superior olive act as coincidence detectors:
  • They receive excitatory inputs from both cochlear nuclear complexes.
  • Arranged in "delay lines": the signal from one side travels further along the chain of neurons before combining with the signal from the other side.
  • The neuron that fires most strongly indicates the time delay, and thus the sound's horizontal location.
• Example: Sound from the left → left signal reaches the superior olive first, travels past neurons A and B, combines with the right signal at neuron C → neuron C fires maximally.
• Limitation: A sound from directly in front or behind produces no time delay (both signals combine at the middle neuron), so this mechanism cannot distinguish front from back.
• Effective for low frequencies.

🔉 Lateral superior olive: interaural intensity difference

• Neurons receive excitatory input from the ipsilateral cochlear nuclear complex and inhibitory input from the contralateral complex.
• Detects the reduction in intensity as sound travels around the head (the head "shadows" the sound).
• The intensity drop is greater for higher frequency sounds.
• Effective for high frequencies.

Complementary mechanisms: Interaural time delay favors low frequencies; interaural intensity difference favors high frequencies.

🎓 Top-down cues

• Bottom-up methods rely solely on incoming data.
• Additional cue: High frequency components diminish more than low frequency components over distance.
  • To use this cue, you must know the expected properties of the sound (prior experience required).
• Combining frequency, intensity, and localization information creates a full auditory percept.
• Complex stimuli (e.g., music) involve cooperation of multiple brain structures, including areas for memory and emotion.

🩺 Hearing loss: types, impact, and treatment

🩺 Categories by location of impairment

Conductive hearing loss: impairment in the outer or middle ear; conduction of sound to the cochlea is interrupted.

Cochlear hearing loss: damage to the cochlea itself.

Retrocochlear hearing loss: damage to the cochlear nerve or brain areas processing sound.

• Cochlear and retrocochlear are often grouped as sensorineural hearing loss.

🩺 Categories by extent of impairment

Classification	Hearing level (dB HL)	Impairment description
Mild	20–39	Following speech is difficult, especially in noise
Moderate	40–69	Difficulty following speech without visual cues
Severe	70–89	Usually need to lip-read or use sign language; hearing aid helpful
Profound	90–120	Usually need to lip-read or use sign language; hearing aid often ineffective

• dB HL (hearing level): the amount by which intensity must be increased above the threshold of a healthy young listener (0 dB) for the person to detect the sound.
• Example: If intensity must be raised by 45 dB for detection → 45 dB HL → moderate hearing loss.

🩺 Effects of hearing loss

• Threshold: the quietest sound someone can hear in a controlled environment.
• Discrimination: ability to concentrate on a sound in a noisy environment.

🧒 Conductive hearing loss: glue ear (otitis media with effusion)

🧒 What it is

• Most common cause of conductive hearing loss, especially in children.
• Fluid builds up in the middle ear (normally air-filled).
• Why problematic: Fluid reflects most of the sound back; signal does not reach the inner ear for transduction.
• Typically affects one ear but can occur in both; generally causes only mild hearing loss.

🧒 Cause and risk factors

• Cause: Eustachian tube (connects ear to throat) does not drain properly.
  • In young children, adenoid tissue growth can block the throat end of the tube → fluid builds up.
• Risk factors:
  • Iron deficiency, allergies (dust mites), exposure to secondhand smoke, shorter breastfeeding duration.
  • Social: larger family, lower socioeconomic group, longer hours in group childcare.

🧒 Consequences

• Pain, disturbed sleep → behavioral problems.
• Main concern: delays in language development, social isolation, poorer educational outcomes.
• Studies show children with chronic glue ear have poorer educational outcomes, but they can catch up over time (minimal long-lasting impact).

🧒 Treatment

• First line: watch and wait; treat concurrent infections.
• If no improvement in a few months: grommets (tiny plastic inserts in the tympanic membrane to allow fluid to drain).
  • Minor surgery, but risk of scarring the membrane, which may affect elasticity.

🔊 Sensorineural hearing loss: Noise-Induced Hearing Loss (NIHL)

🔊 What it is

• Most common form of sensorineural hearing loss.
• Caused by exposure to high-intensity noises (industrial, military, recreational contexts).
• Develops over time as hair cells are damaged or die; worsens with age.
• Affects ~5% of the population.

🔊 Characteristics

• Bilateral (both ears).
• Affects both threshold and discrimination.
• Frequency-dependent: biggest loss at higher frequencies (~4,000 Hz), which coincide with everyday sounds including speech.
• Severity varies.

🔊 Treatment and prevention

• No treatment currently available.
• Prevention: use of personal protective equipment (PPE).
• Challenges:
  • PPE may not be readily available (e.g., civilians in war zones).
  • PPE may not be practical (e.g., musicians need to hear the sounds they produce).

🔊 Impact on individuals

• Social and psychological: correlated with social isolation, distress, suicide ideation, frustration, anxiety, stress, resentment, depression, fatigue.
• Employment: negative effects on opportunities and productivity.
• Diagnosis challenge: Older people may mistake NIHL for natural age-related decline, delaying preventive action or help-seeking.

Don't confuse: Conductive hearing loss typically affects only threshold (sounds must be louder to be heard); sensorineural hearing loss affects both threshold and discrimination (harder to pick out sounds in noisy environments).

🔗 Commonalities across senses (touch, pain, hearing)

🔗 Transduction mechanisms

Similarities:

• All use mechano-sensitive ion channels (opened by mechanical force).
• All involve influx of a positively charged ion → depolarizing receptor potential.

Differences:

• Touch and hearing use only mechano-sensitive channels; pain also uses thermo-sensitive and chemo-sensitive channels.
• Ion type: In somatosensation (touch/pain), the incoming ion is sodium (typical for depolarization); in hearing, it is potassium (due to the potassium-rich endolymph).

🔗 Pathways to the brain

Common feature: In all three systems, the thalamus receives the signal on the way to the primary sensory cortex, and projections extend to a range of cortical areas after the primary sensory cortex.

🔗 Feature extraction

Common features encoded: All three systems encode intensity and location of the stimulus; touch and hearing also encode frequency.

🧭 Overview

🧠 One-sentence thesis

Chemical detection through taste and smell is the most ancient sensory mechanism in living organisms, converting environmental chemical signals into neural codes that guide adaptive behaviors like food selection, mate finding, and social interaction.

📌 Key points (3–5)

• Two distinct chemical systems: Gustation (taste) detects water-soluble compounds in the mouth; olfaction (smell) detects airborne molecules in the nasal cavity.
• Different transduction mechanisms: Taste uses both ion channels (for salty/sour) and G-protein-coupled receptors (for sweet/bitter/umami); smell relies exclusively on GPCRs with combinatorial coding.
• Unique olfactory pathway: Unlike other senses, olfaction bypasses the thalamus before reaching cortex—the thalamic connection comes downstream from the olfactory cortex.
• Common confusion: Taste buds vs. papillae—the visible bumps on the tongue are papillae (epithelial tissue), which contain thousands of taste buds housing the actual taste receptor cells.
• Individual variation: "Normal" smell perception varies widely between people depending on which odor receptor genes are expressed and in what quantity.

👅 The gustatory system (taste)

🏗️ Anatomical structures

Tastants: Water-soluble or lipid-soluble chemical substances in food or drinks that create taste sensations when detected by taste receptor cells (TRCs).

Papillae: Epithelial tissue bumps on the tongue that contain taste buds in their walls and fissures.

Three types of papillae by location:

• Fungiform papillae: anterior (front) part of the tongue
• Foliate papillae: sides of the posterior section
• Circumvallate papillae: back of the tongue

Each taste bud contains 50–150 taste receptor cells and has a taste pore (upper aperture) where microvilli (hair-like extensions) project out to encounter tastants.

🔬 Three types of taste receptor cells

Type	Function
Type I	Housekeeping (metabolic and physical support)
Type II	Detect sweet, bitter, and umami tastes
Type III	Mediate sour taste perception

When tastants are detected, TRCs release neurotransmitters (usually ATP) and generate action potentials in neurons at their base.

🧠 Neural pathway for taste

1. Cranial nerves (VII, IX, X) carry signals from different tongue regions:
   • Nerve VII: anterior two-thirds (fungiform papillae)
   • Nerve IX (glossopharyngeal): posterior third
   • Nerve X: posterior esophagus and soft palate
2. Nucleus of the solitary tract (NTS) in the brainstem receives input
3. Ventral posterior medial nucleus of the thalamus relays information
4. Primary gustatory cortex (anterior insular cortex/insular taste cortex)
5. Secondary gustatory cortex (medial and lateral orbitofrontal cortex)
6. Other structures: amygdala, hippocampus, striatum, hypothalamus (for decision-making and behavior)

Don't confuse: Taste buds regenerate every two weeks (like skin cells) but also share neuron-like properties (excitable membranes, neurotransmitter release).

⚡ Transduction mechanisms by taste type

Salty and sour (ion channel mechanism):

• Specialized Type II cells express ion channels
• Salty: Na⁺ ions (from NaCl) enter through epithelial sodium channels (ENaC)
• Sour: H⁺ ions (from acids) enter through specific channels
• Ion entry → depolarization → ATP release → action potentials

Example: Mice lacking the ENaC gene completely lost salt attraction and sodium taste responses, proving salt detection requires this specific protein.

Sweet, bitter, and umami (GPCR mechanism):

• Use G-protein-coupled receptors with "key-to-lock" recognition
• Tastant binding → G-protein activation → α and βγ subunits dissociate → intracellular signaling cascade → depolarization and/or calcium increase → neurotransmitter release

Specific receptors:

• Sweet: T1R2+3 (heteromeric GPCR)
• Umami: T1R1+3 (detects monosodium glutamate and related amino acids)
• Bitter: Various GPCRs

Example: Animals lacking T1R2 cannot detect sweet tastes; those lacking T1R1 cannot detect umami. Domestic cats lack T1R2 genes entirely, so they cannot experience sweetness—consistent with their strictly carnivorous diet.

🗺️ Taste topography and coding

Topography (distribution):

• Old view: rigid "taste map" with exclusive zones
• Current view: All tongue areas detect all tastes, but with different sensitivity thresholds
  • Bitter: higher sensitivity posteriorly (back)
  • Sweet and salty: higher sensitivity at tip
  • Sour: higher sensitivity at sides

Information coding:

• Intensity: Proportional to tastant concentration and firing rate of axons
• Quality (identity): Two mechanisms work together:
  1. Labelled-line coding: Which specific cell type is activated labels the taste (e.g., an axon from a sweet receptor is "labelled" as sweetness)
  2. Pattern/ensemble coding: The overall pattern of activity across multiple neuron types

Don't confuse: The insula (gustatory cortex) does not have a simple "gustotopic map" with one region per taste. Instead, distinctive spatial patterns represent tastes, but no single region is assigned to just one tastant.

👃 The olfactory system (smell)

🏗️ Anatomical structures

Odorants: Airborne molecules that enter the nasal cavity and interact with olfactory sensory neurons.

Key structures:

• Olfactory epithelium: Covers dorsal and medial nasal passageway; contains olfactory sensory neurons (OSNs)
• Olfactory cilia: Hair-like extensions from OSN dendrites where odor receptors are embedded
• Cribriform plate (ethmoid bone): OSN axons pass through this bone
• Glomeruli: Structures in the olfactory bulb where OSN axons synapse with mitral cells
• Mitral cells: Convey olfactory information to the brain via cranial nerve I

🧠 Neural pathway for smell

Unique feature: Olfaction bypasses the thalamus initially (unlike other senses).

1. Olfactory bulb receives OSN input at glomeruli
2. Lateral olfactory tract carries signals from mitral cells
3. Primary olfactory cortex (multiple structures, no thalamic relay first):
   • Piriform cortex (junction of frontal and temporal lobes)
   • Olfactory tubercle (ventral striatum)
   • Parts of amygdala
   • Entorhinal cortex (medial temporal lobe)
4. Secondary projections to thalamus, hypothalamus, hippocampus, and orbital/frontal prefrontal cortex

Don't confuse: In olfaction, the thalamus connection is downstream from cortex, not between periphery and cortex as in other senses.

🔬 Olfactory sensory neurons and receptors

Cell types in olfactory epithelium:

• Supporting cells: Metabolic and physical support
• Olfactory sensory neurons (OSNs): Detect and transduce odors
• Basal cells: Constantly divide to replenish OSNs (which have short lifespans due to harsh nasal environment)
• Glandular cells: Produce protective mucus

Receptor organization ("one-to-one-to-one"):

• Each OSN expresses only one type of odor receptor (OR) gene
• All OSNs expressing the same OR project to the same glomerulus
• Glomeruli activation pattern mirrors OR activation pattern

Scale:

• Humans have ~1,000 different OR genes
• Can perceive more than 1 trillion different odors
• Only about one-third of OR genes are actually expressed (varies between individuals)

⚡ Transduction mechanism

Odor receptors are GPCRs:

1. Odorant binds to OR on olfactory cilia
2. Associated G-protein activates → α and βγ subunits dissociate
3. Adenylyl cyclase activated → produces cAMP from ATP
4. Increased cAMP opens cation channels
5. Ca²⁺ and Na⁺ enter → depolarization
6. Action potentials fire (if signal strong enough)
7. Signal travels along OSN axons through cranial nerve I
8. Synaptic contact with mitral cells at glomeruli
9. Information conveyed to brain

🎨 Shape-pattern theory of odor recognition

Shape-pattern theory: Each scent activates unique arrays of olfactory receptors; the molecular attributes of odors determine which ORs can bind to them, creating a distinctive activation pattern the brain recognizes.

How it works:

• One odor molecule activates multiple ORs with varying intensity (like shapes fitting into different locks with varying precision)
• Different odors trigger different OR activation patterns
• Similar odors (e.g., molecules in the same chemical family) trigger overlapping but slightly different patterns
• Scents (combinations of multiple odor molecules) produce even more complex patterns

No topographic map: Unlike other senses, olfaction lacks a spatial map in the cortex. Instead, odors are represented by unique activation patterns across primary olfactory cortex regions.

Example: Coriander perception varies between "lovers" and "haters." Haters detect unsaturated aldehydes (smell like soap) while lovers are insensitive to these compounds and only detect more pleasant characteristics. This difference reflects which OR genes each person expresses.

🧬 Individual variation in smell

Why "normal" varies widely:

• Only ~1/3 of OR genes are expressed (highly variable between individuals)
• Number of expressed ORs varies (e.g., one person might express 358, another 388—both normal)
• Number of copies of specific receptors varies
• Two people with different OR expression will have different sensory experiences of the same odor

Don't confuse: This variation is normal, not pathological—olfactory experience inherently depends on which and how many OR genes each individual expresses.

🔄 Integration and function

🍽️ Flavor perception

• Flavor results from combined perception of taste and smell
• Common sensory neurons in the piriform cortex are activated by both systems
• The orbitofrontal cortex integrates taste with other sensory modalities for complex perceptual experiences

🎯 Behavioral significance

Chemical senses provide crucial environmental information for:

• Finding, selecting, and consuming food
• Distinguishing food from toxins
• Finding potential mates
• Regulating social interactions
• Avoiding danger

Range differences:

• Smell: Long- and short-range signals
• Taste: Short-range only (after ingestion)

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Key regeneration fact: Taste buds have a ~2-week lifespan and can regrow even after damage (e.g., burning your tongue), making them similar to skin cells in regenerative capacity.

🧭 Overview

🧠 One-sentence thesis

The motor system is a hierarchically organized network of brain regions, spinal circuits, and muscles that work together to transform decisions and sensory information into coordinated, adaptive movements ranging from simple reflexes to complex learned skills.

📌 Key points (3–5)

• Hierarchical organization: The motor system consists of multiple levels—forebrain (planning/decision), brainstem and spinal cord (execution), cerebellum (coordination), and basal ganglia (selection/modulation)—each controlling specific functions.
• Two control strategies: Feedback control uses sensory information during movement (slow, sequential), while feedforward control predicts optimal movement from memory and current conditions (fast, ballistic); both are combined for coordinated movement.
• Plasticity enables learning and recovery: Motor cortex maps reorganize with skill acquisition and can be retrained after damage through rehabilitation techniques like constraint-induced movement therapy.
• Common confusion—muscles vs. movements: The primary motor cortex does not simply control individual muscles; it organizes synergies of muscles that produce specific movements or ethologically relevant actions.
• Spinal cord is not just a relay: The spinal cord contains central pattern generators (CPGs) that can produce rhythmic movements like walking independently, though they are modulated by descending commands and sensory feedback.

🧠 Forebrain regions and movement initiation

🎯 Prefrontal cortex: decision to act

The prefrontal cortex is critical for making the decision to execute a particular action.

• This region reacts to goals and instructs the motor system to initiate movement.
• It does not specify how to move, only that a movement should occur.
• Example: Deciding to grab your phone to call a friend—the prefrontal cortex initiates this goal-directed action.

🗂️ Premotor cortex: organizing sequences

The premotor cortex receives information from the prefrontal cortex and prepares the required motor sequences, selecting the movements that are most appropriate for the action in the current circumstances.

• It translates the decision into an organized sequence of movements.
• It considers current environmental conditions (via posterior parietal cortex sensory input).
• Example: Unlocking your phone requires moving fingers from one number to another in a specific remembered sequence—the premotor cortex organizes this.

⚡ Primary motor cortex: executing commands

The primary motor cortex produces the required movements by muscle contraction and relaxation.

• It sends commands that directly generate movement.
• It receives information from premotor cortex and sensory cortex.
• The commands travel via the corticospinal tract to the spinal cord and muscles.

🗺️ Motor cortex organization and plasticity

🗺️ The motor homunculus

Wilder Penfield electrically stimulated the motor cortex in awake patients during epilepsy surgery and discovered a topographical map:

• Different cortical regions control different body parts.
• The map is not proportional to body size—areas requiring fine control (hands, fingers, lips, tongue) occupy disproportionately large cortical regions.
• The organization is not perfectly discrete; facial, arm/trunk, and leg regions overlap and intermingle (fractured somatotopy).

Don't confuse: The homunculus is a simplification. Modern research shows neurons controlling different body parts are intermingled, and the same body part (e.g., fingers) is represented in multiple cortical locations for different tasks.

🎭 Action maps vs. muscle maps

Does the motor cortex control individual muscles or whole movements?

• Single cortical neurons connect to multiple synergistic muscles (muscles that work together).
• Finger representations appear in several cortical regions, linked to particular tasks.
• Long electrical stimulation (500 ms) evokes complex, ethologically relevant actions: hand-to-mouth, defensive movements, reach-to-grasp.
• These actions are organized in zones; damage to a zone impairs the corresponding movement type.

Interpretation: The primary motor cortex is organized to control movements and action synergies, not just individual muscle contractions.

🔄 Plasticity: learning and recovery

The cortical areas involved in the control of movement show amazing plasticity—connections between neurons can change, new ones being made and old ones broken.

During development and skill learning:

• Motor maps are absent initially but become refined and precise as skills are learned.
• Example: Violinists develop highly defined cortical regions controlling individual fingers.

After damage:

• If a cortical motor area is damaged and not rehabilitated, the corresponding body part becomes paralyzed and its cortical representation shrinks.
• Constraint-induced movement therapy forces use of the impaired limb (e.g., casting the good hand), which preserves or restores the cortical map and improves function.
• Techniques like transcranial magnetic stimulation can stimulate damaged motor cortex or inhibit the intact opposite hemisphere to aid recovery.

🧬 Spinal cord: execution and pattern generation

🧬 Spinal cord structure

A cross-section reveals:

• White matter (outer): contains axon tracts carrying information up and down.
• Grey matter (central): contains neuronal cell bodies.
  • Dorsal horn: relays sensory inputs.
  • Ventral horn: contains motor neurons.
  • Intermediate grey matter: contains interneurons that relay inputs to motor neurons.

The spinal cord is divided into cervical, thoracic, lumbar, and sacral sections, each comprising multiple segments. Limb muscles are supplied by nerves from several segments.

🦾 Motor neurons and motor units

A motor unit: a single motor neuron and all the muscle fibres it innervates (up to 150 fibres)—the smallest unit of contraction.

Three types of motor units:

Type	Characteristics	When recruited
Slow	Low, sustained tension	First; for standing, slow movements
Fast fatigue-resistant	Intermediate force	For walking, running
Fast fatigable	High force, tires quickly	Last; for jumping, intense movements

• Force is modulated by recruiting different numbers and types of motor units.
• Contraction strength is also adjusted by changing motor neuron firing frequency at the neuromuscular junction.

🔌 Neuromuscular junction (NMJ)

The neuromuscular junction is the chemical synaptic connection between the terminal end of a motor neuron and a muscle.

How it works:

1. Action potential reaches motor neuron axon terminal.
2. Acetylcholine (ACh) is released.
3. ACh diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors (nAChRs) on the muscle.
4. nAChRs open, allowing Na⁺ into the muscle, causing depolarization (endplate potential).
5. This triggers an action potential in the muscle, leading to contraction.
6. Acetylcholinesterase breaks down ACh to prevent sustained contraction.

Clinical relevance: In congenital myasthenic syndrome, proteins required for NMJ transmission are mutated, producing muscle weakness ranging from drooping eyelids to life-threatening breathing difficulties.

🚶 Central pattern generators (CPGs)

Central Pattern Generators: circuits of interneurons in the spinal cord that generate rhythmic movements like chewing or walking independently of brain inputs.

• Discovered over 100 years ago: the spinal cord disconnected from the brain can still produce stepping in cats.
• CPGs ensure coordinated action of extensors and flexors to produce fluid movements.
• They require pre-motor inputs to select and coordinate the types of motor neurons needed (e.g., walking vs. running).
• Descending inputs from the motor cortex select between gaits; sensory feedback (proprioception, environment) shapes correct execution.

Don't confuse: CPGs can generate rhythmic patterns autonomously, but they are normally modulated by higher brain centers and sensory information for adaptive, context-appropriate movement.

🏥 Spinal cord injury and rehabilitation

Effects of injury:

• Cervical lesion (C4-C6): quadriplegia (arms and legs paralyzed).
• Thoracic lesion: paraplegia (legs paralyzed).

Step training rehabilitation:

• Patient's body weight is supported by a harness over a treadmill.
• Therapists move the patient's legs and joints to simulate normal walking.
• Repetitive sensory inputs from legs, feet, and trunk train the spinal cord circuits.
• After weeks, most patients can generate spontaneous walking with support, enhancing health and well-being.
• For incomplete spinal cord injury, this can stimulate rewiring of descending inputs from the brain.

🎯 Cerebellum: coordination and learning

🎯 Role in movement construction

The cerebellum plays a role in the coordination and planning of movement, not direct execution.

• It comprises 10–20% of brain volume but contains 50% of its neurons (highly organized, densely packed structure).
• Located on the back of the brain, above the brainstem.

Cerebellar ataxia (lack of coordination) from cerebellar lesions includes:

• Hypotonia (weakness).
• Dysmetria (inappropriate displacements like overreaching).
• Dysdiadochokinesis (difficulty making rapid alternating movements).
• Decomposed movements (lack of coordination of different joints).

Insight from patients: "It was as if each movement was being performed for the first time"—suggests the cerebellum enables predictive motor commands.

🔮 Feedforward predictive control

The cerebellum enables learning of internal models (motor programmes):

• Over repeated iterations of a movement (e.g., hitting a tennis ball), an internal model is learned.
• The next time, this cerebellar representation generates appropriate movements in response to sensory inputs, making the action more accurate and automated.
• The cerebellum receives inputs about planned movements from motor cortex and sensory feedback on actual movement.
• It compares planned vs. actual performance and adjusts ongoing movement as part of feedforward predictive control.

⚙️ Basal ganglia: selection and modulation

⚙️ Structure and connections

The basal ganglia are five interconnected nuclei within the forebrain:

• Striatum (caudate nuclei + putamen)
• Globus pallidus
• Substantia nigra (midbrain)
• Subthalamic nucleus (midbrain)

Connections:

• Receive inputs from all areas of neocortex (motor cortex, limbic areas involved in emotions).
• Project back to motor cortex via thalamus relays.
• No direct connections to spinal cord.

Functions: Action selection, association and habit learning, motivation, emotions, motor control—this section focuses on movement selection and force modulation.

🎚️ Volume control theory

The globus pallidus acts like a volume dial controlling movement via the thalamus.

How it works:

• Globus pallidus is inhibitory; it inhibits the thalamus.
• Thalamus is excitatory; it activates motor cortex.
• More globus pallidus activity → more thalamus inhibition → less motor cortex activation → less movement.
• Less globus pallidus activity → less thalamus inhibition → more motor cortex activation → more movement.

This "volume control" allows selection of appropriate goals while rejecting less optimal options.

➡️ Direct pathway: facilitates movement

Pathway: Striatum → internal globus pallidus (inhibitory) → thalamus (disinhibited) → motor cortex (more excitation).

• Striatum inhibits internal globus pallidus.
• This removes inhibition from thalamus.
• Thalamus excites motor cortex more strongly.
• Result: Movement is facilitated.

Dopamine's role: D1 receptors in striatum enhance striatal inhibition of internal globus pallidus, further facilitating movement.

↩️ Indirect pathway: reduces movement

Pathway: Striatum → external globus pallidus (inhibited) → subthalamic nucleus (disinhibited) → internal globus pallidus (excited) → thalamus (more inhibited) → motor cortex (less excitation).

• Striatum inhibits external globus pallidus.
• This disinhibits subthalamic nucleus.
• Subthalamic nucleus excites internal globus pallidus.
• Internal globus pallidus inhibits thalamus more strongly.
• Result: Less motor cortex excitation, less movement.

Dopamine's role: D2 receptors in external globus pallidus reduce its inhibition, allowing it to inhibit subthalamic nucleus more, ultimately facilitating movement.

Balance: The balance between direct and indirect pathways controls the "volume dial" that modulates motor cortex input to select and regulate movement.

🏥 Basal ganglia diseases

Disease	Type	Cause	Symptoms	Treatment
Huntington's disease	Hyperkinetic (excessive movement)	Up to 90% neuronal death in striatum; disrupts indirect pathway	Chorea (uncontrolled, abrupt, random movements); later dementia and death	Antipsychotics (block dopamine, e.g., clozapine); anxiolytics/anticonvulsants (increase GABA inhibition, e.g., clonazepam)
Parkinson's disease	Hypokinetic (reduced movement)	Loss of dopaminergic neurons in substantia nigra; reduced dopamine levels	Resting tremor, stiffened muscles, slowness of movement, small shuffling steps	L-DOPA (dopamine precursor that crosses blood-brain barrier); dopamine receptor agonists; dopamine breakdown inhibitors; deep brain stimulation of subthalamic nucleus or internal globus pallidus

Don't confuse: Huntington's involves loss of striatal neurons (disrupting the indirect pathway, leading to excessive movement), while Parkinson's involves loss of dopaminergic neurons (affecting both pathways, leading to reduced movement).

🔄 Control strategies: feedback vs. feedforward

🔄 Feedback control

Feedback control: the output is monitored by sensory systems and signals are relayed into the CNS to inform regions that generate motor outputs.

• Sensory information is processed as the movement progresses, allowing adjustment.
• Limitation: Relatively slow; suitable only for slow movements and sequential actions.
• Example: Processing visual cues when catching a ball may take 700 ms, but the movement only takes 150–200 ms—too slow for fast movements.

⏩ Feedforward control

Feedforward control: the optimal movement is predicted from current sensory conditions and from memory of past strategies.

• Used for fast, ballistic movements.
• Example: Seeing snow and ice, you predict slipping risk and walk differently (small steps, slow pace, arms out for balance) based on past experience.
• Example: Catching a ball—knowing initial arm/hand conditions and predicting ball trajectory, a stored motor programme is selected.
• Key feature: Improves with learning.

Integration: Feedback and feedforward controls are not mutually exclusive; they are combined to optimally generate coordinated movements.

🧩 Key integration: the peach-picking example

Imagine picking a ripe peach—this seemingly simple movement requires:

1. Visual cortex: Processes visual information to locate the fruit.
2. Motor regions of frontal lobe: Plan the movement and send command signals.
3. Spinal cord: Generates movement through motor neuron activation.
4. Motor neurons: Induce coordinated contraction and relaxation of arm and hand muscles to grasp the peach.
5. Sensory receptors (fingers): Relay tactile and proprioceptive information back to spinal cord and somatosensory cortex.
6. Somatosensory cortex → motor cortex: Confirm you are grasping the fruit.
7. Basal ganglia: Judge grasp force (a ripe peach is delicate; correct pressure avoids bruising).
8. Cerebellum: Regulate timing and accuracy of the movement.

This illustrates the hierarchical organization, parallel processing (can produce other movements simultaneously, like maintaining posture), and independence of brain areas (can coordinate complex activity with relatively general commands, allowing rapid, precise, unconscious movement).

🧭 Overview

🧠 One-sentence thesis

The brain evolved primarily to coordinate sensory information into adaptive motor actions, enabling animals to move through and interact with their environment in real time.

📌 Key points (3–5)

• Why brains exist: The main evolutionary advantage of having a brain is to allow movement and environmental interaction (illustrated by the sea squirt example).
• Hierarchy of complexity: Sensorimotor integration ranges from simple spinal reflexes (no brain needed) to complex voluntary actions requiring multiple brain systems working together.
• Brain override of reflexes: The brain can inhibit automatic spinal reflexes when context demands a different response (e.g., not dropping a hot cup of coffee).
• Common confusion: Simple tasks like moving chess pieces are actually harder for machines than winning chess games, because physical coordination requires real-time integration of noisy, multi-dimensional sensory information.
• Prediction and learning: The brain uses prior experience combined with current sensory input to predict outcomes and improve future actions through dopamine-based error signals.

🧬 Why animals have brains

🦑 The sea squirt example

• The sea squirt is a marine invertebrate with a two-stage life cycle that demonstrates the link between brains and movement.
• Juvenile stage: Swims around using a rudimentary nervous system (~200 neurons) to find a suitable rock.
• Adult stage: Once attached to a rock, becomes immobile (sessile) and literally eats its own brain as an energy source.
• Key insight: When movement is no longer needed, neither is a brain.

The main advantage of having a brain is to allow its carrier to move around and interact with the environment.

🤖 Why robots struggle with simple tasks

• Computers can beat world chess champions (Deep Blue defeated Kasparov in 1997) because chess has finite, known rules.
• But robots still cannot easily perform tasks simple for children, like tying shoelaces or breaking an egg.
• The difference: Physical tasks require real-time integration and analysis of noisy, multi-dimensional sensory information—rules the nervous system uses but engineers haven't fully replicated.

🔄 Simple reflexes: sensorimotor integration without the brain

🦵 Monosynaptic spinal reflex

Monosynaptic spinal reflex: the simplest sensorimotor integration structure, comprising one sensory neuron and one motor neuron connected by a single synapse.

How it works:

• Sensory neuron in muscle detects stretch via stretch-sensitive terminals.
• When stretch exceeds threshold → sensory neuron fires action potentials.
• Sensory neuron releases neurotransmitters → activates motor neuron.
• Motor neuron releases acetylcholine (ACh) → muscle contracts.

Function: Prevents overstretching and muscle damage.

Example: The knee patellar reflex—gentle hit to patellar tendon causes quadriceps contraction within 20–30 milliseconds.

🔥 Polysynaptic reflex

• Similar to monosynaptic reflex but includes an interneuron between sensory and motor neurons.
• Function: Prevents damage to body parts (e.g., rapidly withdrawing hand from hot iron).

Why bypass the brain?

• Speed: Spinal reflexes respond in 20–30 ms vs. ~200 ms for voluntary brain-controlled actions.
• The biological function (preventing immediate tissue damage) requires the fastest possible response.

🧠 When the brain overrides reflexes

☕ The hot coffee cup scenario

Situation: You pick up an overheated coffee cup from the microwave.

What happens:

• The polysynaptic reflex is activated by heat (would normally make you drop the cup).
• But your brain inhibits the reflex by activating descending interneurons from the brain.
• Instead of dropping the cup, you look for a nearby surface to set it down safely.

Why this matters:

• The brain integrates multiple information sources: sensory input (heat), internal state (intention to drink coffee), prediction (anticipating hot object).
• This produces a more adaptive response than the automatic reflex alone.
• Don't confuse: Reflexes are not always executed—the brain can suppress them when context requires a different action.

🎾 Complex voluntary actions: hitting a tennis ball

👂👁️ Tracking the ball: audition and vision

Auditory information:

• Sound of ball being hit provides early indication of ball trajectory.
• Volume (too low/high → ball likely out of bounds) and pitch/quality help decide whether to track the ball.
• Inner ear cochlea detects sound frequencies; inner hair cells code intensity by firing rate.

Visual information:

• Eyes track the moving (looming) ball to keep it focused in the fovea (best daylight resolution).
• Photoreceptors in fovea translate light into electrical signals → bipolar cells → ganglion cells → brain (as action potentials).

👀 Eye movements and the oculomotor loop

Saccades: rapid eye movements used to track moving objects and acquire environmental information.

Brain regions involved:

• Posterior parietal cortex: Neurons increase firing just before a saccade; lesions cause spatial neglect.
• Superior colliculus (basal ganglia): Contains visual fixation neurons that fire after saccades to inhibit eye movement away from target.
• Oculomotor loop: Connects cerebral cortex, basal ganglia, and thalamus to control eye tracking.

🚶 Navigating the court: visual pathways

Pathway	Route	Function
Geniculostriate	Optic nerve → lateral geniculate nucleus (thalamus) → primary visual cortex V1	Processes visual attributes
- Dorsal stream	From V1	Motion and spatial relationships ("how" information)
- Ventral stream	From V1	Contrast, contour, color ("what" information)
Tectopulvinar	Optic nerve → superior colliculus (midbrain) → pulvinar nucleus (thalamus)	Spatial location of objects; navigation without hitting stationary objects

🕶️ Blindsight phenomenon

• Patients with V1 stroke are technically blind (fail object detection tests).
• Yet they can navigate corridors avoiding obstacles without conscious visual perception.
• Explanation: The tectopulvinar pathway (which doesn't use V1) still determines object positions for navigation.
• This shows how different visual pathways serve different functions.

🎯 Action execution and coordination

🧮 Bayesian prediction

Bayesian analysis: The brain combines prior experience with ongoing sensory information to calculate the most probable outcome.

In tennis:

• Prior information: Good players aim for balls to bounce near court lines (from experience).
• Live sensory information: Current estimate of where ball is going based on visual tracking.
• Prediction: Brain overlaps prior + present information to predict bounce location.
• As ball gets closer, prediction becomes more accurate → better action selection.

🏃 Motor loops for action

Body movement loop:

• Connects motor cortex, premotor cortex, somatosensory cortex, basal ganglia, and thalamus.
• Thalamus sends feedback to cortex for constant action monitoring and modification.
• Striatum and globus pallidus (basal ganglia): Important for action selection, initiation, termination, and relating actions to consequences.

Cerebellum involvement:

• Activated during tasks requiring high coordination between eye tracking and hand movements.
• Essential for hitting the ball properly while keeping eyes on it.

💪 Muscle activation

Neuromuscular junction:

• Motor neuron action potentials reach axon terminals.
• Calcium (Ca²⁺) concentration increases → synaptic vesicles release acetylcholine (ACh).
• ACh activates receptor channels in muscle fiber membrane.
• Muscle fiber membrane depolarizes → muscle contracts.

🎁 Learning from outcomes: the reward system

🧪 Dopamine and prediction error

After the action:

• Brain monitors whether outcome matches expectations.
• If outcome matches: No error signal; neural connections responsible for that behavior are maintained.
• If outcome differs (missed ball, hit net, went out): Prediction error signal generated via dopamine release.

Function of dopamine signal:

• Affects how different brain regions connect to each other.
• Allows modification of future actions (approaching or hitting the ball differently next time).
• Enables the sensorimotor system to learn from its own performance and improve.

Brain regions involved: Multiple areas receive dopamine signals as part of the reward system.

Don't confuse: This is not just about "reward" in the everyday sense—it's about any mismatch between prediction and outcome, which drives learning and adaptation.

🧭 Overview

🧠 One-sentence thesis

Feeding behaviour is driven both by homeostatic mechanisms that maintain physiological balance and by non-homeostatic factors such as learning, emotion, and incentive motivation that operate independently of nutritional needs.

📌 Key points (3–5)

• Homeostatic regulation: The body maintains variables like glucose levels and body fat within narrow limits through negative feedback mechanisms involving sensors, control centres, and effectors.
• Brain structures: The lateral and ventromedial hypothalamus were initially thought to be dedicated "start/stop eating" centres, but research shows they are involved in broader motivated behaviours.
• Hormonal signals: Peptide hormones like ghrelin (hunger), leptin (satiety), and others signal nutritional state to the brain, though their role is more complex than simple on/off switches.
• Non-homeostatic motivation: Learning (cue-potentiated feeding), conditioned associations, and incentive motivation can drive eating even when physiologically satiated.
• Common confusion: "Liking" vs "wanting"—hedonic pleasure (liking) and motivational drive (wanting) are separate processes mediated by different brain systems (opioid vs dopamine), and can be dissociated.

🏠 Homeostatic systems and negative feedback

🌡️ What homeostasis means

Homeostatic systems: physiological mechanisms that maintain balance by regulating variables within narrow limits around a set point.

• The body has optimal set points for temperature (36.5-37.5°C), hydration levels, and nutrient concentrations.
• When the actual state deviates from the set point, homeostatic processes activate to restore equilibrium.
• This concept builds on Walter Cannon's negative feedback principle and Clark Hull's Drive Reduction theory (1943).

🔄 How negative feedback works

A homeostatic system requires four components:

Component	Function	Example (temperature)
System variable	The physiological measure being controlled	Body temperature
Set point	The optimal value or narrow range	36.5-37.5°C
Sensors/receptors	Measure the actual value	Temperature receptors
Control centre	Detects deviations from set point	Hypothalamus
Effector system	Initiates corrective responses	Sweating, shivering, behaviour

Negative feedback: a process by which the effect produced by an action serves to diminish or terminate that action.

• Example: A home thermostat set to 21°C detects when actual temperature drops to 18°C, activates the boiler (effector), which heats the home back to 21°C, then switches off.
• The correction reduces the deviation, creating a self-regulating loop.

🔋 Energy use and sources

The body uses energy for three purposes:

• 55% for basal metabolism (maintaining body heat, breathing, circulation; brain uses 19% of this)
• 33% for digestion and nutrient extraction
• 12-13% for active behaviour (varies with exercise level)

Energy comes from three dietary sources:

• Carbohydrates → converted to glucose (primary fuel)
• Amino acids (from proteins) → can be converted to glucose; nine are essential
• Lipids (fats) → stored long-term in adipose tissue or converted to glucose

Don't confuse: Carbohydrates are non-essential as energy sources (the body can make glucose from proteins and fats), but amino acids and lipids are essential as building blocks for cells.

🍽️ Homeostatic control of feeding

🩸 Glucostatic theory

The glucostatic theory (Jean Mayer, 1954-1955) proposed that blood glucose concentration is the key regulated variable:

• System variable: Blood glucose level
• Sensors: Glucose receptors in the lateral hypothalamus and liver
• Prediction: Falling blood glucose triggers meal initiation; rising glucose triggers meal termination

Research support:

• Campfield and Smith (2003) found that drops in blood glucose correlated with rats beginning to eat.
• Eating caused blood glucose to rise again.

The lipostatic theory complemented this by proposing long-term regulation of body fat levels, suggesting multiple variables may be regulated simultaneously.

🧠 The dual centre model

Early lesion studies (1940s-1950s) suggested two hypothalamic "centres":

Region	Effect of lesion	Proposed function
Ventromedial hypothalamus	Animal overeats and gains weight	"Satiety centre" (stops eating)
Lateral hypothalamus	Animal eats less and loses weight	"Hunger centre" (starts eating)

• Optogenetic stimulation of lateral hypothalamus causes animals to initiate eating.
• This seemed to support the idea of dedicated start/stop eating centres.

⚠️ Limitations of the dual centre model

James Olds and Elliott Valenstein's self-stimulation experiments challenged this view:

• Animals would press a lever to electrically stimulate their own lateral hypothalamus, often to exhaustion.
• If lateral hypothalamus = hunger centre, why would animals seek to create a hunger state?
• When researchers controlled stimulation, animals would eat if food was present, drink if water was present, fight if an intruder appeared, or mate if a receptive partner was present.

Key insight: The lateral hypothalamus is not a dedicated hunger centre but is involved in motivated behaviours more generally, depending on context.

💊 Hormonal signals

Research shifted focus from dedicated brain locations to dedicated hormones:

Hunger signals:

• Ghrelin: Secreted from the gut; stimulates food intake
• Orexin: From adipose tissue and hypothalamus; stimulates feeding and regulates body clock

Satiety signals:

• Cholecystokinin (CCK): Released from intestines in response to fat intake; inhibits feeding when injected into hungry rats
• Peptide YY (PYY): Released from stomach and intestines; inhibits eating; may be abnormally low in obese individuals
• Leptin: Discovered 1994 in Jeffrey Friedman's lab; produced by adipose tissue; acts on ventromedial hypothalamus receptors to signal satiety

The leptin story:

• Genetically obese mice (ob−/ob−) lack circulating leptin, resulting in overeating, decreased metabolism, and low activity.
• Leptin delivery can help obese individuals lose weight, but most obese people have plenty of leptin yet show "leptin resistance."
• Don't confuse: Having high leptin levels doesn't mean the system is working—resistance means the signal isn't effective.

🎯 Non-homeostatic motivation to eat

⏰ Anticipatory eating

Feeding doesn't only occur in response to hunger:

• Babies: Before 3 months, feed heavily in morning (homeostatic). After 3-6 months, feed heavily at night in anticipation of difficulty obtaining night-feeds (anticipatory).
• Rats: Nocturnal animals that normally eat when lights are off. They show increased eating/drinking just before lights go on (anticipatory), even when lights are kept constantly off, suggesting internal body clock regulation.

This demonstrates that feeding can anticipate future needs rather than just respond to current deficits.

🔔 Cue-potentiated feeding

Learning and conditioning can drive eating in the absence of hunger:

Rat experiments (Holland lab):

• Hungry rats learned to associate a tone with food delivery (Pavlovian conditioning).
• Rats were then allowed to eat until full (no homeostatic hunger).
• When the food-associated tone was played, rats ate again (cue-potentiated feeding).
• When a control tone (not associated with food) was played, rats consumed less.
• This mechanism depends on connections between the amygdala and lateral hypothalamus.

Human experiments (Birch et al., 1989):

• Preschool students learned to associate specific lights and music with favourite snacks.
• After eating until full, students ate again when the learned cues were presented.
• They began eating sooner when cues predicted their favourite foods.

Don't confuse: This is not homeostatic regulation—the drive to eat comes from learned associations, not nutritional need.

🎁 Incentive motivation: liking vs wanting

🚫 Moving beyond drive reduction

Self-stimulation experiments contradicted Hull's Drive Reduction theory:

• If lateral hypothalamus stimulation created hunger (a negative state), animals should avoid it.
• Instead, animals eagerly self-stimulated, suggesting the experience was rewarding, not aversive.
• This led to abandoning "drive reduction" in favour of "incentive motivation" theories.

🎯 Incentive motivation theories

Developed by Robert C. Bolles, Dalbir Bindra, and Frederick Toates (1970s-1980s):

Incentive motivation: behaviour is motivated by the prospect of an external reward or incentive, mediated by learning about reward availability.

• If a behaviour leads to a rewarding outcome, motivation to repeat that behaviour increases.
• If a stimulus predicts a reward (Pavlovian association), motivation to seek that stimulus increases.
• Physiological states moderate incentive value (e.g., a hot bath is more rewarding when cold).

The Bindra-Toates model proposed that rewards are both "liked" and "wanted," and these were considered synonymous.

💎 Separating liking from wanting

Kent Berridge and Terry Robinson's incentive salience model proposed that liking and wanting are separate:

Liking:

• The hedonic pleasure associated with a reward
• Measured by mouth-licking responses to sweet tastes (in rats and babies)
• Mediated by opioid, GABA, and cannabinoid systems in the nucleus accumbens

Wanting (incentive salience):

• The motivational drive to obtain a reward
• How much effort an animal will expend to get the reward
• Mediated by dopamine in the nucleus accumbens

🧪 Experimental dissociation

Dopamine depletion experiments:

• Rats with depleted nucleus accumbens dopamine became aphagic (didn't eat) and adipsic (didn't drink)—no "wanting."
• But when forced to taste something sweet, they showed normal licking responses—intact "liking."

Dopamine enhancement experiments:

• Mice with high nucleus accumbens dopamine worked harder to obtain sucrose (increased "wanting").
• But "liking" responses (licking) were unchanged compared to normal mice.

Opioid receptor stimulation (Ann Kelley's work, 1990s):

• Stimulating opioid receptors in nucleus accumbens enhanced intake specifically of palatable sweet or high-fat foods.
• This affected "liking" rather than general food intake.

Example: You might "want" to eat ice cream on a cold day (high motivational drive due to learned associations) even though you don't "like" it as much as you would on a hot day (lower hedonic pleasure).

Don't confuse: Liking and wanting usually coincide but can be dissociated—you can want something you don't particularly like, or like something you're not motivated to pursue.

🧩 Limbic system and emotion in motivation

🧠 The amygdala's role

The amygdala has long been associated with emotion and motivation:

Klüver-Bucy syndrome (from amygdala lesions in monkeys):

• No behavioural responses to normally threatening stimuli
• Increased exploration of familiar objects as if unfamiliar
• Feeding on inedible objects (rocks)
• Inappropriate sexual behaviours
• Can occur in humans with medial temporal lobe damage

Current understanding:

• The amygdala is involved in motivational processes involving learned associations between environmental cues and rewarding or aversive outcomes.
• It's not solely about emotion or motivation but about linking cues to outcomes.
• The amygdala-to-lateral-hypothalamus pathway is critical for cue-potentiated feeding.

🔗 Integration of systems

Motivation involves multiple interacting systems:

System	Primary role	Key structures
Homeostatic	Maintain physiological balance	Hypothalamus, brainstem, gut hormones
Learning/memory	Associate cues with outcomes	Amygdala, cortex
Reward/incentive	Assign value and drive behaviour	Nucleus accumbens, dopamine system
Emotional	Approach/avoid based on affect	Amygdala, limbic system

These systems work together to produce the full range of motivated behaviours, from basic survival needs to complex goal-directed actions.

Human motivation is often non-regulatory, requiring explanations beyond simple homeostatic mechanisms—we eat not just because we lack nutrition, but because of learned associations, social contexts, emotional states, and anticipated pleasure.

🧭 Overview

🧠 One-sentence thesis

Drug addiction is a compulsive, motivationally-driven disorder mediated by sensitization of the mesolimbic dopamine pathway, which hijacks natural reward circuits to create enduring cravings that persist even when pleasure from the drug diminishes.

📌 Key points (3–5)

• What addiction is: compulsive drug-taking behavior where the individual feels driven to take the drug despite harmful consequences to survival behaviors, relationships, and daily functioning.
• Four stages: initiation → maintenance → abstinence → relapse, each driven by different mechanisms, with maintenance characterized by compulsion and sensitization.
• Central mechanism: all addictive drugs increase dopamine release in the mesolimbic pathway (VTA to nucleus accumbens), despite having different primary pharmacologies.
• Common confusion: "wanting" vs "liking"—addiction involves sensitization of motivational drive (wanting) while hedonic pleasure (liking) decreases or remains unchanged; these are dissociable processes.
• Why it persists: neuroadaptive changes are largely irreversible, and conditioned cues/environments can trigger cravings and relapse even after years of abstinence.

🔬 Defining addiction and its stages

📖 What addiction is (dependence)

Drug addiction (dependence): taking a chemical substance for non-nutritional and non-medical reasons, where the drug-taking behavior is compulsive—the addict feels driven to take it without control.

• Lives become centered around acquiring and consuming the drug
• Survival behaviors (eating, drinking) are neglected
• Risky or illegal behavior to obtain drugs
• Tolerance develops: more drug needed to produce the same effect
• Distinguish from: drug use (small quantities, infrequent, no damage) and drug abuse (frequent/excessive, disrupts function but not compulsive)

🔄 Four stages of addiction

Stage	Key features	Mechanisms
Initiation	First-time use	Hedonic impact, stress relief, peer pressure, experimentation
Maintenance	Compulsive taking, loss of control	Sensitization increases motivational drive; hedonic impact decreases
Abstinence	Refraining from drug	Addiction still present but not expressed; cravings may remain strong
Relapse	Restarting drug use	Triggered by stress or conditioned cues; single dose can reinstate maintenance

💊 Tolerance and sensitization

Tolerance: a drug becomes less effective (weaker response) after repeated administration.

Sensitization: a drug becomes more effective (stronger response) after repeated administration.

• Both involve neuroadaptation: changes in neurotransmitter synthesis/release, receptor density, reuptake, second messengers, gene expression
• Sensitization processes are very long-lasting, possibly irreversible
• NMDA glutamate receptors in VTA are involved in sensitization (similar to learning mechanisms)
• Example: the motivational drive to take drugs increases (sensitization) while the pleasure decreases (tolerance)

🚪 Withdrawal symptoms

• Behavioral changes opposite to drug effects, often very aversive
• Strongest in early abstinence, then subside over time
• Avoiding withdrawal provides motivation for relapse early on
• As abstinence continues, withdrawal symptoms decrease but cravings can persist for years

🧠 Brain circuits and the mesolimbic pathway

🎯 The mesolimbic dopamine pathway

• Anatomy: cell bodies in ventral tegmental area (VTA) → axons project to nucleus accumbens
• Olds & Milner (1956): rats will press a lever to receive electrical stimulation to this pathway
• Animals will work repeatedly for this stimulation, even neglecting food and water
• Critical role of dopamine: amphetamine/cocaine (which enhance dopamine) increase lever pressing; dopamine antagonists reduce it
• Location is very specific: stimulation outside these regions does not support self-stimulation

💉 Drug self-administration experiments

• Animals will press a lever to receive intravenous injections of addictive drugs (amphetamine, cocaine, nicotine, morphine, heroin, ethanol)
• Will also self-administer amphetamine/cocaine into nucleus accumbens, morphine into VTA
• Only certain drugs support self-administration
• Only specific brain regions (VTA, nucleus accumbens) support self-administration
• 6-OHDA lesions of mesolimbic pathway abolish self-administration
• Dopamine antagonists at high doses abolish self-administration; at low doses increase lever pressing (trying to overcome the blockade)

🍎 Natural rewards and the same pathway

• Animals naturally motivated to pursue survival behaviors: eating, drinking, reproducing
• Lever pressing for food/water also depends on mesolimbic dopamine pathway
• 6-OHDA lesions or dopamine antagonists abolish lever pressing for natural rewards
• Amphetamine/cocaine enhance lever pressing for natural rewards
• Key insight: addictive drugs hijack the neural pathway that evolved to motivate survival behaviors

📊 Direct measurement of dopamine release

• Microdialysis and fast-scan cyclic voltammetry (FSCV) measure neurotransmitter release in awake, freely moving animals
• Dopamine release in nucleus accumbens (not other regions) increases during:
  • Appetitive behaviors (eating, drinking)
  • Electrical stimulation of VTA
  • Administration of drugs that support self-administration
• Different drugs increase mesolimbic dopamine through different mechanisms:
  • Nicotine, morphine, heroin, alcohol: act on VTA cell bodies/dendrites
  • Amphetamine, cocaine: affect dopamine reuptake in terminals (nucleus accumbens)

🔗 Conditioned associations and learning

Conditioned place preference:

• Animals trained that one compartment contains a reinforcer (food, water, or drug)
• At test (no reinforcer present), animals spend more time in the previously reinforced compartment
• Effect is abolished by 6-OHDA lesions, enhanced by amphetamine/cocaine, reduced by dopamine antagonists
• Shows animals learn about environments associated with reinforcers

Cue conditioning:

• If a neutral stimulus (e.g., light) is presented before a lever becomes available, animals will approach and try to press the lever when the light appears alone
• Dopamine release in nucleus accumbens increases during presentation of the conditioned stimulus, even without the reinforcer
• Critical for addiction: cues and environments associated with drug-taking can evoke dopamine release and craving long after drug withdrawal
• Parallels human addicts: empty vodka bottle, needle, or drug-taking environment can trigger strong cravings years after abstinence

🧩 Stress and relapse

• Stress is a major factor in developing dependence and triggering relapse
• Rats trained to self-administer cocaine, then left drug-free (modeling abstinence), stop pressing the lever
• Foot shock (stress) reinstates lever pressing (modeling relapse)
• Corticotropin-releasing hormone antagonists prevent this reinstatement
• Emphasizes role of hypothalamus-pituitary-adrenal axis stress response

🏗️ Where sensitization occurs

Experiment localizing neuroadaptation:

• Repeated amphetamine injections into nucleus accumbens → hyperlocomotion but no sensitization
• Repeated amphetamine injections into VTA → no immediate behavioral response but sensitization develops
• After one week drug-free, systemic amphetamine challenge shows augmented response only in VTA-injected group
• Conclusion: VTA is critical for sensitization, even though behavioral effects occur at terminals

🧩 Models of addiction

📚 Aberrant learning model

• Proposes abnormally strong learning associated with drug-taking
• Two components:
  1. Explicit learning: action-outcome association abnormally strengthened (expectation of hedonic effect)
  2. Implicit learning: action-outcome becomes automatic stimulus-response (habit)
• Limitations:
  • Most addicts don't report expecting positive hedonic effect
  • Doesn't explain compulsive nature (implies purely automatic behavior)
  • Doesn't explain behavioral flexibility addicts show in obtaining drugs

⚖️ Opponent process model

• Based on homeostatic control mechanisms
• A-process: direct drug effect (hedonic "high")
• B-process: body's reaction to restore homeostatic state (withdrawal)
• Over repeated use: tolerance to A-process (reduced pleasure), strengthening of B-process (stronger withdrawal)
• Motivation shifts from seeking positive state to avoiding negative withdrawal state
• Limitations:
  • Avoiding withdrawal is not the major motivator for drug-taking
  • Many addictive drugs don't evoke strong withdrawal
  • Withdrawal symptoms peak in days after abstinence, but cravings last years

🎯 Incentive sensitization model (Robinson & Berridge, 1993)

Core concept: dissociation between two components of reinforcement:

Hedonic impact ("liking"): the subjective pleasure from taking the drug

Incentive salience ("wanting"): the motivational importance of stimuli, making them attractive and wanted

Key features:

• The two processes are dissociable behaviorally and physiologically
• Under normal conditions with natural rewards, they work together
• With addictive drugs, they dissociate:
  • "Wanting" is sensitized: increases over repeated drug-taking
  • "Liking" is unchanged or decreases: through tolerance
• Incentive learning (explicit and implicit) provides the route through which drug-associated stimuli acquire incentive salience
• Mesolimbic dopamine pathway controls incentive salience ("wanting")
• Other basal ganglia circuits (opioids, acetylcholine) control hedonic impact ("liking")

🔬 Experimental evidence for dissociation

Measuring "liking": facial expressions related to palatability (tongue protrusions for sweet, gapes for bitter)

• Amphetamine had no effect on "liking" or slightly increased aversion

Measuring "wanting": lever press responses to conditioned stimuli

• Animals trained that one auditory stimulus (CS+) signals lever press will deliver sucrose
• Different auditory stimulus (CS-) signals no sucrose
• Amphetamine selectively enhanced lever pressing for CS+ but not CS-
• Conclusion: amphetamine enhanced motivational element ("wanting") without increasing or while decreasing "liking"

🔄 From goal-directed to compulsive

• Work by Everitt, Robbins suggests switch to compulsive drug-taking involves shift in dopamine pathway
• Early (goal-directed): neurones terminating in nucleus accumbens
• Later (compulsive): neurones terminating in dorsal striatum
• Explains transition from use/abuse to dependence

💡 Why the model explains addiction

• Accounts for addicts continuing to seek drugs despite little/no pleasure
• Explains awareness of physical, emotional, social damage yet continued drug-taking
• Accounts for enduring cravings after long abstinence (sensitization is largely irreversible)
• Explains power of conditioned cues and environments to trigger relapse

🏥 Treatment approaches

🎯 General principles

• Best long-term therapy is abstinence
• Cues, people, environments can produce strong cravings leading to relapse
• Critical requirement: individual must recognize addiction and be motivated to overcome it
• Treatments are physically and emotionally demanding

🧠 Psychological therapies

Cognitive Behavioral Therapy (CBT):

• Recognize unhealthy behavioral patterns
• Identify triggers for relapse
• Develop coping strategies
• May include contingency management (rewards for avoiding drugs)

Stepped management schemes:

• Group therapy format
• Identifies negative consequences
• Develops strategies through support networks
• Addresses life aspects beyond addiction
• Improves stress management (stress is major relapse factor)

💊 Pharmacological approaches (detoxification)

Four main approaches:

Approach	Method	Issues
Drug elimination	Simply stop taking drug, either abruptly or gradual reduction	Withdrawal symptoms can be extremely unpleasant, major motivator for relapse
Antagonist therapy	Give antagonist to block drug action	Induces very severe withdrawal; requires anesthesia/heavy sedation; rarely used
Agonist therapy	Give agonist or the drug itself in controlled way, gradually reducing	Most widely used; less harmful drug/route of delivery
Aversion therapy	Pair drug-taking with aversive stimulus (e.g., emetic)	Uses conditioning; not widely used

🔑 Supporting detoxification

• Pharmacological treatments can reduce withdrawal symptoms and cravings
• Help during the detoxification process
• Must be combined with psychological support

🎲 Addictive behaviors

🎰 Non-drug compulsive behaviors

• Behaviors like gambling, exercise can become compulsive
• Share features with drug addiction: compulsive, detrimental to daily function/relationships
• Common feature: dopaminergic component to motivation
• May involve endorphin (endogenous opioid) systems activating mesolimbic dopamine
• Research question: are these different manifestations of the same process or different processes?

🧭 Overview

🧠 One-sentence thesis

Affective disorders—primarily bipolar disorder and major depression—are characterised by abnormal emotional states that current treatments target through monoamine neurotransmitter systems, though emerging evidence points to stress-response (HPA-axis) dysfunction as a core underlying mechanism.

📌 Key points (3–5)

• Two main conditions: bipolar disorder (alternating depression and mania) and major depression (unipolar depression alone), each with severity variants.
• Monoamine theory: depression arises from reduced serotonin and noradrenaline function; current antidepressants (SSRIs, SNRIs, MAOIs, tricyclics) aim to increase these neurotransmitters.
• Limitations of current drugs: 4–6 week onset delay, only ~50% of patients show good symptom control, and side effects cause many to discontinue treatment.
• Common confusion: the monoamine theory explains drug action but not the delay in effect or incomplete efficacy—this suggests monoamines may not be the core deficit.
• Novel HPA-axis hypothesis: chronic stress and dysregulated hypothalamus-pituitary-adrenal cortex signalling, including hippocampal damage and elevated cortisol, may underlie depression and inform future treatments.

🔀 Bipolar disorder: cycles of mania and depression

🎢 What defines bipolar disorder

Bipolar disorder: characterised by cycles of extreme mood changes, from severely depressed states to periods of extreme euphoria, high activity, and excitement (mania).

• During mania: inflated self-esteem, poor judgement, risky behaviours, reduced need for sleep, restlessness, physical agitation, reduced concentration, irritability.
• During depression: symptoms resemble major depression (see below).
• Genetic factors account for ~50% of vulnerability; environmental and social factors also important.
• No specific genes identified yet.

🔢 Three severity levels

Type	Severity	Manic episodes	Depressive episodes	Hospitalisation
Bipolar I	Most severe	≥1 week, intense	≥2 weeks, severe	Often required
Bipolar II	Moderate	Shorter, less intense (hypomania)	≥2 weeks	Rarely required
Cyclothymia	Least severe	Mild to moderate	Mild to moderate	Rarely required

• Bipolar II can progress to bipolar I (~10% risk with correct management).
• Cyclothymia: repeated, unpredictable mood swings, but only mild or moderate.

📋 Diagnosis criteria (DSM-5)

• Must meet criteria for both depressive symptoms and manic episode.
• Manic episode: ≥1 week of elevated/expansive/irritable mood + increased energy, present most of the day, nearly every day.
• Must have ≥3 of: inflated self-esteem/grandiosity, decreased need for sleep, more talkative, flight of ideas/racing thoughts, distractibility, increased goal-directed activity, excessive involvement in high-risk activities.
• Mood disturbance must cause marked impairment or necessitate hospitalisation.
• Not attributable to substance use or another medical condition.

📊 Incidence and demographics

• ~2% of population overall; bipolar I (1%) more common than bipolar II (0.4%).
• Equally prevalent in males and females (unlike major depression).
• Peak onset 15–25 years; average onset bipolar I (18 years), bipolar II (22 years).
• Rare in pre-adolescents.
• Major cause of cognitive/functional impairment and suicide in young people.

🧬 Pathology: intracellular signalling abnormalities

• Brain abnormalities in cortex, amygdala, hippocampus, basal ganglia.
• Dysregulation of intracellular signalling pathways that regulate dopamine, serotonin, glutamate, GABA function.
• Decreased brain tissue volume (reduced number, density, size of neurons) linked to compromised neurotrophic pathways and mild neuro-inflammation/neurodegeneration.
• Mania likely derives from abnormalities in intracellular signalling cascades, perhaps related to localised neurodegeneration through decreased neurotrophic factors.

💊 Treatment approaches

First line: antipsychotics

• Haloperidol, olanzapine, quetiapine, risperidone.
• Target dopamine and serotonin signalling (likely downstream of primary abnormalities).

Second line: mood stabilisers

• Lithium, valproate, lamotrigine (alone or combined with antipsychotics).
• Lithium: introduced 1949; mechanisms still poorly understood; modulates intracellular signalling (adenyl cyclase, inositol phosphate, protein kinase C) by competing with metal ions (sodium, calcium, magnesium).
• Valproate and lamotrigine also modulate the same intracellular signalling cascades.
• Evidence supports abnormalities in these pathways in mania.

Psychotherapy

• Cognitive behaviour therapy: manage stress, replace negative beliefs with positive ones.
• Well-being therapy: improve quality of life, manage stress.
• Particularly important for cyclothymia to prevent progression to bipolar I/II.

😔 Major depression: persistent sadness and loss of interest

😢 Core features

Major depression: characterised by persistent feelings of sadness, loss of interest (anhedonia), feelings of worthlessness, and low self-esteem.

• Emotional: enduring, pervasive sadness that "blocks out" all other emotions.
• Anhedonia: loss of interest in life aspects, from general lethargy to complete loss of interest in health and well-being.
• Physiological/behavioural: sleep disturbances, psychomotor retardation or agitation, catatonia, fatigue, loss of energy.
• Cognitive: poor concentration/attention, indecisiveness, worthlessness, guilt, poor self-esteem, hopelessness, suicidal thoughts, delusions with depressing themes.

🔍 Dysthymia vs major depression

• Dysthymia (persistent depressive disorder): similar symptoms but less severe and more chronic.
• Double depression: individual suffers from both major depression and dysthymia.
• Don't confuse: dysthymia is milder but longer-lasting; major depression is more severe but episodic.

📋 Diagnosis (DSM-5)

• ≥5 symptoms present during same 2-week period, including at least one of: (a) depressed mood or (b) loss of interest/pleasure.
• Symptoms: depressed most of the day nearly every day; markedly diminished interest/pleasure; significant weight loss/gain or appetite change; insomnia/hypersomnia; psychomotor agitation/retardation; fatigue; feelings of worthlessness/guilt; diminished ability to think/concentrate; recurrent thoughts of death/suicidal ideation.
• Must cause clinically significant distress or impairment.
• Not attributable to substance use or another medical condition.
• Never had a manic or hypomanic episode (which would indicate bipolar).

📊 Incidence and demographics

• ~5% worldwide prevalence.
• Women 2× more likely (5–6%) than men (2–4%).
• Very low in pre-adolescents; emerges in adolescence, peaks in late middle age, declines in old age.
• Leading cause of loss of functionality worldwide (work absence, treatment costs).
• Most prevalent mental disorder associated with suicide risk.

🧬 Causes: genetic, environmental, social

Genetic factors

• Offspring of people with major depression: 2–3× more likely to develop it; 4–5× if parent had recurrent or early-onset depression.
• ~50% heritable in identical twins (higher for severe depression).
• No single gene responsible; combinations of genetic changes promote vulnerability.

Environmental and social factors

• Adoption studies: higher risk if adoptive (unrelated) parent has depression → social influence clear.
• Stress is the most important environmental factor.

Stress-diathesis model

• Interaction between stress and genetic background determines expression of depression.
• Childhood trauma (emotional abuse, neglect, sexual abuse): ~3-fold increased likelihood of future depression.
• ~80% of adult depressive episodes preceded by major stressful life events.
• Stressful events are both vulnerability and precipitatory factors.

🧠 Beck's cognitive triad

• Early life experiences + acute stress → negative views of oneself, the world, and the future (the cognitive triad).
• Creates negative schema with cognitive bias: overemphasis on negative aspects, negative inferences, overgeneralisation of negative connotations.
• These factors may invoke a depressive episode, more likely in those with genetic predisposition.

Example: A person with childhood trauma and genetic vulnerability experiences job loss (stressor) → negative automatic thoughts ("I'm worthless, the world is hostile, my future is hopeless") → depressive symptoms.

🧩 Brain structural abnormalities

• No consistent abnormalities identified.
• Some reports: decreased tissue volumes in prefrontal cortex, anterior cingulate cortex, hippocampus (inconsistent across studies).
• Reduced hippocampal volume → more prone to relapse.

Functional abnormalities (neuroimaging)

• Prefrontal and anterior cingulate cortices most likely areas of dysfunction (inconsistent between studies).
• Decreased metabolism in dorsal prefrontal cortex (reversed after antidepressant treatment).
• Decreased metabolism in ventral anterior cingulate cortex (connected to amygdala, orbitofrontal cortex, medial prefrontal cortex—regions involved in mood regulation).
• Increased insular volume and activation in response to negative stimuli → heightened sensitivity to adverse stimuli.
• Depression may result from imbalances of connectivity across multiple brain regions, not a single region.
• Corticostriatal network dysregulation: decreased frontal cortex metabolism correlates with increased striatal metabolism.

🧪 The monoamine theory of depression

🔬 Historical evidence

• Reserpine (Indian snake root plant): used as tranquilliser and for hypertension; caused severe, often suicidal tendencies.
• 1960s: reserpine depletes releasable monoamine neurotransmitters (dopamine, noradrenaline, serotonin) by preventing vesicle storage.
• Joseph Schildkraut (1965): monoamine theory of depression—depression caused by reduced monoamine neurotransmitter function.
• Primary importance: serotonin and noradrenaline (dopamine plays lesser role).

🧬 Serotonin involvement

• Serotonin involved in pain sensitivity, emotionality, responses to negative consequences—all disrupted in depression.
• Some studies: reduced serotonin metabolite (5HIAA) in CSF of depressed patients (data inconsistent).
• Low 5HIAA particularly associated with aggressive, hostile, impulsive behaviour and violent suicide attempts.
• Decreased serotonin in some post mortem brains of depressed patients (inconsistent).
• Overall: depression associated with decreased brain serotonin function.

🧬 Noradrenaline involvement

• Little evidence of decreased noradrenaline in post mortem brains.
• No consistent decrease in noradrenaline metabolite (MHPG) in CSF or blood.
• Increased MHPG after successful antidepressant treatment (consistent with antidepressants increasing noradrenaline function).
• Precise relationship unclear, but some involvement suggested.

💊 Pharmacological treatments for depression

⚡ Early treatments: shock therapy

• Prior to 1950s: no suitable drug treatments; non-specific sedation, poor symptom relief, dependence, toxic reactions.
• Shock therapy (1930s–1940s): inducing seizures seen as beneficial.
• Insulin shock, chemical shock (Cardiazol), then electroconvulsive therapy (ECT) (1940s): electrical current through brain.
• ECT safer than insulin/Cardiazol; widely used.
• Early ECT: severe seizures caused fractures, broken teeth, torn muscles/ligaments, long-term amnesia, personality changes.
• Modern ECT: controlled environment, lower currents, muscle relaxants, general anaesthetic; still used in extreme cases (non-responders to drugs).
• Mechanism unclear; causes brain chemistry changes that rapidly alleviate symptoms.
• One of the most effective treatments for severe depression.

🧪 Monoamine oxidase inhibitors (MAOIs)

Discovery

• Early 1950s: iproniazid (tuberculosis antibiotic) elevated mood.
• Tested on depressed patients; alleviated symptoms.
• 1956: first formal report of antidepressant effect (Kline).
• Marketed as antidepressant.

Mechanism

Monoamine oxidase inhibitor (MAOI): blocks the enzyme monoamine oxidase, which breaks down serotonin, noradrenaline, and dopamine, thus increasing their concentrations in the synaptic cleft.

• Iproniazid blocks MAO-A (breaks down serotonin and noradrenaline preferentially); dopamine broken down by MAO-B.
• Evidence that serotonin and noradrenaline more important in depression than dopamine.

Side effects

• Brain-mediated: insomnia, confusion, drowsiness, nausea.
• Tyramine-induced hypertension crisis (most problematic): MAOIs also block tyramine breakdown in liver → increased blood tyramine → dangerous blood pressure increases, intracranial bleeding (can be fatal).
• Diet care necessary: many foods high in tyramine (cheese, wine, chocolate) → "cheese effect."

Reversible MAOIs (RIMAs)

• Example: moclobemide.
• Binding is reversible; when tyramine increases, it competes with drug for enzyme binding → tyramine never reaches dangerous levels.

🔄 Tricyclic antidepressants

Discovery

• Imipramine (approved 1959): structurally similar to chlorpromazine (antipsychotic); developed to find drug with antipsychotic properties but without motor side effects.
• Little antipsychotic effect, but antidepressant properties.
• Other tricyclics: amitriptyline, clomipramine, desipramine, nortriptyline.

Mechanism

Tricyclic antidepressants: inhibit the reuptake of serotonin and noradrenaline back into the terminal after release, prolonging their time in the synaptic cleft and increasing trans-synaptic signalling.

• Tricyclics that primarily block serotonin and noradrenaline reuptake have best antidepressant profile.
• Those blocking dopamine reuptake less effective → dopamine less involved in depression.

Side effects

• Not very specific: also antagonists at acetylcholine, noradrenaline, histamine receptors.
• Hypotension, cardiac arrhythmia/arrest, sedation, memory disturbances (some fatal, especially in overdose).
• Effective and cheap, but side effects limit compliance; no longer first-line treatment.

🎯 Selective reuptake inhibitors (SSRIs, SNRIs, NRIs)

Development rationale

• More specific drugs with required therapeutic action but without problematic side effects.

SSRIs (Serotonin Reuptake Inhibitors)

SSRIs: powerful inhibitors of serotonin reuptake, with minimal effects on noradrenaline reuptake or other neurotransmitter systems.

• Examples: fluoxetine, paroxetine, sertraline, citalopram.
• Fewer side effects than tricyclics, but still some (mediated through serotonin systems outside brain): acute anxiety, panic attacks, akathisia (constant restlessness, inability to remain still), sleep disturbances, nausea.

SNRIs (Serotonin and Noradrenaline Reuptake Inhibitors)

• Inhibit reuptake of both serotonin and noradrenaline.
• Similar reuptake blocking action to tricyclics, but without receptor-mediated side effects.
• Examples: duloxetine, venlafaxine.
• Side effects: nausea, insomnia, loss of appetite.

NRIs (Noradrenaline Reuptake Inhibitors)

• Block only noradrenaline reuptake.
• Examples: atomoxetine, reboxetine.
• Generally less effective as antidepressants, but preferable for severe depression and depression with significant anxiety.

📊 Current treatment status

• First line: SSRIs or SNRIs.
• Efficacy: ~50% show good symptom control; ~25% show some improvement but still debilitating symptoms.
• Onset delay: 4–6 weeks before antidepressant effect emerges (direct pharmacological effect occurs within 1–2 hours → implies more complex action than simply blocking reuptake).
• Side effects: not severe or life-threatening, but unpleasant, disrupt daily life → many discontinue after recovery → high relapse risk.
• Challenge: develop drugs with faster action, effective in all patients, fewer side effects.

🧲 Transcranial Magnetic Stimulation (TMS)

• Targeted brain stimulation.
• Stimulating dorsolateral prefrontal cortex (areas with reduced metabolism in depression) shows some success.
• Potential to become more effective as understanding of brain circuit abnormalities improves.

🔬 Novel approaches: the HPA-axis hypothesis

🧩 Why look beyond monoamines?

• Monoamine drugs only moderately effective; onset delay; efficacy issues suggest they may not target core deficit.
• Two key lines of evidence:
  1. Prominence of stress as predisposing and precipitating factor in psychological models.
  2. Many animal models involve applying stressors (forced swim test, learned helplessness, chronic mild stress, maternal separation).
• Suggests body's stress response system (HPA-axis) may be involved and compromised in depression.

🔄 The HPA-axis system

Hypothalamus-pituitary-adrenal cortex system (HPA-axis): crucial in controlling the body's response to stressors and aversive situations.

How it works

• Neurosecretory cells in hypothalamus release corticotrophin releasing hormone (CRH) into pituitary portal blood capillaries.
• CRH activates posterior pituitary (median eminence) to release adrenocorticotrophin (ACTH) into blood.
• ACTH triggers adrenal cortex (on kidneys) to release glucocorticoids (cortisol in humans).
• Cortisol responsible for stress reactions: blood pressure, heart rate, reduced gut motility, arousal.

Negative feedback

• High cortisol in blood acts as negative feedback in brain to switch off HPA-axis by reducing CRH cell activity in hypothalamus.
• Stress response is self-limiting; returns to normal when stressor removed.

Regulatory inputs

• Hippocampus → inhibits CRH cells (negative control).
• Amygdala → activates CRH cells (positive control; important in responses to aversive stimulation).
• Balance between amygdala excitation (during stressor) and hippocampal inhibition (including negative feedback) controls HPA-axis activity.

🧬 Evidence for HPA dysfunction in depression

Clinical evidence

• Many depressed patients: elevated ACTH and cortisol, enlarged pituitary and adrenal glands, raised CRH in CSF, abnormal circadian rhythm of cortisol.
• All indicative of HPA-axis dysregulation.
• Current antidepressant drugs reduce CRH levels in depressed patients (mechanism unclear) → effective treatment normalises HPA dysfunction.
• Cushing's disease (excessive glucocorticoid secretion) commonly followed by depression.
• Corticosteroids (arthritis treatment) often cause depression.

Animal evidence

• CRH administration in rodents: increases cortisol + increases depression-like behaviours (insomnia, loss of appetite); reversed by antidepressant drugs.
• Maternal separation (models childhood trauma): elevates stress-induced CRH, ACTH, cortisol release in adulthood; increased CRH gene expression; reversed by antidepressants.
• Effects on gene expression particularly interesting: may account for delay in therapeutic effectiveness (gene expression changes take weeks, not hours).

🧠 Hippocampal damage and cortisol toxicity

Hippocampal role

• Hippocampus provides direct inhibitory control of CRH-secreting cells.
• Circulating cortisol activates hippocampus → increases inhibition of hypothalamus → negative feedback curtails HPA activation.
• Damage to hippocampus → prolonged HPA activation → increased CRH, ACTH, cortisol.

Evidence of hippocampal damage

• MRI studies: decreased hippocampal volume in severely depressed patients.
• Cortisol has regulatory influence (positive and negative) on many brain genes → behavioural changes, including depressed mood, after continued overexposure.

Animal studies: cortisol neurotoxicity

• High circulating cortisol has neurotoxic effects on hippocampal neurons: decreased dendritic branching, loss of dendritic spines (synapse locations), reduced hippocampal neurogenesis.
• Mediated through reduced brain-derived neurotrophic factor (BDNF) (essential for maintaining healthy neurons).
• Reduced BDNF compromises neuronal function → severe functional deterioration or death.
• Low BDNF may be responsible for reduced dendrites with prolonged high cortisol.

BDNF evidence

• BDNF levels decreased in brains of people committing suicide.
• Chronic stress reduces hippocampal BDNF in rats.
• Suggests promoting BDNF activity as therapeutic target.

Antidepressant effects on BDNF

• Monoamine antidepressants may protect vulnerable cells by preventing BDNF decrease.
• Dependent on chronic treatment (consistent with onset delay).
• Chronic (not acute) antidepressant treatment increases BDNF in animals and humans; prevents stress-induced BDNF reductions.
• Probably through up-regulation of intracellular second messenger pathways responsible for BDNF production.

🔄 Self-perpetuating cycle

• Compromised hippocampal function → ineffective negative feedback → HPA-axis remains active → high circulating cortisol → further hippocampal damage → self-perpetuating cycle.
• Chronic stress → amygdala remains active → drives HPA-system → maintains potentially toxic cortisol levels for extended period → compromises hippocampal function.
• During neurodevelopment: hippocampal cells particularly susceptible to high cortisol → potentially irreversible changes → explains why childhood trauma particularly damaging.

💊 Novel therapeutic strategies from HPA research

CRH-related therapy

• Animal studies: CRH antagonists show antidepressant-like profile (e.g., LWH234 decreases immobility in forced swim test).
• Clinical trials: CRH antagonist R121919 shows significant improvement in depression with minimal side effects.
• Notably: depression worsens after end of drug treatment.

Neurokinin-related therapy

• Neurokinin peptides (including substance P) involved in signalling about aversive stimuli, particularly in amygdala.
• Some studies: increased substance P in CSF of depressed patients → abnormalities in substance P signalling.
• Could be normalised with neurokinin (NK) receptor antagonists.
• Animal models: NK-1 receptor antagonists show antidepressant-like effects.
• Clinical trials: NK-1 antagonist MK869 reduces depressive symptoms to similar extent as SSRIs.
• Notably: time course similar to SSRIs (delayed response) → may share same delayed response as current medicines.

Ketamine and esketamine

• Ketamine (especially S-ketamine/esketamine): well-known anaesthetic; recently received attention for depression.
• Provides rapid onset (within 4 hours) antidepressant effect in treatment-resistant depression.
• Licensed in United States for treatment-resistant depression; uncertainties about functional outcomes, side effects, cost-effectiveness delay adoption elsewhere.

Mechanism unclear

• Main documented action: non-competitive antagonist at NMDA-type glutamate receptors.
• Also affects monoamine, opioid, cholinergic mechanisms (all may contribute).
• Powerful regulation of intracellular signalling cascades that increase neuronal and glial trophic factors (BDNF, GDNF); inhibits microglia associated with inflammation.
• Leads to decreased neurodegeneration, increased neuronal proliferation and synaptogenesis.
• Particularly pertinent given hippocampal degeneration and lowered BDNF in depression.
• Chronic ketamine reverses reduced hippocampal BDNF in depression.
• Renewed impetus to search for intracellular regulation mechanisms as novel antidepressant targets.

🌦️ Other depressive illnesses

🌞 Seasonal Affective Disorder (SAD)

Seasonal Affective Disorder (SAD; DSM-5: Major Depressive Disorder with Seasonal Pattern): depression with similar features to major depression, brought about by seasonal change.

• ~2% of population; most often young adults; women more affected than men.
• Decreased sunlight in winter months and increased sunlight in summer affect natural diurnal rhythms controlling hormones, sleep, moods.
• Particularly prevalent in extreme northerly/southerly regions (greatest daylight differences between summer and winter).
• Majority associated with decreased sunlight in winter (~90%); ~10% with increased sunlight in summer.

Treatment

• Light therapy (winter SAD): exposure to light of certain wavelengths from specialised light box for ~30 minutes/day; reasonably effective.
• Standard antidepressants and cognitive behavioural therapy also effective.

👶 Pregnancy and postpartum depression

Depression during pregnancy

• ~15% of women experience depressive symptoms during pregnancy.
• Often mild, but can be severe in some cases.

"Baby blues"

• 60–80% of mothers experience mild depression after birth.
• Normally transient; each bout lasts ≤1 hour.
• Does not occur beyond 2–3 weeks after birth.
• Does not generally require treatment beyond practical and emotional support.

Postpartum depression

• ~10% of new mothers.
• More severe symptoms; bouts last longer; continues for months or even years after birth.
• Also found in 5–10% of new fathers → cannot be entirely hormonal; stress of changed lifestyle also important trigger.

Cause

• Thought to relate to rapid and extreme hormonal changes during pregnancy and childbirth.
• Social stress and trauma may trigger or exacerbate.

Treatment

• Psychological therapy (cognitive behaviour therapy) and lifestyle advice (exercise, diet) effective in most cases.
• Antidepressants appropriate for more severe symptoms and non-responders to psychological treatments.
• If left untreated, can develop into persistent major depression.

📝 Summary

🔑 Key distinctions

• Bipolar disorder: fluctuations between severe depression and mania; three severity levels (bipolar I, II, cyclothymia); equally prevalent in males and females; treated with antipsychotics and mood stabilisers (lithium, valproate, lamotrigine).
• Major depression: severe depression alone; dysthymia is less severe variant; women 2× more likely than men; treated with monoamine-targeting drugs.

🧪 Monoamine theory and current treatments

• Decreased serotonin and noradrenaline functionality in depression.
• Current treatments: SSRIs (block serotonin reuptake), SNRIs (block serotonin and noradrenaline reuptake), tricyclic antidepressants (block both), MAOIs (prevent enzymatic breakdown).
• Limitations: not effective in all patients (~50% good control), 4–6 week onset delay, problematic side effects → inadequate symptom control for many.

🔬 HPA-axis hypothesis

• Compromised stress responses mediated through hypothalamus-pituitary-adrenal cortex (HPA) axis proposed as underlying cause.
• Dysregulation of inhibitory (hippocampus) and excitatory (amygdala) inputs to HPA-axis.
• Decreased hippocampal function → reduced HPA-axis inhibition → enhanced/extended stress response.
• High cortisol → hippocampal damage (reduced BDNF, dendritic loss, reduced neurogenesis) → self-perpetuating cycle.
• Monoamine antidepressants modulate HPA-function (especially with chronic treatment) → plausible route for therapeutic action and explanation for onset delay.
• Novel treatments targeting HPA-axis (CRH antagonists, NK-1 antagonists, ketamine) show promise.

🧭 Overview

🧠 One-sentence thesis

Schizophrenia is a severe mental disorder arising from interactions among genetic, biological, and social vulnerabilities that disrupt brain connectivity and neurotransmitter systems—particularly dopamine and glutamate—leading to positive, negative, and cognitive symptoms that respond variably to current treatments.

📌 Key points (3–5)

• Three symptom clusters: positive (hallucinations, delusions), negative (social withdrawal, apathy), and cognitive (memory, attention, planning deficits); negative and cognitive symptoms often appear first and persist longest.
• Multifactorial aetiology: genetic predisposition (~50% heritability), biological factors (pregnancy/birth complications, infections), and social factors (urban environment, trauma) interact; precipitatory factors like stress trigger episodes in vulnerable individuals.
• Neurodevelopmental origins: vulnerabilities arise during foetal development (second trimester) and early childhood, but symptoms typically emerge in late adolescence/early adulthood (17–30 years).
• Common confusion—dopamine vs. glutamate: dopamine dysregulation (especially mesolimbic pathway) underlies positive symptoms and responds to antipsychotics, but glutamate dysfunction may be the primary deficit affecting all symptom domains.
• Treatment limitations: current antipsychotics (dopamine/serotonin antagonists) moderately control positive symptoms but poorly address negative and cognitive symptoms, which cause the most long-term debilitation.

🧬 Origins and vulnerability factors

🧬 Genetic contribution

Genetic factors contribute approximately 50% of the vulnerability for schizophrenia.

• Twin study evidence: monozygotic (identical) twins show 40–65% concordance; dizygotic (fraternal) twins show 15–25% concordance; general population shows 0.3–0.7%.
• These rates are much lower than the 100% and 50% expected if schizophrenia were entirely genetic, indicating environmental factors also matter.
• Adoption studies: twins raised separately show similar concordance rates, ruling out shared upbringing as the cause.
• Not a single gene: likely involves combinations of multiple "vulnerability genes" across the genome, which may explain variation in symptom presentation across individuals.

🤰 Biological risk factors

• Pregnancy complications: maternal infection (especially second trimester), malnutrition, vitamin D deficiency increase risk.
• Seasonal birth pattern: higher incidence in spring births (March–April in northern hemisphere), when second trimester coincides with winter viral infections.
• Birth trauma: premature labour, low birthweight, asphyxiation, forceps delivery all associated with increased risk.
• Mechanism: pro-inflammatory cytokines from maternal infection may alter foetal neurodevelopment during critical periods of neurogenesis and neuronal migration.

🏙️ Social factors

• Urban environment: increased incidence in people raised in cities, possibly due to social crowding, adversity, isolation, poor housing—or confounded by poverty, poor diet, and toxin exposure.
• Childhood trauma: dysfunction, neglect, or abuse may worsen severity and outcome but unclear if causally linked to onset.
• Evidence limitations: longitudinal studies needed to establish specific relationships; social factors may interact with biological vulnerabilities rather than act independently.

⚡ Precipitatory factors (triggers)

Precipitatory factors are triggers which evoke schizophrenia in people who are at risk.

• Stress from life events: bereavement, accidents, relationship breakup, unemployment, homelessness, abuse.
• Not sufficient alone: these events trigger episodes only in individuals with existing vulnerability.
• Bidirectional possibility: premorbid changes (early negative/cognitive symptoms) may alter perception of or ability to cope with traumatic events.

🧠 Neurodevelopmental basis

🧠 The neurodevelopmental hypothesis

• Timing paradox: vulnerabilities laid down during pregnancy, birth, and early childhood, but symptoms emerge 15–20 years later in early adulthood.
• Structural evidence: reduced cortical volume and cortical thinning in schizophrenia, but without increased glial cells (which would indicate degeneration), supporting developmental rather than degenerative origin.
• Critical periods: second trimester (neurogenesis, neuronal migration) through birth and early childhood (synaptogenesis) are most vulnerable to stress, inflammation, malnutrition, or drugs.

🔗 The disconnection hypothesis

The disconnection theory proposes a dysregulation of connectivity between regions in neural networks.

• Not localized damage: brain regions may appear structurally and functionally normal individually, but their interactions within networks are abnormal.
• Failure of synaptic connection: improper patterns established during neuronal migration and synaptogenesis (second trimester onward).
• Functional integration failure: abnormal output occurs when regions depend on activity from other areas; e.g., frontal cortex receives incorrect information from temporal cortex.
• Key distinction: "pathological interaction of two cortical areas" vs. "normal interaction of two pathological areas."
• Don't confuse: this is about faulty wiring between healthy regions, not damage to the regions themselves.

📉 Neurodegeneration debate

• Some evidence for progression: psychotic episodes increase in severity over time; response to medication decreases; suggests progressive damage.
• Implication: psychotic episodes themselves may damage the brain, emphasizing importance of early intervention.
• Premorbid markers: negative and cognitive symptoms may predate positive symptoms, offering opportunity for psychological intervention before first psychotic episode.

🎭 Symptom clusters

➕ Positive symptoms (Type 1)

Positive symptoms manifest as an enhancement or exaggeration of normal behaviour, where a patient loses touch with reality (psychosis).

Hallucinations (sensing things not present):

• Most common symptom (~75% of patients).
• Usually auditory ("hearing voices" that comment, command, insult).
• Can be visual, somatosensory, or olfactory.
• Frightening and distressing though not always debilitating.

Delusions (false beliefs that persist despite evidence):

• Persecutory: belief that others (friends, family, government, MI5, CIA) are working against them.
• Grandiose: belief in exceptional talent or fame.
• Somatic: belief in illness or deformity.
• Control: belief that thoughts are controlled externally (thought insertion, removal, broadcasting).
• Often reflect delusional perceptions (normal perceptions take on erroneous meaning) and abnormal salience attribution (assigning importance to unimportant stimuli).

Disorganised thought/speech:

• Fragmented discourse lacking logical progression.
• Neologisms (non-existent words).
• Severe cases: "word salad" (incoherent jumble).
• Reflects poverty of thought content.

Brain correlates: temporal lobe dysfunction; dopamine abnormalities in basal ganglia (mesolimbic pathway); respond reasonably well to antipsychotic medication.

➖ Negative symptoms (Type 2)

Negative symptoms manifest as general social withdrawal, reduced affective responsiveness (emotional blunting), lack of interest (apathy), desire (avolition), motivation (abulia), and reduced pleasure (anhedonia).

• Extreme cases: mutism (not speaking), catatonia (immobility for extended periods).
• May be present in premorbid phase before first psychotic episode.
• Brain correlates: frontal cortex abnormalities implicated.
• Treatment resistance: do not respond well to current medications; particularly debilitating long-term.

🧩 Cognitive symptoms

• Difficulties with learning, memory, attention, planning, problem-solving.
• Occur in majority (if not all) patients; can be extremely severe and persistent.
• Timing: normally occur before first psychotic episode; may contribute to abnormal perceptions and attribution that manifest as positive symptoms.
• Predictive value: degree of cognitive impairment predicts long-term outcome.
• Brain correlates: frontal cortex dysfunction.
• Treatment resistance: do not respond well to antipsychotics; major unmet clinical need.

🧪 Biochemical theories

🧪 The dopamine theory

The dopamine theory posits that schizophrenia is caused by an increase in sub-cortical dopamine function, particularly in the mesolimbic dopamine pathway.

Three main observations:

1. Drugs increasing dopamine (amphetamine, cocaine, L-DOPA) cause schizophrenia-like symptoms.
2. First-generation antipsychotics (typical) are dopamine receptor antagonists.
3. Evidence for perturbed dopamine signalling in post-mortem schizophrenic brains.

Limitations:

• Dopaminomimetic drugs evoke only positive symptoms, not negative or cognitive.
• Typical antipsychotics treat positive symptoms moderately well but poorly treat (or worsen) negative and cognitive symptoms.
• May exacerbate symptoms through actions in frontal cortex, where dopamine is reportedly reduced.

🔄 Dopamine as "final common pathway" (Version III)

• Reconceptualization: abnormality lies in inputs to dopaminergic neurons, not the neurons themselves.
• Dysfunction in frontal and temporal cortex increases mesolimbic dopamine release.
• Multiple dysfunctional inputs converge on dopamine systems; different combinations may produce different symptom profiles.
• Salience attribution: mesolimbic dopamine systems assign importance to stimuli; dysregulation causes abnormal salience attribution underlying positive symptoms.
• Implication: future drugs should target mechanisms converging on dopamine systems, not dopamine itself.

🧬 The glutamate theory

Glutamate underactivity, particularly at NMDA receptors, may underlie schizophrenia.

• NMDA receptor antagonists (phencyclidine, ketamine, MK-801) cause behavioural changes resembling schizophrenia in normal people.
• Unlike dopaminergic drugs, they provoke symptoms in all three domains—positive, negative, and cognitive.
• Implication: glutamate dysregulation may be the core deficit; dopamine abnormalities are downstream.
• Evidence: reduced glutamate levels, increased cortical glutamate binding in post-mortem brains; increased receptor density in living brains.

🧠 Other neurotransmitters

• Serotonin: LSD (5HT agonist) causes hallucinations and reality distortions; atypical antipsychotics are 5HT-2 antagonists; but little evidence for serotonin abnormalities in schizophrenic brains.
• GABA: cortical GABA signalling dysfunctional, but unclear how this impacts symptoms.

💊 Treatment approaches

💊 Typical (first-generation) antipsychotics

• Example: chlorpromazine (1950s breakthrough), haloperidol (current choice).
• Mechanism: dopamine D2-like receptor antagonists.
• Efficacy: moderately effective on positive symptoms only; ~25% fail to respond; ~25% show some improvement with residual symptoms.
• Side effects: sedation; motor effects (resting tremor, akathisia resembling Parkinson's; tardive dyskinesia—irreversible and progressive); caused by D2 antagonism in dorsal striatum.
• Onset delay: several weeks before antipsychotic effect establishes.

💊 Atypical (second-generation) antipsychotics

• Example: clozapine (most effective but restricted use), olanzapine (first-line), quetiapine, risperidone, lurasidone.
• Mechanism: dual D2 and 5HT-2 receptor antagonists (plus other actions).
• Advantages: minimal motor side effects; some limited efficacy on negative and cognitive symptoms; effective in some treatment-resistant patients.
• Clozapine limitations: 1% risk of agranulocytosis, 3% neutropenia; requires strict blood monitoring (weekly for 18 weeks, then fortnightly to 1 year, then monthly); only used after two other antipsychotics fail.
• Other side effects: substantial weight gain, excessive salivation.
• Onset: often slower than typical antipsychotics.

💊 Third-generation antipsychotics

• Examples: aripiprazole, brexpiprazole, cariprazine.
• Mechanism: D2 receptor partial agonists (dopamine "stabilizers"); reduce effect when endogenous dopamine high, enhance when low; some have 5HT partial agonist actions.
• Advantages: as effective as other antipsychotics with reduced side effects and better tolerance.
• Limitations: still not effective on negative and cognitive symptoms.

💊 Future directions (fourth generation)

• Experimental approaches targeting glutamate, acetylcholine, trace amines.
• Goal: address unmet clinical need for negative and cognitive symptom control.

🗣️ Psychological therapy

Cognitive Behavioural Therapy (CBT):

• Helps individuals understand and overcome abnormal perceptions.

Family therapy:

• Works with patient and family to create less stressful, more supportive environment.

Limitations during acute episodes: psychotic symptoms make communication difficult and patients suspicious.

Best timing: after pharmacological stabilization; can maintain stability and allow drug reduction or cessation.

Premorbid intervention: some success in vulnerable individuals showing negative/cognitive symptoms but no psychotic episode yet; focuses on adverse life events and reactions; may prevent psychotic episodes (important given evidence that episodes cause damage).

📋 Current first-line treatment

1. Atypical antipsychotic (usually olanzapine) + individual CBT + family therapy.
2. If ineffective or intolerable side effects, try second drug (another atypical or sometimes typical).
3. Clozapine only after two other antipsychotics tried (one must be atypical).
4. Post-acute: continue pharmacological and psychological therapy to prevent relapse; sometimes possible to reduce drugs slowly with monitoring.
5. Adherence issue: ~20% relapse rate from patients stopping medication (believing cured or preferring relapse risk to side effects).
6. Long-acting injectables (LAIs): depot preparations for unreliable adherence (haloperidol, flupentixol, fluphenazine; also olanzapine, risperidone, aripiprazole).

🏥 Diagnosis and outcome

🏥 Diagnostic criteria (ICD-11)

At least two symptoms present most of the time for ≥1 month; at least one from (a)–(d):

• (a) Persistent delusions
• (b) Persistent hallucinations
• (c) Disorganized thinking (formal thought disorder)
• (d) Experiences of influence, passivity, or control
• (e) Negative symptoms
• (f) Grossly disorganized behaviour; psychomotor disturbances
• (g) Not due to another medical condition or substance

📊 Clinical outcome

Recovery level	Percentage	Description
Near full recovery (with treatment)	~50%	Able to live independently or with family
Moderate recovery	~25%	Require substantial support; supervised housing
Little/no improvement	~25%	Persistent severe debilitation
Near full recovery (without treatment)	~20%	Rare; likely never full recovery

• Key point: negative and cognitive symptoms do not respond well to treatment and form most debilitating long-term dysfunctions.

🧠 Brain structure changes

🧠 General findings

• Reduction in overall brain volume, particularly grey matter.
• Cortical thinning.
• Increased ventricle size.
• Not unique: also seen in normal aging and other diseases.
• No glial cell increase: supports neurodevelopmental (not neurodegenerative) explanation.

🧠 Specific regions

Prefrontal cortex:

• Cortical thinning observed.
• Important for logical thinking, inference, problem-solving, working memory.
• Functional imaging: reduced activity during cognitive tasks.
• May explain disorganized thoughts and disrupted executive function.

Medial temporal lobe (entorhinal cortex, hippocampus):

• Reduced tissue volume.
• Important for attention and working memory.

Basal ganglia (nucleus accumbens/ventral striatum):

• Receives substantial connectivity from temporal and prefrontal cortex.
• Critically involved in salience detection and response selection.
• Disrupted dopamine transmission (perhaps under abnormal cortical direction) may underlie salience attribution deficits.

Overall interpretation: subtle changes in brain connectivity (not localized damage) translate into schizophrenia dysfunctions; consistent with disconnection hypothesis.

🧭 Overview

🧠 One-sentence thesis

Ageing is a gradual, inevitable process driven by genetic and environmental factors that produces widespread biological and cognitive changes, though these changes are not uniform across all systems and can be moderated by lifestyle interventions.

📌 Key points (3–5)

• What ageing is: a continuous process of natural, unavoidable changes beginning in early adulthood, influenced by genetics and external factors (diet, exercise, stress, smoking).
• Biological changes: brain volume shrinkage (especially frontal cortex), synaptic alterations, neurotransmitter declines (dopamine, serotonin, glutamate), oxidative stress, inflammation, and vascular changes.
• Cognitive changes: general slowing across all tasks; episodic memory and working memory decline more than semantic or procedural memory; attentional control and inhibition deficits emerge, especially for voluntary/complex processes.
• Sensory changes: vision (reduced acuity, colour discrimination, motion perception), hearing (high-frequency loss, speech-in-noise difficulty), touch, taste, and smell all decline, but not uniformly.
• Common confusion: chronological age vs biological age—how old someone is in years vs how old they seem physiologically; also, normal ageing vs dementia (dementia is beyond expected ageing and interferes with daily life).

🧬 Biological foundations of ageing

🧬 Defining ageing and its scope

Ageing: a gradual and continuous process of changes which are natural, inevitable and begin in early adulthood.

• Globally, populations are ageing due to increased life expectancy, raising health, social, and political challenges.
• Ageing produces both physical and mental changes; timing varies individually but changes are expected and unavoidable.
• Chronological age: how many years old a person is.
• Biological age: how old a person seems in terms of physiological function or disease presence.
• Gerontology: the study of ageing processes and individuals across the lifespan, encompassing social, cultural, psychological, cognitive, and biological aspects.
• Don't confuse: ageing increases risk of disorders like dementia, but these are not inevitable consequences of ageing itself.

🏗️ Structural brain changes

• Brain volume shrinks with age, most pronounced in the frontal cortex, followed by striatum, and to a lesser extent temporal lobe, cerebellar hemispheres, and hippocampus.
• Both grey matter (neuronal cell bodies) and white matter (axonal tracts) decrease, though at different life stages.
• MRI studies show these decreases lead to expansion of the brain's ventricles (fluid-filled spaces).
• The cerebral cortex thins with age, following a similar pattern (frontal and temporal lobes most affected).
• Some studies suggest sex differences in which brain areas shrink most.

🔬 Cellular and molecular mechanisms

Synaptic and circuit changes:

• Neuroplasticity (the brain's ability to adapt structure and function in response to stimuli) declines with age.
• Dendrites shrink, branching becomes less complex, and dendritic spines are lost → reduced surface area for synaptic connections → less effective neural circuitry and plasticity.
• These synaptic changes are a major contributor to age-related cognitive decline.

Pathological features:

• Beta amyloid (Aβ) plaques and neurofibrillary tangles occur in smaller amounts and more diffusely in normal ageing (vs concentrated in dementia).
• They contribute to cell death and neuronal dysfunction even in ageing without dementia.

Oxidative stress:

• Free radicals released during metabolism damage cells; the brain is particularly sensitive.
• Causes DNA damage, inhibits DNA repair, and accumulates over the lifespan → cellular dysfunction and death.

Inflammation:

• Persistent systemic inflammation with age: increased pro-inflammatory cytokines and chemokines in blood.
• Microglia (brain's resident immune cells) become chronically activated, producing constant neuroinflammation → detrimental to cognitive function.

Vascular changes:

• Decreased microvascular density, vessel thickening, increased stiffness, and tortuosity (twisting).
• Compromised cerebral blood flow → cognitive function changes.

🧪 Neurotransmitter alterations

Neurotransmitter	Role	Age-related change	Consequence
Dopamine	Executive function, motor control, motivation, reward	Declines ~10% per decade from early adulthood	Declining motor and cognitive performance; may be due to reduced production, dopamine neurons, or responsive synapses
Serotonin (5-HT)	Mood, behaviour, sleep, memory	Decreasing receptor levels and transporter (5-HTT)	Declines in mood, behaviour, sleep, memory; loss especially in frontal cortex, thalamus, midbrain, putamen, hippocampus
Glutamate	Primary excitatory neurotransmitter; motor behaviour, memory, emotion	Declines with age (lower in motor cortex, parietal grey matter, basal ganglia, frontal white matter)	Affected motor behaviour, memory, emotion; high levels cause neurotoxicity in neurodegenerative disorders

🧬 Genetic factors

• Lifespan duration is partly genetically determined: close family of centenarians live longer; identical twins have more similar lifespans than non-identical twins.
• Telomeres: repeated DNA segments at chromosome ends; each cell division loses repeats.
• When telomeres reach a certain size, the cell cannot divide further and dies → cannot be replaced.
• However, this is likely oversimplified; multiple genetic factors combined with environmental factors contribute to ageing.

🧠 Cognitive changes with ageing

⏱️ General slowing

• One of the strongest findings: older people respond more slowly than younger people in virtually every task.
• Reflects many biological changes described above.
• Important methodological point: must control or account for slowing before considering other cognitive theories.
• Slowing can have subtle effects: if a cognitive process requires multiple steps, a delay in the first step can prevent the entire processing stream from proceeding or synchronising.

🧠 Memory systems

Episodic memory (personally experienced events):

• Shows the clearest decline with age, especially after age 60.
• Recall tasks (freely recalling items) decline more than recognition tasks (judging whether items were seen before).
• Recollection of context/detail declines significantly; ability to judge familiarity of a prior occurrence declines much less.

Other memory types:

• Semantic memory (facts and information): shows less decline.
• Procedural memory and short-term memory: relatively preserved.
• Working memory (processing or manipulating items in memory): declines with age.

Variability:

• Considerable individual variability even in domains with consistent decline.
• Likely due to differences in rate of brain structure loss ("brain reserve") and ability to cope or find alternative strategies.
• Example: some older people interpret familiarity differently and are more likely to infer they recalled an event.
• Higher education earlier in life and higher physical/mental activity later in life are associated with better memory.

👁️ Attentional control

Cueing responses:

• Response to cues becomes slower with age, but the extent differs by cue type:
  • Alerting cues (increase vigilance and task readiness): older people slower to show alerting response.
  • Symbolic cues (e.g., arrow pointing to a location): older people comparatively slower.
  • Automatic capture cues (e.g., loud noise, bright light): older people maintain automatic orienting response.
• Sensory changes (e.g., vision) can affect these results; older people may be slower to respond to small arrow cues but not larger ones.

Visual search:

• Participants search for a target among distractors; target may be specified in advance or defined by relation to distractors.
• Feature-based search (target differs by one feature, e.g., red H among blue As): relatively preserved in older people; often automatic and involuntary.
• Conjunction search (target shares some features with distractors, e.g., red H among red As and blue As): older people show slower performance; requires more complex and voluntary processes.
• Older people slower when more attentional shifts are required to find the target.
• Declines in discrimination, inhibition, disengagement, and general slowing also play a role.

🚫 Inhibition

Inhibition: the ability to ignore, avoid, or suppress irrelevant actions or stimuli.

• Measured by Stroop task (name word, ignore ink colour), go/no-go task (press button for target, avoid press for different stimulus), flanker/distracter tasks (performance with vs without distraction).
• Hasher and Zacks (1988): proposed age-related decline in inhibition underlies many performance differences.
• Deficits found in many inhibition-based tasks:
  • Older people's reaction times more affected by salient distractors in visual search.
  • Weaker "negative priming" (when a previous distracter becomes the current target, performance is affected; attributed to distracter inhibition).
• However, some findings can be attributed to other factors:
  • Stroop differences partly due to speed of processing colours and words with age.
  • Inhibition of responses rather than sensory profile of distracter itself.
• Meta-analysis (Rey-Mermet & Gade, 2018): older people's inhibitory deficit likely limited to inhibition of dominant responses.

👁️👂 Sensory changes with ageing

👁️ Vision

Optical changes:

• Reduced focusing at near distances → almost everyone needs reading glasses eventually.
• Lens thickens and yellows → less light enters optic nerve and brain → affects colour and shape perception.

Colour vision:

• Yellowing of eye affects shorter wavelengths (blues and greens) more.
• Example: when matching red and green to appear the same brightness, older people need more green added.

Shape perception:

• Reduced light through eye reduces ability to resolve fine detail.
• Neural loss and decay also contribute, especially for determining object shape.
• For coarser patterns (lower spatial frequencies): differences likely due to cortical changes.
• For finer detailed patterns (high spatial frequencies): loss more likely due to optical factors.
• Note: glasses correct for acuity (mostly fine detail discrimination), but visual losses are far more wide-ranging and subtle.

Motion perception:

• Older people tend to misjudge speed of moving items.
• Minimum speed required to discriminate direction of motion is higher for older people.
• However, some studies find age-related deficits absent or specific to particular stimuli; some report improvements (e.g., quicker to discriminate direction of large moving patterns).
• Many motion processing deficits are not due to motion processing per se, but to sensitivity deficits earlier in the processing stream.
• Slight changes in stimuli details (speed, contrast) might make dramatic visibility changes for older vs younger adults.

👂 Hearing

Frequency sensitivity:

• Ear loses sensitivity with age, starting with high tones (high frequencies), then affecting low tones.
• Similar to vision: reduction in sensitivity to high frequencies.

Speech-in-noise:

• One of the most commonly reported issues: loss of ability to discriminate speech in background noise.
• Causes trouble hearing conversations in crowds, dialogue in films/TV.
• Found in both subjective and objective measures.
• Association between speech-in-noise ability and cognitive decline; possible explanations:
  • General loss across all brain systems.
  • Effort and load of coping with declining sensory systems causes worse performance on cognitive tasks.

✋ Touch

• Least well understood sense in ageing.
• Used to sense texture, shape (pressing or stroking surfaces); entire body sensitive to touch (e.g., feet for balance, body for comfort).
• Skin changes: reduced hydration, elasticity, and compliance → affects ability to sense texture and shape differences.
• Changes in brain areas processing touch and pathways connecting skin and brain → affects basic tactile sensitivity.
• Movement control also changes with age, affecting touch perception.

👅👃 Taste and smell

• Critically important for quality of life and health; show decline with ageing.
• Loss of appetite common in old age; loss of smell and taste contribute.
• Makes food unpalatable; difficult to identify when food is spoiled or dirt is present.
• Change is gradual over lifespan; by age 65, measurable differences in ability to detect flavours or smells.

🛠️ Strategies to promote healthy cognitive ageing

🎯 Cognitive (brain) training

• Program of regular mental activities to maintain or improve cognitive abilities.
• Assumptions: practice improves performance; similar cognitive mechanisms underlie various tasks; practicing one task improves closely related skills/tasks.
• Encompasses cognitive stimulation and strategy-based interventions.
• Typically administered via computer or electronic medium.
• Aims to restore or augment specific cognitive functions via challenging tasks that adapt to individual performance and become progressively more difficult.
• Meta-analyses of randomized controlled trials in healthy older adults and patients with mild cognitive impairment (MCI): positive results on targeted cognitive functions.

⚡ Neuromodulation

Transcranial direct current stimulation (tDCS):

• Delivers weak electrical current via scalp electrodes to directly stimulate cortical targets.
• Approved as safe neuromodulatory technique.

Repetitive transcranial magnetic stimulation (rTMS):

• Uses electromagnetic coil to deliver magnetic pulse targeted at specific cortical regions.
• Modulates neuronal activity and promotes plasticity.

Evidence:

• Both shown to moderately improve cognitive functioning in older people.
• Improve cognitive performance in patients with MCI.
• Some studies combine cognitive training and neuromodulation, but limited evidence of enhanced performance beyond either approach used alone.

🏃 Physical activity

• Structured physical activity (moderate to vigorous aerobic exercise) preserves and enhances cognitive functions in older adults.
• Moderately improves global cognitive function in older adults.
• Improves attention, memory, and executive function in patients with MCI.
• Mechanisms not fully understood; likely vary depending on individual factors (age, affective mood, underlying health status).

📊 Methodological considerations for ageing research

📊 Study designs

Study type	Description	Advantages	Disadvantages
Longitudinal	Data collected from same participants repeatedly over time	Easier to control for cohort effects (only one group); requires fewer participants	Participant dropout increases over time; resource intensive; practice effects
Cross-sectional	Data collected at single time point for more than one cohort, separated into age groups	Efficient—all data collection completed within short time frame; easily replicated	Difficult to match age groups; differences due to cohort/historical differences in environment, economy, etc.
Sequential longitudinal/cross-sectional	Two or more longitudinal or cross-sectional designs, separated by time	Repeating/replicating helps separate cohort effects from age effects	Complex to plan; can be expensive
Accelerated longitudinal	Wide age range recruited, split into groups, each followed for a few years	Longitudinal data from same participants over time; cross-sectional data within shorter time frame	Does not completely avoid cohort effects

⚠️ Key methodological issues

Life experience accumulation:

• Older people have experienced more life events, even if chances are the same throughout life.
• More likely to have experienced accidents, recovered from disease, or have undiagnosed conditions.

Cohort effects:

• People of different ages lived at different times, experiencing different social, economic, and public health factors.
• Example: rationing drastically changed health of people who grew up mid-20th century; Coronavirus pandemic likely to have long-term effects.

Increased variability:

• The older people get, the more variable their life paths become.
• More variability in data from older people; environmental factors have strong effect on behavioural data.

Non-psychological effects on psychology:

• Example: attention often shifted by moving head or eyes; reduced range or speed of motion with age directly impacts attention shifts.
• Not all attention shifts involve overt head or eye movements.

Generalised effects:

• Generalised slowing needs to be controlled for or considered before proposing more complex/subtle effects.
• Use analysis techniques like z-scores, ratios, or Brindley plots to compare age groups.
• Ensure there is always a within-age-group baseline or control condition.

🧭 Overview

🧠 One-sentence thesis

Dementia is a progressive syndrome caused by various underlying conditions—most commonly Alzheimer's disease—that leads to cognitive decline beyond normal ageing, with no current cures but some treatments available to slow symptom progression.

📌 Key points (3–5)

• What dementia is: a syndrome of progressive brain function decline (memory, language, judgement, motor control) that interferes with daily activities, going beyond normal biological ageing.
• Main causes: Alzheimer's disease (60–80% of cases), vascular dementia, dementia with Lewy bodies, and others; each has distinct pathology and symptom patterns.
• Common confusion—dementia vs normal ageing: memory loss may occur in normal ageing, but dementia involves deterioration severe enough to disrupt daily life and independence.
• Risk factors: age is strongest, but modifiable factors (smoking, alcohol, inactivity, diet) and non-modifiable factors (genetics) interact; mild cognitive impairment (MCI) increases risk.
• Treatment landscape: no cures exist; pharmacological options (AChE inhibitors, memantine) provide symptomatic relief; psychological approaches (cognitive stimulation, reminiscence therapy) improve quality of life.

🧩 Core concepts of dementia

🧩 What dementia is

Dementia: a syndrome associated with progressive decline in brain functioning, most commonly affecting memory, with symptoms severe enough to interfere with daily activities.

• It is not simply "getting older"—the deterioration goes beyond what is expected from normal biological ageing.
• Symptoms are wide-ranging and vary hugely between individuals: memory loss, apathy, language difficulties, impaired judgement, motor control problems, slowed cognitive processing.
• People may also experience paranoia, hallucinations, and challenges in decision-making and living independently.
• Example: forgetting names occasionally is normal ageing; forgetting how to perform daily tasks or getting lost in familiar places signals dementia.

🔍 Dementia vs normal ageing vs MCI

Condition	Memory/cognition	Daily function	Risk
Normal ageing	Some memory lapses expected	Independent	Baseline
Mild Cognitive Impairment (MCI)	Decline beyond normal ageing	Can still live independently and perform most daily activities	Higher risk of developing dementia, especially AD
Dementia	Severe decline interfering with daily life	Impaired independence	Progressive worsening

• Don't confuse: MCI is not a type of dementia, but it is associated with higher risk of progression to dementia.
• MCI involves memory loss or other cognitive decline (language, visual/spatial perception) beyond normal ageing, yet the person maintains independence.

🧬 Alzheimer's disease (AD)

🧬 What AD is and its scale

Alzheimer's disease: a neurodegenerative disorder characterised pathologically by extracellular beta-amyloid (Aβ) plaques, neurofibrillary tangles, and neuroinflammation, leading to cognitive decline and memory loss.

• Most common form of dementia: accounts for 60–80% of all dementia cases.
• First described by Alois Alzheimer in 1907.
• Scale: 30 million people worldwide currently; predicted to rise to 90 million by 2050. In the UK, over 500,000 people live with AD; forecast to reach 1 million by 2025 and 2 million by 2050.
• Risk increases with age: 1 in 20 under 65, 1 in 14 over 65, 1 in 6 over 80.
• In England and Wales (2021), AD was a leading cause of death, accounting for over 10% of registered deaths.

🧬 Early-onset vs late-onset AD

Type	Age of diagnosis	Prevalence	Cause
Early-onset AD (EOAD, familial)	Before 65	Up to 5% of AD cases	Mutations in APP, PSEN1, or PSEN2 genes → increased Aβ plaque production
Late-onset AD (LOAD, sporadic)	After 65	~95% of AD cases	Complex interplay of genetic and environmental factors; strongest genetic risk is APOE4 gene

• Don't confuse: EOAD is rare and driven by single-gene mutations; LOAD is far more common and involves multiple risk factors.
• Recent genome-wide studies implicate genes linked to the innate immune system and microglia (e.g., CD33, TREM2).

🧠 Symptoms of AD

Early symptoms:

• Declarative memory disruption: inability to learn and remember new facts (semantic memory deficit) and recall past experiences (episodic memory deficit).
• Abnormally rapid forgetfulness.
• Forgetting names of objects/places, misplacing items (e.g., losing house keys), repetition (asking the same question multiple times).
• Key distinction: episodic memory deficits are one of the best early indicators of AD compared to other dementias; reported even in pre-clinical stages.

As AD progresses:

• Other cognitive deficits: language disruption (aphasia), spatial orientation problems (e.g., judging distances), attention and executive function impairments.
• Procedural memory (habits and skills) remains relatively unaffected until late stages, when both short- and long-term memory are significantly impaired.

Behavioural and psychological symptoms (BPSD):

• Depression, anxiety, apathy, irritability, aggression, disinhibition, reduced curiosity.
• Can appear early or late and fluctuate throughout disease progression.
• Research suggests BPSD may contribute to cognitive decline as the disease progresses.

Other symptoms:

• Sleep-wake disturbances: increased daytime sleepiness, increased nighttime wakefulness, circadian shifts (waking/sleeping later).
• Circadian shifts in eating: tendency for biggest meal at breakfast, preference for sweet food, but also considerable weight loss leading to frailty.
• Over time, ability to perform everyday activities becomes increasingly impaired, leading to permanent dependence on caregivers.

🔬 Neuropathology of AD

Macroscopic features (visible on imaging/post-mortem):

• Cortical atrophy (thinning): enlarged sulcal spaces and atrophy of gyri, prominent in frontal and temporal cortices.
• Reduction in brain weight and ventricular enlargement.
• Hippocampal atrophy: crucial region for learning and memory shows atrophy due to neuronal loss.
• Caution: these features suggest AD but can sometimes appear in other dementias and even in clinically normal people.

Microscopic features (key hallmarks):

• Aβ plaques (senile plaques): insoluble aggregates of Aβ found in brain parenchyma.
  • In EOAD, genetic mutations affect amyloid precursor protein (APP) processing: normally cleaved by α-secretase then γ-secretase, but in EOAD cleaved by β- and γ-secretase → produces Aβ species prone to aggregation.
• Neurofibrillary tangles: composed of hyperphosphorylated tau inside neurons.
  • Normally, tau stabilises microtubules and facilitates axonal transport.
  • In AD, hyperphosphorylated tau forms tangles, disturbing microtubule structure → major neuronal dysfunction → neuronal cell death.
• Location: initially in temporal lobe structures (hippocampus, entorhinal cortex), spreading to other areas as disease progresses.
• Don't confuse: plaques and tangles also appear in normal ageing, but the density and location are distinct in AD.

Other pathological features:

• Synaptic loss: precedes neuronal loss and strongly correlates with cognitive decline.
• Inflammatory response: microglia and astrocyte activation around Aβ plaques, thought to contribute to disease pathogenesis.

🩺 Diagnosis of AD

No simple, reliable test exists. Diagnosis involves multiple assessments:

Cognitive testing:

• Mini Mental State Exam (MMSE): 30-point assessment introduced in 1975 by Marshal Folstein and colleagues.
  • Measures: short-term memory (e.g., memorising and recalling an address), attention and concentration (e.g., spelling a word backwards), language (naming objects), orientation to time and place (knowing where you are, day of the week), comprehension and motor skills (copying intersecting pentagons).
  • Scoring: 24 or higher = normal cognition; below 24 = mild (19–23), moderate (10–18), or severe (≤9) cognitive impairment.
  • Can indicate symptom severity and, if repeated, assess progression speed.
• Limitation: cognitive impairment appears in several dementia types (e.g., vascular dementia), so MMSE alone cannot confirm AD.

Brain imaging:

• Structural MRI: detects cerebral atrophy and ventricular enlargement.
• PET imaging: detects brain hypometabolism (decreased glucose consumption) and Aβ burden; more common in research than clinical diagnosis.
• Why imaging helps: distinguishes AD from other dementias (e.g., hippocampal atrophy suggests AD; frontal/temporal atrophy suggests frontotemporal dementia).

Other assessments:

• Medical history, blood tests (to rule out other conditions mimicking dementia, e.g., liver/kidney/thyroid dysfunction).
• Don't confuse: cognitive impairment onset indicates severe neurodegeneration has already occurred; earlier diagnosis is needed.

💊 Treatments for AD

No cure exists. Treatments are limited to symptomatic relief and non-pharmacological interventions.

Pharmacological treatments (UK-licensed):

Drug class	Examples	Mechanism	Use	Effects
Acetylcholinesterase (AChE) inhibitors	Donepezil (Aricept), rivastigmine (Exelon), galantamine (Reminyl)	Increase acetylcholine (ACh) levels in the brain by blocking AChE enzyme that breaks down ACh	Mild to moderate AD	Improve thinking, memory, communication, day-to-day activities; may slow symptom worsening
NMDA receptor antagonist	Memantine (Namenda)	Blocks NMDA receptor over-activity caused by excess glutamate, preventing neuronal cell death and calcium-dependent neurotoxicity	Severe AD, or moderate AD when AChE inhibitors cannot be used; often combined with AChE inhibitors	Reduces symptoms

• Why AChE inhibitors work: In AD, there is loss of cholinergic neurons (especially in hippocampus, cortex, amygdala) → reduced ACh. AChE inhibitors increase ACh levels.
• Common side effects: AChE inhibitors—diarrhoea, nausea/vomiting, trouble sleeping, muscle cramps, tiredness. Memantine—drowsiness, dizziness, constipation, headaches, shortness of breath.
• Limitation: these drugs only reduce symptom severity and may increase quality of life, but do not alter disease course or progression.

Other pharmacological options:

• Antipsychotics (risperidone, haloperidol) or antidepressants for BPSD symptoms (anxiety, depression).

Disease-modifying treatments:

• Not licensed in the UK as of the excerpt's writing.
• In 2021, US FDA approved aducanumab (Aduhelm), a monoclonal antibody designed to bind and eliminate aggregated Aβ, but uncertainties remain about its benefits.
• Effective interventions to halt or reverse neurodegeneration are still needed.

Non-pharmacological (psychological) approaches:

• Aim to improve cognitive abilities, emotional well-being, reduce behavioural symptoms, promote everyday functioning.
• Do not prevent or delay disease progression, but improve quality of life for patients and caregivers.

Examples:

• Cognitive training/stimulation: adapted from neurological rehabilitation (e.g., stroke, traumatic brain injury). Strategies include memory training, problem-solving (games, puzzles), mnemonic devices, external memory aids (notebooks, calendars).
• Reminiscence therapy: discussing past events/experiences to stimulate memories and mental activity, improve well-being. Supported by photos, music, objects; may involve individual or group discussion.
• Music/art therapy: improves mood, alertness, engagement. Triggers memories, stimulates communication, builds confidence. Allows self-expression; shown to reduce agitation and distressing behaviour.

🩸 Vascular dementia

🩸 What vascular dementia is

Vascular dementia: the second most common cause of dementia after AD, occurring as a consequence of reduced blood flow to the brain.

• Brain cells require constant oxygen and nutrients delivered via the brain's vascular network.
• Any interruption or reduction in blood flow (e.g., from stroke) → impaired brain cell function, cell death, disruption of cognitive and motor processes.

🩸 Symptoms and onset

• Symptoms vary considerably between individuals, depending on location of damage.
• May develop suddenly (e.g., following a stroke) or gradually (e.g., with small vessel disease).
• Key distinction from AD: memory loss is typical of early AD, but is not usually the main early symptom of vascular dementia.
• Most common early symptoms: problems with planning/organising, decision-making, slower cognitive processing speed, inattention, short periods of confusion.

🩸 Three main types

Type	Cause	Key features
Subcortical vascular dementia	Small vessel disease: very small arteries in subcortical regions thicken → vessel lumen narrows → reduced blood flow → brain damage (infarcts)	Most common type; subcortical structures process complex activities (memory, emotions). Distinguished from AD by more extensive white matter infarcts and less severe hippocampal atrophy.
Multi-infarct dementia	Series of mini-strokes (transient ischemic attacks) → temporary reduction in blood flow → generation of infarcts. Cumulative damage over time → dementia symptoms.	Temporary symptoms at time of mini-stroke; infarcts accumulate.
Post-stroke dementia	About 20% of individuals who experience an ischaemic stroke develop dementia within 6 months. Ischaemic stroke caused by clot in blood vessel → reduced blood flow → tissue loss and brain dysfunction.	Risk factors: hypertension, high cholesterol (same factors that increase cardiovascular disease and stroke risk also increase cognitive decline risk post-stroke).

• Example: An individual experiences a series of mini-strokes over several years. Each causes temporary symptoms, but infarcts accumulate. Eventually, the cumulative damage is sufficient to produce dementia symptoms.

🧪 Dementia with Lewy bodies (DLB)

🧪 What DLB is

Dementia with Lewy bodies (DLB): a progressive disease associated with abnormal deposits of alpha-synuclein protein in neuronal and non-neuronal cells within the brain, forming Lewy bodies.

• Lewy bodies: named after FH Lewy, the German doctor who first identified them.
• Affect neurotransmitter functioning, particularly acetylcholine (ACh) and dopamine → disrupts cognitive functioning, movement, behaviour, mood.

🧪 Symptoms and diagnosis challenges

• DLB causes symptoms shared with both AD and Parkinson's disease → commonly misdiagnosed.
• Symptoms more commonly associated with DLB (vs other dementias): sleep disturbances, visual hallucinations, motor symptoms.
• Don't confuse: DLB shares some symptoms with AD and Parkinson's, but the combination of visual hallucinations, sleep disturbances, and motor symptoms is more characteristic of DLB.

🧪 Risk factors and genetics

• Having a family member with DLB may increase risk, but DLB is not considered a genetic disease.
• Variants in three genes associated with increased risk: APOE, synuclein alpha (SNCA), glucocerebrosidase (GBA).
• For the majority of DLB cases, the cause is unknown.

🧪 Other dementias

🧪 Mixed dementia

• Diagnosed when a person has more than one underlying cause of dementia.
• Most common combination: AD and vascular dementia; other combinations possible (e.g., AD and DLB).
• More common in older age groups (over 75 years).
• Accounts for 10% of all dementia diagnoses.

🧪 Frontotemporal dementia (FTD)

Frontotemporal dementia (FTD): a rare form of dementia (also called Pick's disease or frontal lobe dementia) caused by selective degeneration within the frontal and temporal lobes.

• Age of onset: typically younger than other dementias; 60% of cases occur in people aged 45–64.
• Early symptoms: changes to personality and behaviour, and/or aphasia (difficulty with language or speech, usually caused by damage to left temporal lobe).
• Key distinction from AD: patients with FTD tend to have good memory performance in early stages, although memory worsens progressively as disease advances.

🩺 Testing for dementia (general approach)

No single test exists. Doctors use information from multiple approaches to determine if dementia is present and identify the underlying cause. Understanding the cause informs treatment and predicts disease progression.

Approaches:

Method	Purpose	Examples
Medical history	Assess how symptoms affect daily life; ensure other medical conditions (e.g., hypertension) are treated appropriately	Interview patient and family
Cognitive ability tests	Assess memory, attention, problem-solving, awareness of time and place	Neuropsychological tests (e.g., MMSE)
Blood tests	Rule out other conditions mimicking dementia symptoms	Check liver, kidney, thyroid function
Brain scans	Detect signs of brain damage; help identify underlying cause	MRI (detailed info on blood vessel damage → vascular dementia; atrophy patterns → hippocampal atrophy suggests AD; frontal/temporal atrophy suggests FTD). CT scan (rule out brain tumour). PET scan (used more in research to identify markers like glucose, evaluate disease progression/new therapeutics).

• Note: the majority of individuals will not receive a brain scan if other tests and assessments show dementia is a likely diagnosis.

🔑 Risk factors for dementia

🔑 Age and other risk factors

• Age is the strongest known risk factor, but dementia does not occur as an inevitable consequence of biological ageing.
• Young-onset dementia: onset before age 65, accounts for up to 9% of all dementia cases.

Modifiable risk factors:

• Smoking
• Excessive alcohol use
• Low levels of physical activity
• High cholesterol
• Atherosclerosis
• Social isolation
• Obesity
• Mild cognitive impairment (MCI)

Non-modifiable risk factors:

• Genetic factors (e.g., APOE4 for AD; SNCA, GBA for DLB)

• Key point: dementia likely develops from a combination of various risk factors—some modifiable, some not.

• Example: An individual with high cholesterol, low physical activity, and a family history of AD has multiple risk factors interacting to increase dementia risk.

🧭 Overview

🧠 One-sentence thesis

Placebo effects are real, measurable responses produced by inert treatments through psychological mechanisms (expectation, conditioning, decision-making) and biological pathways (opioid, dopamine, cannabinoid systems), with therapeutic potential and critical importance in clinical trial design.

📌 Key points (3–5)

• What a placebo is: an inert substance (sugar pill, saline injection, sham procedure) that produces measurable physiological and psychological effects due to the context of administration and patient expectation.
• Psychological mechanisms: expectancy theory (positive expectations reduce anxiety and change behavior), classical conditioning (pairing situational cues with active drugs), and decision-making errors (liberal criterion leading to false positives).
• Biological basis: placebo effects activate endogenous opioids, dopamine, and cannabinoids in brain regions like the anterior cingulate cortex and nucleus accumbens; genetics influence placebo responsiveness.
• Common confusion: placebo effect vs. natural symptom fluctuation—clinical trials must distinguish genuine placebo responses from spontaneous remission or disease course changes.
• Clinical importance: placebos are essential controls in randomized controlled trials (RCTs) to eliminate expectation bias; ethical considerations include responder identification and nocebo (negative expectation) effects.

🧠 Psychological mechanisms

🎯 Expectancy theory

The placebo produces an effect because the patient expects it to produce such effect.

• How expectations form: shaped by therapeutic relationship, professional authority, branding, cost, and even pill color.
  • Brand-name placebos reduce headache more effectively than generic-labeled placebos (Faase et al., 2016).
  • Red/orange pills are associated with stimulant effects; blue/green with sedative effects (de Craen et al., 1996).
• How expectations work:
  • Reduce anxiety: stress and anxiety worsen symptoms; placebos lower anxiety, easing symptomatology.
  • Change cognitions: expectation of improvement promotes a sense of control, helps patients disregard negative thoughts, and interpret ambiguous stimuli more favorably.
  • Change behavior: expecting improvement leads patients to resume daily routines, improving mood and distracting from symptoms.
• Example: A patient given a placebo for pain expects relief → reduced anxiety → less focus on pain → actual pain experience decreases.

🎲 Decision-making and Signal Detection Theory

• The patient's decision problem: after treatment (active or placebo), the patient must decide whether symptoms improved—a binary choice in an ambiguous, noisy environment (symptom intensity fluctuates naturally).
• Signal Detection Theory (SDT) framework:

Patient's decision	Active agent given	Placebo given
Alleviation experienced	Correct Positive	False Positive (placebo effect)
No effect experienced	False Rejection	Correct Rejection

• Liberal vs. conservative criterion:
  • Liberal criterion: any change is interpreted as improvement → higher chance of false positive (placebo effect).
  • Conservative criterion: only clear improvement counts → higher chance of false rejection.
• Why patients adopt a liberal criterion: avoiding a false rejection (claiming an accepted treatment doesn't work) would challenge medical authority and embarrass the physician; patients prefer the "mistake" that pleases the doctor and aligns with established science.
• Don't confuse: this is not lying or wishful thinking—it's a genuine perceptual/decision bias in ambiguous situations.

🔔 Classical conditioning

Repeated pairing of situational cues (context, administration method, health worker) with an active drug allows the cues alone to elicit a conditioned therapeutic response, even without the active agent.

• How it works:
  • Unconditional stimulus (US): active drug (e.g., morphine).
  • Unconditional response (UR): therapeutic effect (e.g., pain relief).
  • Conditional stimulus (CS): situational cues (syringe, injection setting).
  • Conditional response (CR): therapeutic effect triggered by cues alone (placebo effect).
• Historical evidence: Pavlov (1927) described dogs injected with morphine (causes nausea, salivation, vomiting, sleep); after 5–6 injections, the injection preliminaries alone produced all these symptoms.
• Clinical applications:
  • Immunosuppression: Giang et al. (1996) paired anise-flavored syrup with cyclophosphamide (immunosuppressant for multiple sclerosis); later, syrup + small ineffective dose produced conditioned immunosuppression in 8/10 patients → allows dose reduction, minimizing side effects.
  • Pain treatment: Guo et al. (2010) trained mice with morphine or aspirin before hotplate test; saline injection alone later delayed paw withdrawal (conditioned analgesia). Naloxone (opioid antagonist) blocked the effect in morphine-trained mice but not aspirin-trained mice → shows opioid-mediated conditioning.
• Caution: conditioning can also produce conditioned hyperalgesia (opposite of desired effect) under some parameters; the mechanisms are complex and not fully understood.
• Don't confuse: conditioning is automatic and unconscious, whereas expectancy involves conscious cognition.

🧬 Biological mechanisms

💊 Opioid pathways

• Key evidence: placebo analgesia is abolished by naloxone (opioid antagonist) under some conditions → endogenous opioids mediate the effect.
• Brain regions involved:
  • Opioid and dopamine activation in nucleus accumbens (reward/expectation).
  • Reduced activation in pain neuromatrix regions: anterior cingulate cortex, insula.
  • High placebo responders show greater activation of brain regions with opioid receptors.
• Beyond pain: opioid-mediated placebo effects include conditioned respiratory depression, decreased heart rate, and reduced β-adrenergic activity (all reversed by naloxone).
• Mechanism of pain relief: opioids induce relaxation; placebos may reduce negative emotions (fear, anxiety) associated with pain rather than the pain sensation itself (e.g., placebo decreases cingulate cortex activation but not somatosensory cortex).
• Example: Functional brain imaging shows opioids and placebos activate the same brain regions and both reduce pain-region activity (Wager et al., 2004).

🧪 Non-opioid pathways

• Dopamine system:
  • Placebo administration increases dopamine release and uptake; dopamine receptors activate in anticipation of benefit.
  • Suggests dopamine underlies the expectation of reward (Scott et al., 2008).
  • Genetics: patients with reduced dopamine metabolism (higher brain dopamine) are more likely to experience strong placebo effects.
• Endocannabinoid system:
  • Non-opioid placebo effects can be blocked by CB1 cannabinoid receptor antagonist (Benedetti et al., 2011).
• Genetics:
  • Patients with less active opioid receptors are less likely to be placebo responders.
  • Genetic variation influences placebo effect strength (Hall et al., 2015).
• Hormonal responses: placebo treatments affect hormones via forebrain control of the hypothalamus-pituitary-hormone system.

🧠 Condition-specific mechanisms

• Parkinson's disease: placebo induces dopamine release in the striatum; changes in basal ganglia and thalamic neuron firing.
• Depression:
  • In clinical trials, ~50% of reported benefit is due to placebo effect, 25% to active medication, 25% to other factors (spontaneous remission).
  • Higher opioid receptor activity in anterior cingulate cortex, nucleus accumbens, and amygdala (emotion/stress regulation areas) predicts better placebo response (Zubieta et al., 2005).
  • The endogenous opioid system, dysregulated in depression, mediates placebo effects.
• Don't confuse: placebo mechanisms in conditions other than pain are less well understood; most neurobiological evidence comes from pain/analgesia research.

🏥 Clinical trial design and ethics

🧪 Role of placebos in trials

Placebos are essential controls to eliminate the influence of patient expectation and psychosocial context, ensuring that observed effects are due to the active treatment.

• Randomized Controlled Trials (RCTs):
  • Patients randomly allocated to active treatment or placebo groups.
  • Double-blind: neither patient nor medical staff knows group assignment; treatments and placebos look identical and are coded.
  • Purpose: control for both patient and experimenter expectancies.
• Three phases of clinical trials:
  • Phase I: healthy volunteers; assess human physiological/biochemical reactions and safety.
  • Phase II: patients with the target disorder; determine effectiveness.
  • Phase III: larger patient numbers, multiple sites/countries; less controlled but broader.
• Block design: due to ethical considerations, most trials use alternating blocks of active treatment and placebo so all patients have equal chance of receiving benefit if the treatment proves effective.
• Challenge: as trials progress, placebo group responses may reflect natural disease course or symptom fluctuations, making it harder to discern genuine placebo responses.

⚖️ Ethical considerations

• Responder vs. non-responder characterization:
  • Some individuals consistently respond to placebos; others do not.
  • Ethical question: should responders be targeted with placebo treatments (positive response) or excluded from trials (to avoid compromising results)?
• Deception: the assumption is that patients must be deceived about whether they receive active treatment or placebo to truly examine biological effects and exclude psychosocial context influence.
• Access to effective treatment: if a new treatment is found effective during a trial, it would be unethical to deny participants access → block designs ensure fairness.

⚠️ Nocebo effect

Negative expectations of a treatment decrease therapeutic effect or increase side effects—the opposite of placebo.

• Biological basis:
  • Cholecystokinin (CCK) peptide induces anticipatory anxiety, playing a role in nocebo hyperalgesia; blocking CCK reduces nocebo effects (Benedetti et al., 1995).
  • Deactivation of dopamine in nucleus accumbens during nocebo hyperalgesia.
  • Brain imaging: activation of hippocampus and regions involved in anticipatory anxiety (different from placebo-activated regions).
• Example: A patient told a treatment may cause pain experiences increased pain even with an inert substance.
• Don't confuse: nocebo is not simply "no placebo effect"—it is an active worsening due to negative expectation.

🩺 Clinical applications and examples

💉 Pain management

• Why pain is a good model: pain is highly complex, individual, and influenced by behavioral, chemical, hormonal, and neuronal responses; chronic pain substantially impacts quality of life.
• Placebo as pain reliever: placebo effects have been reported to act as analgesics in certain patient groups, offering a viable therapeutic option (Miller & Colloca, 2009).
• Conditioning approach: pairing opioid administration with situational cues allows dose reduction while maintaining therapeutic effect, avoiding tolerance, addiction, and opioid-induced hyperalgesia (OIH).
• Example: Mice trained with morphine + hotplate showed conditioned analgesia when given saline alone (Guo et al., 2010); naloxone blocked the effect, confirming opioid involvement.
• Don't confuse: conditioned analgesia (therapeutic) vs. conditioned hyperalgesia (worsening pain)—parameters that promote one vs. the other are not fully understood.

🧠 Depression treatment

• Placebo prevalence: in major depression trials, approximately 50% of patient-reported benefit is due to placebo effect.
• Mechanism: endogenous opioid system (dysregulated in depression) mediates placebo effects; higher opioid receptor activity in emotion/stress regulation areas predicts better placebo response.
• Challenge: many trials fail to show significant benefit of novel treatments over placebo, which may reflect positive placebo benefits rather than ineffective treatments.

🧬 Autoimmune diseases

• Cyclophosphamide conditioning: Giang et al. (1996) paired anise syrup with cyclophosphamide (immunosuppressant for multiple sclerosis); 8/10 patients showed conditioned immunosuppression with syrup + small dose.
• Benefit: reduces serious side effects (infection risk, cardiovascular disease, bone marrow depletion) by lowering drug dose while maintaining therapeutic effect.

🔬 Key distinctions and confusions

🔄 Placebo effect vs. natural course

• Confusion: observed improvement in placebo group may be due to:
  • Genuine placebo response (psychological/biological mechanisms).
  • Spontaneous remission of symptoms.
  • Natural fluctuations in disease course.
• How to distinguish: clinical trial design must account for these factors; block designs and careful monitoring help separate genuine placebo responses from other causes.

🧠 Expectancy vs. conditioning

Mechanism	Nature	Example	Key feature
Expectancy	Conscious cognition	Patient told treatment will relieve pain → experiences relief	Requires awareness and belief
Conditioning	Automatic learning	Repeated morphine injections in same context → context alone produces relief	Unconscious, associative

• Interaction: both mechanisms can shape different instances of the placebo effect and can interact to determine the outcome (Stewart-Williams & Podd, 2004).
• Don't confuse: conditioning cannot fully explain all placebo effects (e.g., verbal suggestion alone can produce effects without prior pairing).

🧬 Opioid vs. non-opioid mediated

• Opioid-mediated: blocked by naloxone; involves endogenous opioid release; seen in pain, respiratory depression, heart rate changes.
• Non-opioid-mediated: blocked by CB1 cannabinoid antagonist; involves dopamine, endocannabinoids; seen in some pain contexts and other conditions.
• Don't confuse: the same placebo intervention (e.g., saline injection) can activate different pathways depending on the conditioning history (morphine vs. aspirin training in mice).

🎯 Placebo vs. nocebo

Effect	Expectation	Outcome	Biological marker
Placebo	Positive (benefit expected)	Symptom relief, therapeutic effect	Opioid/dopamine activation
Nocebo	Negative (harm expected)	Increased symptoms, side effects	CCK activation, dopamine deactivation

• Both are real, measurable, and mediated by distinct biological pathways.
• Example: Same inert pill can relieve pain (if patient expects benefit) or worsen pain (if patient expects harm).