Higher Order Cerebral Function


  • Subcortical structures almost always work with association cortex
    • Consequently, lesions of subcortical structures (e.g., thalamus or basal ganglia) as well as white matter can produce deficits such as aphasia or neglect that resemble lesions of the association cortex
  • Functions of association cortex: higher-order sensory processing, motor planning, language processing/production, abstract thought, etc.
  • Historically there has been a debate between theories of brain function: localization versus networks of structures – in reality both networks and localized mechanisms participate in brain functions


Unimodal AC

  • Modality-specific (e.g., somatosensory AC, auditory AC, visual AC)
  • Receives input from primary cortices (e.g., sensory, auditory, visual) and performs higher-order sensory processing for that modality

Heteromodal AC

  • Higher order processes (prefrontal cortex, parieto-occipito-temporal junctions)
  • Bi-directional connections with AC of all modalities and limbic cortex
  • Allows integration of abstract sensory and motor information from unimodal Acs and emotional and motivational information from limbic cortex
  • Found in the frontal lobes and at the parieto-occipitotemporal junctions


  • Although each hemisphere controls simple movements of the contralateral limbs, skilled complex motor tasks for both right and left limbs are programmed mainly b the dominant (usually left) hemisphere
    • Therefore, apraxia is more commonly associated with lesions of the dominant hemisphere
  • Although each hemisphere controls attention to the contralateral environment, only the right side is significantly involved in attending to both sides
    • Therefore, neglect is more often seen in lesions of the right hemisphere (even if right dominant for language)
    • Right hemisphere specialization may therefore be even more highly conserved than left hemisphere dominance for language

Hemispheric Specialization

  • Usually present by age 3 or 4
    • Lesions before this age may lead to major reorganization of function without noticeable deficits
  • 90% of population is right handed
    • Left hemisphere is dominant for over 95% of right handers and over 60-70% of left handers
    • Persons with family history of left handedness or ambidextrousness may have more significant bilateral representation of language and may recover language more quickly than right handers


  • Language processing and related functions

Primary Auditory Cortex

  • Superior bank of Sylvian fissure in the temporal lobe
  • Perceives sound

Wernicke’s Area

  • Superior temporal gyrus/ Brodmann’s area 22
  • Site of auditory association cortex where sounds are identified and understood
  • Wernicke’s area connects with parietal and temporal lobes to help with language comprehension and lexicon (mapping sounds to meaning for both comprehension and production of meaningful language)
  • Lesions to Brodmann’s areas 22, 37 (inferior temporal language area), 39 (angular gyrus), and 40 (supramarginal gyrus) produce Wernicke’s aphasia

Primary Motor Cortex

  • The face area of the motor cortex is responsible for articulation of sounds
  • Inferior portion of the precentral gyrus

Broca’s Area

  • Inferior frontal gyrus (opercular and triangular portions)/Brodmann’s areas 44 and 45
  • Auditory AC which programs the motor sequences of sounds to produce words
  • Lesions to Brodmann’s areas 44-47, 6, and 8-10 produce Broca’s aphasia
  • Broca’s area connects with prefrontal cortex, premotor cortex, and supplementary motor cortex for higher-order motor aspects of speech formulation and planning and syntax

Arcuate Fasciculus

  • Subcortical white matter pathway that connects Broca’s and Wernicke’s areas

Other Important Issues About Language

  • Reading
    • Depends on connections involving the visual primary cortex, visual association cortex, angular gyrus (Brodmann’s area 39) and Wernicke’s area
  • Corpus Callosum
    • Allows nondominant hemisphere to participate in language by recognition and production of affective elements of speech; these connections may help nondominant hemisphere take over some language functions allowing for partial recovery


Gerstmann’s Syndrome

  • Characterized by:
    • Agraphia
    • Acalculia
    • Right-left disorientation
    • Finger agnosia
  • Any one of these deficits in isolation could be caused by lesions in a number of locations, but in combination, they are very localizing to the dominant (usually left) inferior parietal lobe in the region of the angular gyrus
  • Often associated with contralateral visual field cut, alexia, anomia, or more severe aphasia


Ideomotor Apraxia

  • Inability to formulate correct motor sequences
  • Can affect orofacial, proximal or distal movements differently
  • Not well localized but at least a third of patients with aphasia also have apraxia
  • Body part substitution (using fingers cutting as opposed to correctly holding imaginary scissors while cutting) is indicative of mild apraxia

Aphemia (verbal apraxia or foreign accent syndrome)

  • Severe apraxia of the speech articulatory apparatus
  • Characterized by effortful, poorly articulated speech; severe aphemia can produce muteness
  • Caused by a small lesion to the dominant frontal operculum restricted to Broca’s area (however, written language is intact)
  • Can occur as a developmental disorder (referred to as verbal apraxia in those cases)


Cortical Deafness

  • Awareness that a sound has occurred but cannot interpret the sound whether verbal (e.g., words) or nonverbal (e.g., phone ringing)
  • Caused by bilateral lesions of the primary auditory cortex in Heschl’s gyrus

Pure Word Deafness (aka verbal auditory agnosia)

  • Can identify nonverbal sounds but not spoken words
  • Can read and write normally and speech is usually normal although some paraphasic errors may be present acutely
  • Caused by infarct in the auditory area of the dominant hemisphere that extends to subcortical white matter, cutting off auditory input from contralateral hemisphere, as well
  • Can also be caused by bilateral lesions of superior temporal gyrus

Nonverbal Auditory Agnosia

  • Patients understand speech but not nonverbal sounds
  • Caused by lesions in the nondominant hemisphere


  • Naturally occurring lesions involving the corpus callosum primarily are rare but can be caused by MS, gliomas, metastases, lymphoma, lipona, and infarcts (especially ACA or PCA)
  • Corpus Callosotomy (surgery severing the corpus callosum) is sometimes performed in patients with refractory epilepsy in which falls are a major problem – goal is to prevent secondary generalization, not to cure the seizures.
    • Following surgery, the right hemisphere is unable to access language from the left hemisphere, which results in left hand agraphia, inability to name objects placed in left hand with eyes closed, and inability to read in left hemifield (hard to illicit with special apparatus)


  • Nondominant hemisphere is more important for attention and for generating an integrated visual-spatial gestalt


  • Global (i.e., vigilance, concentration, arousal)
  • Selective or directed (focusing attention)
    • Depends on the activating systems discussed in chapter 14 (e.g., reticular formation, diencephalic structures) and cingulate gyrus and limbic, frontal, and parietal association cortices
  • Right Hemisphere
    • More important than left hemisphere for attention mechanisms in most persons
    • Responds to stimuli on both sides whereas the left hemisphere responds to stimuli on right side only
    • Lesions of right hemisphere often lead to prominent and long-lasting deficits in attention to the contralateral side while left hemisphere lesions lead to relatively mild or undetectable neglect

Spatial Analysis and Integration

  • Parietal Association Cortex
    • Analyzes where, i.e., location and movement of visual objects in space
  • Gestalt
    • Patients with right hemisphere lesions often have difficulty appreciating the gestalt, or overall spatial arrangement, of visual information while patients with left (usually parietal) lesions tend to understand the gestalt but omit certain important details
  • Posterior parietal cortex also integrates spatial analysis incorporating visual, proprioceptive, vestibular and auditory information

Emotional or Personality Change

  • Generally associated with right parietal or frontal lobes
  • Patients may appear bland or apathetic, and in addition to hemineglect, they may display an overall decrease in the level of alertness and attention; on the other hand, irritability is common
  • Anosodiaphoria
  • When patients are aware that they have severe deficits, yet show no emotional concern or distress about it
  • Hemiasomatognosia
    • When patients deny that the neglected part of their body belongs to them
  • Contralateral Hemineglect
    • Occurs primarily with lesions of right parietal or frontal lobes, but can also occur with lesions of the cingulate gyrus, thalamus, basal ganglia or reticular formation
    • Allesthesia: When a patient erroneously reports the location of a stimulus to one side of the body as being on the other side
    • Allokinesia: When the patient inappropriately moves the normal limb when asked to move the neglected limb
    • Spatial akinesia: When movements of the limbs are worse when they are located in the neglected hemispace
  • Right-sided lesions, especially right parietal infarcts, can also cause bilateral ptosis (keeping both eyes forcibly closed) and psychotic symptoms
    • Right sided lesions can also reduce comprehension of emotional content of others’ speech (receptive aprosody) and conveying appropriate emotional expression in their own speech (expressive aprosody) can be impaired.
  • Impaired Geographic Orientation (sense of direction)
    • Caused by lesions of right parietal or right occipitotemporal cortex.
  • Déjà vu
    • Experienced more frequently by patients with right temporal seizures or lesions
  • Capgras Syndrome
    • Patients insist their family members have been replaced by identical-looking imposters – thought to be caused by right hemisphere lesions
  • Reduplicative Paramnesia
    • Patients believe a person, place, or object exists as two identical copies – seen in patients with right hemisphere lesions

Contralateral Hemineglect Syndrome

  • Usually caused by lesions to the right parietal and frontal lobes but also can be caused by lesions of cingulate gyrus, thalamus, basal ganglia, or midbrain reticular formation
  • Can be identified by 4 types of testing
    • Sensory Neglect
      • Visual, auditory, and tactile stimulation such as that done on the Sensory Perceptual Exam of HRB. Patients may exhibit allesthesia
    • Motor-Intentional Neglect
      • Notice that the patient performs fewer movements with contralateral limb using methods like tactile response test (instruct patient to move whichever limb is touched – used with patients who have trouble following commands such as “left” and “right”) or crossed response test (instruct patient to move the limb opposite of the one touched)
      • Some of these patients may exhibit spatial akinesia (tested by asking patients to cross their arms and perform movements)
      • Patients may exhibit allokinesia, which is when they move the normal limb when asked to move the neglected limb
    • Combined Sensory-Motor Neglect
      • Elicited by tests like Line Bisection and Clock Drawing
    • Conceptual Neglect
      • Neglect of internal representations of their own bodies or external world
      • Anosognosia (unawareness of deficits) is common in hemineglect syndrome and can also be seen with Wernicke’s aphasia, frontal lobe disorders, and cortical blindness
      • Less common forms of conceptual neglect are anosodiaphoria and hemiasomatognosia


  • Due to the diversity of the functions of the frontal lobes, the author discusses their functions in three broad areas:
    • Restraint
      • Inhibition of inappropriate behaviors
    • Initiative
      • Motivation to pursue positive or productive activities
    • Order
      • The capacity to correctly perform sequencing tasks

Prefrontal Cortex

  • Largest part of the frontal lobes
  • Consists of the higher-order heteromodal association cortex
  • Has connections to other cortical (i.e., parietal, occipital, and temporal ACs, limbic cortex, anterior cingulate gyrus, and orbitofrontal cortex) and subcortical (e.g., amygdala, thalamic nuclei, basal ganglia, hypothalamus, septal region, cerebellum, and midbrain) regions
    • Most connections are bi-directional
  • Also receives projections from multiple subcortical and brainstem modulatory neurotransmitter systems

Functions of Frontal Lobes

  • Working Memory and Shifting Cognitive Set
    • Functional imaging indicates dorsolateral prefrontal cortex underlies this skill
  • Learning New Material
    • Both dorsolateral prefrontal cortex and medial temporal lobes show activation on functional imaging (usually left side for verbal material and right side for nonverbal material)
  • Selective Attention
  • Decision Making
    • Frontal lobes integrate information from the limbic and heteromodal association cortex for this function


  • Utilization behavior/environmental dependency – when patients tend to respond to whatever stimuli are at hand, even when inappropriate
  • Witzelsucht: Inappropriate jocularity
  • Incontinence: Sometimes seen in frontal lobe disorders, especially those affecting the medial frontal regions
  • Patients are characteristically unconcerned about their incontinence

Dorsolateral Convexity Lesions

  • Produce apathetic, lifeless, abulic state
  • Abulia: Passive, exhibiting little spontaneous activity, markedly delayed responses, tendency to speak briefly or softly; in the extreme may be immobile, akinetic and mute, but will continue to appear awake, sitting with their eyes open

Orbitofrontal Lesions

  • Impulsive and disinhibited behavior
  • Left frontal more associated with depression and right frontal more associated with mania


  • Dorsal Pathway
    • Projects to the parieto-occipital association cortex
    • Answers the question Where? by analyzing motion and spatial relationships between objects and between the body and visual stimuli
  • Ventral Pathways
    • Projects to occipitotemporal association cortex
    • Answers the question What? By analyzing form, with specific regions identifying colors, face, letters, and other visual stimuli

Primary Visual Cortex Syndromes

  • Blindsight
    • When individuals can perform tasks without conscious visual perception (e.g., they cannot “see” a mail slot, but they can insert an envelope into the slot)
    • Some studies have shown that there may be small islands of preserved vision in the blind hemifield that may influence behavior although conscious vision is not recognized
  • Cortical Blindness (aka Anton’s syndrome)
    • Patients have complete visual loss on confrontational testing but are completely unaware of loss
    • Show a loss of blink to threat, loss of eye closure in bright light, and loss of optokinetic nystagmus. Some have blindsight, too
    • Results from bilateral lesions
  • Anosognosia for Visual Loss
    • Also seen with combined occipital and frontal lesions (results in confabulation) and combined occipital and parietal lesions (results in neglect)
  • Color Agnosia (aka color anomia)
    • Patients cannot name or point to colors presented visually despite intact perception of color (patients can match colors presented visually)
    • Caused by lesions of dominant hemisphere’s primary visual cortex and extending into corpus callosum
    • Often associated with alexia without agraphia and right hemianopia
    • Not a true anomia, b/c patient can name the color of an object if it is described verbally



  • Inability to recognize faces (including animal faces) usually from bilateral lesions especially if deficit does not resolve
  • Often associated with achromatopsia (see below) and sometimes associated with alexia and with upper quadrant or bilateral upper visual field defects


  • Like cortical blindness only for color perception – cannot name, point to, or match colors presented visually but can name appropriate color for an object described verbally
  • These patients often describe vision as shades of gray
  • Deficits can be in one quadrant, a hemifield, or the entire visual field
  • As with prosopagnosia, it is sometimes associated with alexia and with upper quadrant or bilateral upper visual field defects
  • When the whole visual field is affected, usually associated with prosopagnosia and bilateral lesions
  • Hemiachromatopsia is caused by lesions to the contralateral inferior occipitotemporal cortex


  • Objects appear unusually small (can occur in only part of the visual field)


  • Objects appear unusually large (can occur in only part of the visual field)


  • Objects have distorted shapes and sizes
  • The “Alice in Wonderland” syndrome – can be caused by migraines, infarct, hemorrhage, tumor, or other disorders of the inferior or lateral visual AC. Also occasionally seen in retinal pathology or toxic or metabolic disturbances

Visual Reorientation

  • Environment appears tilted or inverted


  • When a previously seen object reappears periodically (e.g., patient saw a plant and a few minutes later sees the plant going out of her sandwich) – can be caused by meds like Trazadone

Cerebral Diplopia (aka polyopia)

  • Patients see 2 or more images of objects – sometimes can be psychiatric in origin


  • Unnatural coloring of visual field, like gold, red, or purple – can be see with certain drugs, such as in digitalis toxicity, in which objects have a yellowish halo


Balint’s Syndrome

  • Caused by bilateral lesions and resulting in a clinical triad of symptoms
  • Simultagnosia
    • Impaired ability to perceived parts of a visual scene as a whole (can perceive only a small part of the visual field at a time and this region shifts unpredictably so they have trouble with complex scenes and identifying moving objects)
  • Optic Ataxia
    • Impaired ability to reach for or point to objects in space under visual guidance (unlike cerebellar ataxia because proprioceptive and auditory cues are intact allowing the patient to perform smooth movements back and forth to an object once it has been touched one time)
  • Ocular Apraxia
    • Difficulty directing gaze toward objects in peripheral vision through saccades (patients need to move their heads to initiate a voluntary redirection of gaze
  • Associated Deficits
    • May include inferior-quadrant visual field cuts, aphasia, or hemineglect.
  • Most Common Etiology
    • Most bilateral lesions in this brain region are caused by MCA-PCA watershed infarcts, although bilateral hemorrhage, tumors, or other lesions can produce this syndrome

Optic Allesthesia

  • False localization of objects in visual space – sometimes seen in patients with bilateral lesions that do not present with a full Balint’s syndrome

Cerebral Akinetopsia

  • An inability to perceive moving objects – sometimes seen in patients with bilateral lesions that do not present with a full Balint’s syndrome



  • Persistent ringing tone or buzzing in one or both ears, usually caused by peripheral auditory disorders affecting the tympanic membrane, middle ear ossicles, cochlea, or 8th cranial nerve

Self-Audible Bruits

  • Pulsating “whooshing” sounds that can be associated with turbulent flow in AVMs, carotid dissection, or the extracranial-to-intracranial pressure gradient produced by elevated intracranial pressure

Release Phenomenon

  • Analogous to Bonnet syndrome (visual hallucination caused by visual loss) in that patients hear elaborate auditory hallucinations (e.g., music, voices) – most often associated with sensorineural deafness but in rare cases can be caused by lesions or ischemia of the pontine tegmentum


  • A sound that is heard once is then heard repeatedly (analogous to palinopsia) – very rare

Musical Hallucinations

  • Most often caused by seizures in the nondominant hemisphere


Widespread Projection Systems

  • Important for arousal but also involved in attention
  • Upper Brainstem Projection Systems
    • Include cholinergic (pedunculopontine and laterodorsal tegmental nuclei) and noncholinergic (pontomesencephalic reticular formation, possibly glutamatergic) projections to thalamus, hypothalamus, and basal forebrain systems, which in turn, have widespread cortical projections. Also include noradrenergic (locus ceruleus and lateral tegmental area) and serotonergic (dorsal and medial raphe) systems that project to cortex and other structures and dopaminergic (substantia nigra pars reticulata, ventral tegmental area) systems project to striatum, limbic cortex, and prefrontal cortex
  • Thalamic Systems
    • Intralaminar, midline, ventral medial, and other thalamic nuclei that transfer inputs from the upper brainstem reticular formation and cholinergic nuclei to widespread areas of the cerebral cortex are involved in arousal, and the thalamic reticular nucleus is thought to play a role in gating information transfer through the thalamus because it receives inputs form the cortex, thalamus, and brainstem systems and sends inhibitory (GABAergic) projections to the thalamus (and possibly back to the brainstem)
  • Hypothalamic Systems
    • Posterior lateral hypothalamic histaminergic neurons are important for arousal – they receive inputs from basal forebrain, anterior hypothalamus, and brainstem and project widely to cortex and thalamus
  • Basal Forebrain Systems
    • Nucleus basalis, diagonal band, and medial septal cholinergic and GABAergic neurons are involved in arousal – they receive inputs from the brainstem and project to the entire cortex and thalamus

Frontal and Parietal AC

  • Communicate with each other through strong reciprocal connections
  • Lateral Parietal Cortex
    • Its location at the temporal-parietal-occipital junction makes it a perfect place of heteromodal integration in attention
  • Prefrontal Cortex
    • The region of the prefrontal eye fields is important for directed attention to the contralateral side and in the initiation of eye movements toward attended to targets – also may play a role in motor-intentional aspects of attention toward the contralateral side – crucial for sustaining attention and reducing distractibility

Anterior Cingulate Cortex and Limbic Pathways

  • The anterior cingulated is important in motivational aspects of attention and works together with amygdala, medial orbitofrontal cortex, thalamic mediodorsal nucleus, and other limbic structures to direct and sustain attention toward relevant or interesting stimuli

Tectum, Pretectal Area, and Pulvinar

  • Work with the parietotemporo-occipital cortex and frontal eye fields in directing visual attention toward relevant visual stimuli for saccadic eye movements – directed attention for other modalities (e.g., audition) may also be processed by these pathways

Basal Ganglia and Cerebellum

  • There is accumulating evidence that these areas participate in directed attention.

Awareness of Self and Environment

  • The mechanisms involved in our subjective and personal experience of awareness are unknown, but it is likely to be a combination of a network with both specialized regions of local processing and widespread regions of distributed processing
  • Because of the frequent comorbidity of hemineglect syndromes and anosognosia, it is possible that the mechanisms involved in attention play a role


Acute Delusional States (e.g., delirium, encephalopathy)

  • Typically develop over the course of days to months, have prominent attentional disturbances, tend to wax and wane over the course of hours, often have marked slowing on EEG, and are most often caused by toxic or metabolic disorders, head trauma, infection, and seizures

Chronic Mental Status Changes (i.e., dementias)

  • Usually develop over months to years, do not tend to fluctuate as rapidly (although exacerbations of function can occur in certain settings), and early in their course tend to have less prominent disturbances in attention and a relatively normal EEG
  • Static Encephalopathy
    • Another term for chronic mental status changes but usually refers to permanent nonprogressive brain damage that results from head injury, anoxia, or congenital abnormalities of brain development (e.g., mental retardation)
  • Cortical Dementias
    • Refer to dementias with prominent disturbances of language, praxis, visuospatial functions, and other typically cortical functions
  • Subcortical Dementias
    • Refers to dementia in disorders such as Huntington’s disease that do not have such prominent cortical features; however, the use of the cortical/subcortical distinction has been questioned (due to the frequency of disruption among cortical-subcortical circuits in all progressive dementias)
  • Primary Dementia
    • Typically associated with neurodegenerative conditions for which definitive treatments are unavailable
  • Secondary Dementia
    • Caused by conditions that may be reversible, such as electrolyte abnormalities (esp. of calcium, magnesium, or sodium), hepatic, renal, or pulmonary failure, hyper/hypothyroidism, vitamin B12 deficiency, chronic meningitis, lyme disease, neurosyphilis, Wilson’s disease (liver unable to excrete copper) – approximately 10% of all dementia cases
  • Sundowning
    • Cute mental status change superimposed on a dementia process
  • Cortical-Basal Ganglionic Degeneration (aka corticobasal degeneration)
    • Asymmetrical onset of a movement disorder (e.g., dystonia) accompanied by cortical features most often consisting of a marked apraxia
  • Primary Progressive Aphasia
    • Likely a family of degenerative conditions in which aphasia is the predominant symptom
  • Vascular Dementia
    • Second most common cause of dementia (10-15% of cases)
  • Binswanger’s disease
    • Diffuse subcortical infarcts often associated with chronic hypertension
  • Leukoaraiosis
    • Diffuse white matter changes often seen in older patients but not always associated with dementia
  • Cerebral Amyloid Angiopathy
    • Can cause dementia through multifocal recurrent hemorrhages, as well as through white matter ischemic disease – often familial
  • Psychiatric Pseudodementia
    • Resulting from depression or conversion disorder
  • Dementia due to Alcoholism
    • Likely multifactorial, with possible causes including thiamine deficiency, other nutritional deficiencies, multiple head injuries, and seizures
    • The jury is still out with regard to whether or not alcohol itself causes permanent cortical neuronal injury, although it likely causes cerebellar degeneration