•basal forebrain nuclei	acetylcholine
•tuberoinfundibular (hypothalamus)	histamine
•tegmentum (midbrain)	dopamine
•raphe nucleus (midbrain)	serotonin
•cerulean nucleus (pons)	norepinephrine

These five sets of neurons are of particular relevance to psychiatry and are considered in Chapter 34.

Efferents

All efferents from the cerebral cortex are axons of pyramidal cells, and all are excitatory in nature. Axons of some pyramidal cells contribute to short or long association fibers. Others form commissural or projection fibers.

• Examples of short association fiber projections are those entering the motor cortex from the sensory cortex and vice versa (Figure 29.1). Examples of long association fiber projections are the numerous backward projections from the prefrontal cortex – the cortex anterior to the motor areas (see below) to sensory association areas.

• The commissural fibers of the brain are entirely composed of pyramidal cell axons running across in the corpus callosum and anterior commissure (and in other, minor commissures) to matching areas in the opposite hemisphere.

• Projection fibers from the primary sensory and motor cortex form the largest input to the basal ganglia (Ch. 33). The thalamus receives projection fibers from all parts of the cortex. Other major projection systems are corticopontine (to the ipsilateral nuclei pontis), corticonuclear (to contralateral motor and somatic sensory cranial nerve nuclei in pons and medulla), and corticospinal (to anterior horn motor neurons).

Cortical Areas

The most widely used reference map is that of Brodmann, who divided the cortex into 47 areas on the basis of cytoarchitectural differences. Most of these areas are shown in Figure 29.4. Colored in that figure are the three principal primary sensory areas (somatic, visual, auditory) and the single primary motor area, together with the respective unimodal association areas. The rest of the neocortex comprises multimodal (polymodal) association areas receiving association fibers from more than one unimodal association area (e.g. receiving tactile and visual inputs, or visual and auditory).

Investigating functional anatomy

Two dominant methods are in use for localization of functions in the human brain. Both techniques depend upon the local increases in blood flow that meet the additional oxygen demand imposed by localized neural activity.

Positron emission tomography

Positron emission tomography (PET) measures oxygen consumption following injection of water labeled with oxygen-15 into a forearm vein. ¹⁵O is a positron-emitting isotope of oxygen; the positrons react with nearby electrons in the blood to create gamma rays which are counted by gamma-ray detectors. Alternatively, fluorine-18-labeled deoxyglucose may be used to measure glucose consumption. ¹⁸F-deoxyglucose is taken up by neurons as readily as glucose.

Image subtraction and image averaging are required for meaningful interpretation of PET studies, as explained in the caption to Figure 29.5.

Figure 29.5 Image subtraction and image averaging in PET scans.

Top: The middle image is from a control mode, where the subject lies at rest. Uptake of ¹⁵O is active throughout the cortex and subcortical gray matter. The left image is from the same subject staring at dots moving on a screen. The high level of background activity obscures the effect. The right image is produced by subtracting the control value to reveal the additional activity in the visual cortex produced by the staring task.

Middle: Four other subjects have performed the same task. Subtraction of background ‘noise’ reveals varying differences among the five. Because brains vary in size between individuals, activities in all five brains have been projected onto a common, ‘average’ brain (hence the identical brain profiles in this row).

Bottom: A mean value for the five brains produces a ‘mean difference image’ representative of the five as a group.

(Adapted from Posner and Raichle, Images of Mind, Sci. Amer. Library, 1994, p. 65, with permission.)

For specialized investigations, radiolabeled drugs are used to quantify receptor function, e.g. radiolabeled dopamine in the corpus striatum in relation to Parkinson’s disease (Ch. 33); radiolabeled serotonin in brainstem and cortex in relation to depression (Ch. 26), and radiolabeled acetylcholinesterase in relation to Alzheimer disease (Ch. 34).

Functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) (Figure 29.6) does not require introduction of any extraneous material. It depends upon the different magnetic susceptibility of oxygenated versus deoxygenated blood. As it happens, the local increases in blood flow are more than sufficient to meet oxygen demands, and it is the increase in the ratio of oxyhemoglobin to deoxyhemoglobin that is exploited to generate the MR signal.

Figure 29.6 Patient with visual impairment undergoing fMRI investigation during object recognition and object grasping tasks.

(Kindly provided by Dr. T.W. James, Vanderbilt University Visual Research Center, Nashville, Tennessee.)

Sensory Areas

Somatic sensory cortex (areas 3, 1, 2)

Components

The somatic sensory or somesthetic cortex occupies the entire postcentral gyrus (Figure 29.7). Representation of contralateral body parts is inverted except for the face, and the hand, lips, and tongue have disproportionately large representations. The homunculus diagram shown in Figure 29.7A was intended to be only schematic and ignored the extensive overlap of body part representations.

Figure 29.7 (A) Figurine (adapted from Penfield and Rasmussen, 1960) depicting the inverted disposition of the motor homunculus in the left precentral gyrus excepting the face. Overlap among body part representations is not shown.

(B) The primary motor cortex (red) and primary somatosensory cortex (blue) viewed from above. The relatively larger representation of the motor and sensory areas in the left hemisphere is typical of right-handed individuals. On the right hemisphere is shown the extensive overlap of the (left) face and tongue representations.

(Adapted from Kretschmann, H-J. and Weinrich, W. Neurofunctional Systems: 3D Reconstructions with Correlated Neuroimaging: Text and CD-ROM. 1998 New York: Thieme, with permission.)

In vertical sections, represented in Figure 29.8, the somesthetic cortex is divisible into areas 3, 2, and 1. Area 3 is divided into smaller area 3a, in receipt of information relayed from muscle spindles, and a larger area 3b, receiving information relayed from cutaneous receptors. Area 3b is highly granular and is regarded as the true primary somatosensory cortex (S1).

Figure 29.8 Sensory sequence enabling identification of a key by touch alone.

(A)Coded information from the right hand is traveling along second-order sensory (crossed) neurons in the medial part of the left posterior column–medial lemniscal pathway in the upper brainstem. ML, medial lemniscus.

(B)The hand area of the ventral posterior lateral nucleus (VPLN) of the thalamus contains somas of third-order sensory neurons.

(C)The third-order neurons project to areas 3, 1 (indirectly), and 2 of the somatic sensory cortex.

(D)SDM, single digit module.

(E)MDM, multidigit module.

(F)Surface view of the left parietal lobe.* Indicates the level of section C through the hand area. Area 7 receives short association fibers from areas 1, 2 and 5, and integrates information from skin, muscle spindles and joint capsules.

(G)Connections with tactile memory stores here and in area 5 enable an image of the key to be perceived without the aid of vision.

Modules in area 1 have peripheral receptive fields confined to a single digit (Figure 29.8D). In monkeys, needle electrodes recording from area 1 reveal feature extraction, e.g. some modules are rapidly adapting, some are slowly adapting, some respond only to skin stroking in a specific direction, and some respond only to noxious stimulation of the skin. Modules in area 2 (Figure 29.8C) have multidigit receptive fields and receive from muscles and joint capsules in addition to skin.

Afferents

In addition to thalamic afferents from the ventral posterior nucleus (Figure 29.8B), the somesthetic cortex receives commissural fibers from the opposite somatic sensory cortex through the corpus callosum, and short association fibers from the adjacent primary motor cortex. Many of the fibers from the motor cortex are collaterals of corticospinal fibers traveling to the anterior horn of the spinal cord, and they may contribute to the sense of weight when an object is lifted.

It is not unusual for the somesthetic cortex to be compromised by bleeding from a striate branch of the middle cerebral artery supplying the sensory thalamocortical projection, within the upper part of the internal capsule. Cortical-type sensory loss in such cases is shown by a reduction in sensory acuity on the opposite side of the body, especially in forearm and hand, evidenced by a raised sensory threshold, poor two-point discrimination, and impaired vibration sense and position sense. The term stereoanesthesia is sometimes used with reference to inability to identify an unseen object held in the hand, as a consequence of cortical-type sensory loss.

Efferents

Efferents from the somesthetic cortex comprise association, commissural, and projection fibers. Association fibers pass to the ipsilateral motor cortex, to area 5 and to area 40 (the supramarginal gyrus). Commissural fibers pass to the contralateral somesthetic cortex. Projection fibers descend within the posterior part of the pyramidal tract and terminate upon internuncial neurons in sensory relay nuclei, namely the ventral posterior nucleus of the thalamus of the same side, and the posterior column and spinal posterior gray horn of the opposite side. As explained in Chapter 16, sensory transmission in the spinothalamic pathway may be suppressed (via inhibitory internuncials, during vigorous activities such as running, whereas in the posterior column–medial lemniscal pathway, transmission may be enhanced (via excitatory internuncials) during exploratory activities such as palpation of textured surfaces.

Somatic sensory association area

This term is used with respect to area 5, directly behind the somatic sensory cortex. Most area 5 modules are active during reaching movements of the contralateral arm taking place under visual guidance (the dorsal visual pathway is discussed later).

Superior parietal lobule

Clinically, the term superior parietal lobule is equated with area 7. The lower part of area 7 receives inputs from areas 1, 2 and 5. Receipt of tactile and proprioceptive information from skin, muscles, and joints causes area 7 to tap into its own memory stores concerning the shapes of objects held in the (opposite) hand, whereby an unseen object can be identified (Figure 29.8). This ability is known as stereognosis, a term signifying ability to perceive objects ‘in the round’.

The upper part of area 7 contains a cell station in the ‘Where’ visual pathway (see later).

Inferior parietal lobule

The inferior parietal lobule comprises areas 39 (angular gyrus) and 40 (supramarginal gyrus). Both are concerned with language, a mainly left hemisphere function described in Chapter 32.

Intraparietal cortex

The cortex in the walls of the intraparietal sulcus is especially active during tasks involving visuomotor coordination, e.g. reaching for and grasping objects identified in the contralateral visual field and subjecting them to simultaneous visual and tactile three-dimensional analysis. This area includes the parietal eye field (see later).

Secondary somatic sensory area

On the medial surface of the parietal operculum of the insula is a small secondary somatic sensory area (SII). It receives a nociceptive projection from the thalamus and it is highlighted during PET scans of the brain during peripheral painful stimulation (Ch. 34). SII also appears to collaborate with SI in aspects of tactile discrimination.

Plasticity of the somatic sensory cortex

In monkeys, cortical sensory representations of the individual digits of the hand can be defined very exactly by recording the electrical response of cortical cell columns to tactile stimulation of each digit in turn. These digital maps can be altered by peripheral sensory experience, as the following experiments indicate:

• The median nerve supplies the ventral surface of the outer three digits of the hand, whereas the radial nerve supplies their dorsal surfaces. If the median nerve is crushed, the representation of the dorsal surface on the digital map increases at the expense of the ventral representation. The increase begins within hours and progresses slowly over a period of weeks. With regeneration of the median nerve, the cortical map reverts to normal.

• If the middle digit is denervated, the corresponding cortical area is unresponsive for a few hours, then becomes progressively (over weeks) taken over by expansion of the representations of the second and fourth digits.

• If the pad skin of a digit is chronically stimulated, e.g. by having to press a rotating sanded disc in order to release pellets of food, representation of the pad may increase to twice its original size over a period of weeks, reverting to normal after the experiment is discontinued.

These experiments show that somatic sensory maps are plastic, being modified by peripheral events. A purely anatomical explanation (e.g. sprouting of nerve branches within the CNS, or peripherally) is not appropriate for the earliest changes, which begin within hours. Instead, they can be accounted for on the basis of sensory competition.

Sensory competition

Sensory maps made at the level of the posterior gray horn, posterior column nuclei, thalamus, and somesthetic cortex all show evidence of anatomical overlap. For example, the thalamocortical somesthetic projection for the third digit overlaps the projections for the second and fourth. Within the zone of overlap, cortical columns are shared by afferents from two adjacent digits. As already explained, smooth stellate cells exert lateral inhibition upon weakly stimulated columns. Under experimental conditions (in cats), the number of columns responding to a particular thalamocortical input can be increased by local infusion of a GABA antagonist drug (bicuculline), which suppresses lateral inhibition. The effect of removal of a peripheral sensory field may be comparable: if one set of thalamocortical neurons falls silent owing to loss of sensory input, it no longer exerts lateral inhibition and cortical columns within its territory are taken over by neighboring, active sets.

In the human somatosensory body map, the digits are represented next to the face. In several well-documented cases of upper limb amputation, patients had later experiences of ‘phantom finger’ sensations on touching their face on that side with an implement such as a comb held in the other hand. This illusion may occur within 2 weeks of amputation. It can be explained on the basis of the unmasking of pre-existing overlap of thalamocortical neurons.

Visual cortex (areas 17, 18, 19)

The visual cortex comprises the primary visual cortex (area 17) and the visual association cortex (areas 18 and 19).

Primary visual cortex (Figure 29.4)

As noted in Chapter 28, the primary visual cortex is the target of the geniculocalcarine tract, which relays information from the ipsilateral halves of both retinas, and therefore from the contralateral visual field. This myelinated tract creates a pale visual stria within the primary visual cortex before synapsing upon spiny stellate cells of the highly granular lamina IV. The visual stria (first noted by medical student Francesco Gennari circa 1775) has provided the alternative name, striate cortex, for area 17.

The spiny stellate cells belong to ocular dominance columns, so named because alternating columns are dominated by inputs from the left and right eyes (Ch. 28). In a surface view of the visual cortex, the columnar arrangement takes the form of whorls, resembling finger prints. The geniculocalcarine projection is so ordered that matching points from the two retinas are registered side by side in contiguous columns. This arrangement is ideal for binocular vision because modules at the edge of a column respond to inputs from both eyes.

Under experimental conditions (monkeys), spiny stellate cells of the primary visual cortex give ‘simple’ responses to slits of light of a particular orientation. Some of the pyramidal cells give ‘complex’ responses to bars (broad slits) of a particular orientation; for many cells, the bar must be moving broadside in a specific direction. Other pyramidal cells are ‘hypercomplex,’ responding to L-shapes. This hierarchy of responses can be explained on the basis of convergence of several simple-cell axons onto complex cells and convergence of complex-cell axons onto hypercomplex cells.

In volunteers, two additional areas of cortex become active when items of special interest appear. Shown in Figure 29.8, and mentioned again later, is the dorsolateral prefrontal cortex (DLPFC), a significant decision-making area, notably in relation to an approach or withdraw decision. Shown in Figure 29.10 is a patch in the cortex of the anterior cingulate gyrus. This area is considered in Chapter 34 but it may be mentioned here that it is activated by the dorsolateral cortex when subjects are paying attention to a visual task.

The ‘What?’ visual pathway (Figure 29.10)

The ventral visual pathway converges onto the anteromedial part of area 19, mainly within the fusiform gyrus part of the occipitotemporal gyrus. This region is concerned with three kinds of visual identification, indicated in Figure 29.10B:

• Relatively lateral are modules activated by the forms (shapes) of objects of all kinds, including the shapes of letters. It is regarded as a center for generic (categorical/canonical) object identification (e.g. a dog as such, without connotation).

• In the midregion are modules specifically devoted to the generic identification of human faces.

• Relatively medial is the color recognition area, essential for recognition of all colors except black and white. A state of achromatopsia may occur following a sustained fall in blood pressure within both posterior cerebral arteries, caused, e.g., by an embolus blocking the top of the parent basilar artery. Such patients see everything only in black and white (gray scale).

Figure 29.10 (A) Medial view of right hemisphere, showing the ‘What?’ pathway. The asterisk marks the visual identification area within the fusiform gyrus on the inferior surface. Ventral area 19 is enlarged in (B).

Recognition of individual objects and faces is a function of the anterior part of the ‘What?’ pathway in the inferotemporal cortex (area 20) and in the cortex of the temporal pole (area 38). These two areas are engaged during identification of, for example, Mary’s face or my dog. Failure of facial recognition (prosopagnosia) is a frequent and distressing feature of Alzheimer disease (Ch. 34), where the patient may cease to recognize family members despite retaining the sense of familiarity of common objects.

Threatening sights or faces cause areas 20 and 38 to activate the amygdala, especially in the right (emotional) hemisphere; the right amygdala in turn activates the fear-associated right orbitofrontal cortex (see Ch. 30).

How are visual association areas activated, e.g. in execution of a decision to look for an apple in a bowl of mixed fruit, or for a particular word in a page of text? In PET studies, the frontal lobe is active whenever attention is being paid to a task at hand. The DLPFC is particularly active during visual tasks involving form and color. During visual searching, the role of the frontal lobe seems to be to activate memory stores within the visual association areas, so that the relevant memories are held on-line during the search. The anterior part of the cingulate cortex is also active.

The V1–V5 nomenclature

Specialists in vision research use the following designations in relation to cortical visual processing:

V1equates with Brodmann area 17.

V2and V3 equate with Brodmann areas 18 and 19, respectively.

V4includes the three sets of identification modules in the fusiform gyrus (anteromedial Brodmann area 19).

V5equates with the movement detection modules in the lateral occipital cortex (anterolateral Brodmann area 19).

Auditory cortex (areas 41, 42, 22)

The primary auditory cortex occupies the anterior transverse temporal gyrus of Heschl, described in Chapter 20. Heschl’s gyrus corresponds to areas 41 and 42 on the upper surface of the superior temporal gyrus. Columnar organization in the primary auditory cortex takes the form of isofrequency stripes, each stripe responding to a particular tonal frequency. Higher frequencies activate lateral stripes in Heschl’s gyrus, lower frequencies activate medial stripes. Because of incomplete crossover of the central auditory pathway in the brainstem (Ch. 20), each ear is represented bilaterally. In experimental recordings, the primary cortex responds equally well from both ears in response to monaural stimulation but the contralateral cortex is more responsive during simultaneous binaural stimulation.

The auditory association cortex corresponds to area 22, for speech perception (considered in Ch. 32). Visual and auditory data are brought together in the polymodal cortex bordering the superior temporal sulcus (junction of areas 21 and 22).

Excision of the entire auditory cortex (in the course of removal of a tumor) has no obvious effect on auditory perception. The only significant defect is loss of stereoacusis: on testing, the patient has difficulty in appreciating the direction and the distance of a source of sound.

Motor Areas

Primary motor cortex

The primary motor cortex (area 4) is a strip of agranular cortex within the precentral gyrus. It gives rise to 60–80% (estimates vary) of the pyramidal tract (PT). The remaining PT fibers originate in the premotor and supplementary motor areas and in the parietal cortex, as illustrated in Chapter 16.

There is an inverted somatotopic representation of contralateral body parts except the face, with relatively large areas devoted to the hand, circumoral region, and tongue (Figure 29.7). The hand area can usually be identified as a backward projecting knob 6–7 cm from the upper margin of the hemisphere.

Ipsilateral body parts are also represented in the somatotopic map, ipsilateral motor neurons being supplied by the 10% of PT fibers that remain uncrossed.

A computerized graphic reconstruction of the motor cortex and corticospinal tracts from a postmortem brain is shown in Figure 29.11.

Figure 29.11 Computerized graphic reconstruction of postmortem brain; anterior view showing the precentral gyri, and the relationships of the corticospinal tracts (CST) to the ventricular system. Some corticospinal fibers have been added to the original.

(Reproduced from Kretschmann, H-J. and Weinrich, W. Neurofunctional Systems: 3D Reconstructions with Correlated Neuroimaging: Text and CD-ROM. 1998 New York: Thieme, with kind permission of the authors and publisher.)

Direct stimulation of the human motor cortex indicates that the cell columns control movement direction. Individual PT fibers are known to branch extensively as they approach the anterior gray horn, and to terminate on motor neuronal dendrites in nuclei serving several different muscles. The pattern of distribution of PT fibers is directed toward movement synergy, which in this context means the simultaneous contraction of all of the muscles concerned, with a bias among them suited to the task at hand. The act of picking up a pen, e.g., requires a moderate contraction of opponens pollicis as prime mover, a matching level of contraction of the portion of flexor digitorum profundus providing the tendon to the terminal phalanx of the index finger, and lesser levels of contraction of adductor and flexor brevis pollicis. Steadying the upper limb as a whole during any kind of manipulative activity is a function of the premotor cortex (see later).

Plasticity in the motor cortex

In monkeys and in lower mammals, small lesions of the motor cortex produce an initial paralysis of the corresponding body part, followed within a few days (sometimes within hours) by progressive recovery. The recovery is attributable to a change of allegiance of cell columns close to the lesion, which take on the missing motor function. Instead of inflicting a lesion, it is possible to enlarge the motor territory of a patch of cortex merely by injecting a GABA antagonist drug locally into the cortex. Expansion of motor territories at spinal cord level is already provided for by extensive overlap of projections from area 4 to the motor cell columns in the ventral gray horn.

Sources of afferents to the primary motor cortex

1 The opposite motor cortex, through the corpus callosum. The strongest commissural linkages are between matching cell columns that control the vertebral and abdominal musculature. This is to be expected since these muscle groups routinely act bilaterally in maintaining the upright position of the trunk and head. The weakest commissural linkages are between cell columns controlling the distal limb muscles, where the two sides tend to act independently.

2 Somatosensory cortex. Cutaneous cell columns in areas 1, 2, and 3 feed forward via short association fibers. Linkages for the hand are especially numerous; the distance is short because the hand areas of the motor and somatic sensory cortex mainly occupy the corresponding walls of the central sulcus. Proprioceptive cell columns in area 3a receive afferent relays from the annulospiral endings of muscle spindles; they send short association fibers to the corresponding motor columns for execution of the long-loop stretch reflex (Ch. 25).

3 Contralateral dentate nucleus. The cerebellum assists in the selection of appropriate muscles for synergic activities, and in the timing and strength of their contractions.

4 Supplementary motor area.

Premotor cortex

The premotor cortex (PMC, area 6 on the lateral surface of the hemisphere) is about six times larger than the primary motor cortex. It receives cognitive inputs from the frontal lobe in the context of motor intentions, and a rich sensory input from the parietal lobe (area 7) incorporating tactile and visuospatial signals. It is especially active when motor routines are run in response to visual or somatic sensory cues, e.g. reaching for an object in full view or identifying an object out of sight by manipulation. The PMC is usually active bilaterally if at all. One explanation is the need for interhemispheric transfer of motor plans through the corpus callosum. It is also the case that the PMC has a major projection to the brainstem nuclei that give origin to the reticulospinal tracts (and a minor one to the pyramidal tract). Lesions confined to the human PMC are rare, but they are characterized by postural instability of the contralateral shoulder and hip. A significant function of the PMC therefore seems to be that of bilateral postural fixation, e.g. to fixate the shoulders during bimanual tasks and to stabilize the hips during walking. The PMC may contribute to recovery of function in cases of pure motor hemiplegia (Ch. 35) following a vascular lesion confined to the corticospinal tract within the corona radiata. The PMC shows increased activity on PET scans following such a lesion; the corticoreticulospinal pathway descends anterior to the corticospinal tract.

Supplementary motor area

In contrast to the PMC’s responsiveness to external cues, the supplementary motor area (SMA, area 6 on the medial surface of the hemisphere) responds to internal cues. In particular, it is involved in motor planning, as exemplified by the fact that SMA is activated by the frontal lobe (DLPFC) the moment we intend to make a movement, even if the movement is not performed. The principal function of SMA seems to be that of preprogramming movement sequences that have already been built into motor memory. It functions in collaboration with a motor loop passing through the basal ganglia (Ch. 33) and projects to area 4 as well as contributing directly to the pyramidal tract. Unilateral lesions of SMA are associated with akinesia (inability to initiate movement) of the contralateral arm and leg. Bilateral lesions are accompanied by total akinesia, including akinesia for speech initiation.

Cortical eye fields

Figure 29.12 illustrates six cortical eye fields involved in scanning movements (saccades). Their connections and functions are summarized in Table 29.1.