Textbook

A Brief History of Cognitive Neuroscience

• Historical Perspective & Terminology

  • Cognitive Neuroscience: Coined in the late 1970s in the back of a New York City taxi by Michael S. Gazzaniga and cognitive psychologist George A. Miller while traveling to a dinner meeting at the Algonquin Hotel for scientists from Rockefeller University and Cornell University.

  • It synthesizes cognition (the process of knowing, derived from awareness, perception, and reasoning) and neuroscience (the study of how the nervous system is organized and functions).

  • Evolutionary Context:

  • Earth formed approximately $4.5 \times 10^9\,\text{years}$ ago; life appeared around $3.8 \times 10^9\,\text{years}$ ago.

  • Primate brains emerged between $34 \times 10^6$ and $23 \times 10^6\,\text{years}$ ago during the Oligocene epoch.

  • Great ape brains developed during the Miocene epoch ($23 \times 10^6$ to $7 \times 10^6\,\text{years}$ ago).

  • Human lineage diverged from the common chimpanzee ancestor approximately $5 \times 10^6$ to $7 \times 10^6\,\text{years}$ ago.

  • Modern Homo sapiens brains in their present anatomical form have existed for roughly $100,000\,\text{years}$.

  • Pre-Socratic Thought: Thales rejected supernatural explanations, asserting that all events have natural causes.

• The Brain Story: Localizationism vs. Aggregate Field Theory

  • Anne Green (1650): Hanged for alleged infanticide in Oxford; resurrected on the dissection table of Thomas Willis and William Petty; pardoned by arguing divine intervention. Her case provided funding and prominence for Thomas Willis.

  • Thomas Willis (1621–1675): Coined the term neurology. First anatomist to link specific structural brain damage to distinct behavioral deficits and conceptualized neuronal conduction. Collaborated with architect Christopher Wren to illustrate the brain.

• Anatomical Terms Coined by Thomas Willis:

  • Anterior commissure: Axonal fibers connecting the middle and inferior temporal gyri between hemispheres.

  • Cerebellar peduncles: Axonal tracts connecting the cerebellum and brainstem.

  • Claustrum: Thin sheath of gray matter between the external capsule and putamen.

  • Corpus striatum: Basal ganglia structure comprising the caudate nucleus and lenticular nucleus.

  • Inferior olives: Brainstem structure modulating cerebellar processing.

  • Internal capsule: White matter pathways conveying information from the thalamus to the cortex.

  • Medullary pyramids: Medulla structure consisting of corticospinal fibers.

  • Neurology: The study of the nervous system and its disorders.

  • Optic thalamus: Thalamic region relating to visual processing.

  • Spinal accessory nerve: The 11th cranial nerve innervating head and shoulders.

  • Stria terminalis: White matter pathway sending projections from the amygdala to the basal forebrain.

  • Striatum: Gray matter structure of the basal ganglia.

  • Vagus nerve: The 10th cranial nerve providing visceral motor control to the heart and other organs.

• Phrenology (Anatomical Personology): Promoted by Franz Joseph Gall and Johann Spurzheim. Postulated that the brain is organized into 35 or more discrete functions; localized overuse of a faculty leads to physical brain growth, causing visible bumps on the skull.

• Aggregate Field Theory: Advanced by Marie-Jean-Pierre Flourens (1824). Experimental lesions in pigeons and rabbits led him to conclude that the entire cerebral hemisphere participates in perception, volition, and cognition as a holistic unit.

• Resurgence of Localizationism:

  • Marc Dax (1836): Presented 3 clinical cases linking speech loss to left-hemisphere lesions.

  • John Hughlings Jackson: Documented epileptic seizure progression ("Jacksonian march"), deducing a topographic cortical map of the body. Noted right-hemisphere involvement in visuospatial processing and observed that functions are rarely lost completely.

  • Paul Broca (1861): Autopsied patient Leborgne ("Tan"), discovering a lesion in the left inferior frontal gyrus (Broca's area) causing expressive aphasia.

  • Carl Wernicke (1876): Reported a patient with fluent but nonsensical speech and comprehension deficits caused by a lesion in the left posterior superior temporal/parietal junction (Wernicke's area).

- *Gustav Fritsch & Eduard Hitzig (1870)*: Electrically stimulated dog cerebral cortex to produce specific, characteristic motor movements.

• Cytoarchitectonics and the Neuron Doctrine

  • Korbinian Brodmann (1909): Divided the cerebral cortex into 52 distinct regions based on cell structure and organization (cytoarchitectonics) using Nissl tissue stains.

• Camillo Golgi: Developed la reazione nera (the black reaction), a silver chromate stain that visualizes complete individual neurons. Adhered to the syncytium theory (that the brain is a continuous mass of tissue sharing cytoplasm).

• Santiago Ramón y Cajal: "Father of modern neuroscience." Utilized Golgi's stain to establish the Neuron Doctrine—the concept that the nervous system is composed of discrete individual cells. Discovered that electrical signal transmission travels unidirectionally from dendrites down to the axon tip. Shared the 1906 Nobel Prize in Physiology or Medicine with Golgi.

• Jan Evangelista Purkinje (1837): Described the first nerve cell in the nervous system (Purkinje cell of the cerebellum); invented the stroboscope.

• Hermann von Helmholtz: Measured the velocity of nerve conduction, proving electrical currents are the active transmission medium rather than a metabolic byproduct.

• Sir Charles Sherrington: Coined the term synapse to describe the junction between neurons (1932 Nobel Prize).

• Claude Bernard (1865): Emphasized that isolated anatomical parts must be understood in the context of the whole organism.

  • The Psychological Story: Rationalism, Empiricism, and Associationism

• Franciscus Donders (1869): Introduced reaction time differences to infer the duration of mental processing steps.

• Rationalism: Position that all knowledge is gained through reason alone (Descartes, Spinoza, Leibniz).

• Empiricism: Position that knowledge originates from sensory experience; the mind begins as a tabula rasa (blank slate) (Hobbes, Locke, Hume, Mill).

• Associationism: Theory that complex mental ideas arise from associations among simple sensory experiences.

  • Hermann Ebbinghaus: Applied psychophysical measurement methods (Weber and Fechner) to measure memory and forgetting.

  • Edward L. Thorndike (1911): Formulated the Law of Effect in Animal Intelligence; actions followed by rewards are reinforced.

  • John B. Watson: Founded behaviorism; insisted psychology must focus strictly on publicly observable behavior and rejected internal mental representations.

• The Cognitive Revolution:

  • Wilder Penfield & Herbert Jasper: Developed the Montreal procedure for surgical epilepsy treatment via electrical stimulation mapping awake patients.

  • Donald O. Hebb (1949): Published The Organization of Behavior; proposed that learning has a neural basis via cell assemblies ("cells that fire together, wire together").

  • Brenda Milner: Documented multiple memory systems through long-term testing of Penfield's surgical patients (including patient H.M.).

  • George A. Miller: Rejected behaviorism on September 11, 1956, during the Second Symposium on Information Theory at MIT. Published "The Magical Number Seven, Plus-or-Minus Two" (1956) and Psychology, the Science of Mental Life (1962).

  • Noam Chomsky (1956): Published Three Models for the Description of Language; proved that language acquisition cannot be explained by behaviorist associationism/Skinnerian conditioning, but relies on innate, universal grammatical rules.

  • Patricia Goldman-Rakic (1987): Mapped the neural circuitry of the prefrontal cortex and its relationship to working memory and dopamine modulation.

  • Development of Neuroimaging Instruments

• Electroencephalography (EEG): Richard Caton (1875) measured cortical currents in dogs/apes using a galvanometer; Willem Einthoven invented the string galvanometer; Hans Berger (1929) published the first human electroencephalogram.

• Cerebral Blood Flow: Angelo Mosso recorded brain pulsations over skull defects during mental arithmetic; John Fulton (1928) reported patient Walter K. experiencing visual cortex bruits during visual effort; Seymour Kety (1940s–1950s) developed the nitrous oxide technique to measure global and regional cerebral blood flow.

• Computed Tomography (CT/CAT): Alessandro Vallebona developed tomographic radiography (1930s); William Oldendorf (1961) described the theoretical concept; Godfrey Hounsfield developed the first clinical CT scanner in 1972 at EMI, Ltd. (funded by Beatles record sales).

• Positron Emission Tomography (PET): Irène Joliot-Curie & Frédéric Joliot-Curie (1934) discovered artificial radioactivity; Ernest O. Lawrence invented the cyclotron; Gordon Brownell & William Sweet (1953) built a sodium iodide detector scanner; David E. Kuhl & Roy Edwards (1959) created emission tomography; Michel Ter-Pogossian & William Powers (1958) used $^{15}\text{O}$-labeled water; Ter-Pogossian & Michael Phelps (1975) built the PETT scanner; Joanna Fowler & Al Wolf (1978) synthesized $^{18}\text{F}\text{-2-fluorodeoxy-D-glucose (2FDG)}$.

• Magnetic Resonance Imaging (MRI): Isidor Rabi (1938) discovered nuclear magnetic resonance (NMR); Felix Bloch & Edward Purcell (1946) extended NMR to liquids/solids; Paul Lauterbur (1973) created the first spatial MRI scanner at SUNY Stony Brook; Belliveau et al. (1990) introduced contrast-enhanced functional MRI.

• Functional MRI (fMRI): Linus Pauling & Charles Coryell (1936) discovered that oxygenated and deoxygenated hemoglobin differ in magnetic susceptibility; Keith Thulborn (1982) demonstrated in vivo oxygenation measurement; Seiji Ogawa (1990) developed Blood Oxygen Level-Dependent (BOLD) contrast at AT&T Bell Labs; Peter Fox & Marc Raichle (1986, 1988) discovered the uncoupling of blood flow and oxygen consumption during neural activity.

Structure and Function of the Nervous System

• Structure of Neurons

  • The nervous system contains two main cell classes: Neurons (primary signaling units) and Glial cells (non-neural support cells).

• Neuron Anatomy:

  • Soma (Cell Body): Contains metabolic machinery (nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, ribosomes) suspended in cytoplasm.

  • Dendrites: Branching extensions that receive inputs from other cells. Frequently feature dendritic spines (small knobs along the dendritic tree) to receive synaptic inputs.

  • Axon: Single output process extending from the cell body at the axon hillock. May branch into axon collaterals and terminates at the axon terminals.

  • Myelin: Fatty insulating sheath formed by glial cells, interrupted at regular intervals by nodes of Ranvier.

• Synapse: Specialized structure where presynaptic and postsynaptic cells come into close contact for signal transfer.

  • Neuronal Signaling and Membrane Dynamics

• Resting Membrane Potential:

  • Voltage difference across the neuronal membrane at rest, typically $-70\,\text{mV}$ (inside negative relative to outside).

  • Dependent on asymmetric distribution of ions across the lipid bilayer:

    • Intracellular: High concentration of Potassium ($K^+$) and large impermable proteins ($A^-$).

    • Extracellular: High concentration of Sodium ($Na^+$) and Chloride ($Cl^-$).

• Ion Channels and Pumps:

  • Nongated (Passive) Channels: Unregulated channels continuously open to specific ions (membrane is significantly more permeable to $K^+$ than $Na^+$ due to an abundance of passive $K^+$ channels).

  • Gated Ion Channels: Open or close in response to voltage, chemical (ligand), or physical stimuli.

  • $Na^+/K^+$ ATPase Pump: Active transport enzyme that hydrolyzes 1 ATP molecule to export $3\,Na^+$ ions out of the cell and import $2\,K^+$ ions into the cell, preserving the concentration gradient.

  • Electrochemical Equilibrium: Occurs when the outward force of the $K^+$ concentration gradient equals the inward force of the electrical gradient.

• Electrotonic (Decremental) Conduction: Passive current flow through the cytoplasm. Decays exponentially with distance; effective only over maximum distances of roughly $1\,\text{mm}$.

• Action Potential Generation:

  • Regenerative, non-decremental all-or-none electrical impulse initiated at the spike-triggering zone in the axon hillock.

  • Threshold potential: Approximately $-55\,\text{mV}$.

• Step-by-Step Action Potential Phases:

  1. Depolarization reaches threshold ($-55\,\text{mV}$).

  2. Hodgkin-Huxley Cycle: Voltage-gated $Na^+$ channels open, leading to rapid $Na^+$ influx and membrane depolarization toward $+40\,\text{mV}$.

  3. Voltage-gated $Na^+$ channels close (inactivate); voltage-gated $K^+$ channels open, causing $K^+$ efflux and initiating repolarization.

  4. Undershoot (Hyperpolarization): Continued $K^+$ efflux drives the membrane potential closer to the $K^+$ equilibrium potential ($\approx -80\,\text{mV}$).

  5. Voltage-gated $K^+$ channels close, and passive channels and $Na^+/K^+$ pumps restore resting potential ($-70\,\text{mV}$).

• Refractory Periods:

  • Absolute Refractory Period: Voltage-gated $Na^+$ channels are inactivated; another action potential cannot fire regardless of stimulus strength. Limits maximum firing rate to $\approx 200\,\text{spikes/sec}$.

  • Relative Refractory Period: Membrane is hyperpolarized; an action potential can fire, but requires a larger-than-normal depolarizing current.

• Saltatory Conduction: Rapid propagation of action potentials in myelinated axons, jumping from one node of Ranvier to the next.

  • Synaptic Transmission

• Chemical Transmission:

1. Action potential arrives at the presynaptic terminal, depolarizing the membrane.
2. Voltage-gated Calcium ($Ca^{2+}$) channels open; $Ca^{2+}$ flows into the presynaptic terminal.
3. $Ca^{2+}$ influx triggers synaptic vesicles to undergo exocytosis, fusing with the presynaptic membrane and releasing neurotransmitters into the **synaptic cleft**.
4. Neurotransmitters diffuse across the cleft and bind to specific postsynaptic receptors.
5. Binding opens ion channels, producing an **Excitatory Postsynaptic Potential (EPSP)** via depolarization or an **Inhibitory Postsynaptic Potential (IPSP)** via hyperpolarization.

• Biochemical Classes of Neurotransmitters:

  • Amino Acids: Aspartate, Gamma-Aminobutyric Acid (GABA—primary inhibitor), Glutamate (primary excitor), Glycine.

  • Biogenic Amines: Acetylcholine (ACh); Catecholamines (Dopamine, Norepinephrine, Epinephrine); Serotonin ($5\text{-HT}$); Histamine.

  • Neuropeptides: Tachykinins (Substance P); Neurohypophyseal hormones (Oxytocin, Vasopressin); Hypothalamic releasing hormones (CRH, Somatostatin); Opioid peptides (Endorphins, Enkephalins).

• Inactivation Mechanisms: Active reuptake via presynaptic transmembrane transporters; enzymatic degradation (e.g., Acetylcholinesterase/AChE breaking down ACh); passive diffusion away from the cleft. Presynaptic autoreceptors monitor transmitter concentration.

• Electrical Transmission: Neurons touch at gap junctions containing continuous cytoplasm pores. Transmission is direct, instantaneous, non-amplified, and usually bidirectional (except in rectifying synapses).

  • Types and Roles of Glial Cells

• Astrocytes: Large, radial central nervous system (CNS) glia with end-feet enveloping capillaries. Form the Blood-Brain Barrier (BBB), controlling passage of substances from blood to neural tissue; actively modulate neuronal activity, synaptic strength, and transmitter reuptake.

• Microglia: Small, phagocytic CNS glia that devour cellular debris following injury or disease.

• Myelin-Forming Glia:

  • Oligodendrocytes: Form myelin sheaths around multiple axons in the CNS.

  • Schwann cells: Form myelin sheaths around single axon segments in the Peripheral Nervous System (PNS).

  • Gross Anatomy of the Nervous System

• Peripheral Nervous System (PNS):

  • Somatic Motor System: Voluntary muscular control.

  • Autonomic Nervous System (ANS): Involuntary control of smooth muscles, heart, and glands. Divided into:

    • Sympathetic Branch: Uses norepinephrine; mediates "fight-or-flight" (increases heart rate, dilates bronchi, diverts blood to skeletal muscles).

    • Parasympathetic Branch: Uses acetylcholine; mediates "rest-and-digest" (slows heart rate, stimulates digestion, constricts pupils).

• Central Nervous System (CNS): Brain and spinal cord. Protected by bones and three meninges: dura mater (outer thick layer), arachnoid mater (middle spiderweb-like layer), and pia mater (delicate inner layer adhering directly to brain surface). Cerebrospinal fluid (CSF) fills the subarachnoid space and the 4 brain ventricles (produced by choroid plexus).

• Spinal Cord: 31 segments (cervical, thoracic, lumbar, sacral). Inner butterfly-shaped gray matter contains dorsal horn (sensory interneurons) and ventral horn (motor neurons). Outer white matter contains ascending sensory and descending motor columns. Sensory axons enter via dorsal roots (cell bodies in dorsal-root ganglion); motor axons exit via ventral roots.

• Brainstem Structures:

  • Medulla (Myelencephalon): Houses motor/sensory nuclei for cranial nerves IX–XII; controls respiration, heart rate, and blood pressure. Corticospinal fibers cross in the pyramidal decussation.

  • Pons (Metencephalon): Bridge between brainstem and cerebellum. Contains nuclei for cranial nerves V–VIII. Houses the superior olive and reticular formation; generates REM sleep.

  • Cerebellum (Metencephalon): Houses over 69 billion of the brain's 86 billion neurons. Features Purkinje cells and 4 deep nuclei (dentate, fastigial, interposed). Coordinates motor output, balance, posture, and participates in language, timing, and attention.

  • Midbrain (Mesencephalon): Contains the tectum (superior colliculus [visuomotor/orienting] and inferior colliculus [auditory localization]), tegmentum, red nucleus, and mesencephalic reticular formation.

• Diencephalon:

  • Thalamus: Relay station for all sensory modalities (except olfaction) en route to cortex. Includes Lateral Geniculate Nucleus (LGN—vision), Medial Geniculate Nucleus (MGN—audition), Ventral Posterior Nucleus (VPN—somatosensation), and Pulvinar Nucleus (attention).

  • Hypothalamus: Controls autonomic functions and endocrine system to maintain homeostasis. Regulates circadian rhythms via suprachiasmatic nucleus. Controls anterior pituitary via median eminence releasing factors, and posterior pituitary via vasopressin/oxytocin release from supraoptic and paraventricular nuclei.

• Telencephalon:

  • Limbic System: Cingulate gyrus, hypothalamus, anterior thalamic nuclei, hippocampus, amygdala, and orbitofrontal cortex. Regulates emotion, learning, and memory.

  • Basal Ganglia: Caudate nucleus, putamen (together forming the striatum), globus pallidus, subthalamic nucleus, and substantia nigra. Involved in motor control, action selection, gating, and dopamine-mediated reward learning.

  • Cerebral Cortex: Outermost sheet of folded tissue ($1.5$ to $4.5\,\text{mm}$ thick, average $3\,\text{mm}$). Total surface area $2,200$ to $2,400\,\text{cm}^2$ ($2/3$ buried in sulci).

    • Neocortex: 6-layered cortex ($90\%$ of cortex).

    • Mesocortex: 6-layered paralimbic cortex (cingulate, parahippocampal, insula, orbitofrontal).

    • Allocortex: 1- to 4-layered cortex (hippocampus/archicortex, primary olfactory cortex/paleocortex).

• Cortical Lamination & Columns: Layer IV is the primary input layer (receives thalamic projections); Layer V/VI are output layers projecting to subcortical and spinal targets. Neurons form perpendicular functional minicolumns.

• Brain Cell Quantifications (Herculano-Houzel, 2009): Human brain contains $\approx 86 \times 10^9$ neurons ($69 \times 10^9$ in the cerebellum, $17 \times 10^9$ in the cerebral cortex, $1 \times 10^9$ in remaining structures).

  • Development of the Nervous System

• Neurulation: Ectoderm forms the neural plate $\rightarrow$ neural groove $\rightarrow$ neural tube. Anterior neuropore closure failure causes anencephaly; posterior neuropore closure failure causes spina bifida.

• Cell Proliferation: Neural precursors divide symmetrically in the subventricular and ventricular zones for 5–6 weeks, then divide asymmetrically. Migrating neurons travel radially along radial glial cells from the inside out (Layer VI formed first, Layer I formed last).

• Radial Unit Hypothesis (Pasko Rakic): Columnar organization of the adult cortex is determined during embryogenesis by progenitor cells in the ventricular zone.

• Adult Neurogenesis: Confirmed in the dentate gyrus of the hippocampus and the subventricular zone/olfactory bulb in humans (Eriksson et al., 1998, via BrdU labeling).

• Postnatal Maturation: Quadrupling of brain volume from birth to adulthood is driven by synaptogenesis, dendritic arborization, myelination, and glial cell proliferation, followed by competitive synapse elimination (pruning).

Methods of Cognitive Neuroscience

• Behavioral Methods in Cognitive Psychology

  • Mental Representations: Internal representations undergo transformations.

  • Posner Letter-Matching Task: Measures reaction time across conditions (Physical identity [AA] vs. Phonetic identity [Aa] vs. Category identity [vowels AU vs. consonants SC]). Demonstrates that physical representations are derived first, phonetic second, and category representations last.

  • Sternberg Memory Comparison Task: Evaluates mental search in working memory across 4 stages (Encode, Compare, Decide, Respond). Results demonstrate a serial, exhaustive search (linear increase in reaction time as memory set size increases).

  • Word Superiority Effect (Reicher, 1969): Letters are identified more accurately when embedded in real words than in nonwords or random strings, indicating parallel activation of letter and word representations.

  • Stroop Task (J. R. Stroop, 1935): Demonstrates automaticity of word reading, which interferes with color-naming performance when ink color and word meaning are incongruent.

• Neurological Dysfunction and Lesion Studies

  • Causes of Neurological Dysfunction:

  • Vascular Disorders: Ischemia (inadequate blood supply due to embolus, thrombus, or atherosclerosis), infarction (tissue death), cerebral hemorrhage (vessel rupture), aneurysms, or arteriosclerosis.

  • Tumors (Neoplasms): Gliomas, meningiomas, schwannomas; can be benign or malignant.

  • Degenerative/Infectious Disorders: Alzheimer's disease (cortical atrophy, amyloid plaques, neurofibrillary tangles), Parkinson's disease (loss of dopaminergic neurons in substantia nigra), Huntington's disease (basal ganglia/caudate destruction), Pick's disease, PSP, Multiple Sclerosis (demyelination), AIDS dementia, Herpes simplex (temporal/limbic destruction), Korsakoff's syndrome (diencephalon/thalamus destruction due to thiamine deficiency).

  • Traumatic Brain Injury (TBI): Open or closed head injuries; coup (damage at impact site) and countercoup (damage opposite impact site due to rebound against skull). Orbitofrontal regions are particularly susceptible due to jagged interior skull surface.

  • Epilepsy: Abnormally synchronous electrical activity confirmed by EEG.

  • Logic of Lesion Studies:

  • Single Dissociation: Patient group shows impairment on Task A but not Task Y relative to controls. Limited by potential differences in task difficulty/sensitivity.

  • Double Dissociation: Patient Group 1 is impaired on Task X but not Task Y; Patient Group 2 is impaired on Task Y but not Task X. Provides conclusive evidence that the two tasks rely on functionally and anatomically independent neural processes.

• Methods to Perturb Neural Function

  • Pharmacological Manipulations: Administration of agonists (mimic neurotransmitters) or antagonists (block receptors). Systemic administration vs. focal microinjections (e.g., D1 vs. D2 dopamine receptor antagonists injected into rat ACC to dissociate effort-based decision making).

  • Transcranial Magnetic Stimulation (TMS): Delivers a brief, high-intensity magnetic pulse via a surface coil to induce an electrical current in underlying cortex ($\approx 1.0\text{--}1.5\,\text{cm}^3$ area), creating a transient "virtual lesion".

  • Transcranial Direct Current Stimulation (tDCS): Applies low constant current ($1\text{--}2\,\text{mA}$) between an anode and cathode on the scalp. Anodal tDCS depolarizes neurons (increases excitability); cathodal tDCS hyperpolarizes neurons (decreases excitability).

  • Genetic Manipulations: Gene knockout models (e.g., weaver mice lacking cerebellar Purkinje cells; NMDA receptor knockout in hippocampal CA1 region by Susumu Tonegawa).

  • Optogenetics: Uses viral vectors to insert genes for light-sensitive ion channels (e.g., Channelrhodopsin-2 [ChR-2] from Chlamydomonas reinhardtii) into specific neurons, allowing sub-millisecond millisecond-level optical control of action potentials using blue light pulses.

• Structural Analysis of the Brain

  • Computed Tomography (CT/CAT): Reconstructs 3-D structural images from a series of 2-D X-ray projections taken across a $180^\circ$ arc. Measures tissue density; spatial resolution $0.5\text{--}1.0\,\text{cm}$.

  • Magnetic Resonance Imaging (MRI): Exploits the nuclear magnetic resonance of hydrogen protons. A strong static magnetic field ($0.5\text{--}3.0\,\text{Tesla}$) aligns proton spin axes. Radio frequency (RF) pulses perturb the alignment, and detectors measure RF energy emitted as protons relax back to equilibrium. Provides high spatial resolution ($<1\,\text{mm}$).

  • Diffusion Tensor Imaging (DTI): Uses MRI to measure the directionality of water diffusion (anisotropy) along myelinated axon bundles, allowing visualization and reconstruction of white matter tracts.

• Methods for Studying Neural Function

  • Single-Cell / Multiunit Recording: Inserts microelectrodes intracellularly or extracellularly into animal brains to measure action potentials. Plots data on spike raster plots and peristimulus time histograms. Single-cell human recordings are performed in surgical epilepsy patients (e.g., Itzhak Fried's discovery of concept-specific cells like the "Halle Berry neuron").

  • Electroencephalography (EEG): Noninvasive scalp recording of continuous electrical potentials generated by postsynaptic currents in large populations of synchronized cortical neurons.

  • Event-Related Potentials (ERP): Averaging time-locked EEG traces across many repeated experimental trials to extract small signal waveforms triggered by specific sensory, cognitive, or motor events.

  • ERP Components: N100/P100 (sensory/attentional selection); N200/Mismatch Negativity (physical deviance); P300 (novelty/target detection); N400 (semantic inconsistency); P600 (syntactic violation).

  • Magnetoencephalography (MEG): Measures small magnetic fields generated by intracellular dendritic currents using Superconducting Quantum Interference Devices (SQUIDs). Provides millisecond temporal resolution and superior spatial localization compared to EEG.

  • Electrocorticogram (ECoG): Subdural or epidural placement of electrode grids directly on the exposed cortical surface during neurosurgery; records high-frequency gamma power ($90\text{--}130\,\text{Hz}$) with excellent spatial and temporal precision.

  • Positron Emission Tomography (PET): Injects radioactive tracers (e.g., $^{15}\text{O}$-water, ^{18}\text{F}$-2FDG, Pittsburgh Compound B [PiB] for beta-amyloid). Radioactive decay emits a positron, which collides with an electron to produce two 511\,\text{keV}$annihilation gamma-ray photons traveling at$180^\circ apart. Reconstructs regional cerebral blood flow (rCBF) or glucose metabolism.\n - **Functional Magnetic Resonance Imaging (fMRI)**: Measures Blood Oxygen Level-Dependent (BOLD) contrast—the ratio of oxygenated to deoxygenated hemoglobin. Deoxyhemoglobin is paramagnetic, causing local magnetic field distortions. Hemodynamic response peaks 6\text{--}10\,\text{seconds} after neural activation.\n - *Designs*: Block design (integrates BOLD signal over 20–40s task blocks; higher statistical power) vs. Event-related design (models BOLD signal to individual randomized trials; Wagner et al. memory encoding study).\n - **Brain Graphs**: Mathematical models of brain networks consisting of **nodes** (brain regions/voxels) and **edges** (functional or structural connections).\n - **Computer Modeling**: Artificial intelligence and connectionist neural networks that simulate cognitive processes via parallel processing units. Enables artificial lesioning and testing of explicit computational hypotheses (e.g., Kali & Dayan model of episodic memory consolidation).\n\n# Hemispheric Specialization\n\n- **Anatomy and Asymmetries of the Hemispheres**\n - **Wada Test (Sodium Amobarbital Procedure)**: Anesthetizes one hemisphere via carotid artery injection to confirm language and memory lateralization prior to surgery. Confirms left-hemisphere language dominance in 96\%$of right-handers and$60\% of left-handers.\n - **Macroscopic Structural Asymmetries**:\n - *Right Hemisphere*: Protrudes anteriorly (chubbier frontal pole); larger frontal volume.\n - *Left Hemisphere*: Protrudes posteriorly (larger occipital pole); Sylvian fissure is flatter and extends horizontally.\n - *Planum Temporale*: Located in Wernicke's area; larger in the left hemisphere in 65\%$of brains ($11\%$right-larger,$24\% symmetrical). Symmetrical in children with dyslexia.\n\n\n\n - **Microscopic Asymmetries**:\n - Left hemisphere language regions feature larger Layer III pyramidal cell bodies, wider spacing between cortical microcolumns, and longer high-order dendritic branching than homotopic right-hemisphere areas.\n\n- **Corpus Callosum and Commissures**\n - **Corpus Callosum**: Largest white matter commissure (\approx 250 \times 10^6 axons). Divided into:\n - *Genu*: Anterior region; connects prefrontal cortices (small-diameter, slow-conducting fibers).\n - *Body*: Middle region; connects motor, premotor, and somatosensory cortices.\n - *Splenium*: Posterior region; connects occipital, parietal, and temporal cortices (large-diameter fibers).\n\n\n\n - **Types of Connections**:\n - *Homotopic*: Connects identical anatomical regions in opposite hemispheres (e.g., left V1 to right V1).\n - *Heterotopic*: Connects different anatomical regions in opposite hemispheres (e.g., left prefrontal to right premotor).\n - **Anterior Commissure**: 1/10th the size of callosum; connects inferior temporal structures, amygdalae, and decussating olfactory fibers.\n - **Posterior Commissure**: Small pathway mediating the pupillary light reflex.\n\n- **Split-Brain Research and Functional Disconnection**\n - **Surgical Procedure**: Complete or partial corpus callosotomy performed to treat intractable grand mal epilepsy (first performed by William Van Wagenen in 1940; refined by Joseph Bogen and Philip Vogel in the 1960s with patient W.J.).\n - **Tachistoscopic Testing Methodology**: Stimuli flash for <200\,\text{ms} (faster than saccadic eye movements) to a single visual field:\n\n\n\n - Right Visual Field (RVF) \rightarrow Left Hemisphere (LH).\n - Left Visual Field (LVF) \rightarrow Right Hemisphere (RH).\n\n\n\n - **Functional Consequences**:\n - *Speech and Naming*: Split-brain patients can name objects presented to the RVF/LH. When presented to the LVF/RH, the patient verbally reports seeing "nothing," but the left hand (controlled by the RH) can retrieve or draw the correct object.\n - *Partial Callosotomy*: Sparing the splenium allows visual information transfer while blocking tactile transfer; sparing the anterior callosum allows semantic transfer of visual concepts without specific perceptual details.\n\n- **Hemispheric Specializations**\n - **Language & Speech**:\n - *Left Hemisphere*: Houses generative syntax, grammar, and speech production.\n - *Right Hemisphere*: Contains a limited auditory/visual lexicon; understands single words, but lacks grammar, syntax, and speech production capabilities (except in rare patients like P.S. or V.P.). Processes **emotional prosody** (tone of voice).\n - **Visuospatial Abilities**:\n - *Right Hemisphere*: Superior at block design tasks, 3-D drawing, spatial orientation, and discriminating similar upright faces.\n - *Left Hemisphere*: Superior at self-face recognition; relies on feature tagging.\n - **Facial Expressions**:\n - *Voluntary Facial Expressions*: Initiated by the left hemisphere via direct corticobulbar projections to the contralateral facial nucleus (CN VII) and transcallosally to the ipsilateral facial nucleus. A left-hemisphere lesion impairs voluntary movement of the left lower face.\n - *Spontaneous (Emotional) Facial Expressions*: Initiated by ancient subcortical circuits (basal ganglia, red nucleus). Intact in cortical stroke patients; lost in Parkinson's disease ("masked facies").\n - **Global vs. Local Processing**:\n - *Navon Hierarchical Figures*: Left hemisphere is specialized for **local** detailed processing (letters making up a shape); Right hemisphere is specialized for **global** overall shape processing.\n - Patients with left-hemisphere lesions draw the overall global shape but miss local details; patients with right-hemisphere lesions draw local details scattered randomly without global structure.\n - **Theory of Mind (ToM)**:\n - Moral belief attribution is localized to the right temporoparietal junction (rTPJ). Split-brain patients tested on moral reasoning (e.g., Grace putting toxic powder believing it was sugar) judge accidental harm as morally unacceptable because the speaking left hemisphere is cut off from the right hemisphere's belief-attribution module.\n - **The Interpreter**:\n - A specialized left-hemisphere mechanism that formulates causal inferences, constructs hypotheses, and synthesizes actions and emotional states into a continuous, coherent narrative.\n - *Probability-Guessing Paradigm*: Left hemisphere uses **frequency matching** (suboptimal hypothesis testing); Right hemisphere uses **maximizing** (optimal overall strategy, like rats or goldfishes).\n - *Causal Perception vs. Causal Inference*: Right hemisphere excels at causal perception (detecting immediate physical collision events in time/space); Left hemisphere excels at causal inference (abstract logical deduction).\n\n# Sensation and Perception\n\n- **General Principles of Sensory Processing**\n - **Sensation**: Transduction of environmental energy into neural impulses by specialized receptor cells.\n - **Perception**: Construction of a mental representation (percept) from sensory inputs, heavily modulated by memory, expectation, and attention.\n - **Shared Properties**:\n - *Range*: Human vision (400\text{--}700\,\text{nm}$); Audition ($20\text{--}20,000\,\text{Hz}).\n - *Adaptation*: Adjusting sensitvity in response to constant environmental stimulation.\n - *Acuity*: Precision in distinguishing stimuli; depends on receptor density (e.g., fovea, fingertips).\n - *Thalamic Relay*: All senses except olfaction synapse in specific thalamic nuclei (LGN, MGN, VPN, VPM) before projecting to primary sensory cortex.\n\n- **Audition**\n - **Anatomy & Pathway**:\n - Sound waves \rightarrow$Auditory canal$\rightarrow$Tympanic membrane$\rightarrow$Ossicles (Malleus, Incus, Stapes)$\rightarrow$Oval window$\rightarrow Fluid-filled **Cochlea**.\n - **Basilar Membrane**: Tonotopically organized. Base is narrow/stiff (responds to high frequencies up to 20,000\,\text{Hz}$); Apex is wide/flexible (responds to low frequencies down to$20\,\text{Hz}).\n - **Hair Cells (Stereocilia)**: Mechanoreceptors that depolarize when bent, opening mechanically gated K^+$and$Ca^{2+} channels to release neurotransmitter onto the **cochlear nerve** (CN VIII).\n\n\n\n - *Ascending Route*: Cochlear nerve \rightarrow$Cochlear nucleus (medulla)$\rightarrow$Superior olivary nucleus (pons)$\rightarrow$Nucleus of lateral lemniscus$\rightarrow$Inferior colliculus (midbrain)$\rightarrow$Medial Geniculate Nucleus (MGN, thalamus)$\rightarrow Primary Auditory Cortex (A1, Heschl's gyrus, BA 41/42, superior temporal gyrus).\n - **Sound Localization**:\n - *Interaural Time Difference (ITD)*: Measured by **coincidence detectors** and delay lines in the medial superior olive (Mark Konishi's barn owl model).\n - *Interaural Intensity Difference (IID)*: Measured in the lateral superior olive based on sound shadow attenuation.\n\n- **Olfaction**\n - **Anatomy & Pathway**:\n - Odorants \rightarrow$Nasal cavity$\rightarrow$Olfactory epithelium$Libraries of 1,000 bipolar receptor types$$\rightarrow$Glomeruli in Olfactory Bulb$\rightarrow$Olfactory Nerve (CN I)$\rightarrow$Primary Olfactory Cortex (Pyriform cortex)$\rightarrow Secondary Olfactory Cortex (Orbitofrontal cortex).\n - *Unique Characteristics*: Projections are predominantly ipsilateral; bypasses the thalamus prior to primary cortex.\n - **Sniffing vs. Smelling (Noam Sobel)**: Sniffing activates primary olfactory cortex (rate-of-change/sampling detector); presence of odor activates orbitofrontal cortex. Asymmetric nostril airflow (one high-flow, one low-flow nostril) optimizes absorption of diverse odorants.\n\n- **Gustation**\n - **Anatomy & Pathway**:\n - Tastants \rightarrow$Taste pores$\rightarrow Taste buds in Papillae (Fungiform, Foliate, Circumvallate).\n - Five basic tastes: Salty (Na^+$), Sour ($H^+), Sweet (carbohydrate/G-protein), Bitter (warning/toxin), Umami (savory/amino acids).\n - *Pathways*: Taste cells \rightarrow$Chorda tympani$\rightarrow$Facial (CN VII), Glossopharyngeal (CN IX), Vagus (CN X) nerves$\rightarrow$Gustatory nucleus (Nucleus of the Solitary Tract, medulla)$\rightarrow$Ventral Posterior Medial (VPM) nucleus of thalamus$\rightarrow Primary Gustatory Cortex (Insula & Operculum) \rightarrow Secondary Gustatory Cortex (Orbitofrontal cortex—encodes reward value/pleasantness; Dana Small chocolate study).\n\n- **Somatosensation**\n - **Receptors**:\n - *Touch*: Meissner's corpuscles (light touch/fast adapting), Merkel's cells (regular pressure/slow adapting), Pacinian corpuscles (deep pressure/vibration/fast adapting), Ruffini corpuscles (stretch/slow adapting).\n - *Nociceptors*: Free nerve endings (thermal, mechanical, polymodal). Myelinated A-delta fibers (fast, sharp pain); unmyelinated C fibers (slow, dull pain).\n - *Proprioceptors*: Muscle spindles and Golgi tendon organs (body position).\n - **Pathway**: Dorsal-root ganglion \rightarrow$Dorsal horn$\rightarrow$Dorsal column-medial lemniscal system (crosses at medulla)$\rightarrow$Ventral Posterior Nucleus (VPN, thalamus)$\rightarrow$Primary Somatosensory Cortex (S1, BA 1, 2, 3, postcentral gyrus)$\rightarrow Secondary Somatosensory Cortex (S2).\n - **Cortical Plasticity**: Reorganization of somatotopic maps following deafferentation or amputation (Ramachandran's phantom limb mapping on face). Expanded representations in musicians (Elbert et al., string players' left hand fingers).\n\n- **Vision**\n - **Anatomy & Pathway**:\n - Light \rightarrow$Cornea, Lens$\rightarrow Retina.\n - **Photoreceptors**: Rods (scotopic/night, rhodopsin, high convergence) and Cones (photopic/day, photopsin, fovea, 3 types: S/blue [430\,\text{nm}$], M/green [$530\,\text{nm}$], L/red [$560\,\text{nm}]).\n - *Retinal Network*: Photoreceptors \rightarrow$Bipolar cells$\rightarrow Ganglion cells (M cells & P cells) \rightarrow$Optic Nerve (CN II)$\rightarrow$Optic Chiasm (nasal fibers cross)$\rightarrow$Optic Tract$\rightarrow$Lateral Geniculate Nucleus (LGN, thalamus; 6 layers: 1-2 magnocellular, 3-6 parvocellular)$\rightarrow$Optic Radiations$\rightarrow$$ Primary Visual Cortex (V1, BA 17, striate cortex, calcarine fissure).

• Cortical Visual Areas: Over 30 distinct areas (V1, V2, V3, V4 [color/shape], V5/MT [motion]). Retinotopic mapping.

• Subcortical vs. Cortical Pathways: 10% of optic fibers project to superior colliculus and pulvinar. Schneider hamster study demonstrated a double dissociation: superior colliculus lesions impair visual localization/orientation ("where"), whereas visual cortex lesions impair discrimination/acuity ("what").

• Visual Deficits:

  • Achromatopsia: Inability to perceive colors due to V4/anterior lesions; retains form vision.

  • Akinetopsia: Inability to perceive motion (patient M.P.) due to bilateral V5/MT lesions; sees the world in static snapshots.

  • Multimodal Perception and Reorganization

• Multimodal Integration: Superior colliculus integrates spatial maps from visual, auditory, and somatosensory inputs. Multisensory enhancement occurs when stimuli are coincident in space and time.

• Illusions: McGurk effect (lip movements alter speech sound perception); Rubber hand illusion; Auditory driving (2 beeps convert 1 light flash into 2 perceived flashes).

• Synesthesia: Involuntary mixing of senses (e.g., colored-graphemes, word-tasting). Associated with hyperconnectivity/increased anisotropy (DTI) in inferior temporal and parietal regions.

• Plasticity in Sensory Deprivation: In congenitally or early blind individuals, tactile exploration and Braille reading recruit the deprived visual cortex (Sadato et al.; Pascual-Leone 5-day blindfold study).

Object Recognition

• Principles and Visual Streams

  • Visual Agnosia: Modality-specific failure of visual object recognition, unexplainable by simple loss of visual acuity, language, or memory.

  • Dual Streams:

  • Ventral Stream (Occipitotemporal Pathway): "What" pathway; terminates in inferotemporal cortex (IT); dedicated to object perception and identification ("vision for recognition").

  • Dorsal Stream (Occipitoparietal Pathway): "Where" or "How" pathway; terminates in posteroparietal cortex; dedicated to spatial perception and guiding interaction with objects ("vision for action").

• Double Dissociation of Pathways:

  • Ungerleider & Mishkin Monkey Studies: Temporal lesions produced shape discrimination ("what") deficits; parietal lesions produced landmark localization ("where") deficits.

  • Patient D.F. (Milner & Goodale): Bilateral ventral stream/LOC damage. Failed the explicit orientation matching task (could not recognize orientation), but excelled at the action task (rapidly posted the card into the oriented slot).

- *Optic Ataxia*: Parietal cortex lesions. Patients can recognize objects, but cannot use visual information to accurately guide reaching/grasping movements.

• Computational Problems in Object Recognition

  • Object Constancy: Ability to recognize objects despite variations in viewing angle, illumination, scale, and background/occlusion.

  • Reference Frames:

  • View-Dependent Frame of Reference: Requires storing multiple representations of an object from different viewpoints; novel views require mental rotation or interpolation.

  • View-Invariant Frame of Reference: Extracts structural, viewpoint-independent properties (e.g., geons, major axes).

  • fMRI Repetition Suppression: Left fusiform area shows view-invariant repetition suppression; Right fusiform area shows view-dependent repetition suppression.

  • Shape Encoding: Lateral Occipital Cortex (LOC) exhibits cue invariance—it responds to shape regardless of whether the boundaries are defined by lines, motion, or color.

  • Hierarchical Coding vs. Ensemble Coding:

  • Gnostic Unit / Grandmother Cell Hypothesis: A single neuron at the top of a processing hierarchy fires only to a specific, complex percept (e.g., one's grandmother, Jennifer Aniston, or Halle Berry). Unlikely due to error vulnerability, inability to code novel objects, and cell death.

  • Ensemble Coding Hypothesis: Objects are recognized by the collective, simultaneous activation of a population of feature-detecting neurons.

• Taxonomy of Visual Agnosia

  • Apperceptive Agnosia: Failure of basic perceptual processing that prevents achieving object constancy. Patients can identify objects in standard views, but fail when presented with unusual views or shadowed stimuli (Unusual Views Test, Shadows Test). Associated with right posterior lesions.

  • Integrative Agnosia: Inability to integrate features into parts or group parts of an object into a coherent whole (patient H.J.A., patient C.K.). Patients can copy drawings line-by-line, but fail to parse overlapping figures.

  • Associative Agnosia: Inability to link a intact, well-formed visual percept with semantic knowledge/meaning (patient F.R.A.). Patients can copy drawings accurately and segment complex scenes, but cannot name the objects or perform the Matching-by-Function Test. Associated with left posterior lesions.

  • Category-Specific Agnosia: Disproportionate loss of recognition for living/animate objects (animals, plants) relative to nonliving/inanimate objects (tools, household items; e.g., patient J.B.R.). Explained by the sensorimotor hypothesis: nonliving items possess additional motor/kinesthetic representations in motor cortex that facilitate recognition.