Six-Layer Neocortex

• The neocortex (isocortex) comprises ~90% of the cerebral cortex and has a uniform 6-layer architecture
• The remaining cortex is allocortex — 3-layered (hippocampus = archicortex; olfactory cortex = paleocortex)

Granular vs. Agranular Cortex

Cortical Columns & Brodmann Areas

• Cortical columns — functional units that span all 6 layers; neurons in a column share similar receptive fields and response properties
• Best characterized in V1 (ocular dominance columns, orientation columns) and S1 (somatotopic columns)
• Brodmann areas — 52 cytoarchitecturally distinct regions mapped by Korbinian Brodmann (1909); many correspond to functional areas

• Largest lobe — ~1/3 of cortical surface
• Boundaries: anterior to central sulcus, superior to lateral (Sylvian) fissure
• Blood supply: ACA (medial surface) + MCA (lateral surface)

Primary Motor Cortex (M1) — Brodmann Area 4

• Location: precentral gyrus
• Function: execution of voluntary contralateral movements
• Contains Betz cells (giant pyramidal cells, layer V) — contribute only ~3–5% of corticospinal tract fibers (~30,000 of ~1 million). M1 overall contributes ~30% of CST fibers.
• Motor homunculus — somatotopic organization:
  • Medial surface: lower extremity (foot, leg, hip) → ACA territory
  • Lateral convexity: upper extremity, face, tongue → MCA territory
  • Hand and face have disproportionately large cortical representation (fine motor control)
• Output tracts: corticospinal (body) and corticobulbar (face/bulbar muscles)

Clinical Correlations

• Lesion → contralateral UMN weakness: spasticity, hyperreflexia, extensor plantar response
• ACA stroke → contralateral leg weakness (leg > arm)
• MCA stroke → contralateral face and arm weakness (face/arm > leg)
• Cortical lesion typically causes weakness that respects somatotopy, unlike internal capsule lesion (equal face/arm/leg)

Premotor & Supplementary Motor Areas — Brodmann Area 6

• Premotor cortex (lateral area 6):
  • Motor planning for externally guided movements
  • Integrates visual and sensory input with motor output
  • Lesion → difficulty with visually guided reaching
• Supplementary motor area (SMA, medial area 6):
  • Motor planning for internally generated sequences
  • Bimanual coordination, complex motor sequences
  • Lesion → alien hand syndrome (frontal variant), difficulty initiating movement, impaired sequencing
  • SMA seizures → bilateral tonic posturing, often mistaken for psychogenic events

Broca’s Area — Brodmann Areas 44 & 45

• Location: inferior frontal gyrus (pars opercularis = area 44; pars triangularis = area 45) — dominant hemisphere
• Function: speech production, motor programming of articulation, syntax/grammar
• Lesion → Broca’s aphasia:
  • Non-fluent, effortful, telegraphic speech
  • Comprehension intact (for simple commands; may struggle with complex syntax)
  • Repetition impaired
  • Naming impaired
  • Often accompanied by right hemiparesis (adjacent motor strip involvement)
  • Patient is typically aware and frustrated

Frontal Eye Fields (FEF) — Brodmann Area 8

• Location: posterior middle frontal gyrus
• Function: initiates voluntary conjugate saccades to the contralateral side

Prefrontal Cortex

Dorsolateral Prefrontal Cortex (DLPFC)

• Executive function: planning, organization, cognitive flexibility, working memory
• Lesion → dysexecutive syndrome: poor planning, perseveration, impaired working memory, poor abstraction
• Tested by: Wisconsin Card Sort Test, Trail Making B, digit span backward

Orbitofrontal Cortex (OFC)

• Social behavior, judgment, impulse control, emotional regulation
• Lesion → disinhibition syndrome: impulsivity, inappropriate social behavior, poor judgment, emotional lability, echopraxia (involuntary imitation of others’ movements) and utilization behavior
• Witzelsucht — inappropriate joking, punning, sexual remarks, and an inappropriately jocular affect; classic orbitofrontal/right-frontal disinhibition presentation (also seen in behavioral-variant FTD)
• Classic example: Phineas Gage (OFC damaged by iron rod)
• Also seen in: frontotemporal dementia (behavioral variant)

Medial Prefrontal / Anterior Cingulate Cortex

• Motivation, initiation of behavior, emotional processing
• Lesion → abulia (lack of will/initiative) or akinetic mutism (bilateral) — alert but no spontaneous speech or movement
• Bilateral ACA infarction is a classic cause
• Treatment: trials of dopaminergic agents — methylphenidate, amantadine, bromocriptine, modafinil — sometimes improve drive and initiation; evidence is anecdotal/case-series

Frontal Lobe Clinical Syndromes

• Boundaries: central sulcus (anterior), parieto-occipital sulcus (posterior), lateral fissure (inferior)
• Blood supply: MCA (lateral) + ACA (medial parasagittal strip)

Primary Somatosensory Cortex (S1) — Brodmann Areas 3, 1, 2

• Location: postcentral gyrus
• Function: processing of contralateral somatosensory information
• Sensory homunculus: somatotopic map (medial = leg [ACA]; lateral = face/arm [MCA]); lips, tongue, and fingers have disproportionately large representation

Functional Sub-Areas of S1

Clinical — Cortical Sensory Loss

• Cortical sensory modalities (impaired with parietal lesions):
  • Stereognosis — object identification by touch (loss = astereognosis)
  • Graphesthesia — recognition of numbers/letters traced on skin (loss = agraphesthesia)
  • Two-point discrimination
  • Sensory extinction on double simultaneous stimulation
• Primary modalities relatively preserved: crude pain, temperature, light touch (mediated at thalamic level). Vibration and discriminative touch may be blunted with cortical lesions.
• Lost: stereognosis, graphesthesia, two-point discrimination, double-simultaneous extinction.
• This dissociation (cortical modalities lost, primary modalities relatively intact) is the hallmark of a cortical vs. thalamic or peripheral lesion

Somatosensory Association Cortex — Brodmann Areas 5 & 7

• Location: superior parietal lobule
• Functions: sensorimotor integration, visuospatial processing, body schema, hand-eye coordination
• Lesion → optic ataxia (misreaching for visual targets), tactile agnosia, impaired spatial awareness

Supramarginal Gyrus — Brodmann Area 40

• Location: inferior parietal lobule (wraps around posterior end of Sylvian fissure)
• Functions: phonological processing, motor planning for skilled movements (praxis)
• Dominant hemisphere lesion → conduction aphasia, ideomotor apraxia
• Non-dominant hemisphere lesion → hemispatial neglect (often in conjunction with area 39/7)

Angular Gyrus — Brodmann Area 39

• Location: inferior parietal lobule (wraps around posterior end of STS)
• Functions: reading comprehension, writing, calculation, cross-modal semantic integration
• Dominant hemisphere lesion → Gerstmann syndrome

Gerstmann Syndrome

• Caused by lesion of the dominant (left) angular gyrus (area 39)
• Tetrad:
  • Acalculia — inability to perform calculations
  • Agraphia — inability to write
  • Finger agnosia — inability to identify individual fingers
  • Left-right disorientation
• Often accompanied by alexia with agraphia
• Classic board question: "patient cannot do math, cannot write, confuses fingers, and confuses left-right" → dominant angular gyrus

Hemispatial Neglect

• Definition: failure to attend to, report, or respond to stimuli on the side contralateral to a brain lesion, not explained by primary sensory/motor deficits
• Most common and severe with RIGHT (non-dominant) parietal lesions (inferior parietal lobule, temporoparietal junction)
• Also involves the right superior temporal gyrus, right frontal lobe, and subcortical structures

Parietal Lobe Syndromes Summary

• Boundaries: inferior to lateral (Sylvian) fissure, anterior to occipital lobe
• Blood supply: MCA (lateral surface), PCA (inferior/medial surface)

Primary Auditory Cortex — Brodmann Areas 41 & 42

• Location: Heschl’s gyrus (transverse temporal gyrus) — located on the superior surface of the temporal lobe, hidden within the Sylvian fissure
• Function: initial cortical processing of auditory information
• Tonotopic organization: different sound frequencies mapped along the gyrus
• Bilateral input: each ear projects to BOTH auditory cortices (unlike vision) → unilateral cortical lesion causes subtle hearing change, NOT deafness
• Unilateral lesion → difficulty with sound localization, impaired auditory discrimination on contralateral side
• Bilateral lesions → cortical deafness (rare)

Wernicke’s Area — Brodmann Area 22

• Location: posterior superior temporal gyrus (dominant hemisphere)
• Function: language comprehension (spoken and written)
• Lesion → Wernicke’s aphasia:
  • Fluent speech — normal rate, rhythm, prosody, but content is empty
  • Comprehension severely impaired
  • Repetition impaired
  • Paraphasic errors: phonemic ("spork" for "fork") and semantic ("knife" for "fork")
  • Neologisms (made-up words) and jargon
  • Patient is typically unaware of deficit (lack of insight / unawareness of language errors)

Auditory Agnosia & Word Deafness

• Auditory agnosia: inability to recognize sounds despite intact hearing → bilateral auditory association cortex lesions
• Pure word deafness: cannot comprehend spoken language but can read, write, and speak normally → bilateral lesions isolating Wernicke’s area from auditory input, or unilateral left temporal lesion disconnecting both auditory cortices from Wernicke’s area
• Auditory verbal agnosia = pure word deafness (selective inability to comprehend spoken words)

Hippocampus & Memory

• Location: medial temporal lobe (floor of inferior horn of lateral ventricle)
• Function: memory consolidation (short-term → long-term); spatial navigation
• Memory types processed:
  • Declarative (explicit) memory = episodic (hippocampus-dependent) + semantic (anterolateral temporal cortex / temporal pole). Hippocampal damage primarily impairs new episodic memory; semantic memory is more selectively impaired in semantic-variant PPA (anterior temporal degeneration).
  • NOT procedural memory (handled by basal ganglia/cerebellum)
• Bilateral hippocampal lesion → severe anterograde amnesia (cannot form new episodic memories)
• Unilateral lesion: dominant (left) → verbal memory deficit; non-dominant (right) → visuospatial memory deficit
• Hippocampal subfield vulnerability: CA1 (Sommer sector) is the most vulnerable to ischemia, hypoglycemia, status epilepticus, and anti-LGI1 / anti-GABA-B encephalitis; CA2 is the most resistant. This selective CA1 vulnerability is the substrate for mesial temporal sclerosis — the most common cause of medically refractory focal epilepsy with impaired awareness (febrile status → HS Type 1).
• Classic cases: Patient H.M. (bilateral medial temporal lobectomy); herpes encephalitis (predilection for temporal lobes)

Amygdala

• Location: anterior medial temporal lobe, anterior to hippocampus
• Functions: emotional processing (especially fear conditioning), emotional memory, social cognition (reading facial expressions)
• Bilateral anterior temporal lobe lesion (amygdala + surrounding temporal cortex/uncus/parahippocampus) → Klüver-Bucy syndrome:
  • Hyperorality — tendency to examine objects with mouth
  • Hypersexuality
  • Placidity — loss of fear/aggression
  • Visual agnosia (psychic blindness)
  • Hypermetamorphosis — compulsive exploration of environment
• Causes: herpes encephalitis, frontotemporal dementia (especially right temporal / semantic-variant — partial features), bilateral temporal lobectomy

Temporal Lobe Epilepsy (TLE)

• Most common focal epilepsy in adults
• Focus: mesial temporal structures (hippocampus, amygdala, parahippocampal gyrus)
• Common pathology: hippocampal sclerosis (mesial temporal sclerosis)
• Semiology:
  • Aura: rising epigastric sensation, déjà vu, jamais vu, fear/anxiety, olfactory/gustatory hallucinations, autonomic symptoms
  • Seizure: behavioral arrest → oroalimentary automatisms (lip smacking, chewing) → manual automatisms (fumbling, picking)
  • Post-ictal: confusion, amnesia, dysphasia (if dominant hemisphere)
• Interictal personality traits (Geschwind syndrome): hypergraphia, hyperreligiosity, altered sexuality, viscosity (circumstantial interpersonal style)

Visual Field Deficit — Meyer’s Loop

• Meyer’s loop carries inferior retinal fibers (representing the contralateral superior visual field) through the temporal lobe
• Temporal lobe lesion → contralateral superior quadrantanopia ("pie in the sky")
• Important in temporal lobe surgery planning (anterior temporal lobectomy for epilepsy)

• Boundaries: posterior to parieto-occipital sulcus
• Blood supply: primarily PCA (calcarine artery). Macular sparing in PCA strokes is most likely due to bilateral cortical representation of the macula combined with the very large cortical magnification of the macula at the occipital pole; the older "dual PCA/MCA blood supply" teaching is not well supported by anatomic/angiographic data (Osborn; Caplan).

Primary Visual Cortex (V1) — Brodmann Area 17

• Location: banks of the calcarine sulcus (medial occipital surface)
• Also called striate cortex (due to line of Gennari — a prominent myelinated stripe in layer IV)
• Receives input from: lateral geniculate nucleus (LGN) of thalamus via optic radiation
• Retinotopic organization:
  • Upper visual field → below calcarine sulcus (lingual gyrus)
  • Lower visual field → above calcarine sulcus (cuneus)
  • Central/macular vision → posterior pole (large cortical area = cortical magnification)
  • Peripheral vision → anterior calcarine cortex

Visual Field Deficits by Lesion Location

Visual Association Areas (V2–V5)

• V2 (area 18) and V3 (area 19): secondary visual processing, border/contour detection
• Two processing streams diverge from V1:

Dorsal Stream — "Where / How" Pathway

• Route: V1 → V2 → V3 → V5/MT → posterior parietal cortex
• Function: spatial location, motion perception, visually guided action
• V5/MT = motion processing area
• Lesion of V5 (bilateral) → akinetopsia (motion blindness — world seen as series of frozen frames)
• Lesion of posterior parietal → optic ataxia (misreaching)

Ventral Stream — "What" Pathway

• Route: V1 → V2 → V4 → inferior temporal cortex
• Function: object recognition, face recognition, color processing
• V4 = color processing area
• Fusiform face area (ventral occipitotemporal) = face recognition
• Lesion of V4 (bilateral) → achromatopsia (loss of color perception; world appears gray)
• Lesion of fusiform face area (right or bilateral, right > left) → prosopagnosia
• Lesion of ventral stream → visual object agnosia (cannot identify objects by sight; can identify by touch)

Occipital Lobe Syndromes

Language Network Overview

• Broca’s area (areas 44/45) — speech production, motor programming
• Wernicke’s area (area 22) — language comprehension
• Arcuate fasciculus — white matter tract connecting Broca’s and Wernicke’s → critical for repetition
• Angular gyrus (area 39) — reading, writing, semantic integration
• Supramarginal gyrus (area 40) — phonological processing
• Supplementary motor area — speech initiation
• All are in the dominant hemisphere (left in ~95% of right-handers, ~70% of left-handers; the remaining ~30% of left-handers are split between right-dominant and bilateral)

Major Association & Commissural White-Matter Tracts

Aphasia Classification Table

Paraphasia Subtypes

• Phonemic (literal) paraphasia — substitution of sounds within a real word ("spaghetti" → "pasghetti"). Conduction and Wernicke's aphasia.
• Semantic paraphasia — substitution of a related word ("fork" → "spoon"). Wernicke's, anomic, semantic-variant PPA.
• Neologism — invented nonsense word with no real meaning ("blibbet" for spoon). Fluent (Wernicke's) aphasia, fluent jargon aphasia.

Thalamic Aphasia

• Left thalamic stroke (especially anterior/dorsomedial nuclei) can cause a fluent aphasia with relatively preserved repetition, impaired naming and comprehension, hypophonic/whispered speech, and prominent behavioral or memory changes. Often improves with recovery; useful clue when an aphasia profile doesn't fit a classical perisylvian cortical lesion.

Motor Speech Disorders — Dysarthria Classification

Dysarthria = neuromuscular speech disorder with consistent, predictable errors from muscle dysfunction (as opposed to apraxia of speech, where errors are variable, prosody is distorted, and articulatory groping is prominent).

Primary Progressive Aphasia (PPA) — Three Variants

Related Language and Disconnection Syndromes

Apraxia

• Definition: inability to perform learned, skilled motor acts despite intact motor strength, sensation, coordination, and comprehension
• Testing: ask patient to pantomime actions (e.g., "show me how you would use a comb") → if failed, demonstrate and ask to imitate → if failed, give actual object

Agnosia

• Definition: inability to recognize stimuli in a particular sensory modality despite intact primary sensory function
• The key is that the patient can perceive the stimulus but cannot assign meaning to it

Anosognosia

• Definition: unawareness or denial of a neurological deficit
• Most commonly associated with right parietal lobe lesions (right MCA stroke)
• Patient may deny hemiplegia, neglect the left side of the body, or deny blindness (Anton syndrome)
• Clinical significance: anosognosia impairs rehabilitation participation, predicts worse functional outcomes, and is distinct from psychiatric denial
• May be temporarily reversed by caloric vestibular stimulation (cold water in left ear)

Cerebral Dominance & Lateralization

• Language dominance by handedness:
  • Right-handers: ~95% left-dominant
  • Left-handers: ~70% left-dominant, ~15% right-dominant, ~15% bilateral
• Wada test (intracarotid amobarbital): used to determine hemispheric language dominance pre-operatively → largely replaced by fMRI

Aprosody — the Right-Hemisphere "Aphasia"

• The right hemisphere processes emotional prosody (tone, melody, affective coloring of speech) in a mirror-image distribution to left-hemisphere language
• Motor aprosodia: damage to right Broca homologue (right inferior frontal gyrus) → flat, monotone speech; comprehension of emotional prosody preserved
• Sensory aprosodia: damage to right Wernicke homologue (right posterior superior temporal gyrus) → cannot comprehend the emotional prosody of others’ speech
• Global aprosodia: large right perisylvian lesion → both motor and sensory aprosody
• Highly testable on the RITE as the "right-sided mirror" of aphasia

Crossed Aphasia

• Definition: aphasia arising from a right-hemisphere lesion in a right-hander
• Occurs in ~1–2% of right-handers
• Reflects atypical (right or bilateral) language lateralization
• Board clue: right MCA stroke + aphasia + strong right-handedness

Foix-Chavany-Marie (Anterior Opercular) Syndrome

• Localization: bilateral opercular (perisylvian) lesions
• Hallmark: automatic-voluntary dissociation of face/tongue/pharynx — patient can chew, swallow, smile, or yawn involuntarily but cannot perform the same movements on command
• Often spared: limb movement, comprehension, alertness
• Causes: bilateral perisylvian strokes (sequential MCA infarcts), encephalitis, central pontine variants, developmental opercular syndromes

Posterior Cortical Atrophy (PCA Syndrome)

• Visual variant of Alzheimer disease (most cases have underlying AD pathology)
• Localization: bilateral parietal-occipital degeneration
• Features: Balint syndrome + Gerstmann syndrome + visual agnosia + alexia + visuospatial dysfunction + apraxia
• Memory relatively preserved until late in the disease course
• MRI: bilateral posterior atrophy (parieto-occipital), with relative sparing of medial temporal lobes early on
• Patients often present to ophthalmology first complaining of trouble reading or finding objects despite normal eye exams

Callosal Disconnection Syndromes (Expanded)

Cortical Deafness vs. Pure Word Deafness vs. Auditory Agnosia

Papez Circuit — Memory Anatomy

• The Papez circuit is the anatomic substrate of episodic memory formation. Damage anywhere along the loop → anterograde amnesia.

• Key lesion sites that cause amnesia by damaging the Papez circuit:
  • Wernicke-Korsakoff syndrome (thiamine deficiency) → mammillary bodies + anterior/medial thalamic nuclei
  • Medial temporal lobe stroke (PCA territory) or herpes simplex encephalitis → hippocampus/entorhinal cortex
  • Anterior communicating artery (ACoA) aneurysm rupture → basal forebrain + fornix
  • Bilateral thalamic stroke (artery of Percheron) → anterior/dorsomedial thalamus

Frontal Release Signs — Pathologic vs. Normative

• Most pathologic: grasp reflex, palmomental (brisk), glabellar (non-suppressible Myerson)
• May be normal in elderly: snout, rooting, mild palmomental
• Localization: bilateral medial frontal disease — FTD, NPH, vascular dementia, hydrocephalus, advanced AD, diffuse brain injury

Key Syndromes by Lobe and Location