Cerebral Physiology Jonathan Bekenstein, M.D., Ph.D.

OBJECTIVES:

1. Know basic concepts about localization of cortical function. 2. Understand localization of and cerebral dominance of the left hemisphere in most humans, based on neuroanatomical and developmental observations. 3. Understand that vascular or other damage in particular parts of cortex produce clinical syndromes that can help localize the lesion. 4. Recognize neural networks that are important for higher cortical function and that many regions may be involved for complex tasks.

I. INTRODUCTION: HISTORY OF STUDIES OF CORTICAL FUNCTION

How did we discover what does?

Autopsy from those with brain injury. Cytoarchitecture (Brodmann areas). Broca’s area (44) Electrical stimulation during resective brain surgery. Sodium amytal test (Wada test) revealed lateralization of language. Functional imaging (PET, fMRI, amobarbital testing, diffusion tensor imaging (fiber tract analysis), magnetic source imaging)

II. LOCALIZATION OF CORTICAL FUNCTION: AN OVERVIEW

A. Newer techniques used to determine cerebral function include , positron emission tomography, and functional magnetic resonance imaging.

1. Magnetoencephalography: measures magnetic fields generated in cortex allowing construction of a three dimensional image of field sources with high temporal resolution.

2. PET: radioactively labeled substances can be used to visualize metabolically active areas of the brain and allow visualization of synaptic activity and receptor localization.

3. fMRI: based on different magnetic properties of oxyhemoglobin and deoxyhemoglobin. Brain activation in specific regions is followed by a change in regional blood flow and also by a change in the relative concentrations of the two forms of hemoglobin, which causes a change in the MRI signal. Figure 1.

B.

1. Primary (area 4): precentral is the site of origin of voluntary movement sending motor impulses through the pyramidal tracts to the anterior horn cells of the spinal cord. Receives subcortical input from cerebellum. Has somatopic organization, known as motor homunculus.

2. Supplementary motor cortex (part of area 6): receives its subcortical input from the basal ganglia. SMA is implicated in actions that are under internal control, such as the performance of a sequence of movements from memory (as opposed to movements guided by a visual cue.)

3. : 30% of the axons in the corticospinal tract arise from neurons in the premotor cortex. Major subcortical input is also from the cerebellum. Major output is to the reticular formation, and is thought to be important for control of girdle musculature. Involved in selection of movement, rather than initiation of movement.

4. : for “executive” function and planning. It contains active representations in working memory, as well as representations of goals and contexts.

5. Expressive language- (Broca’s area)

B.

1. Primary somatosensory cortex: somatotopic representation. Responsible for attention, as lesions cause inattention or neglect. Responsible for and apraxias

2. Responsible for awareness of body surface, distinguishing objects by touch

3. Involvement in memory and learning.

C.

1. Primary : superior temporal gyrus

2. Receptive language.

3. Visual association: color and recognition, visual discrimination

4. Primary olfactory cortex: prepyriform, of

5. Link past and present social and emotional experiences.

D.

1. Primary

2. Color recognition

3. Perception of motion (preoccipital visual area MT)

4. Visual pursuit

E.

1. Taste area

2. Cravings.

III. CEREBRAL DOMINANCE

Dominance develops gradually. In young children with brain injury in one hemisphere, or who undergo hemispherectomy for treatment of intractable epilepsy, the remaining or healthy hemisphere can develop the language, motor, and sensory functions of the lost or damaged hemisphere.

An inherent anatomic asymmetry is present in the brain. The is larger in 65% of brains on the left. This may initially favor language localization in the left hemisphere.

Lateralization, in theory, may allow for more efficient “wiring” and for faster processing speed; however, there is no concrete evidence for this.

Einstein Syndrome: he didn’t speak until age 5. There is a popular theory that late language development allows areas normally used for language to develop into areas used for mathematical calculations.

IV. ANATOMICAL LOCALIZATION OF LANGUAGE

There is prominent lateralization Language is particularly prominent in the left hemisphere. More than 90% of right handers are left hemisphere language dominant and more than 70% of left handers are still left hemisphere dominant.

Cortical and subcortical representation of language is separate from the circuits involved in motor control of pharynx, larynx, tongue and mouth. Letter sequences that do not make words primarily activate visual cortex. Tones that are not words activate auditory cortex in the superior temporal gyrus, usually on the left side of the brain. The can determine words from sounds from either visual or auditory representations, as written or spoken words always activate Wernicke’s area ( 22).

Neural networks are important. Studies indicate that multiple brain regions are involved in language tasks at the same time.

Interhemispheric anatomical asymmetries may reflect left hemisphere specialization for language. The Sylvian fissure is longer in the left hemisphere than in the right in most individuals

Quantitative assessment of fiber tract morphology indicates that the left (connects Wernicke’s and Broca’s areas) is larger and has a greater degree of anisotropic molecular movement along its bundle than the right hemisphere in humans (Powell et al 2006). This suggests that the left arcuate fasciculus is more active than the right and is consistent with left hemispheric specialization for language. Asymmetries are less marked or reversed among individuals with right hemisphere language specialization. These findings suggest that anatomical specialization for basic language is associated with relative enlargement of contributing anatomical structures.

In contrast, the right hemisphere may preferentially process language more broadly. Several lines of research suggest that the right hemisphere in most healthy individuals has limited linguistic ability, but it nonetheless takes part mostly (if not exclusively) in well-learned, "automatic," non-propositional speech that is produced with minimal or no premeditation, such as greeting, recitation by rote, and swearing.

Figure 2.

The classic model is definitely incomplete, but is useful for communication between clinicians.

Broca's and Wernicke's 19th century clinical observations inspired a serial processing model of left hemisphere language function for most right-handers that was highly influential in inspiring current concepts of structural-functional relations in general neuroscience, but is beginning to be regarded largely incomplete (Damasio et al 2004). The model posited that 2 areas are vital for language: (1) Broca’s area in the left frontal , which encodes phonology for expression, and (2) Wernicke’s area in the left posterior superior temporal gyrus, which associates heard speech with meanings. Finally, a white matter bundle that connects these areas, the arcuate fasciculus, is incorporated indicate how Wernicke’s area may control speech expression, connects Wernicke’s and Broca’s areas.

Newer model, though still incomplete: This network, or parallel distributed processing model (Absher and Benson 1993), posits that the brain has regionally specialized functions, but that particular cognitive operations emerge from reciprocal neuronal communication among these diverse areas; thus, restricted lesion does not abolish a regionally specific function, but instead impairs it. Compensated function (recovery) emerges from the enhanced activation of, or reorganized connections among, surviving brain regions. Nonetheless, the model is incomplete, as it does not well address grammatical disturbances or phonemic paraphasias. Figure 3.

Other Brain Areas Affecting Language: Cerebellum

The right cerebellum is metabolically linked with the left frontal cortex on language-related tasks, as demonstrated on positron emission tomography studies of word generation and speech discrimination (Petersen et al 1989; Raichle et al 1994; Karbe et al 1995; Mathiak et al 2002). It is, therefore, not surprising that left frontal injury resulting in nonfluent aphasia is associated with contralateral cerebellar hypometabolism, and that this is less common in fluent aphasia (Metter et al 1987). Whether contralateral cerebellar metabolic dysfunction following left frontal lesion contributes to aphasia is unknown. They concluded that lesions of the right cerebellar hemisphere lead to verbal deficits, while those of the left lead to nonverbal deficits. The generally greater impairment of those patients with a right-sided lesion was interpreted as resulting from the connection of the right cerebellum to the left , which is dominant for language functions and crucial for right hand movements. Jansen and colleagues, using fMRI with healthy subjects, corroborated that crossed cerebral and cerebellar language dominance is a typical characteristic of brain organization (Jansen et al 2005).

The results showed that the cerebellum has reciprocal connections with both left inferior frontal gyrus and left lateral temporal cortex whereas the putamen has unidirectional connections into these two brain regions.

Other Brain Areas Affecting Language: Thalamus

Language disorder syndromes noted following thalamic damage can be categorized into 3 subtypes: (1) medial (left paramedial thalamic area, involving dorsomedial and centromedian nuclei), (2) anterior (left anterolateral nucleus), and (3) lateral (left lateral thalamus). It has been suggested that thalamic nuclei and systems are involved in multiple processes that directly or indirectly support cortical language functions: lexical-semantic functions, working memory, visual processing in reading, and category-specific naming (Crosson 1999). Infarcts in the left posterolateral territory have also been associated with aphasia (Carrera et al 2004). On the other hand, patients may present with classical symptoms suggesting aphasia following thalamotomy (repetition, comprehension, fluency, and naming abnormalities.

Dominant hemisphere thalamic lesions may cause a transient language disturbance (thalamic aphasia)

Reduced spontaneous speech with paraphasic errors and perseveration Impaired auditory comprehension Preserved repetition and reading Impaired spontaneous writing and writing to dictation but normal copying Word-production anomia but spared word selection and word symbolism and distractibility. May be due to left ventrolateral and pulvinar nuclei damage. (G. Ojemann, 1977) Electrical stimulation of ventrolateral thalamus produces acceleration of speaking. (Hassler, R. 1966, in The Thalamus pp 419-438)

V. APHASIAS

A. Broca’s aphasia: speech difficulties; loss of grammatical modifications, and relatively preserved comprehension.

B. Wernicke’s aphasia denotes fluent speech typified by circumlocution and neologisms, and is classically associated with more severe comprehension impairment.

C. Conduction aphasia indicates minimally disturbed comprehension and expression, but with relatively impaired repetition. Global aphasia (or severe aphasia, total aphasia) indicates profoundly impaired general language functions with minimally deficient other cognitive functions.

D. Conduction aphasia (termed because it was thought to result from impaired signal conduction between Wernicke's and Broca's areas in the left hemisphere) is a fluent aphasia typified by phonemic paraphasia and impaired repetition, but with relatively preserved speech comprehension. Conduction aphasics are aware of their deficits, and they try repeatedly to correct their speech errors through minor modifications of single words.

Hyperlalia or excessive fluency may appear following right hemisphere injury with the patient often appearing apathetic and indifferent. Alternatively, hyperlalia may result from posterior left hemisphere injury, in which case its coexistence with impaired comprehension suggests Wernicke aphasia.

Fluency: Absent (no word production on naming tasks) is termed anomia. Reduced Excessive (hyperlalia) Incorrect responses when asked to name are paraphasic errors. Phonemic: a letter or two is wrong Semantic: the wrong word is produced/spoken. With naming objects, retrieval of word memory is involved. With repetition, acoustical analysis of words must be performed to produce identical words.

Figure 4.

VI. MOTOR AND SENSORY LOCALIZATION

Primary somatosensory cortex (areas 3, 2, and 1) correspond roughly to the of the parietal lobe and a small portion of the .

There is point to point (somatotopic) representation of the body’s periphery in the motor and sensory cortex. This is termed the “homunculus” (a “little man”).

Figure 5.

VII. ASSOCIATIONAL CORTEX

A. Unimodal Association Areas

Visual association areas (18 and 19). They receive information from primary visual cortex (area 17) and perform a higher visual analysis of the visual world.

Somatosensory association area lies just behind the primary somatosensory cortex in area 5, .

Auditory association cortex is part of the superior temporal gyrus.

Unimodal association areas receive input through association fibers from the corresponding primary cortical fields, but do not receive direct input from the thalamus.

B. Multimodal Association Cortex

1. Parietal association cortex: the anterior portion processes somatosensory information and the posterior portion integrates somatosensory with visual information to enable complex movements. Lesions of the right parietal cortex lead to the contralateral neglect syndrome. Patients cannot attend to objects or visual input in the left half of visual space or sometimes their own body.

2. Temporal association cortex: lead to difficulty in recognizing, identifying, and naming categories of objects. This is termed . Agnosias may be visual, auditory, or spatial. For example, a patient may not be able to recognize a bottle, or may not be able to recognize a coin when placed in the hand (astereoagnosia).

3. Frontal association cortex (prefrontal cortex): Lesions or damage affect planning, also called “executive function.” Lesions here may prevent someone from making a list or planning a complex task. May also reduce spontaneity. Complex behavioral responses.

Figure 6.

C. Three Principal Frontal Lobe Syndromes (Thimble, M.H., Seminars in Neurology, 10:3, 1990) 1. Orbitofrontal Syndrome (disinhibited) a. Disinhibited, impulsive behavior b. Inappropriate jocular affect c. Emotional lability d. Poor judgment and insight e. Distractability 2. Frontal Convexity Syndrome (apathetic) a. Apathy (occasional brief angry or aggressive outburst common) b. Indifference c. Psychomotor retardation d. Motor perseveration and impersistence e. Loss of self f. Stimulus-bound behavior g. Discrepant motor an verbal behavior h. Motor programming deficits Three-step hand sequence Alternating programs Rhythm tapping Multiple loops i. Poor word list generation j. Poor abstraction and categorization k. Segmented approach to visuospatial analysis 3. Medial Frontal Syndrome (akinetic) a. Paucity of spontaneous movement and b. Sparse verbal output (repetition may be preserved) c. Lower extremity weakness and loss of sensation d. Incontinence

VIII. APRAXIA

Apraxia was coined in the 1870’s by Hughlings Jackson to define the total inability of some aphasic patients to perform certain voluntary movements, such as protruding their tongues, despite the lack of any weakness. These patients did not lack the ability to move the tongue when licking lips. A simple definition is the inability to perform a learned task that cannot be explained by weakness, incoordination, or inattention to commands. Most patients with apraxias are also aphasic.

Motor apraxia: often from lesions of premotor cortex in frontal lobe. May have a gait apraxia in which the feet sort of drag along. Patients have difficulty lifting feet off the floor.

Ideational apraxia: is impairment in carrying out sequences of actions requiring the use of various objects in the correct order necessary to achieve an intended purpose. Most often it is seen in dementia. Example: “Take this piece of paper in your left hand, fold it in half, and place it on the floor.”

IX. MEMORY AND THE CORTEX Long term memory storage occurs throughout the cortex. Memory storage in temporal lobe and the hippocampus is largely transient. While memory is “everywhere” in the cortex of the brain, there are similar mechanisms responsible for memory retention is most regions. There are structural changes in the shape of dendritic spines that occur with learning. This may be associated with directed protein synthesis from polyribosomes at the base of the spines and from specific dendritic transport of proteins needed to maintain synaptic function. Recent investigations stress Epigenetic Regulation of Gene Expression as an important mechanism in long term memory.

Epigentics is a term used to describe the influence on gene expression made by structural changes in chromatin, the complex combination of DNA, RNA, and protein of which chromasomes are composed. In general, chemical changes to histones by way of acetylation are an activating function. Methylation of histones, just as with methylation of DNA, will deactivate function. Studies in animals suggest acetylation is a necessary, but not sufficient step in memory formation. Strategies for pharmacologic therapy for manipulating acetylation and methylation are being developed as possible treatments for memory disorders.