Cerebral Cortex George R. Leichnetz, Ph.D. OBJECTIVES 1. To know the definitions of cytoarchitectural, phylogenetic, and functional subdivisions of the cerebral cortex, and recognize how the cytoarchitecture of specific regions (relative prominence of pyramidal vs. granular layers) is correlated with function. 2. To be able to identify the principal subdivisions of the cerebral cortex into lobes and gyri (inc. sulci) and corresponding Brodmann areal designations. 3. To know the organization, origin, and termination of corticocortical (associational and commissural) and projectional (corticopetal and corticofugal) fiber systems. 4. To understand the sequential intracortical processing in movement and language production, and clinical deficits resulting from "disconnection" of essential links in these chains of events. 5. To understand the clinical consequences of lesions of specific cortical areas. I. INTRODUCTION The cerebral cortex is a laminated gray matter on the surface of the cerebrum. It represents the highest level of organization and development of the central nervous system, and is only present in mammals. As one ascends the phylogenetic scale, there is a large expansion of associational areas of the cortex that are involved in cognition and other higher levels of cortical processing. The cortical mantle is divided by sulci and fissures (grooves) into gyri. There are five anatomical lobes of the cerebral cortex: frontal, parietal, temporal, occipital and insular.

A. General Functional Organization In general terms, the frontal lobe is the effector region of the cortex in that it projects to motor-related nuclei in the brainstem and spinal cord involved in the generation of movement and other behavioral responses of the individual to his environment. Its three subdivisions are involved in different aspects of coordinated motor responses: prefrontal cortex (cognition; executive control; complex behavioral responses; mental rehearsal of movement), premotor cortex (planning of movement), and precentral cortex (execution of the movement). The remaining portions of the cortex (e.g., parietal, temporal, occipital) are primarily concerned with complex sensory processing (visual, auditory, somatosensory), which do not project downstream to motor structures and therefore entertain associational connections with frontal cortical areas which are equipped to orchestrate responses to sensory stimuli. Primary sensory cortices are concerned with the analysis of the sensory signal (its location, size, shape, texture, color, frequency, timbre): primary somatosensory cortex, (postcentral

gyrus); primary visual cortex, (cuneus and lingual gyri); primary auditory cortex, (sup. transverse temporal gyri). B. Phylogenetic/Cytoarchitectural Subdivisions The cerebral cortex can be divided phylogenetically into archipallium (hippocampal formation), paleopallium (olfactory cortex-entorhinal, prepyriform), neopallium (newest cortex); or cytoarchitecturally into allocortex (three layered), juxta-allocortex, and isocortex (six layered). The archi- and paleo- cortical areas are found in the parahippocampal gyrus and hippocampal formation which are discussed in an earlier lecture on the limbic system. This lecture focuses primarily on the neocortex (isocortex) of the remaining portion of the cerebral cortex. Table 1: CEREBRAL CORTEX: DEFINITIONS

Phylogenetic Cytoarchitectural Location

Neocortex Isocortex (6-Layered) Frontal, Parietal, Occipital, and Part of Temporal Lobe

Paleocortex Juxta-allocortex (6 atypical layers) e.g., Entorhinal Cortex

Archicortex Allocortex (3-layered) e.g., Hippocampal Formation (Hippocampus, Dentate Gyrus) II. CYTOARCHITECTURE OF THE CORTEX

A. Cytology - there are two principal cell types in the cerebral cortex, each of which is indicative of the function of the cortical area where they predominate.

The granule or stellate cell, which is primarily "receptive" in function; predominates in sensory cortex, has primarily intrinsic connections (local, within column). Its small size and short axon is indicative of its function in intracolumnar processing of information. Sensory areas the cortex receive their input through specific thalamic afferents or from other regions of the cortex which terminate in the granular layers (e.g., layer IV). The pyramidal cell, which is "effector" in function, predominates in agranular motor cortex, gives rise to connections that leave the cortical region and go to other regions of the cortex (corticocortical connections) such as associational fibers (within the same hemisphere) or commissural fibers (to the opposite hemisphere); or leave the cortex entirely to project to subcortical, brainstem, or spinal cord targets (projectional fibers). Associational (intrahemispheric) and commissural (interhemispheric) fibers originate from small and medium-sized pyramidal cells of layer III, whereas projectional (corticofugal) fibers (requiring longer axons) originate from large and giant pyramidal cells of layer V. The cortex has many other intrinsic cell types (e.g., bipolar, basket, chandelier cells) but these are beyond the scope of this lecture.

B. Laminar Organization - Most of the cortex is neocortex and consists of six cellular laminae (isocortex): I. Molecular, II. External Granular, III. External Pyramidal, IV. Internal Granular, V. Internal Pyramidal and VI. Polymorphic Layer.

* Link to Netter Image 11.89

C. Cytoarchitectural Features of Functional Cortical Areas:

1. Sensory Cortex - In principal sensory regions of the cortex (Area 17 - visual; Area 41,

42 auditory; Area 3 - somatosensory) the internal (IV) granular layer is augmented. The pyramidal cells in III and V are small. Therefore the cortex of the region is thinner and has an overall granular appearance; is called koniocortex. Even the sensory regions (with a well developed layer IV) need to have effector pyramidal cells to get information out - but small pyramidal cells in III and V have short axons and project only to adjacent gyri (e.g., from area 17 to area 18) not distant lobes or other subcortical brain areas. Therefore, cortical processing of sensory information goes through a chain of several cortico-cortical associational connections (eg. visual processing streams) between primary sensory areas and those cortical areas where a sensory stimulus is “perceived” in the context of personal and extrapersonal space While primary sensory cortices are concerned with the analysis of the rudimentary primary sensory signals, perception occurs in broad regions of associational cortex.

2. Motor Cortex - The principal motor areas are located in the frontal lobe. Premotor area 6 cortex, including the supplementary motor area, is responsible for planning of movements, whereas the precentral gyrus (area 4) is concerned with the initiation and execution of movements. The internal (V) pyramidal layer is augmented, and granular layers diminished (layer IV is not discernible) and hence is called agranular cortex. It contains the large pyramidal cells (inc. giant Betz) in layer V of areas 4 and 6 which give rise to descending projection systems to brainstem and spinal cord, e.g.. corticospinals, corticobulbars, corticopontines, etc.

3. Association Cortex - In broad regions of cortex between primary motor and sensory areas in the prefrontal, parietal, temporal, and occipital lobes (referred to as associational cortex) all of the cortical layers are more evenly represented; it is the most typical isocortex, called homotypical. It is in association cortex that higher level processing occurs and where there is a convergence of sensory modalities (visual, auditory, somatosensory).

From Kandel, Schwartz, and Jessel, Principles of Neural Science

*Note: The cortical layers above Layer IV (Layers I-III) are referred to as

“supragranular,” and Layers IV-VI are “infragranular.” The supragranular layers are fairly uniform from region to region, but there are substantial differences in the infragranular layers (especially Layers IV and V) in sensory and motor cortex. Layer IV is thickest in sensory cortex. Layer V is thickest in motor cortex.

D. Brodmann's Areas - subdivisions of the human cortex described in 1909 have shown cytoarchitectural variations which can be correlated with specific functions. These numerical designations are commonly used as synonyms for gyri with which they are associated.

Wilkinson, Neuroanatomy

Areas 3,1,2 - postcentral gyrus, primary somatosensory cortex Area 4 - precentral gyrus, primary motor cortex Area 6 - premotor area (inc. supplementary motor area on medial aspect of hemisphere) Area 8 - frontal eye field (caudal middle frontal gyrus) Area 17 - cuneus and lingual gyri, calcarine cortex - primary visual cortex Area 22 - superior temporal gyrus – spoken words understood. (part of Wernicke's Area) Area 39, 40 - supramarginal (tactile synthesized) and angular (words visualized) gyri of inferior parietal lobule. Post speech cortex (Wernicke's Area) Area 41, 42 - superior transverse temporal gyri - primary auditory cortex Area 44 - Broca's motor speech area of inferior frontal gyrus (anterior speech cortex)

IV. FUNCTIONAL ORGANIZATION OF THE CORTEX

A. Homunculi (Motor and Sensory) - the body surface is somatotopically represented on the cortical surfaces of the precentral and postcentral gyri respectively. Based on the work of Penfield and others, when electrically stimulated, these functional areas of cortex result in movements or sensations in specific body regions. Cortical neurons have their own "receptive fields", a restricted sensitivity to a small region of the body surface; it may also be modality-specific (i.e., pain vs. touch vs. pressure).

From: Kandel et al., Principles of Neural Science

B. Cortical Columns Studies of the cortex have shown that it is subdivided into vertical columnar subunits which run perpendicular to the cortical surface. Earliest observations of this type of functional organization were made in the somatosensory cortex by Mountcastle, and subsequently in the ocular dominance columns of the visual cortex (Hubel and Wiesel), where the ipsilateral and contralateral eye are represented in alternating columns. More recently, however, columnar organization has been found to characterize other regions, even associational cortex. Each column is made up of "mini columns" which correspond to the "ontogenetic cell columns" (vertical migrations of cells) that occur during cortical development.

Receptive fields in the cortex are made up of several columns in which constituent neurons are responsive to a specific sector of visual, auditory, or somatosensory space. Receptive fields are "plastic" (can be remodeled) throughout life by behaviorally-important inputs (Merzenich/Kaas). Repetitive peripheral skin stimulation causes cortical receptive fields to enlarge; if peripheral nerve is cut, fields shrink, then enlarge with regeneration. Receptive fields in cortex can enlarge with increased usage (Merzenich). It used to be thought that only higher associational cortical areas related to learning and memory remained "plastic" in the adult brain and primary sensory/motor areas were fixed - but now there is good evidence that all cortical areas have plasticity.

V. MYELOARCHITECTURE AND CONNECTIONS OF THE CORTEX

A. Associational Fiber Systems - Intrahemispheric corticocortical fibers interconnecting adjacent gyri (short associational bundles) or distant lobes (long associational bundles) within the same hemisphere. They arise from layer III pyramidal cells. Primary sensory areas (i.e., koniocortex of areas 3,17, 41-42) only have short cortico-cortical associational connections to adjacent cortical regions (e.g., area 17 to area 18; area 18 to area 19 etc.), so that much sequential intracortical processing goes on before stimuli reach effector areas of the cortex to elicit an appropriate response behavior. Examples of long assoc. bundles include: superior longitudinal fasciculus (connects occipital and frontal lobes); arcuate fasciculus (connects posterior speech cortex, Wernicke's area, with anterior speech cortex Broca's area; uncinate fasciculus (connects frontal and temporal lobes; cingulum (connects all parts of limbic lobe cortex). There are also functional sequences of cortical processing to progressively higher levels of integration, such as the dorsal and ventral streams of visual processing (V1 to V2 to V3, etc.)

* Link to Netter Image 11.92 * Link to Netter Image 11.94 * Link to Netter Image 11.95

B. Commissural Fiber Systems - Interhemispheric corticocortical fibers interconnecting cortical regions in opposite hemisphere. They arise from layer III pyramidal cells, as

do associational fibers, and primarily interconnect homologous (the same) cortical areas. There are three major cerebral commissures. 1. Corpus Callosum - interconnects frontal lobes through its rostrum and genu; parietal lobes, superior and middle temporal gyri through its body; and occipital lobes through its splenium. 2. Anterior commissure - interconnects inf. temporal, occipitotemporal and parahippocampal gyri (also amygdaloid nuclei, basal forebrain and olfactory bulbs). 3. Hippocampal Commissure - interconnects hippocampi; fibers exchanged between fornices under splenium of corpus callosum; thus hippocampal formation has its own independent commissure. (not pictured here).

C. Projectional Fiber System - includes fibers ascending to (corticopetal) and fibers descending from (corticofugal) the cortex through the subcortical capsules (internal capsule, external capsule, extreme capsule)

1. Corticopetal Projections - predominantly from thalamus (i.e., thalamocortical fibers) Specific thalamic afferents to certain cortical regions are so dense below granular layers (II and IV) they produce prominent lines (lines of Baillarger, lines of

Gennari). Thalamic afferents, like callosal (commissural) and associational afferents, terminate within functional columns of cortex not randomly (e.g., lateral geniculate nuc. to ocular dominance columns). * Link to Netter Image 11.84

2. Extra-thalamic Corticopetal Projections - There are also projections from certain brainstem reticular formation areas that reach cortex directly without first synapsing

in the thalamus (locus ceruleus, NE; midbrain raphe, serotonin; ventral tegmental area, dopamine; nucleus basalis of Meynert, ACh). These projections, in contrast to thalamic, callosal or assoc. afferents, terminate diffusely over regions of cortex (not restricted to columns) and terminate across all cortical layers (not just layer IV). These projections affect the background activity of the cortex rather than conveying specific information; i.e., affecting levels of consciousness (EEG) or "mood" against which background incoming thalamic information is played. * Link to Netter Image 11.96 * Link to Netter Image 11.97 * Link to Netter Image 11.99

3. Corticofugal Projections - includes all the major descending cortical efferent projections to subcortical, brainstem, and spinal cord regions (e.g., corticospinal, corticopontine, corticobulbar, corticostriate). They originate predominantly from large pyramidal cells in layer V.

From Noback and Demarest, The Human Nervous System

Only corticothalamics originate from layer VI. The internal capsule is the main conveyor of thalamic corticopetal and corticofugal projections, to and from the cerebral cortex. * Link to Netter Image 11.93

From: Noback et al., The Human Nervous System

VI. MOTOR-RELATED CORTICAL AREAS

A. Frontal Cortical Regions Involved

1. M-I Primary Motor Cortex - (Area 4) Precentral areas/paracentral lobule Cells of origin of corticospinal and corticobulbar tracts; Initiates movements, i.e.

execution of independent fractionated movements. Receives cerebellar adjustments via VL thalamus (appropriate metric instructions considering position of limbs - proprioception)

2. M-II Supplementary Motor Area and Premotor Cortex (Area 6)

Planning/programming of movement Receives parietal input re: position of limbs (proprioception) within personal space. Receives basal ganglia input from VA thalamus related with automated (remembered) patterns of movement

3. Prefrontal Cortex - involved with "executive control" of behaviors Anticipates consequences of actions, based upon memory. Cognition, decision-

making (decision to move) and strategies (mental rehearsal) for movement to reach a goal influenced by mood (emotion) and personality.

Prefrontal Cortex Decision / Strategy →

Premotor Cortex Programming →

Primary Motor Cortex Execution

MD ↑ (Limbic) VA ↑

from basal ganglia VL ↑ from cerebellum

The cerebellum and basal ganglia have different roles in the production of movement. The cerebellum plays a focal role in motor learning, in "encoding" the appropriate metrics and velocity of movements based upon the position of the body and limbs (receives vestibular and proprioceptive inputs). The cerebellum is constantly "updated" about ongoing movements and changing positions of limbs through the cortico-pontine-ponto cerebellar system. The basal ganglia becomes important once a motor pattern is learned, in motor memory, and functions with the premotor cortex to re-run learned (automated) programs of movement.

VII. CEREBRAL DOMINANCE IN LANGUAGE FUNCTION

Certain aspects of learned behavior in man is exerted predominantly by one or the other of the cerebral hemispheres. The left (major, dominant) hemisphere has essential roles in language and analytic abilities. The right (minor, non-dominant) hemisphere has crucial roles in non-verbal and artistic expression, sensation and appreciation of spatial relations. These specificities in hemispheric function can be illustrated in the twin-brain subject. Language function is not exclusively in left hemisphere. LEFT - More active in syntax and phonetics. RIGHT - More active in visual analysis of word form (spatial).

Twin-Brain Studies with Commissurotomy, cut corpus callosum. (1) Cannot describe orally object felt with left hand i.e. sensory reaches right hemisphere but spatial cannot be transferred to left for language (2) Cannot draw with right hand because motor centers in left hemisphere cannot receive guidance of spatial knowledge on right.

From Noback and Demarest, The Human Nervous System

VIII. LANGUAGE-RELATED CORTICAL AREAS (COMPREHENSION AND SPEECH PRODUCTION)

A. Cortical Areas

1. Anterior Speech Cortex (Broca's area, area 44) - the pars opercularis and triangularis of the inferior frontal gyrus; patterning of speech, speech production. 2. Posterior Speech Cortex (includes Wernicke's area, area 22; and areas 39,40) - in the caudal superior temporal gyrus, and supramarginal and angular gyri of the inferior parietal lobule; perception of words, language comprehension.

B. Cortico-cortical (Associational) Connections

1. Arcuate Fasciculus - intrahemispheric associational bundle interconnects the posterior (Wernicke's) speech area with the anterior speech cortex (Broca's area). 2. Disconnection Syndromes - speech deficits result from lesions within cortical

regions, or associational connections between them, that prevent the sequential intracortical processing of information basic to normal language comprehension and speech production by selectively disrupting a modality-specific aspect of language function,

C. Clinical Deficits/Lesions

1. Aphasias - language dysfunction, either expression by speech, or comprehension of written or spoken language, resulting from brain injury; over 96% of adult aphasics with language disorders have brain damage in the left (major) hemisphere.

a. Receptive Aphasia - parieto/temporal lesion in Wernicke's area; may include inferior parietal lobule (supramarginal area 40, or angular area 39), or caudal sup. temp. gyrus (area 22); failure in understanding spoken or written language.

b. Expressive Aphasia - inferior frontal lesion in Broca's motor speech area (area 44) in dominant hemisphere. Primarily a failure in the formulation of speech. They usually have normal comprehension of language, but speech is labored and crudely articulated with word omissions.

2. Agnosias - Disturbances with failure to recognize, comprehend, or discriminate somatosensory, visual, or auditory aspects of language. Patients with pure agnosia have no deficits within afferent pathway nor in the reception of the primary input in the principal sensory regions of the cortex. a. Tactile agnosia (astereognosis) - inability to recognize common objects through cues from general sensory receptors; lesions in supramarginal gyrus (Area 40) b. Visual agnosia - (word blindness) - words seen but not recognized; lesion in angular gyrus (Area 39) or possibly 19. c. Auditory agnosia (word deafness) - spoken words not recognized. Wernicke's area (Area 22) lesion (caudal superior temporal gyrus)

APHASIAS: DISTURBANCE OF LANGUAGE FUNCTION Table 3

A. Receptive Aphasias- (lesion in Wernicke's Area) disruption of language comprehension, recognition of symbols of language (visual, auditory, somatosensory)

1. Tactile Agnosia (astereognosis) - supramarginal gyrus 2. Visual Agnosia (word blindness) - angular gyrus 3. Auditory Agnosia (word deafness) - caudal sup. temp. gyrus

B. Expressive Aphasias - (lesion of Broca's Area) disruption of speech production; normal comprehension of language, but speech is labored, poor syntax, word omissions

3. Alexia and Agraphia - loss of abilities to read and write, respectively. Lesions of angular gyrus (area 39); patient can comprehend spoken language and speak, but the written word is meaningless. 4. Apraxia - inability to move (i.e., perform movements) due to a deficit in perceiving the position of the limbs in space; thus a sensory deficit can prevent normal movement. It usually occurs as a result of lesions of the superior parietal cortex (area 5/7) containing somatosensory associational cortex.

From: Kandel, Schwartz, and Jessel, Principles of Neural Science

For normal movement, the “percept” of the body (personal space) from the superior parietal cortex must reach premotor cortex to influence “motor planning.”

IX. CORTICAL MECHANISMS OF VISUAL ATTENTION AND PERCEPTION

A. Attention - the posterior parietal cortex is concerned with focussing attention on a visual stimulus. One can “attend” to a stimulus without looking at it. The prefrontal and parietal cortex actually work together in the process of attention. The prefrontal cortex functions in "working memory," temporarily holding an object in memory while an action or behavioral response is planned.

Emotional salience (threatening, non-threatening) of an object, event is probably conveyed to parietal cortex from the amygdala.

B. Hemi-Inattention Syndrome - failure to recognize body scheme. patient is unaware of (or pays no attention to) the contralateral side of the body. It is a multi-modal sensory neglect. Some patients deny contralateral arm belongs to their body; or contralateral face may not be washed or shaved. Usually results from large lesion of parietal cortex.

C. Voluntary Eye Movements (rapid, saccades associated with attention-focusing) –

the frontal eye field (area 8) initiates saccades to "look at" a visual stimulus. FEF Lesion - eyes deviate to side of lesion - produces paralysis of contralateral conjugate eye movements (cannot move eyes contralaterally)

Smooth Pursuit – in slow eye movements the eye velocity must "match" the target velocity in order to "follow" it. The analysis of visual motion occurs in a region of preoccipital cortex known as the MT visual area (middle temporal; V5); communicates via the basilar pontine nuclei (corticopontines) with the cerebellum, which is essential to calculating appropriate eye velocity to track a moving visual target.

Lesions of preoccipital cortex (MT area in primates) result in deficits in smooth pursuit.

“Streams of Visual Processing” - through a multisynaptic sequential chain of associational connections (“streams”), visual information is conveyed forward in the cortex. The dorsal stream is concerned with “where” the visual stimulus is in visual space (perception) and attention, and the ventral stream with “what” the visual stimulus is; visual discrimination of object features, facial recognition.

A Self-Assessment is available for this lecture. * Netter Presenter Image Copyright 2004 Icon Learning Systems. All rights reserved.