Category Archives: B-C

Brainstem III

Internal Structures and Vascular Supply

Functional Brainstem Anatomy

(the author breaks down the brainstem region into 4 functional groupings)

Cranial Nerve Nuclei and Related Structures – Six Columns

(this is a review of material covered in Chap. 12, Table 12:3 and Figure 12:5)

Somatic Motor

  • General Somatic Efferent

Branchial Motor

  • Special Visceral Efferent


  • General Visceral Efferent

Visceral Sensory

  • Special Visceral Afferent and General Visceral Afferent

General Somatic Sensory

  • General Somatic Afferent

Special Somatic Sensory

  • Special Somatic Afferent

Long Tracts


(this is a review of the material covered in Chap. 6 & 7)

  • Lateral corticospinal tract (motor functions)
  • Posterior columns (sensory functions – vibration, joint position, fine touch)
  • Anterolateral pathways (sensory functions – pain, temperature, crude touch)

Cerebellar Circuitry


(this is a preview of the material covered in Chap. 15)

  • Lesions to the cerebellar circuitry result in ataxia, ipsilateral to side of lesion because the cerebellar circuits decussate twice before reaching lower motor neurons.
  • Cerebellum is attached to brainstem via three white matter pathways:
  • Superior cerebellar peduncle (contains mainly cerebellar outputs; the fibers of the superior cerebellar peduncle decussate at the inferior colliculi in the midbrain then continue up the brainstem to reach the red nucleus at the level of the superior colliculi. Other fibers continue rostrally to influence the motor cortex
  • Middle cerebellar peduncle (provides input to the cerebellum arising from the pontine nuclei which receive input from the corticopontine fibers
  • Inferior cerebellar peduncle (carries input to the cerebellum from the spinal cord)

Reticular Formation and Related Structures


  • The reticular formation is a central core of nuclei that runs through the entire length of the brainstem (p. 589 provides a nice illustration)
  • Two main components:
  • Rostral reticular formation (maintains alert conscious state in the brain)
  • Caudal reticular formation (maintains a variety of important motor, reflex, and autonomic functions)
  • Other structures in the brainstem tegentum:
  • Periaqueductal gray matter in the midbrain (involved in pain modulation)
  • Chemotactic trigger zone in the medulla (involved in causing nausea)


Widespread Projection Systems of Brainstem and Forebrain: Consciousness, Attention, and Other Functions

Brainstem Reticular Formation and Thalamus


  • The pontomesencephalic reticular formation (in the region of the rostral reticular formation) forms a circuit together with intralaminar nuclei of the thalamus that is critical to maintaining normal consciousness.
  • The Intralaminar nuclei in turn project to the cerebral cortex.
  • Ascending and descending influences are both critical for consciousness.
  • Coma is caused by dysfunction of he upper brainstem reticular formation or by dysfunction of extensive bilateral regions of the cerebral cortex. Bilateral lesions of the thalamus can also cause coma.

Pontomesencephalic Reticular Formation


  • Also projects to the hypothalamus and basal forebrain which then project to the cortex.


Other Regions of the CNS Project to the Reticular Formation


  • Projections from the limbic system to the reticular formation are responsible for increased alertness in stressful or emotional situations.
  • Projections from the anterolateral pathway of the spinal cord transmit information about pain to the reticular formation.
  • Projections from the association cortices transmit information about cognitive processes (e.g., these areas will stimulate increased arousal/alertness when one needs to engage in problem-solving activity).
  • Other circuits that may play a role in attentional mechanisms include the superior colliculi, cerebellum, and thalamic reticular nucleus.


Identified Neurotransmitter Systems


(this is not a complete list of neurotransmitters but apparently this section of the book focuses on neurotransmitters that have widespread projections and are involved in the maintenance of alertness, arousal, and attention)


  • Major efferent neurotransmitter of the peripheral nervous system (reminder: efferent = a pathway that carries signals away from a structure)
  • Only has a limited role in CNS function
  • Found in the pontomesencephalic region of the brain stem and in the basal forebrain where it plays a role in arousal
  • Main receptor type = muscarinic


  • Found mainly in neurons located in the ventral midbrain (substantia nigra pars compacta & ventral tegmental area)
  • Three projection systems:
  • Mesostriatal pathway to caudate and putamen (this is the one implicated in Parkinson’s disease)
  • Mesolimbic pathway to limbic structures (implicated in positive symptoms of Schizophrenia)
  • Mesocortical pathway to prefrontal cortex (implicated in working memory and other executive skills and cognitve deficits in Parkinson’s disease and negative symptoms of Schizophrenia)


(also called noradrenaline)

  • Primarily found in the locus ceruleus (located near fourth ventricle in the rostral pons)
  • Also found scattered throughout the lateral tegmental area of the pons and medulla
  • Projects to the entire forebrain through the thalamus
  • Functions of the ascending norepinephrine projection system include modulation of attention, sleep-wake states, and mood
  • Psychostimulant treastment of ADD enhances noradrenergic transmission
  • Noradrenergic transmission also seems to be important in mood disorders including depression and bipolar and anxiety disorders


  • Found in neurons of the raphe nuclei of the midbrain, pons, and medulla
  • Rostral raphe nuclei project to entire forebrain including cortex, thalamus, and basal ganglia
  • Plays a role in several psychiatric disorders including depression, anxiety, OCD, and aggressive behavior
  • Caudal raphe nuclei project to the cerebellum, medulla, and spinal cord and are involved in pain modulation


  • Found mainly in the neurons of the posterior hypothalamus
  • Diffuse histaminergic projections from the posterior hypothalamus to the forebrain may be important to maintaining the alert state
  • Histaimine has excitatory effects on thalamic neurons, and both excitatory and inhibitory effects on cortical neurons
  • Antihistamine medications are thought to cause drowsiness by blocking CNS histamine receptors
  • Histaminergic neurons participate in a circuit with the hypothalamus that regulates sleep and arousal


Anatomy of the Sleep-Wake Cycle

  • There are four stages of progressively deeper non-REM sleep followed by REM sleep, and this cycle repeats several times through the night.
  • Sleep-producing regions are located in the medulla.
  • Lesions of the pons can produce excessive sleep (or coma) while lesions of the medulla can result in decreased sleep because of the sleep-producing functions in the medulla.
  • During non-REM sleep, GABA neurons in the preoptic area of the hypothalamus inhibit histaminergic neurons which removes histaminergic activtation from the forebrain and sections of the brainstem.
  • During REM sleep, cells in the pontine reticular formation interact with other brainstem circuits to activate cholinergic inputs to the thalamus, inhibit tonic muscle activity, activate phasic eye movements, and activate other phasic motor activity.

The suprachiasmatic nucleus of the hypothalamus receives retinal inputs and is crucial for setting circadian rhythms and synchronizing them with the light-dark cycle.

Brainstem II

Eye Movements and Pupillary Control

Anatomical and Clinical Review

  • Extraocular Muscles – cause the eyes to move within the orbits
  • Internal Ocular Muscles – control pupillary size and accommodation

Two Levels of Disorders and Pathways


  • Nuclear and Infranuclear Pathways: involve brainstem nuclei of CN III, IV, and VI; the peripheral nerves arising from these nuclei; and the eye movements muscles
  • Supranuclear Pathways: involve brainstem and forebrain circuits that control eye movements through connections with the nuclei of CN III, IV, and VI


Extraocular Muscles, Nerves, and Nuclei

Six Extraocular Muscles Innervation
Lateral rectus (abduction) CN VI (abducens) – moves eye toward ear
Medial rectus (adduction) CN III (oculomotor – inferior division) moves eye towards nose
Superior rectus (elevation and intorsion) CN III (oculomotor – superior division)
Inferior rectus (depression and extorsion) CN III (oculomotor – inferior division)
Superior oblique (depression and intorsion) CN IV (trochlear)
Inferior oblique (elevation and extorsion) CN III (oculomotor – inferior division)

Muscles 1 – 4 are responsible for horizontal and vertical eye movements; muscles 5 & 6 are responsible for torsional movements

Other Eye Muscles


  • Levator Palpebrae Superior: elevates eyelid; innervated by superior division of CN III
  • Pupillary Constrictor Muscle: makes pupil smaller
  • Pupillary Dilator Muscle: makes pupil larger
  • Ciliary Muscle: adjusts thickness of lens in response to viewing distance

A Few Other Points


  • The parasympathetic fibers controlling pupil constriction are susceptible to compression from aneurysms, particularly arising from the nearby posterior communicating artery
  • Unilateral weakness of the levator palpebrae superior, or unilateral papillary dilation, cannot arise from unilateral lesions of the oculomotor nucleus
  • Oculomotor nucleus lesions affect the contralateral superior rectus (further explanation in text, p. 533)
  • Trochlear nerves are only cranial nerves to exit brainstem dorsally and in a completely crossed fashion; they are susceptible to compression from cerebellar tumors and to shear injury from head trauma
  • Abducens nerve is highly susceptible to downward traction injury produced by elevated intracranial pressure



Primary Causes


  • Mechanical problems (e.g., orbital fracture with muscle entrapment)
  • Disorders of the extraocular muscles (e.g., thyroid disease, orbital myositis)
  • Disorders of the neuromuscular junction (e.g., myasthenia gravis)
  • Disorders of CN III, IV, VI, and their central pathways

Of Interest: Monocular diplopia or polyopia (3 or more images) can be caused by ophthalmological disease, d/o of visual cortex, or psychiatric conditions, but not by eye movement abnormality.

Movement Disorders


  • Dysconjugate gaze: results from improperly working extraocular muscle and causes diplopia
  • Exotropia: abnormal lateral deviation of one eye
  • Esotropia: abnormal medial deviation of one eye
  • Hypertropia: abnormal vertical deviation of one eye
  • Phoria: mild weakness present only with one eye covered (as in, exophoria)

Of Interest: In young children, because visual pathways are still developing, congenital eye muscle weakness can produce strabismus (dysconjugate gaze) that over time suppresses one of the images, resulting in amblyopia (decreased vision in one eye). Early intervention is essential.


Oculomotor Palsy (CN III)

Complete disruption of CN III causes paralysis of all extraocular muscles except lateral rectus and superior oblique (i.e., some abduction and some depression/intorsion) —> eye lies in a “down and out” position; also upper lid is closed because of levator palpebrae superior paralysis, and pupil is dilated and unresponsive to light (due to parasympathetic fibers running with CN III)

Common Causes


  • Diabetic neuropathy
  • Head trauma (due to shearing forces)
  • Compression of nerve by intracranial aneurysms, especially those arising from Pcomm
  • Compression of nerve by herniation of the medial temporal lobe over the edge of the tentorium cerebelli
  • Ophthalmoplegic migraine in children

Of Interest: Third nerve palsy should raise high index of suspicion for aneurysm; they often cause a painful oculomotor palsy that involves the pupil. Complete CN III palsy sparing the pupil is not an aneurysm, but usually caused by diabetes.


Trochlear Palsy (CN IV)

  • Trochlear nerve palsy produces depression and intorsion, therefore, there is a vertical diplopia
  • CN IV palsy confirmed by following four steps (Bielschowsky three step test plus the “missing step”)
    • Affected eye has hypertropia
    • Vertical diplopia worsens when the affected eye looks nasally
    • Vertical diplopia improves with head tilt away from the affected eye
    • Vertical diplopia worsens with downgaze
  • CN IV is most commonly injured cranial nerve in head trauma (susceptible to shear)

Other Causes of Vertical Diplopia


  • Disorders of extraocular muscles
  • Myasthenia gravis
  • Lesions of superior division of CN III affecting the superior rectus
  • Skew Deviation (a vertical disparity in the position of the eyes of supranuclear origin)


Abducens Palsy (CN VI)

  • Abducens nerve palsy produces horizontal diplopia (in milder cases, may just be incomplete “burial of the sclera” on lateral gaze)
  • CN VI is particularly susceptible to injury from downward traction caused by elevated intracranial pressure; therefore, abducens palsy is important early sign of supratentorial or infratentorial tumors, pseudotumor cerebri, hydrocephalus, and other intracranial lesions
  • Different from a gaze palsy, in which movements of both eyes in one direction are decreased
  • CN VI lesions often affect fibers of CN VII, resulting in ipsilateral facial weakness

Other Causes of Horizontal Diplopia


  • Myasthenia gravis
  • Disorders of the extraocular muscles caused by thyroid disease, tumors, inflammation, or orbital trauma


The Pupils and Other Ocular Autonomic Pathways

The pupils are controlled by both parasympathetic and sympathetic pathways

Parasympathetic Pathways


(see figure 13.8 on p.541) Light enters eye —> retinal ganglion cells —> projects to both optic tracts —> (extrageniculate pathway) brachium of superior colliculus —> past LGN —> pretectal area —> Edinger-Westphal nucleus —> (preganglionic) ciliary ganglia (in the orbit) via oculomotor nerves —> (postganglionic) pupillary constrictor muscles

  • A light shone in one eye causes a direct response in the same eye and a consensual response in the other eye because information crosses bilaterally at multiple levels

Accommodation Response


(another pathway for bilateral pupillary constriction) Occurs when a visual object moves from far to near, and involves:

  • Pupillary constriction
  • Accommodation of the lens ciliary muscle
  • Convergence of the eyes

Visual signals —> visual cortex —> pretectal nuclei are activated, causing bilateral papillary constriction mediated by above described parasympathetic pathways

  • This same pathway also mediates contraction of the ciliary muscle

Sympathetic Pathways


(see figure 13.10 on p. 542) Hypothalamus —> lateral brainstem/cervical spinal cord —> T1/T2 —> preganglionic sympathetic neurons in the intermediolateral cell column of the upper thoracic cord —> paravertebral sympathetic chain via white rami communicantes —> superior cervical ganglion —> carotid plexus —> pupillary dilator muscle


Pupillary Abnormalities

(see table 13.13 on p. 544) Anisocoria= pupillary asymmetry

Oculomotor Nerve Lesion


  • Impaired pupillary constriction, resulting in a unilateral dilated pupil
  • When lesion is complete, pupil is very large (“blown pupil”)

Horner’s Syndrome


  • Triad of ptosis (upper eyelid droop), miosis (decreased pupillary size), and anhidrosis (decreased sweating of the ipsilateral face and neck)
  • Caused by loss of sympathetic innervation to the pupillary dilator muscle, resulting in impaired dilation of the pupil
  • Lesions at any point in above-described sympathetic pathway may produce the syndrome

Possible Locations for Lesions

  • Lateral brainstem (e.g., infarct, hemorrhage)
  • Spinal cord (e.g., trauma)
  • First and second thoracic roots (e.g., trauma, apical lung tumor)
  • Sympathetic chain (e.g., tumor or trauma)
  • Carotid plexus (e.g., carotid dissection)
  • Cavernous sinus (e.g., thrombosis, infection, aneurysm, neoplasm)
  • Orbit (e.g., infection, neoplasm)
  • Large bilateral lesions of the pons are sometimes associated with pontine pupils (both pupils small but reactive to light)

Afferent Pupillary Defect


  • Marcus Gunn Pupil
  • The direct response to light in affected eye is decreased/absent; consensual response of affected eye to light in opposite eye is normal
  • Caused by decreased sensitivity of affected eye to light, secondary to lesions of optic nerve, retina, or eye
  • Distinguish from hippus (normal brief oscillation of pupil size that may occur in response to light)

Benign (Essential, Physiological) Anisocoria


  • Slight pupillary asymmetry (<.6mm) in 20% of general population; may vary from time to time
  • No other associated abnormal findings

Pharmacological Miosis and Mydriasis


  • Opiates —> bilateral pinpoint pupils
  • Barbiturate overdose —> bilateral small pupils
  • Anticholinergic agents (e.g., scopolamine, atropine) —> dilated pupils

Light-Near Dissociation


  • Pupils constrict much less in response to light than to accommodation
  • Argyll Robertson Pupil – associated with neurosyphilis; light-near dissociation plus small and irregular pupils
  • May be seen in diabetes, Adie’s myotonic pupil, or as part of Parinaud’s syndrome

Adie’s Myotonic Pupil


  • Mid-dilated pupil that reacts poorly to light
  • Characterized by degeneration of the ciliary ganglion or postganglionic parasympathetic neurons
  • No known cause

Midbrain Corectopia


  • Lesions of midbrain may cause an unusual pupillary abnormality in which the pupil assumes an irregular, off-center shape (rare)



Eye Opening – uses levator palpebrae superior (CN III), Muller’s smooth muscle in upper lid (sympathetics), and frontalis muscle (CN VII) Eye Closure – uses orbicularis oculi muscle (CN VII) Ptosis – drooping of the eyelid

Potential Causes


  • Horner’s syndrome
  • Oculomotor nerve palsy
  • Myasthenia gravis
  • Redundant skin folds associated with aging (pseudoptosis)
  • Nondominant parietal lobe lesion (bilateral ptosis)
  • Dorsal lesions of the oculomotor nuclei affecting the central caudate nucleus (bilateral ptosis)
  • Voluntary eye closure (e.g., migrainous photophobia)


Cavernous Sinus and Orbital Apex

(see figure 13.11 on p. 547)

  • Region on either side of the pituitary; CN III, IV, VI, V1, and V2 all run very close to or through here
  • Also, sympathetic fibers and optic nerve are nearby
  • Orbital Apex – region where nearly all nerves, arteries, and veins of the orbit converge before communicating with the intracranial cavity via the optic canal and superior orbital fissure


Cavernous Sinus (CN III, IV, VI, V1) and Orbital Apex (CN II, III, IV, VI, V1) Syndromes

  • Complete lesion of the cavernous sinus —> total ophthalmoplegia, accompanied by a fixed, dilated pupil
  • Orbital apex lesion produces same as above, plus may involve CN II (thus visual loss)

Common Causes


  • Metastatic tumors
  • Direct extension of nasopharyngeal tumors
  • Meningioma
  • Pituitary tumors/apoplexy
  • Aneurysms of the intravenous carotid
  • Cavernous carotid arteriovenous fistula
  • Bacterial infection causing cavernous sinus thrombosis
  • Aseptic thrombosis
  • Idiopathic granulomatous disease (Tolosa-Hunt syndrome)
  • Fungal infections


Supranuclear Control of Eye Movements

  • At least three dedicated circuits in the brainstem are responsible for: horizontal, vertical, and vergence eye movements
  • Saccades – rapid eye movements that bring targets of interest into field of view. Are the only type of eye movement that can be easily performed voluntarily
  • Smooth pursuit – slower eye movements, not under voluntary control, that allow stable viewing of moving objects
  • Vergence – even slower eye movements that maintain fused fixation by both eyes as targets move toward or away from the viewer
  • Reflex eye movements – include optokinetic nystagmus (nystagmus = rhythmic form of reflex eye movements composed of slow eye movements in one direction interrupted by fast saccadelike eye movements in the opposite direction; also called train nystagmus) and vestibulo-ocular reflex

Brainstem Circuits for Horizontal Eye Movements


  • Horizontal eye movements are generated by lateral rectus (CN VI) and medial rectus (CN III) muscles
  • Medial longitudinal fasciculus (MLF) interconnects CN III, IV, VI, and X nuclei
  • Paramedian pontine reticular formation (PPRF) – important horizontal gaze center that provides input from the cortex and other pathways to the abducens nucleus


Brainstem Lesions Affecting Horizontal Gaze

(see figure 13.13 for effects of lesions on horizontal gaze)



  • Abducens nerve —> impaired abduction of ipsilateral eye
  • Abducens nucleus —> ipsilateral lateral gaze palsy in both eyes
  • PPRF —> ipsilateral lateral gaze palsy
  • MLF —> internuclear ophthalmoplegia (INO) – eye ipsilateral to lesion does not fully adduct on attempted horizontal gaze, nystagmus in opposite eye; side of INO is same as side of lesion in MLF
    • Common causes – MS plaques, pontine infarcts, MLF neoplasms
  • MLF and adjacent abducens nucleus or PPRF —> one-and-a-half syndrome – ipsilateral INO plus ipsilateral lateral gaze palsy

Brainstem Circuits for Vertical and Vergence Eye Movements


  • Vertical eye movements are generated by superior and inferior rectus and superior and inferior oblique muscles; brainstem controlling centers are located in rostral midbrain reticular formation and pretectal area
    • Ventral portion mediates downgaze (especially rostral interstitial nucleus of the MLF), dorsal region mediates upgaze

Of Interest: Locked-in syndrome – large pontine lesions disrupt bilateral corticospinal tracts and abducens nuclei, eliminating body movements and horizontal eye movements. Therefore, sometimes the vertical eye movement centers in midbrain are spared, allowing communication entirely through vertical eye movements.

  • Convergence – produced by medial recti
  • Divergence – produced by lateral recti


Parinaud’s Syndrome

Four Components


  • Impairment of vertical gaze, especially upgaze
  • Large, irregular pupils with light-near dissociation
  • Eyelid abnormalities
  • Impaired convergence, and sometimes convergence-retraction nystagmus

Common Causes


  • Pineal region tumors
  • Hydrocephalus

Of Interest: Hydrocephalus in children can produce bilateral setting-sun sign, in which the eyes are deviated inward because of bilateral sixth-nerve palsies and downward because of a Parinaud’s syndrome.

Control of Eye Movements by the Forebrain


Multiple parallel pathways descend from the cerebral cortex to control eye movement circuits in the brainstem:

  • Descending cortical pathways go either directly to brainstem centers for horizontal, vertical, or vergence eye movements, or via relays in the midbrain superior colliculi
  • Frontal eye fields
    • lie at junction between superior frontal sulcus and precentral sulcus (Brodmanns area 6, not area 8)
    • overlap premotor and prefrontal cortices, reflecting roles in eye movement control and selective attention
    • generate saccades in the contralateral direction via the PPRF
  • Parieto-occipital-temporal cortex – responsible for smooth pursuit movements in the ipsilateral direction, via connections with the vestibular nuclei, cerebellum, and PPRF
  • Cortical descending control of eye movements is heavily influenced by visual inputs arriving from primary visual cortex and visual association cortex
  • Basal ganglia also modulate eye movements


Right-Way Eyes and Wrong-Way Eyes

(see figure 13.15 on p. 553)

Right-Way Eyes


  • Cerebral hemisphere lesions normally impair eye movements in the contralateral direction, resulting in gaze preference toward side of the lesion
  • This is normally accompanied by weakness contralateral to the cortical lesion, so the eyes look away from the side of the weakness

Wrong-Way Eyes


  • Eyes look toward the side of weakness
  • Possible causes: seizure activity in the cortex, large lesions such as a thalamic hemorrhage (usually accompanied by deep coma), lesions of the pontine basis and tegmentum

Cerebellar, Vestibular, and Spinal Control of Voluntary and Reflex Eye Movements


Detailed discussion of optokinetic nystagmus (OKN) and vestibulo-ocular reflex (VOR) – seems unimportant; see pp. 552-553 if you’d like this information


Notes from Clinical Cases

Symptoms Left frontal and retro-orbital headaches; history of left eye drifting to the left and diplopia with image from left eye above and to the right of image from right eye, with diplopia worse when looking to the right; left eye with limited but not absent upgaze, downgaze, and adduction, and ptosis, and a fixed dilated pupil

  • Diagnosis Oculomotor nerve palsy (CN III) secondary to an aneurysm


Symptoms History of diabetes; horizontal diplopia, worse on left gaze, with incomplete abduction of the left eye

  • Diagnosis Isolated abducens nerve palsy, caused by microvascular disease


Symptoms Right hypertropia and vertical diplopia worse with downward and leftward gaze and worse with rightward head tilt

  • Diagnosis Isolated right trochlear nerve palsy caused by an idiopathic neuropathy of presumed microvascular origin


Symptoms On right gaze: left eye pain, limited adduction, and horizontal diplopia, with the right image vanishing when the left eye was covered; on left gaze: mild horizontal diplopia, with the left image vanishing when the left eye was covered; pain and erythema of the left orbital conjunctiva

  • Diagnosis (differential: infectious, inflammatory, or neoplastic disorder) orbital myositis (orbital pseudotumor) – uncommon inflammatory condition of the extraocular muscles


Symptoms Initial left abducens palsy, evolving to ophthalmoplegia, ptosis, and a fixed dilated pupil; pain, paresthesia, and decreased sensation to pinprick in the left forehead, eyelid, bridge of nose, and upper cheek

  • Diagnosis Dysfunction of CN III, IV, VI, and V1 –> left cavernous sinus syndrome; hemorrhage from a recurrent pituitary adenoma


Symptoms Left ptosis; small reactive left pupil with decreased ciliospinal reflex; decreased left facial sweating

  • Diagnosis Horner’s syndrome; caused by traumatic injury or carotid dissection


Symptoms Lethargy; rightward gaze preference, with inability to move either eye past the midline toward the left; right face, arm, and leg weakness, with upgoing plantar response on the right

  • Diagnosis “wrong-way eyes”; infarct in the left pons


Symptoms Left eye did not adduct past midline; right eye had sustained end gaze nystagmus on abduction

  • Diagnosis Left INO localized to the left MLF caused by an MS plaque
  • Then Additional sx of inability of either eye to move past midline when looking to the left; no adduction of the left eye; end gaze nystagmus on right eye abduction – left INO plus left horizontal gaze palsy = one-and-a-half syndrome (plaque enlarged to include left abducens nucleus or PPRF)


Symptoms Headaches; large pupils with minimal reaction to light but preserved reaction to accommodation (light-near dissociation); inability to look upward; lid retraction and convergence-retraction nystagmus

  • Diagnosis Parinaud’s syndrome caused by pineal region tumor compressing the dorsal midbrain

Of Interest: When headaches are always on the same side, an intracranial abnormality on that side should be suspected.

Brainstem I

General Information – Brainstem

  • Corridor for all sensory, motor, cerebellar, and cranial nerve information
  • Contains nuclei for the cranial nerves and cerebellum, consciousness, tone, posture, cardiac and respiratory functions, etc.
  • Both Grand Central Station and Central Power Supply


Surface Features of the Brainstem

  • Located within the posterior fossa
  • Cranial nerves emerge roughly in numerical sequence from rostral to caudal
  • Rostral limit of the brainstem occurs at the midbrain-diencephalic junction; Caudal limit of the brainstem occurs at the cervicomedullary junction


Brainstem Anatomy – Overview



Dorsal surface

  • Superior/inferior colliculi (form tectum -“roof”- of midbrain)

Ventral surface

  • Cerebral peduncles




Dorsal surface

  • Limited by 4th ventricle

Dorsolateral surface

  • Attached to cerebellum via the cerebellar peduncles




Ventral surface

  • Pyramids descending to pontomedullary junction to pyramidal decussation

Rostral surface

  • Inferior olivary nuclei

Caudal surface

  • Posterior columns and posterior column nuclei


Sensory and Motor Organization of the Cranial Nerves

  • 3 motor columns and 3 sensory columns that run in an interrupted fashion thru brainstem
  • Cranial nerves analogous to spinal nerves (Motor nuclei is located ventrally while sensory nuclei is located dorsally)



Somatic Motor Nuclei

  • Innervate extraocular and intrinsic tongue muscles

Branchial Motor Nuclei

  • CN V, VII, IX, X, XI
  • Innervate muscles derived from branchial arches, including muscles of mastication, facial expression, middle ear, pharynx, larynx, sternomastoid, and upper portion of trapezius

Parasympathetic Nuclei

  • CN III, VII, IX, X
  • Provide preganglionic parasympathetic fibers innervating glands, smooth muscle, and cardiac muscle of the heart, lungs, and digestive tract




Visceral Sensory Column

  • CN VII, IX, X, IX
  • Receives taste input, as well as inputs for control of cardiac, respiratory, GI, sleep regulation

General Somatosensory Nuclei OR Trigeminal Nuclei

  • CN V, VII, IX, X
  • Mediate touch, pain, temperature, position, vibration sense for face, sinuses, and meninges

Special Somatic Sensory

  • Special senses are olfaction, vision, hearing, vestibular, sense, and taste
    • Olfaction (I) and vision (II) do NOT have primary sensory nuclei in brainstem
    • Brainstem special somatic sensory nuclei mediate hearing and positional equilibrium


Cranial Nerves

Assessed with a neurologic exam

CN I Olfactory Nerve


  • Functional Category: Special somatic sensory

Function: Olfaction

  • Pathway: chemoreceptors in nasal cavities —> olfactory nerves (exit out the cribriform plate) —> olfactory bulbs (orbitofrontal) —> olfactory tracts —> olfactory processing areas
  • Lesion Information
  • Causes: head trauma, neoplasms (typically meningiomas), basal meningitis, etc.
  • Results in: Anosmia (olfactory loss)
  • Unilateral: rarely aware because contralateral can compensate; should test each nostril separately
  • Bilateral: usually aware; will affect taste


CN II Optic Nerve


  • Functional Category: Special somatic sensory

Function: Vision

  • Pathway: retinal ganglion cells —> optic nerve (out optic canal) —> optic chiasm —> optic tract —>
  • General Information
  • Two functions in transmitting light: 1) visual information to cortex and 2) light intensity to brainstem
  • Unlike all other nerves (except bit of acoustic) is coated with myelin so susceptible to CNS illnesses like MS
  • Lesion Information
  • Causes: glaucoma, optic neuritis, elevated ICP, optic glioma, schwannoma, meningioma, trauma
  • Results in: monocular visual loss or monocular scotomas; can be partial


CN III Oculomotor


  • Functional Category: Somatic motor

Function: All extraocular muscles, except superior oblique and lateral rectus

  • Functional Category: Parasympathetic

Function: Pupil constriction and accommodation reflex

  • Location: Nuclei in midbrain; traverses the cavernous sinus, exits skull via superior orbital fissure
  • Lesion Information
  • Leads to distinctive constellation: dilated pupil, ptosis, and outward deviation (abduction)


CN IV Trochlear


  • Functional Category: Somatic Motor

Function: Superior oblique muscle; causes depression and intorsion of eye

  • Location: Nuclei in midbrain; traverses the cavernous sinus, exits skull via superior orbital fissure


CN VI Abducens Nerve


  • Functional Category: Somatic motor

Function: Lateral rectus muscle, causes abduction of eye (turns eye out)

  • Location: Nuclei in pons; traverses the cavernous sinus, exits skull via superior orbital fissure
  • Lesion Information
  • Results in inward deviation, but NO ptosis or pupil changes


CN V Trigeminal Nerve


  • Functional Category: General Somatic Sensory

Function: General sensation for face, mouth, anterior 2/3rds of tongue, nasal sinuses, meninges

  • Functional Category: Motor (small motor root)

Function: Muscles of mastication and tensor tympani muscle

  • General Information

3 major branches: ophthalmic (V1), maxillary (V2), and mandibular (V3)

  • Location: all divisions enter pons; sensory nucleus extends from midbrain to spinal cord
  • Lesion Information
  • Disorders of trigeminal rare except for trigeminal neuralgia (tic douloureux): Patients experience recurrent episodes of brief severe pain; Usually begin after age 35; Often provoked by chewing, shaving, or touching trigger point on face; Cause mostly unknown although can occur in MS
  • Sensory loss in distribution of trigeminal nerve can be caused by trauma, metastatic disease, herpes zoster, aneurysms
  • Lesions of trigeminal brainstem nuclei cause ipsilateral loss of facial sensation


CN VII Facial Nerve


  • Functional Category: Branchial Motor (main function)

Function: Muscles of facial expression, stapedius muscle, and part of digastric muscle

  • Functional Category: Parasympathetic

Function: Parasympathetics to lacrimanal glands and salivary glands (except parotid)

  • Functional Category: Visceral Sensory

Function: Taste from anterior 2/3rds of tongue

  • Functional Category: General somatic sensory

Function: Sensation from a small region near the external auditory meatus

  • Location: nuclei and nerve entry points located in both pons and medulla
  • Lesion Information
  • Important to distinguish between facial weakness caused by UMN and LMN lesions
  • Unilateral UMN lesions: Spares forehead (mainly affects lower portion of contralateral side); also see “neighbor” effects such as arm weakness, sensory changes, aphasia, dysarthria
  • LMN lesions: Affect entire half of face (does NOT spare forehead); do NOT see neighbor effects
  • Bell’s Palsy (unilateral facial weakness): most common facial nerve disorder
  • All divisions of facial nerve impaired within few hours or days; Cause unknown, although perhaps viral or inflammatory; Also see retroauricular pain, hyperacusis, dry eye, ipsilateral loss of taste


CN VIII Vestibulocochlear Nerve


  • Functional Category: Special somatic sensory

Function: Hearing and vestibular sensation

  • Location: nuclei primarily in pons, but also medulla
  • Lesion Information
  • Unilateral hearing loss can result from disorders of external auditory canal, middle ear, cochlea, 8th nerve, or cochlear nuclei
  • Because info crosses bilaterally at multiple levels once enter brainstem, unilateral hearing loss is NOT caused by lesions in the CNS proximal to the cochlear nuclei
  • Impaired hearing divided into:
    • Conductive hearing loss: Caused by abnormalities of external auditory canal or middle ear
    • Sensorineural hearing loss: Caused by disorders of cochlea or 8th nerve
  • Most common tumor in region is acoustic neuroma (almost always unilateral except in NF2, where tumors can be bilateral); Early symptoms include hearing loss, tinnitus, and unsteadiness
  • True Vertigo: Spinning sensation of movement (most indicative of vestibular disease)
  • “Dizziness” vague term to describe many different sensations
  • Vertigo caused by lesions anywhere in vestibular pathway (most are peripheral involving inner ear)
  • In posterior fossa disease, vertigo will accompany other symptoms (diplopia, visual changes, somatosensory changes, weakness, incoordination)
  • Other causes of vertigo:
  • Benign paroxysmal positional vertigo (most common): Vertigo lasting for few seconds
  • Vestibular neuritis: Several days of intense vertigo
  • Meniere’s disease: Recurrent episodes of vertigo
  • Vertebrobasilar ischemia or infarct, encephalitis, tumors, demyelination in posterior fossa, drugs and toxins


CN IX Glossopharyngeal Nerve


  • Functional Category: Branchial Motor

Function: Stylopharyngeus muscle (elevates pharynx during talking/swallowing & contributes to gag reflex)

  • Functional Category: Parasympathetic

Function: Parasympathetics to parotid gland (for salivation)

  • Functional Category: General somatic sensory

Function: Sensation from middle ear, region near external auditory meatus, pharynx, and posterior 1/3 of tongue

  • Functional Category: Visceral Sensory

Function: Taste from posterior 1/3rd of tongue

  • Functional Category: Visceral Sensory

Function: Chemo- and baroreceptors of carotid body

  • Location: nuclei in medulla


CN X Vagus Nerve


  • Means “wandering” in Latin; from wandering course it takes with parasympathetic innervation
  • Functional Category: Branchial Motor

Function: Pharyngeal muscles (swallowing) and laryngeal muscles (voice box)

  • Functional Category: Parasympathetic

Function: Parasympathetics to heart, lungs, and digestive tract

  • Functional Category: General somatic sensory

Function: Sensation from pharynx, meninges, and small region near external auditory meatus

  • Functional Category: Visceral Sensory

Function: Taste from epiglottis and pharynx

  • Functional Category: Visceral Sensory

Function: Chemo- and baroreceptors of aortic arch

  • Location: nuclei in medulla


CN XI Spinal Accessory Nerve


  • Functional Category: Branchial Motor

Function: Sternomastoid and upper part of trapezius muscle

  • Location: Arises not from brainstem, but from upper cervical spinal cord
  • Lesion Information:
  • LMN lesions of CN XI may cause ipsilateral weakness of shoulder shrug or arm elevation AND weakness of head turning away from the lesion
  • UMN lesions can also cause deficits in head turning, toward opposite side of lesion


CN XII Hypoglossal Nerve


  • Functional Category: Somatic Motor

Function: Intrinsic muscles of tongue

  • Location: nuclei in medulla
  • Lesion Information:
  • UMN lesions will cause contralateral tongue weakness
  • LMN lesions cause ipsilateral tongue weakness (toward side of lesion when protruded)


Clinical Information Regarding Cranial Nerves

Disorders of CN IX, X, XI, and XII


  • Most disorders arise from central lesions, but occasionally affected by diabetic neuropathy, demyelination, motor neuron disease, and traumatic, inflammatory, neoplastic, toxic, etc.
  • Glossopharyngeal neuralgia: clinically similar to trigeminal neuralgia but involves sensory distribution of CN IX, causing episodes of severe throat and ear pain
  • Glomus tumors: rare disorder can affect lower cranial nerves

Hoarseness, Dysarthria, and Dysphagia


  • Causes can range from UMN lesions (corticobulbar pathways) to LMN lesions to disorders of the neuromuscular junction or muscles themselves
  • Voice disorders: occur when larynx or vocal cords impacted, which can result from mechanical, neural, or muscle disorders; can also occur from lesions of CN X
  • Hoarseness: disorders of vocal cords causing asynchronous vibratory patterns; often caused by mechanical factors such as swelling, nodules, polyps, or neoplasms of the cords
  • Breathiness: caused by paralysis/paresis of the vocal cord(s), resulting from air leak at glottis; often mistakenly called hoarseness
  • Dysarthria: abnormal articulation of speech, which should be distinguished from aphasia
  • Can occur from muscles of articulation (jaw, lips, palate, pharynx, tongue), the neuromuscular junction, or damage to CN V, VII, IX, X, or XII. Can also occur because of damage to motor cortex, cerebellum, basal ganglia, or corticobulbar pathways
  • Dysphagia: impaired swallowing
  • Can be caused by dysfunction of muscles of tongue, palate, pharynx, epiglottis, larynx, or esophagus; by lesions of CN IX, X, XII, or by dysfunction at neuromuscular junction or corticobulbar tracts; Often occurs with dysarthria.
  • Swallowing includes:
    • oral prep phase: prep of food bolus by mastication
    • oral phase: movement of bolus in anterior-posterior direction by tongue
    • pharyngeal phase: propulsion of bolus through pharynx
    • esophageal phase: opening of upper esophageal sphincter, peristalsis, and into stomach

Laughing and Crying


  • (Brainstem nuclei: CN VII, IX, X, and XII)
  • Pseudobulbar affect: uncontrollable bouts of laughter or crying without feeling the usual associated emotions; emotional incontinence. Caused by: abnormal reflex activation of laughter and crying circuits in brainstem
  • Pseudobulbar palsy: used to describe dysarthria and dysphagia caused by UMN lesions in corticobulbar pathway (e.g., frontal lobe) NOT brainstem (“bulb”) – thus, pseudo
  • Gelastic epilepsy: rare seizure disorder causing episodes of inappropriate laughter usually associated with lesions of hypothalamus (occasionally in temporal lobe seizures)

Bulbar Cranial Nerves IX, X, XI


  • Bulbar injury = Bulbar palsy, which includes: Dysarthria, dysphagia, and hypoactive jaw/gag reflex NOT associated with cognitive changes (whereas pseudobulbar palsy is)


Cranial Nerve Summary Sheet

Cranial Nerve Sensory Motor Chief Functions Examination Symptoms of Dysfunction
I – Olfactory Sensory Smell Odors applied to each nostril Anosmia
II – Optic Sensory Vision Visual acuity; visual fields Anopsia
III – Oculomotor Motor Moves eyes in all directions but those served by IV and VI Reaction to light, eyelid movement; Medial and vertical eye movements Dilated pupil; ptosis; outward deviation; diplopia; uneven dilation of pupils
  Parasympathetic Pupillary constriction and accommodation    
IV – Trochlear Motor Moves eye down and in Down and in eye movements Diplopia
V – Trigeminal Sensory General senses for head Light touch, pain by pinprick; hot/cold; corneal reflex; jaw reflex; jaw movements Decreased sensation in face; attacks of severe pain (trigeminal neuralgia); jaw weakness; asymmetric chewing
  Motor Chewing    
VI – Abducens Motor Moves eye out Lateral movements of the eye Diplopia; deviation of eye inward
VII – Facial Sensory Taste for anterior 2/3rds of tongue Facial movements/expression; taste Unilateral facial paralysis (Bell’s palsy); loss of taste on anterior 2/3rds of tongue
  Motor Moves face    
  Parasympathetic Salivation and lacrimation (tearing)    
VIII – Vestibulocochlear Sensory Hearing; position and movement of head Audiogram tests hearing; stimulate by rotating patient or by irrigating ear (caloric test) Deafness; tinnitus; dysequilibrium; feelings of disorientation in space
IX – Glossopharyngeal Sensory Posterior 1/3 of tongue, tonsil, pharynx, middle ear Taste; Test pharyngeal or gag reflex by touching walls of pharynx Spasms of pain in posterior pharynx
  Motor Swallowing    
  Parasympathetic Salivation    
X – Vagus Sensory General sensation for pharynx, larynx, esophagus, external ear; chemo/baroreception for heart; visceral sensation for thoracic/abdominal Observe palate in phonation; partial reflex by touching walls of pharynx Hoarseness, poor swallowing, and loss of gag reflex
  Motor Speech, swallowing    
  Parasympathetic Cardiovascular, respiratory, gastrointestinal    
XI – Spinal Accessory Motor Movement of head and shoulder Movement, strength, and bulk of neck and shoulder muscles Wasting of neck with weakened rotation; Inability to shrug
XII – Hypoglossal Motor Movement of tongue Tongue movements; tremor, wasting or wrinkling of tongue Wasting of tongue with deviation to the side of lesion on protrusion

Sensory: 1, 2, 8; Midbrain: 3, 4, (5); Motor: 3, 4, 6, 11, 12; Pons: 5, 6, 7, 8; Mixed: 5, 7, 9, 10; Medulla: (5) (7) (8) 9, 10, 11, 12

Brain Development II


  • Influences – physiology of egg and sperm, intrauterine environment, genetic transmission, errors, mutations. Psychosocial environment influences via mothers’ stress hormones and self-care behaviors.
  • 2 weeks-6 months: Neurons divide and multiply. NO new neurons develop postnatally. Problems –> fewer neurons at beginning of life (e.g., MR)
  • 6 weeks-6 months: Neurons migrate. Move from central ventricle toward skull, forming layers, each built on top or earlier ones. Problems –> neurons in wrong layer of brain; abnormal connections
  • 6 weeks – 6 months: Axons form basic links. Use genetic blueprints and chemical cues
  • Neurons send electrical signals (from dendrite to end of axon) and chemical signals (from end of axon to nearby neurons or muscle cells). Problems –> seizures, mood/attention problems
  • Neural Tube Development: during 3rd and 4th week gestation, the dorsal ectoderm invaginates to form a closed midline neural tube that eventually gives rise to the CNS. Defects in closure are magnified throughout gestation.
    • Ectoderm – forms CNS and skin
    • Mesoderm – forms coverings of CNS (meninges, vertebrae, and skull)



  • Influences – genetic propensities of child and family, child’s physiology (metabolism, nutrition, hormone and neurotransmitter and immune activity, toxins, infections), child’s physical environment (birth trauma, head injury, physical shelter and dangers), child’s psychosocial environment (family, peers, school, community, culture). Child’s biology, in turn, influences psychosocial environment
  • Growth of axons. Problems –> abnormal connections
  • Increase complexity of dendrites and axons on each neuron. Problems –> sparse, skinny dendrites or fewer receptors
  • Formation of synapses between neurons, or with muscle cells. If the link isn’t active it dies or moves away.
  • Death of unused synapses and neurons. Problems –> persisting nonfunctional cells make abnormal connections or develop other problems (e.g., seizures, tumors)
  • Myelination of axons. Problems –> weak or absent communication between brain areas, or between brain and muscles
  • Cell populations mature through developmental stages at different times and in different regions of the brain. Stages are: proliferation, migration, differentiation, myelination, cell death
  • Brain weight at birth is 25% of adult weight; about 80% by age 2 years



  • Brain develops from the “neck up”, and the spinal cord develops from the “neck down”, roughly in this order:
  • Brainstem (medulla, pons, midbrain, cranial nerves). Problems –> crossed or lazy eyes, deafness, sleep disturbances, hallucinations, etc.
  • Cerebellum and basal ganglia. Problems –> ataxia, involuntary movements, “floppiness”
  • Limbic system (thalamus, hypothalamus, amygdala). Problems –> ADD, emotional disorders, obesity, precocious puberty, etc.
  • Primary sensory input areas of the cortex. Problems –> central auditory disorders
  • Motor output areas of the cortex. Problems –> incoordination, spasticity
  • Association, integration, memory, and planning areas. Problems –> ADD, LD
  • Alternate way of describing development:
    • Primary Zones: modality specific; fully functional by end of 1st year
    • Secondary zones: integrate modality-specific info into perceptive info. Become fully functional within first 5 years of life
    • Tertiary zones: associative, supramodal areas encompassing borders of parietal, temporal, and occipital zones as well as prefrontal region with its cortical and subcortical connections. Integrate info across modalities and control executive, purposive, and conative aspects of functioning. Become functional between ages 5 and 8, prefrontal somewhat later (maybe by age 12)

Evidence that Social Environment Influences Brain Development

  • Environmental deprivation and/or stress can alter neuronal, hormonal, and immune systems. The alterations may impair normal development (or impair recovery from brain trauma) in a transient or long-term way. Environmental enrichment may increase neuronal complexity, improve brain function, and facilitate recovery from brain injury.
    • Cortisol reactivity to stress, hippocampus and immune changes (McEwen, Gunnar)
    • PET scan and behavior changes in Romanian orphans (Carlson & Earls)
    • EEG differences related to cognitive development (Nelson, Thatcher, Fischer)
    • EEG differences related to emotional traits and caregiver responsivity (Dawson, Davidson, Fox, Calkins, Bell)
    • EEG differences related to medical status and caregiver responsivity (Als, Gilkerson)
    • Medical and behavioral development of preemies related to touch/massage (Field)
    • Dendritic complexity of rats in enriched environments (Diamond, Greenough)
    • Social behavior and brain changes in socially isolated monkeys (Harlow; Suomi)
    • Speculation about possible effects of child abuse and neglect (Perry; Teicher; Schore)
  • Environmental influences on specific abilities are more pronounced during sensitive periods
    • Axon growth and synapse formation in visual processing areas of kittens exposed to postnatal visual experience (Hubel & Wiesel)
    • Brain growth and behavior of deafened songbirds (Marler)
    • EEG changes in prelingually and postlingually deafened adults, in brain areas that react to visual vs. auditory inputs, and response to grammatical vs. content words (Neville)
    • Age differences in phoneme detection and language-learning (Kuhl, Stromswold)
    • Age differences in recovery from brain damage involve age at injury, age at testing, and type of test administered, sensitive and “insensitive periods occur (Kolb)
  • Some individual brain-behavior differences may be relatively subtle
    • EEG activation patterns may be associated with emotional intensity and valence which are seen as temperament differences (Dawson, Davidson, Fox, Nelson)
    • Stability of early phonological awareness, vocabulary, and later reading and math abilities (Molfese, Hart, & Risley; Morrison; Fletcher & Shaywirtz) despite transitory impact of specific expressive language disorders (Whitehurst; Rapin)
  • Children with a particular brain disorder rarely show a specific, unique pattern of behavior. Effects of brain disorders vary with nature of the brain insult, environmental support and stress; sex and handedness; age at time of injury; age at time of outcome measurement; and nature of the outcome measures (Fletcher, Yeates, Taylor, Dennis, Shapiro, Satz, Baron, etc., etc.)

Some points regarding intervention:

  • Enrichment/deprivation powerful at all ages, though deprivation may be particularly deleterious during initial development of key abilities
  • Critical to NOT deprive of visual, auditory, and tactile stimulation, language input, and responsive “stress buffering” care providers during infancy
  • Phonological awareness and vocabulary at kindergarten predict long-term school success
  • Children may be maximally attuned to sounds of own language between birth and five; decreased skills for learning speech sounds after that
  • Early accurate diagnosis better than a “wait-and-see” approach
  • Younger age at acquired injury (after first few months of life) associated with more severe cognitive and behavioral impairments
  • Best intervention is PREVENTION – vast majority of brain damage is preventable via social/environmental factors (especially injuries). FYI, best prevention involves training in supervisory practices and environmental modifications, NOT safety education programs.


Miscellaneous Developmental Issues

  • Effects of brain injury tend to be less specific in children than adults, particularly if damage incurred before age 5-7 years

Frontal functions develop in a step-wise fashion with some functions developed by about 6-7 years of age and others continuing to mature into adolescence.

Brain Development I

Principles of Neural Development

Steps of Development and Placement of Neurons

  • Proliferation (cell generation by mitosis) occurs inside neural tube. Neurogenesis term used to describe nerve cell production
  • Mitotic cycle of each cell follows a fixed sequence, resulting in production of neuroblasts (nerve cell precursors) or glioblasts (glial cell precursors)
  • Migration – after proliferative phase (but not before 6 wks gestation), neuroblasts move to permanent location. The migration process is as follows:
    • Early neural tube consists of ventricular zone of mitotic cells and marginal zone of cellular processes
    • Intermediate zone forms with cell proliferation
    • By 8-10 weeks after conception, intermediate zone enlarges to form cortical plate
    • Initial formation of cortical plate occurs by migration of cells to sixth layer of cortex and subsequent migrations follow an inside-out pattern (thus, top layer is formed last by neurons that must migrate past cells of the deeper layers)
    • Second migratory wave is at 11-15 weeks gestation
    • Cells migrate in sheets called laminae
    • Migration occurs by guidance by radial fibers
    • Radially oriented glia – group of glial cells radially oriented from ventricular to basal surface and guides migration of neurons
    • Migration in cerebellum occurs in outside-in pattern- b/w 9-13 wks gestation, neuroblasts migrate to outermost layer of cerebellum and proliferate. Bergmann glia responsible for migration
    • By 18 weeks gestation, all cortical neurons have reached designated location
    • Migratory defects include complete failure of migration; curtailment of migratory cells along migratory pathway; aberrant placement of postmitotic neurons within target structure (ectopia)
  • Aggregation – during migratory cycles, neurons selectively aggregate to form cellular masses, or layers. This is called lamination. Two events in aggregation process
    • neurons come together and establish adhesion between necessary cells
    • align themselves with respect to immediate neighbors
  • Cytodifferentiation (cellular differentiation) – four major concurrent aspects
    • Development of cell body
    • Selective cell death: 40-75% of all neurons die during development; only a limited number of neurons succeed in sending axons to correct targets
    • Axonal and dendritic development
      • As migrating neuronal cells reach designated position, dendrites begin to sprout (arborization).
      • Extensions (spines) begin to extend from dendrites
      • Dendritic growth begins prenatally and proceeds slowly
      • Majority of arborization and spine growth occurs postnatally, with most intensive period occurring birth to 18 months
      • Development highly sensitive to environmental stimulation
      • Chemospecificity – biochemical specificity programmed into each nerve cell determining that contacts between cells are made. As neuron forms axon and dendrites, sends out advance spray of cellular processes (microfilaments) that seek chemical attraction, forming appropriate connections with nerve cells.
    • Synaptogenesis – termination of axonal growth, selection of synaptic sites, and formation of synapse; regional increases in synaptic density accompany the emergence of function:
      • Visual cortex – dendritic and synaptic growth stops at age 8 months, but process of synapse elimination continues to 3 years of age
      • Frontal cortex – dendritic and synaptic density reach peak in infancy and early childhood and decline b/w 2 and 16 yrs
    • Pruning – neurons overproduced and many initial connections are random; subsequent development eliminates (prunes) neurons.
      • Process often begins at dendritic spines
      • Purposeful sculpting of brain; eliminates weakly reinforced or redundant connections
      • Promotes neural efficiency
      • Primarily a postnatal process, eliminating 40% of cortical neurons during childhood
      • Proceeds at different times and rates. Ex- pruning of visual cortex begins at 1 and complete by 12 yrs; pruning of prefrontal from 5-16 yrs


Glial Cell Development and Myelogenetic Cycles

Glial cells include:

  • astrocytes
  • oligodendrocytes
  • microglia
  • Functions – respond to injury; regulate neuronal metabolism, contributing to BBB; through myelination, play role in electrical activity
  • Glial cells are relatively immature in early stages of CNS development (no gliosis to penetrating wound in newborn brain)
  • Most important role is myelination
  • Myelination starts in spinal cord, spreads to medulla, pons, midbrain, finally to diencephalon and telencephalon
  • Cortical regions myelination begins posterior and moves anterior, with parietal and frontal lobes last
  • Frontal and parietal myelination begins after birth and continues to adolescence and adulthood
  • Increase in brain weight postnatally primarily myelination
  • Myelination of regions correlates with emergence of function

Myelogenesis – development of myelin

  • Primordial (“premature”) fields myelinate before birth – somesthetic cortex, primary visual cortex, primary auditory cortex
  • Intermediate (“postmature”) fields myelinate during first 3 postnatal months – secondary association areas
  • Terminal fields myelinate between fourth postnatal month and 14 yrs of age – classical association areas


Metabolic and Biochemical Agents

  1. Nucleic acids – DNA, RNA
  • brain content high during early phases of development, then gradually decreases
  • DNA content reliable predictor of cell number
  • Two periods of cell proliferation detected by measuring DNA: 15-20 wks gestation is neuroblast proliferation; 25 wks gestation to 2 yrs age glial cell multiplication
  • Lesch-Nyhan syndrome – mutation of gene affects enzyme involved in making of nucleotide bases of nucleic acids
  1. Amino acids
  • Absorption of amino acids from blood and rates of protein synthesis higher for newborns than adults
  • Inborn errors of amino acid metabolism – PKU
  1. Lipid
  • In fetal brain, little difference found between lipids in gray and white matter
  • Adult pattern attained during myelination, which increase in three major lipids (cholesterol, cerebrosides, sphingomyelin)
  • Disorders of lipid metabolism – Tay-Sachs, Niemann-Pick
  1. Neurotransmitters
  • acetylcholine, dopamine, glutamate, epinephrine, norepinephrine
  • increase in levels serve as developmental signals for neural tube formation, germinal cell proliferation, and neuronal and glial differentiation


Chronology of Gross Neural Development

In general, CNS, brain and spinal cord development is:

  • head (cephalic) to tail (caudal)
  • near (proximal) to far (distal)
  • inferior (subcortical) to dorsal (cortical)



Development of neural tube:

  • 18 days – CNS and PNS develop from midline ectoderm layer of fertilized egg
  • Neural plate appears from dorsal ectoderm
  • In the center of the plate, the cells on edge become narrower on inner surface, while those surrounding become narrower on outer surface, forming neural groove formed of neural folds.
  • This gradually deepens, and folds over onto itself. It starts to close starting at midpoint and extending in both rostral and caudal directions.
  • As it closes, there are two open ends (neuropores), which close at 25 days gestation, forming neural tube
  • Anterior end gives rise to brain, posterior end forms spinal cord
  • Process of conversion from open groove to sealed tube is neurulation
  • Neural tube defects occur third to four weeks gestation: neural tube has difficulty closing (anterior- anencephaly; caudal- spina bifida)

Neural crest cells are adjacent to neural tube. They are free of overlying ectoderm and form irregular bundle of tissue surrounding tube. These clumps of cells migrate and differentiate to form ganglia

Regional Development

  • Three vesicles develop at anterior end of neural tube
  1. prosencephalic (becomes forebrain)
  2. mesencephalic (becomes midbrain)
  3. rhombencephalic (becomes hindbrain)
  • 5th week gestation

prosencephalic vesicle divides into telencephalon and diencephalon rhombencephalic vesicle divides into metencephalon and mylencephalon

  • 7th week of gestation

telencephalon transformed into cerebral hemispheres diencephalon into thalamus and related structures metencephalon into cerebellum and pons myelencephalon into medulla oblongata

  • In vestigial form, the neural tube becomes the cerebral ventricles and cerebral aqueduct
  • Caudal (tail end) becomes spinal cord, elongating and developing into segments, each of which is associated with sensory and motor innervation
  • Spinal cord keeps remnant of neural tube as central canal
  • In cord, neural tissue desegregates into two main bodies of neurons – dorsal (posterior) horns and ventral (anterior) horns, divided by sulcus limitans
  • Dorsal horns, also called alar plate, receive axons from dorsal root ganglia and involved in sensory events
  • Ventral horns, also called basal plate, contain cell bodies of axons that innervate muscles and considered part of motor system

Development of Cortex

  • Corticogenesis begins 6th week gestation
  • 6th week gestation – basal ganglia visible
  • 8-10 weeks gestation – early cortical plate forms from migrating cells; four layers of cortex are visible (ventricular, subventricular, intermediate, and marginal)
  • As cortex develops, first expands anteriorly to form frontal lobes, then dorsally to form parietal lobes, then posteriorly and inferiorly to form temporal and occipital lobes
  • Posterior and inferior expansion pushes cortex into a C shape, which shapes many of the underlying structures (lat vents, head of caudate of BG, hippocampus)
  • 5th month gestation – increasing number of cortical cells causes smooth surface of brain to develop pattern of convolutions and sulci
  • Pattern of convolutions and sulci – primary, then secondary, then tertiary
    • hippocampal sulcus: 13-15 wks
    • parieto-occipital, calcarine, olfactory bulb sulci: 19 wks
    • sylvan (lateral) and rolandic (central) sulci: Spreen says 24 wks; other article says 14 wks
    • secondary sulci (first temporal sulcus, superior frontal sulci): 28 wks
    • tertiary not formed until third trimester and continue development after birth
  • Gyral pattern of adult present at birth
  • Gyri and sulci patterns form after neuronal migration and reflect processes of neuronal specialization, dendritic arborization, synaptic formation, and pruning
  • Formation of gyri signals that intracortical connections are established
  • Extreme alterations suggest deviations in cortical connections and potential deficits: polymicrogyria – small, densely packed gyri associated with LD, MR, and epilepsy
  • 6th month gestation – cortical plate thickens due to migrating neurons and more layers are formed, giving cortex final six-layered composition

Development of Intercerebral Commissures

  • Growth is slow and related to maturation of association cortex
  • First commissural fibers cross in rostral end of forebrain at 50 days gestation, creating anterior commissure and hippocampal commissure
  • Fibers of CC cross develop in parallel with various cerebral lobes and process not complete until after birth
  • Failure results in agenesis of CC

Development of Ventricles

  • Cavities within cerebral vesicles of neural tube form vents and central canal of spinal cord
  • Cavities of cerebral vesicles differentiate into
    • two lateral vents
    • aqueduct of Sylvius
    • fourth vent



  • Brain weighs b/w 300-350 g and grows rapidly, reaching 80% of adult weight at 4 yrs.
  • Cortical surface area of hemispheres doubles, reaching adult dimensions by age 2
  • Increase in brain size inferred from head circumference
  • Growth of brain due to increase in size, complexity, and myelination (rather than number) of nerve cells
  • Primary sensory and motor areas are most advanced, followed by progressive development of adjacent sensory association areas, and finally parietal and temporal association areas.
  • Prefrontal lobes least developed at birth, not much development until after second year
  • Functional organization of nervous system reflecting increased responsiveness to environmental stim
  • Functional elaboration of association fibers and tracts; increasing connectivity
  • EEG changes – after birth irregular and low amplitude; by 4 months of age, first slow rhythm (3-4 discharges per second) becomes evident, primarily over occipital cortex; frequency of EEG discharge increases over tie until characteristic stable alpha rhythms (11-12 per second) is attained

Maturation of the Cortex in Early Postnatal Period

  • Neurogenesis begins at front edge of cortex where frontal cortex abuts inferotemporal cortex and proceeds back to primary visual cortex
  • Primary sensory nuclei in thalamus, including ventrobasal complex (somatosensory), medial geniculate body (auditory), and lateral geniculate body (visual) generated first and establish axonal connections to cortex first.
  • Nuclei that innervate frontal, parietal, and inferotemporal cortex are last




  • Sensory areas myelinate before motor (may be responsible for comprehension/ production language disparity)
  • Myelination of callosal and associational cortical regions may continue into third and fourth decade of life


  • Synaptogenesis and synapse elimination co-occur over most of early postnatal development
  • Primary mode of learning in nervous system takes place when juncture is formed or modified as a function of experience
  • Synaptic connectivity is considered the primary means by which knowledge is represented in the brain
  • Generation of synapses in isocortex accelerates around birth; simultaneous peaking of synaptogenesis across all cortical areas
  • Brain suddenly starts to generate massive numbers of synapses just before environmental experience (ie, birth) in all regions associated with sensory, motor, motivational, and linguistic ability
  • Synapse generation overshoots by a substantial proportion in first six months, then declines to adult values
  • Five stages of synaptogenesis
    • Synapses present in preplate
    • Synapses generated in cortical plate
    • Synaptogenesis synchronized in global perinatal “burst”
    • Stabilized high level lasting from late infancy until puberty
    • Synapses steadily decline in density and number from puberty through adulthood


Timing of Events – A Summary

First Trimester

  • Development of neural tube
  • Every neuron in nervous system generated in first trimester, with exception of tail of distribution of last layer of isocortex and external granular layer of cerebellum (hippocampal dentate gyrus and olfactory bulb neurons are generated throughout life
  • Basic axonal pathways of brainstem laid down
  • Migration of cells
  • Differentiation of cells

Second Trimester

  • Basic wiring of brain (large patterns of connectivity between neural regions)
  • Connection of thalamus to all regions of isocortex- pattern of connections resembles adult pattern
  • Intracortical pathways begin to be established
  • Appearance of CC around 90 day gestation
  • Apoptotic neuronal death (“apoptotic” suggests that it is organized cell death, not disorganized dissolution of the cell)
  • Activity-dependent self-organization of the nervous system- first motor activity of fetus begins

Third Trimester

  • Reciprocal connectivity from higher-order cortical areas to primary areas
  • Initial myelination
  • Large descending pathways from cortex- “top down” connectivity with sensory and motor systems
  • Synaptic connections between isocortex and related structures

By Birth

  • all cells are generated
  • all major incoming sensory pathways are in place and have gone through period of refinement of total cells, connections, and topographic organization
  • intracortical and connectional pathways well developed (output pathways lag)
  • microstructure of features such as motion and orientation in visual system present
  • “Big” cortical regions (primary sensory and motor) have adult input and topography


Evidence that Social Environment Influences Brain Development

Environmental deprivation and/or stress

Environmental deprivation and/or stress can alter neuronal, hormonal, and immune systems. The alterations may impair normal development (or impair recovery from brain trauma) in a transient or long-term way. Environmental enrichment may increase neuronal complexity, improve brain function, and facilitate recovery from brain injury.

  • Cortisol reactivity to stress, hippocampus and immune changes (McEwen, Gunnar)
  • PET scan and behavior changes in Romanian orphans (Carlson & Earls)
  • EEG differences related to cognitive development (Nelson, Thatcher, Fischer)
  • EEG differences related to emotional traits and caregiver responsivity (Dawson, Davidson, Fox, Calkins, Bell)
  • EEG differences related to medical status and caregiver responsivity (Als, Gilkerson)
  • Medical and behavioral development of preemies related to touch/massage (Field)
  • Dendritic complexity of rats in enriched environments (Diamond, Greenough)
  • Social behavior and brain changes in socially isolated monkeys (Harlow; Suomi)
  • Speculation about possible effects of child abuse and neglect (Perry; Teicher; Schore)


Sensitive Periods

Environmental influences on specific abilities are more pronounced during sensitive periods

  • Axon growth and synapse formation in visual processing areas of kittens exposed to postnatal visual experience (Hubel & Wiesel)
  • Brain growth and behavior of deafened songbirds (Marler)
  • EEG changes in prelingually and postlingually deafened adults, in brain areas that react to visual vs. auditory inputs, and response to grammatical vs. content words (Neville)
  • Age differences in phoneme detection and language-learning (Kuhl, Stromswold)
  • Age differences in recovery from brain damage involve age at injury, age at testing, and type of test administered, sensitive and “insensitive periods occur (Kolb)


Individual Differences

Some individual brain-behavior differences may be relatively subtle

  • EEG activation patterns may be associated with emotional intensity and valence which are seen as temperament differences (Dawson, Davidson, Fox, Nelson)
  • Stability of early phonological awareness, vocabulary, and later reading and math abilities (Molfese, Hart, & Risley; Morrison; Fletcher & Shaywirtz) despite transitory impact of specific expressive language disorders (Whitehurst; Rapin)


Phenotypic Variation

Children with a particular brain disorder rarely show a specific, unique pattern of behavior. Effects of brain disorders vary with nature of the brain insult, environmental support and stress; sex and handedness; age at time of injury; age at time of outcome measurement; and nature of the outcome measures (Fletcher, Yeates, Taylor, Dennis, Shapiro, Satz, Baron, etc., etc.)


Some points regarding intervention

  • Enrichment/deprivation powerful at all ages, though deprivation may be particularly deleterious during initial development of key abilities
  • Critical to NOT deprive of visual, auditory, and tactile stimulation, language input, and responsive “stress buffering” care providers during infancy
  • Phonological awareness and vocabulary at kindergarten predict long-term school success
  • Children may be maximally attuned to sounds of own language between birth and five; decreased skills for learning speech sounds after that
  • Early accurate diagnosis better than a “wait-and-see” approach
  • Younger age at acquired injury (after first few months of life) associated with more severe cognitive and behavioral impairments
  • Best intervention is PREVENTION – vast majority of brain damage is preventable via social/environmental factors (especially injuries). FYI, best prevention involves training in supervisory practices and environmental modifications, NOT safety education programs.


Behavioral Neuroanatomy – Mesulam


Structural foundations of cog and beh domains take the form of partially overlapping large-scale networks organized around reciprocally interconnected cortical epicenters

  • Spatial Attention Network (Rt hemisphere)
  • Lang Network (Lt hemisphere)
  • Memory-Emotion Network (Limbic)
  • Executive Function-Comportment Network (Prefrontal)
  • Face-and-Object Identification Network (Ventral occipitotemporal)


Parts of the Cerebral Cortex

  • Human cortex contains approximately 20 billion neurons
  • Difficult to map
    • Brodmann’s map – microscopically identified variations
    • Today, folks use Brodmann’s in topographic way – problematic
    • Probably more accurate to say, for e.g., “middle temp gyrus”. Can be identified topographically and doesn’t need to be verified microscopically


5 major fxal subdomains of cerebral cortex

  1. Limbic
  • Corticoid (cortex-like) – simplified cytoarchitecture; certain basal forebrain structures
  • Allocortex – 2 formations: hippocampal complex and piriform cortex
    • Extensively interconnected with the hypothalamus
    • important in regulating the internal milieu and preserving self/species
    • specifically: mem, emtn, motiv, hormonal balance, and autonomic balance
  1. Paralimbic (Mesocortex)
  • Between allocortex and isocortex
  • Includes 5 formations: orbitofrontal, insula, temp pole, parahippocampal, cingulate
  • Divided into 2 grps: 1) Olfactocentric and 2) Hippocampocentric
  • Plays a critical role in channeling emotion to behaviorally relevant motor acts, mental content, and extrapersonal events
  1. Heteromodal Ass’n (Isocortex) – 6 layer homotypical architecture; High-order ass’n cortex
  • Includes: Prefrontal, post parietal, lateral temporal, and portions of parahippocampal
  • Most closely involved in perceptual elaboration and motor planning
  • 3 essential characteristics
    • neuronal responses not confined to single sens modality
    • sens inputs come from unimodal areas in mult modalities
    • lesions multimodal; never confined to tasks under control sing modality
  1. Unimodal Ass’n (Isocortex) – 6 layer homotypical architecture
  • Most closely involved in perceptual elaboration and motor planning
  • Upstream: only one synapse away from primary sensory area
    • Visual: BA18-19
    • Auditory: ?Sup temp gyrus (BA22); maybe BA21
    • Somatosens: unclear up/dwnstrm: sup parietal lobule(BA5, BA7); ? inf par
  • Downstream: 2 or more synapses from primary area
    • Visual: Fusiform, inf temp, middle temp
    • Auditory: ?anterior part of superior temp cortex (BA22)
  • 3 essential characteristics of unimodal
    • respond to stim in only single sensory modality
    • sens info comes from primary sens cortex
    • lesions yield deficits only in tasks guided by that modality
  • Primary Sensory-Motor (Idiotypic cortex)
    • Visual: Covers banks of calcarine fissure (BA17)
    • Auditory: Covers Heschl’s gyrus (BA41-42)
    • Somatosensory: Postcentral gyrus (BA3a, 3b, 1, 2)
    • Motor: Precentral gyrus (BA4 and probably BA6)
    • Vestibular: Posterior sylvian fissure (where temp lobe joins insula and parietal lobe)
    • Gustatory: BA43
    • Olfactory: At confluence of insular, orbitofrontal, and temporopolar areas
      • Vestibular, gustatory, and olfactory sensations – not same prominence as others in primate


Cortical Organization, Connectivity, and Transmodal Areas

  • 5 areas above have extramural (w/ other fxal zones) and intramural connections (w/ same zone)
  • Essential characteristic of primate brains – obligatory synaptic relays between stim and response
    • Allows for integrative processing (psych outcomes: cognition, consciousness, comportment)
    • This processing has two roles:
      • keeps motivationally-driven internal milieu from dominating
      • allows identical stimuli to trigger diff responses depending on context, experience, needs, consequences


Functions of Individual Cortical Zones: Primary Sensory/Motor Areas

  • Primary Visual “Striate” Cortex (BA17) – covers occipital pole and banks of calcarine fissure
    • 70% of retinal input is relayed to striate thru LGN
    • Entire visual field is mapped onto striate cortex with great spatial precision
    • Contralateral representation
    • Lesion of geniculostriate pathway – characteristic visual field deficits
  • Primary Auditory Cortex (BA41, 42) – located on Heschl’s gyrus
    • Inputs from MGN
    • Tonotopic organization in A1 so that low freq are represented more anteriorly
    • Does NOT display strict contralateral representation that visual and somatosensory display
    • MGN has projections both to A1 and aud ass’n areas; thus, complete cort deafness unlikely
    • Lesion to A1 (unilateral) – difficult to detect clinically
  • Primary Somatosensory – postcentral gyrus
    • Input primarily from ventroposterior lateral thalamic nucleus
    • Contralateral half of body surface is somatotopically mapped onto S1 in each hemisphere
    • Lesion to S1 – selective impairment in “cortical sensations” (e.g., 2-pt discrimination, touch localization, graphethesia, position sense, and stereognosis…..touch, pain, temp intact)
  • Primary Motor Cortex – precentral gyrus; closely parallels S1
    • Dominated by large pyramidal neurons
    • Lesions to M1 – poorly understood; may impair distal movements leave muscle tone and strength of proximal muscles intact??
    • Like S1, hand and foot in M1 have no callosal connectivity – rlted to handedness


Functions of Modality-Specific (Unimodal) Sensory Association Areas

  • Info processing enters first ‘associative’ area within modality specific (unimodal) ass’n area
  • Lesions give rise to 2 beh deficits:
    • Selective perceptual deficits that leave other fxs of that modality intact (e.g., achromatopsia)
    • Modality-specific agnosias (e.g., prosopagnosia, pure word deafness)

Visual Unimodal Ass’n – peristriate (BA18-19), parts of fusiform, inf temp, mid temp (BA37, 20, 21)

  • Each node continuously passing on info to others; connections are reciprocal; display relative rather than absolute specializations
  • Color (V4, maybe V8)
    • Posterior parts of lingual and fusiform sensitive to color
    • Lesions (unilateral) – contralateral loss of color perception (hemi-achromatopsia); if disrupt connections to lang cortex “color anomia”
  • Movement (V5, MST)
    • Middle temporal gyrus
    • Lesions (bilateral) – akinetopsia (can’t perceive visual motion)
  • Form and Complex Patterns (parts of fusiform, lingual, inf occipital gyri)
    • Elementary sens features above used by areas along ventral path for discrimination of form/complex patterns
  • Ventral Pathway: Faces, Objects, and Words
    • Fourth synaptic level – promote rapid identification of faces, objects, words
    • Face/object: Midportion of fusiform
      • Lesions – prosopagnosia, associative visual object agnosia
    • Word-form: fusiform, perhaps lateral occipitotemporal region; probably mediate a sort of processing where words are handled more like objects than symbols
      • Lesions – pure alexia
    • Dorsal Pathway: Spatial Orientation; Dorsal Occipitoparietal region (junction of BA19 and BA7)
      • Fourth synaptic level – encodes info in form of spatial vectors
      • Lesions: visuospatial disorientation syndromes (visual neglect; dressing apraxia; simultanagnosia; optic ataxia-deficit in reaching toward target; optic apraxia-oculomotor exploration deficits)
        • Balint’s Syndrome – optic ataxia, optic apraxia, simultanagnosia

Auditory Unimodal Association Areas (A1)

  • May also have ventral and dorsal organization
  • A1-pure tones and pitch; mid to anterior parts of sup temp gyrus-phonetic parameters
  • Lesions of unimodal aud ass’n cortex-auditory perceptual impairments (cortical deafness; pure word deafness; auditory agnosia for sounds; phonoagnosia-inability to recognize familiar voices)

Somatosensory Association Areas and Secondary Somatosensory cortex (BA1,2)

  • S2 area – participates in pain perception; lesions-loss of pain w/out loss of other somatosens
  • Somatosensory ass’n (BA5, 7 and ?anterior BA40&posterior insula)
    • Essential role in touch localization, manual exploration, coordination of reaching/grasping, and encoding of somatosensory memories
  • Lesions
    • Between SS cortex and parietal heteromodal-somatosensory integration deficits ass’d w/ dressing apraxia, neglect, and other aspects of spatial disorientation
    • Between SS and temoroparietal SS object recognition deficit-tactile agnosia
    • Between SS and lang network-pure agraphesthesia (analog of pure word deafness/pure alexia)
    • Between SS and premotor-modality specific tactile apraxia


Motor Association Areas

(Premotor-BA6, Supp Motor-mostlyBA6, Frontal Eye Fields-post parts of Broca’s and parts of BA8)

  • Motor ass’n areas anterior to M1 source of almost all cortical projections to M1
    • Stim will produce movements but higher threshold than M1-movement patterns much more intricate (e.g., bilateral)
    • Lesions: Reflect a disconnection between cognition and action; not impairment in strength or mobility; complex deficits of movement in absence of weakness, dystonia, dysmetria, or hyperreeflexia
  • Premotor
    • Receive input from # of unimodal/heteromodal areas so have access to info in all sens modalities
    • Respond to sens stimuli but usually according to movement that would follow
    • Intricate connections between post parietal and premotor areas
    • Lesions in premotor part Broca’s – dysarthria for speech but not singing
    • Lesions between BA6 and post lang network-ideomotor apraxia (inability to pantomime use of object upon command)
  • Supplementary
    • Role in coordinating multistep movement strategies ?maybe also in encoding procedural mem
    • Along w/ premotor-imp roles in motor planning and response selection; also initiation of motor; selection of motor responses
    • Lesions – may interfere with motor initiation but not other phases of movement
  • Lesion between pre/supp motor and Brocas->Transcortical motor aphasia; aphemia(nonaphasic, nondysarthric impairment of fluency)
  • Frontal Eye Fields
    • Lesions-impaired exploratory eye movements even when spot eye movements intact
  • Broca’s (premotor in BA44 and adjacent heteromodal cortex)
    • Critical role in translating neural word forms into articulatory sequence; in seq words/endings into utterances that have a meaning-appropriate syntactic structure


Temporal Heteromodal Cortex and Agnosias

(Recognition of Faces, Objects, Voices)

  • Heteromodal cortices in mid temp gyrus may link visual representation of faces with other assns (eg, name, voice)
    • Associative prosopagnosia – bilateral lesions in mid-to-ant parts of lingual and fusiform
      • When info from nonvisual modality is available, can recognize
    • Apperceptive prosopagnosia – deficit in spat integration of vis percept
      • Unable to determine if 2 faces alike
    • Pts with prosopagnosia can recog and name object classes (this is a face, car, etc), but not particular faces
    • Other associative agnosias – arise when unimodal areas specialized for perceptual encoding of objects damaged or when they fail to access the transmodal gateways allowing for integration
      • Associative Visual Object Agnosia – extends to level of categorical recognition; may represent lesion more upstream
      • Auditory agnosia – may reflect a disconnection of unimodal auditory areas from transmodal
        • eg, don’t associate ringing of telephone or ambulance siren
      • Phonoagnosia – (aud analog of prosopagnosia)-inability to recognize identity of familiar voices
      • Tactile agnosia – inability to recognize objects by palpation (Associative deficit)
    • Stereognosis – apperceptive deficit


Wernicke’s Areas as a Temporoparietal Transmodal Gateway for Language

  • Broca’s -BA44 and adjacent heteromodal prefrontal cortices
    • Synaptic/Articulatory pole
  • Wernicke’s-no accepted boundary (Post 1/3 of BA22, adjacent pars BA39-40, and ?mid temp gyrus)
    • Lexical/Semantic pole
    • Transmodal gateway coordinating reciprocal interactions btwn sensory reps of word forms and symbolic assns – give meaning to words
  • Aspects of lang network
    • Word forms – encoded within unimodal auditory and visual areas
    • Lexical labeling – component of object recognition (name is attribute like color, location, etc)
    • Word comp – object recognition task where perceptual features first lead to word is a word
    • Identification of individual word
    • Establishment of assns – define meaning using transmodal nodes in Wernicke’s
  • Lesions: Verbal associative agnosias
    • Pure alexia(word blindness) – disconnect between areas encode vis word form and vis input
      • Can arise when lesion of V1 in L and Splenium (region of CC conveys vis info across)
    • Pure word deafness – unimodal auditory cortex cut off frm aud input or can’t access transmodal
    • Pure agraphethesia-disconnect somatosensory ass’n from wernicke’s/lang network
    • Maybe from post parietal lesion


Functions and Syndromes of Posterior Parietal Heteromodal Cortex

Posterior Parietal Heteromodal area (BA37, 39, 40) – interactions related to praxis, language, visuomotor integration, generation of motor plans, and spatial attention


  • Inf parietal lobule – Ideomotor apraxia – can’t use or understand pantomime of using object
  • Angular gyrus of Lang-dominant – anomia, alexia, acalculia, dysgraphia, finger identification, left-rt naming difficulties (last four – Gerstmann syndrome)
  • Heteromodal inferior par lobule in rt hemisphere – deficits in spat attn, visuospat integration, and drawing (Rt parietal syndrome) also, anosognosia, dressing apraxia, confusional states, route finding deficits, and disturbances in navigating body with respect to objects
  • Parietotemporal heteromodal – disturbances in mood and motivation


Prefrontal Heteromodal Cortex and Frontal Lobe Syndromes

  • Frontal lobes – represent 1/3 of cerebral hemispheres
  • Three functional sectors
    • Motor-Premotor – BA4, BA6, supp motor area, frontal eye fields (BA6), parts of Broca’s
      • Lesions: weakness, alteration of muscle tone, release of grasp reflexes, incontinence, akinesia, mutism, aprosody, apraxia, and some motor components of neglect and Broca’s aphasia
    • Paralimbic – ventral and medial part of frontal-part of ant cingulate (BA23, 32), parolfactory gyrus (gyrus rectus, BA25), and post orbitofrontal regions (BA11-13)
    • Heteromodal – BA9-10, ant. BA11-12, and BA45-47
  • Prefrontal cortex (generally refer to paralimbic and heteromodal areas)
    • Two fx axes:
      • Working memory-executive fx-attn (transmodal centers-prefrontal and post parietal)
      • Comportment (transmodal centers in prefrontal and orbitofrontal paralimbic cortex
    • Two general types of frontal lobe syndromes
      • Syndrome of frontal abulia – loss of creativity, initiative, and curiosity; apathy, emot blunting
        • Lesions to heteromodal cortex (ie, dorsolateral frontal area)
      • Syndrome of frontal disinhibition – loss of judgment, insight, and foresight
        • Lesions to paralimbic cortex (ie, orbitofrontal and medial frontal)
      • Neuropsychology of Frontal Lobe Disease
        • Attention
          • P300 response to novel stim critically dependent on prefrontal cortex
          • Frontal eye fields – part of network for exploring extrapers space and seeking motivationally relevant targets
        • Working Memory (volitional manipulation and on-line holding of info)
          • Unimodal ass’n cortex participate in working mem of own area of specialization
          • Lateral prefrontal cortex – supramodal role in orchestrating working mem in all domains
            • (like role of temp transmodal cortex in object recog; Wernicke’s in lang)
          • Two groups of processes: volitional manipulation and on-line holding
            • Volitional manipulation: Central Executive; prefrontal dorsolateral cortex
            • On-line maintenance: both prefrontal and post parietal cortex
          • Lesions to prefrontal or post par can disrupt working memory
          • Prefrontal- orient att’n focus toward internal mental processes; lesions – tilt emphasis away from internal mental processes toward stim-bound behavior
          • Posterior Parietal – orients toward extrapersonal space; lesions – tilt emphasis away from external sensory events and promote sens neglect
        • Metaphysiology of Prefrontal cortex
          • Even massive damage to prefrontal leaves all sens, perception, movement, and homeostasis fx intact
          • Prefrontal cortex has many interconnections with almost all other heteromodal, unimodal, paralimbic, and limbic areas; so, can activate, suppress, orchestrate networks of fxing
          • Important role in inhibiting impulses not appropriate to context
          • Neurons of prefrontal help to establish subjective reality; sensitive to behavioral relevance of stim – not surface properties
          • Cuz of working mem can simultaneously maintain mult external and internal phenomena
          • Orbitofrontal and other paralimbic components – transmodal nodes for binding thoughts, memories, and experiences with visceral and emot states
        • Frontal lobe versus Frontal network syndromes; tricky saying frontal lobe cuz of intricate connections; probably more accurate to refer to “Frontal network syndrome”
          • Manifestations of frontal lobe syndrome could result from:
            • Lesions in the head of the caudate or in mediodorsal thalamus
            • Multifocal white matter diseases
            • Metabolic encephalopathy
            • Multifocal partial lesions


Paralimbic (Mesocortical) Areas

  • Olfactocentric formations – temporal pole, insula, and post orbitofronal cortex
  • Hippocampocentric formations – parahippocampal “rhinal” cortices, retrosplenial area, cing gyrus, and subcallosal (paraolfactory) regions
  • Link cognition with visceral states and emotion; emphasize beh relevance over physical aspects
  • Critical to: 1)mem/learning; 2)channeling of emotion; 3)linkage of visceral state, immune responses, and endocrine balance to mental state; 4)perception *of pain, smell, and taste
  • Insula – abuts upon frontal and parietal opercula dorsally and supratemporal plane ventrally
    • Contains gustatory cortex, piriform olfactory cortex, and aud/vestibular areas
    • Also imp in mediating tactile learning and reaction to pain; may help link Wernicke/Broca’s
    • Lesions: pain asymbolia, tactile learning deficits
  • Orbitofrontal Cortex- designate entire ventral surface of frontal lobes
    • Critical role in integration of visceral and emotional states w/ cog and comportment
    • Posterior – behaviorally more “limbic”
    • Anterior – similar to dorsolateral
  • Temporal Pole – caps anterior tip of temporal lobe; jx with insula thru piriform cortex
    • Medially – olfactory-gustatory-visceral medially
    • Dorsally – auditory fx
    • Ventrally – visual
    • Laterally – multimodal integration
  • Cingulate complex and Medial Frontal Area – part of hippocampocentric grp
    • Includes: retrosplenial region; cing gyrus; and paraolfactory (essentially around CC)


Limbic Structures of the Septal Area, Nucleus Basalis, and Piriform Cortex

  • Behavioral specializations of these areas similar to paralimbic but more closely related to memory, drive, emotion
  • Septal Nuclei and the Nucleus Basalis of the Substantia Innominata
    • Basal Forebrain (medial septal nucleus, nuclei of Broca’s diagonal band, nucleus basalis of Meynert)
      • major cholinergic innervation of cortical surface; also contain GABA neurons
    • Piriform Cortex (primary olfactory cortex)
      • Inputs from the olfactory bulb; interconnected with the hypothalamus
      • Olfactory info does NOT have to be relayed thru thalamus
      • Unique importance of olfactory sensation to sexual, territorial, and feeding behaviors


The Amygdala, Emotion, and Affiliative Behaviors (Neuro of Value)

  • Extensive connections with the hypothalamus, hippocampus, and other limbic and paralimbic areas
  • Receives olfactory, gustatory and somatosensory, auditory, and visual info
  • Critical role of amygdala – channeling drive and emotion; acts as a transmodal gateway for linking sensory representations of reinforcers with each other and with the mental and autonomic correlates of emot and motiv valence
  • Lesions (hypoemotionality)
    • Hippocampal lesions – interfere with explicit recall of specific events but not with autonomic rxs
    • Amygdala lesions – leave explicit recall intact but abolish associated autonomic responses
    • Bilateral lesions of ant temp lobe, including amygdala – “Kluver-Bucy Syndrome”
      • Breakdown in the channeling of drive to appropriate visual target
        • indiscriminately initiate sexual activity
        • no longer show aggressive-aversive reaction to humans
        • mouth all objects – lose ability to distinguish edible from nonedible
      • Amygdala plays crucial role in modulating neural impact of sensory stimuli on each of 3 factors
        • Hedonistic value – amygdala is activated by aversive (not neutral) olfactory stim and fearful (not neutral) faces
        • Acquired assns – neutral stim don’t activate amygdala initially but do so after conditioned with fear
        • Motivational state – amygdala activated by pictures of food only when hungry
      • Dual role related to attn and memory
        • Attn – selective enhance processing resources allocated to events with emot value
        • Mem – mediate impact of emot valence on memory and also encode emot valence of stimuli
      • Participates in wide range of behaviors related to conspecific affiliative behaviors, social emotions, and their communication


The Hippocampus & Binding of Info into Explicit Memory (Neuro of Recollection)

  • Encoding of distance, color, movement, and form displays species-specific invariance
  • However, much of mental content, dependent on arbitrary assns – limbic/paralimbic (esp hippocampus and entorhinal cortex) imp in creating these assns
  • Hippocampo-entorhinal complex
    • Participates in regulation of emotion, but principle beh affiliation is memory and learning
    • Recalling *stable* knowledge – use transmodal areas outside of limbic/paralimbic
    • Recalling *new* info (obviously imp in sustaining knowledge) – use transmodal gateways within the limbic system (primarily hippo-entorhinal complex)
    • Lesions: dissociation btwn explicit learning of new experience and implicit-procedural learning
    • Suggests limbic system plays role in memory and learning by acting as neural gateway for encoding and retrieval NOT site where memories (engrams) are stored
    • Role – orchestrates the coherent storage and reactivation of this distributed info
  • Amnesic states
    • Severe only occur when hippocampo-entorhinal (and diencephalic connections) damaged
  • also see some memory impairments after lesions to the orbitofrontal, cingulate, or retrosplenial cortex
  • Why learning dependent on limbic structures – CNS needs to be protected from learning too rapidly and indiscriminately; initial screening is attnal systems; limbic system second line of defense
    • particularly prone to LTP; one of few areas that continue to display axonal sprouting
  • Implicit vs. Explicit Memory
    • Implicit memory – info remains sequestered, w/in unimodal and heteromodal ass’n areas
    • Explicit memory – info incorporated into a context thru the binding fx of the limbic nodes
  • Role of prefrontal cortex in memory
    • reconstruction of context and temporal order
    • on-line manipulation of encoding and retrieval (working memory)
    • associative search of internal data stores
    • contextual constraints to keep retrieved memory plausible


Limbic System

  • Components
    • Hypothalamus
    • Limbic components of cortex (allocortical and corticoid)
    • Paralimbic cortical belt
    • Limbic striatum, pallidum, ventral tegmental area, and the habenula
    • Limbic and paralimbic thalamic nuclei
  • Papez circuit (crucial in memory/learning; connections very, very strong)
    • Hippocampus-mammilary body-anterior thalamic nuclei-cingulate gyrus-presubiculum-entorhinal cortex-hippocampus
  • Components have greater capacity for synaptic plasticity; highly suited to encoding of new info but also highly vulnerable to pathological processes such as kindling and epilepsy
  • Behavioral specializations
    • Binding of distributed info related to recent events – supports memory
    • Channeling of emotion and drive (hunger, libido)
    • Linking of mental activity with autonomic, hormonal, and immunologic states
    • Coordination of affiliative behaviors related to social cohesion
    • Perception of smell, taste, and pain
  • Generally two spheres of influence
    • Amygdaloid – Olfactocentric paralimbic areas (emotion, motivation, affiliative behs, and autonomic-hormonal-immunological fxs)
    • Hippocampal – Papez components (learning and memory fxs)
  • Lesions
    • Limbic lesions: almost always give rise to multimodal impairment
    • Lesions interrupting connections btwn unimodal and limbic system give rise to modality specific disconnection syndromes like asymbolia for pain, visual hypoemotionality, visual amnesia, tactile lrning deficits
  • Limbic system most likely site of dysfx for many psychiatric diseases


Basal Ganglia and Cerebellum

  • Basal ganglia: critical role in automatic execution of learned motor plans
  • Cerebellum: regulates rate, range, and force of movement
  • Striatum (caudate, putamen, nucleus accumbens, olfactory tubercle)
    • Neural inputs from sub nigra and cereb cortex; does NOT send many projections back to cortex
    • Output of striatum predominantly to the globus pallidus then….striato-pallido-thalmo-cortico-striatal loop
    • Neostriatum – caudate and putamen
      • May play a critical role in acquisition and retention of procedural knowledge
      • Motor deficits – more linked with putamen
      • Cognitive deficits – more linked with caudate
    • Limbic striatum – nucleus accumbens and olfactory tubercle
      • Involved in neuropatholgy of Parkinson’s, Alzheimer’s, maybe Huntington’s
    • Behavioral specialization depends on where connected
      • g., caudate lesions can develop abulic form of frontal network syndrome
      • Mental state impairments with features of frontal lobe syndrome emerge in almost all basal ganglia diseases
    • Globus Pallidus
      • Crucial role in motor control; probably role in nonmotor fxs as well
      • Lesions – severe rigidity and bradykinesia; deficits in motivation, judgment, and insight (frontal syndrome like)
    • Cerebellum
      • Input from ipsilateral side of body and is interconnected with contralateral hemisphere
      • Lesions: give rise to ipsilesional motor symptoms
      • Intricate connections
        • Thru diaschisis frontal infarctions can cause acute contralateral cerebellar hypometabolism
      • Nonmotor affiliations – unlikely plays major role in explicit mem, lang, or spatial fxing
        • May globally influence state of info processing in all domains (like ascending cholinergic and noradrenergic pathways)
        • Lesions can impair perf on attention (digits), verb fluency, and reasoning (“frontal”)



  • Almost all nuclei have extensive reciprocal connections with cerebral cortex
  • Most nuclei have preferred cortical targets and each cortical area has principal source of thalamic input
  • Nuclei of primary sensory and motor areas
    • Sensory – ventroposterior lateral nucleus, ventromedial nucleus, ventroposterior inferior nucleus
    • LGN: relay nucleus for visual modality
    • MGN: relay for auditory modality
    • Motor – ventrolateral nucleus, ventroposterior lateral nucleus
  • Nuclei of modality-specific (unimodal) ass’n cortex
    • MGN – projections to A1 AND auditory ass’n cortex
    • Ventrolateral nucleus – motor association cortex; principal nuclei thru which basal ganglia and cerebellum influence of cerebral cortex
  • Transmodal nuclei of heteromodal, paralimbic, and limbic cortex
    • Medial dorsal nucleus – prefrontal heteromodal cortex
    • Medial pulvinar and lateral posterior nucleus – inf. Parietal lobule heteromodal cortices
    • Nuclei of “Anterior tubercle” – anterior nucleus and laterodorsal nucleus – connections to posterior cingulate cortex, retrosplenial area, Entorhinal cortex and hippocampal cortex
  • Reticular and intralaminar nuclei
    • Strong assns with reticular activating system


Channel Functions and State Functions

  • Many axonal pathways that interconnect one cortical area to another are organized in the form of point-to-point channels where sites of origin and termination are of approximately equal size
    • Language, spatial orientation, memory and emotion each subserved by large-scale networks which contain multiple point-to-point channels. Encode perceptual, motor, visceral, and affective components
  • In addition, each cortical area receives widespread modulatory connections which innervate entire cerebral cortex
    • Employ small amines and GABA as transmitters
    • Determine overall STATE of info processing rather than content of info that is being transmitted along the point-to-point channels
    • Most accessible to therapeutic manipulation – major targets of therapeutic efforts
    • Play very imp role in coordinating beh states related to arousal, attn, mood, and motivation
    • Small grp of neurons can induce rapid modulations in state of info processing
    • ABSENCE of reciprocal projections from cortex
    • Shift info processing based on demands of limbic system and internal milieu
    • Can alter tone, coloring, and interpretation of experience rather than content
    • Many psychiatric disturbances linked to these pathways
    • pathological biases in interpretation of events and experiences
  • Cholinergic and GABA from basal forebrain to cerebral cortex
    • Particularly responsive to novel and motivationally relevant sensory events
    • Enhance immediate neural impact and LT memory of motivationally relevant events
    • Acetycholine may also play role in working memory
  • Histaminergic from hypothalamus to cerebral cortex
  • Serotonergic from raphe nuclei to cerebral cortex
    • May modulate sensory gating of beh relevant cues
    • Also influence state of hunger and aggresivity
  • Noradrenergic projections from locus ceruleus to cerebral cortex
    • More responsive to motivational relevance (meaning) than to sensorial properties
    • Modulates novelty-seeking behaviors, focusing of attn, and resistance to distraction
  • Dopaminergic from substantia nigra and ventral tegmental area to cerebral cortex
    • Responsive to motivationally relevant stim; encode discrepancies between prediction and occurrence of reward
    • Important role in mediating processes related to substance addiction
    • Also working memory
  • Cholinergic from reticular formation to thalamus


Hemispheric Specialization and Asymmetry

  • Asymmetry of structure and fx NOT unique to humans
  • Purpose is unknown but may reflect biological advantage of concentrating the controlling components of network within single hemisphere in order to minimize transcallosal conduction delays
  • Left hemisphere specializations: Praxis and Language
    • 90% of population is said to be right-handed
    • L hemisphere more specialized for skilled movements (praxis)
      • Apraxias more commonly seen after damage to L hemisphere
      • Right motor cortex displays activation only when complex finger movements are performed by the contralat L hand whereas L hemisphere active during movement of either hand
      • Left hemisphere thus controls movements in both sides of body; R hemi controls contralat
    • 90% of right-handers and 60% of left-handers develop aphasia after damage to left hemisphere
    • Acalculia also more common after damage to left hemisphere
  • Right hemisphere specializations: Complex non-linguistic perceptual skills (including face identification)
    • R hemi better for melody and pitch; depth perception, spatial localization, identify geo shapes
      • R specialization esp apparent with COMPLEX tasks. (e.g., naïve listeners R hem superiority for melodies, tone sequences). Musically exp greater L hem specialization for these but particularly complex musical material still show R hemisphere activation
    • R hemi also better for faces
      • Altho, severe prosopagnosia seen after bilateral lesions (both hemispheres imp)
    • R lesions – impairment of complex visuospatial tasks
    • Memory processes also show hemispheric asymmetry
  • Right hemisphere specialization for Spatial Attention
    • R specialized for distributing attn for extrapersonal space; more tightly preserved than even L hem lang fx
    • Right hem – shift attn to both sides of space
    • Left hem – shift attn almost exclusively to contralateral hemispace
  • Right hemisphere specialization for Emotion and Affect
    • R hem may normally introduce a negative emot bias whereas left hem may introduce more pos bias
    • R hem more imp for coordinating nearly all aspects of affect and mood
      • Both expressing (prosody, fac expression gesture) and understanding
    • R hem specialization for experience of emotions as well
    • Modulation of mood and affect coordinated by limbic and nonlimbic components
      • Limbic – fund role in generating emotions, linking to visceral rxs, and channeling to targets
        • fx asymmetry probably much less pronounced at this level
      • Nonlimbic – integrating, interpreting, and communicating emotions
    • Right hemisphere specialization for paralinguistic aspects of communication
      • Left hem (Linguistic components) phoneme production, word choice, syntax, and grammar
      • Right hem – prosody, etc.; modulation of verbal output; pitch


Distributed Large-Scale Networks and their Cortical Epicenters

  • Structural foundations of cog and beh domains take the form of partially overlapping large-scale networks organized around reciprocally interconnected cortical epicenters
  • Enables parallel processing and contains multiple nodes where seamless transitions btwn parallel and serial processing can occur
  • Although various areas of networks are more specialized for certain behaviors, also play role in behaviors from other areas
  • Rt hemisphere dominant spatial attention network
    • Epicenter: Dorsal post parietal cortex, frontal eye fields, & cingulate gyrus
    • Parietal – specialization for perceptual representation of beh relevant locations
    • Frontal eye flds – choose and sequence exploratory and orienting movements
    • Cingulate – distribution of effort and motivation
    • Damage – deficits in spatial attn and exploration (neglect, simultanagnosia, Balint’s syndrome
  • Lt hemisphere dominant lang network
    • Epicenter: Wernicke’s and Broca’s
    • Broca’s – articulatory, syntactic, and grammatical aspects
    • Wernicke’s – lexical and semantic aspects
    • Damage – aphasia, alexia, agraphia
  • Limbic Memory-Emotion network
    • Epicenter: Hippocampo-entorhinal regions & amygdaloid complex
    • Hippocampal-entorhinal – memory and learning
    • Amygdala – drive, emotion, and visceral tone
    • Damage – deficits in memory, affiliative behs, and autonomic regulation
  • Prefrontal executive function-comportment network
    • Epicenter: Lateral prefrontal, orbitofrontal, and posterior parietal cortex
    • Prefrontal and orbitofrontal – coordination of comportment
    • Prefrontal and posterior parietal – working memory and related executive fxs
    • Damage to orbitofrontal/medial frontal – deficits in comportment
    • Damage to dorsolateral prefrontal – deficits of executive fx and working memory
  • Ventral occipitotemporal Face-and-object identification network
    • Epicenter: middle temporal gyrus and temporal pole
    • Damage – recognition deficits (object agnosia, prosopagnosia) usually bilateral lesions

fusiform gyrus common site of lesions probably cuz only area where vascular supply makes bilateral damage likely

Basal Ganglia Lesions

About the Basal Ganglia

  • The Basal Ganglia give rise to the extrapyramidal tract, which modulates the corticospinal (pyramidal) tract.
    • This tract controls muscle tone, regulates motor activity, and generates postural reflexes
    • However, the extrapyramidal tract’s efferent fibers communicate via the cerebral cortex and thalamus – they do NOT communicate directly with the spinal cord


Lesions to the Basal Ganglia

  • When damage is restricted to extrapyramidal tract, patients have NO paresis or neuropsychological impairments
  • Characteristic features of basal ganglia (i.e., extrapyramidal) injury involve the following involuntary movement disorders:
    • Parkinsonism – combination of resting tremor, rigidity, bradykinesia/akinesia, and postural abnormalities
    • Athetosis – slow continuous, writhing movements of the fingers, hands, face, and throat
    • Chorea – intermittent jerking of limbs and trunk
    • Hemiballismus – intermittent flinging of the arm and leg on one side of the body


Lewy Body Disease

  • Possibly accounts for up to 30% of cases diagnosed as Alzheimer’s Disease
  • May be a variant of Alzheimer’s rather than a distinct illness
  • Unlike Alzheimer’s, it has a relatively rapid development of dementia
  • It is accompanied by mild extrapyramidal features such as:
    • Masked face
    • Bradykinesia
    • Resting tremor
    • Gait impairment pronounced enough to lead to falls
    • Can also present with depression, delusions, and visual hallucinations

Definitive diagnosis confirmed with an abundant presence and unusual location of Lewy Bodies distributed diffusely throughout the cerebral cortex

Basal Ganglia

Anatomical And Clinical Review

The basal ganglia (BG) participate in the complex neural networks that influence:

  • Descending motor systems
  • Control of emotions
  • Cognition
  • Eye movements

Note: The BG do not project directly to the periphery

Lesions of the BG may cause:

  • Hyperkinetic movement disorders such as Huntington’s disease (HD) or
  • Hypokinetic movement disorders such as Parkinson’s disease (PD) or
  • A mixture of the two types of movement disorders (occurring in some patients)


Basic Three-Dimensional Anatomy of the BG

Main components of the BG:

  • Caudate nucleus
  • Putamen
  • Globus pallidus
  • Subthalamic nucleus
  • Substantia nigra (pars compacta & pars reticulata)
  • (Nucleus accumbens)
  • (Ventral pallidum)

Neostriatum or striatum = caudate + putamen

  • Striatum receives all input to the BG

Caudate and putamen are separated by internal capsule fibers, but are joined together at junctions called cellular bridges, which appear as stripes neuroanatomically

Caudate (which means possessing a tail) has three parts:

  • Head
  • Body
  • Tail

Putamen is a large nucleus forming the lateral aspect of the BG. Anteroventrally it fuses with the head of the caudate and is known as the ventral striatum, which consists of the nucleus accumbens

Globus pallidus (pallidum, which means pale globe) lies medial to the putamen

  • Composed of an internal and external segment

Globus pallidus + putamen = lenticular or lentiform nucleus

Note: the internal capsule is a V-shaped fiber bundle with connections to/from the cortex The anterior limb of the internal capsule passes between the lentiform nucleus and the head of the caudate The posterior limb of the internal capsule passes between the lentiform nucleus and the thalamus and contains the corticobulbar and corticospinal tracts

Note: the caudate and the thalamus are always medial to the internal capsule and the lentiform nucleus is always lateral to the internal capsule Substantia nigra

  • Lies just dorsal to the cerebral peduncles
  • Substantia nigra pars reticulata is the ventral portion, which contains cells that are similar to those in the internal segment of the globus pallidus
  • Internal capsule separates the internal segment of the globus pallidus from the substantia nigra pars reticulata

Substantia nigra pars compacta is the more dorsal component, which contains the darkly pigmented dopaminergic (DA) cells that give this nucleus its name and distinctive appearance Degeneration of these DA neurons is an important pathogenetic mechanism in PD

Subthalamic nucleus, which lies under the thalamus, has a distinct spindle- or cigar-shaped appearance

Note: the blood supply to the striatum and globus pallidus is mainly from the lenticulostriate branches of the middle cerebral artery (MCA), although branches of the internal carotid artery and anterior cerebral artery also often supply the medial globus pallidus and the caudate nucleus/lentiform nuclei, respectively.


Input, Output, and Intrinsic Connections of the Basal Ganglia

Virtually all input to the BG arrives via the striatum (caudate, putamen, & nucleus accumbens)

Output leaves the BG via the internal segment of the globus pallidus and the substantia nigra pars reticulata.

Four parallel pathways exist within the BG which participate in different functions:

  • General motor control
  • Eye movements
  • Cognitive functions
  • Emotional functions

Input to the Basal Ganglia [See Figure 16.5]

  • Cerebral cortex provides the main input to the BG (via the striatum)
  • Putamen is the most important input nucleus for the motor control pathways
  • Most cortical inputs to the striatum are excitatory and use glutamate

Substantia nigra pars compacta provides input to the striatum, which is dopaminergic in nature and has both excitatory and inhibitory actions within the striatum

Output from the Basal Ganglia [See Figure 16.6]

  • Internal segment of the globus pallidus – conveys information regarding motor control for much of the body
  • Substantia nigra pars reticulata – conveys information regarding motor control for the head and neck
  • Output pathways are inhibitory and use gamma-aminobutyric acid (GABA)

Main output pathways are to the ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus via the thalamic fasciculus. Thalamic neurons convey information from the BG to the entire frontal lobe, although information for motor control travels predominantly to the premotor cortex, supplementary motor area, and the primary motor cortex

Additional BG output to the thalamus project to the:

  • Intralaminar nuclei – with projections back to the striatum
  • Mediodorsal nucleus – with extensive connections to the limbic system

Additional projections from the GP:

  • Internal segment of the GP and substantia nigra pars reticulata also project to the pontomedullary reticular formation, with influence on the descending reticulospinal tract
  • Substantia nigra pars reticulata also projects to the superior colliculus, which influences the tectospinal pathways


Hyperkinetic and Hypokinetic Movement Disorders

  • Parkinson’s disease
  • DA-containing neurons in the substantia nigra pars compacta degenerate
  • DA excites neurons of the direct pathway and inhibits neurons of the indirect pathway, with a net excitatory action on the thalamus
  • Loss of DA results in net inhibition of the thalamus, leading to the paucity of movements in PD
  • Aspiny neurons are large interneurons located in the striatum, which contain acetylcholine (ACh)
  • These interneurons may preferentially form excitatory synapses onto striatal neurons of the indirect pathway and removal of the cholinergic excitation leads to a net decrease of thalamic inhibition
  • Anticholinergic drugs often are beneficial in the treatment of PD

Hemiballismus is characterized by wild flinging movements of the extremities contralateral to the lesion in the basal ganglia

  • This typically involves damage to the subthalamic nucleus, which likely decreases excitation of the internal segment of the globus pallidus, resulting in less inhibition of the thalamus  hyperkinetic disorder

Huntington’s disease (HD)

  • Characterized by degeneration of striatal neurons in the caudate and putamen, with perhaps the most severe destruction occurring in the enkephalin-containing striatal neurons of the indirect pathway
  • Removal of inhibition from the external segment of the globus pallidus, thereby permitting it to inhibit the subthalamic nucleus
  • In advanced stages of HD both direct and indirect pathways degenerate, resulting in a rigid hypokinetic parkinsonian state


Parallel Basal Ganglia Pathways for Movement, Eye Movement, Cognition and Emotion

Motor channel

  • Best known channel, with cortical inputs to the putamen and output from the internal segment of the globus pallidus and the substantia nigra pars reticulata, with connections to the VL and VA nuclei of the thalamus
  • Thalamic outputs project to the supplementary motor cortex, premotor cortex, and primary motor cortex

Oculomotor channel

  • Involved in the mediation of eye movements
  • Input for this channel is derived primarily from the body of the caudate nucleus
  • Output reaches the frontal eye fields and the supplementary eye fields of the frontal lobes and is involved in higher control of eye movements

Prefrontal channel

  • Involved in the cognitive processes mediated by the frontal lobes (i.e., executive functions)
  • Input is derived primarily from the head of the caudate and output is largely to the prefrontal cortex

Limbic channel

  • Important ventral pathway through the basal ganglia, which is involved in limbic regulation of emotions and motivational drives
  • Input arises from major areas of the limbic system (e.g., limbic cortex, hippocampus, and amygdala), which travel to the nucleus accumbens and other regions of the ventral striatum
  • Output arises from the ventral pallidum and project to thalamic nuclei (e.g., mediodorsal and ventral anterior nuclei), which project on to the limbic cortex of the anterior cingulate gyrus and medial orbital frontal nuclei
  • Another component of this pathway arises from the DA neurons of the ventral tegmental area (located medial and dorsal to the substantia nigra of the midbrain)
  • The ventral tegmental area projects to the nucleus accumbens, other limbic structures, and the frontal lobes, and may be involved in the pathophysiology of schizophrenia


MOVEMENT DISORDERS – Key Clinical Concept

  • Abnormal movements can be caused by dysfunction anywhere in the complex hierarchical motor network with the central and/or peripheral nervous system
  • Movement disorders typically refer to abnormal movements resulting from pathology in the BG

Note: The basal ganglia are part of a network of complex loops that exert their influence on the descending motor systems through their projections to the motor and premotor cortex, although they are sometimes referred to as “extrapyramidal syndromes”


  • Spasticity – slow, clumsy, stiff movements and hyperreflexia resulting from corticospinal, upper motor neuron lesions
  • Ataxia – irregular, uncoordinated movements caused by lesions of cerebellar circuitry
  • Dyskinesia – abnormal movements caused by basal ganglia dysfunction; Rule out for dyskinesia should include abnormalities in upper or lower motor neuron signs, sensory loss or ataxia

Note: Abnormal movements also may be caused by psychological conditions such as Conversion Disorder

Classifying Movement Disorders

  • Slow to fast – One common, albeit simplified, way of classifying movement disorders is on a spectrum from slow to fast
  • Movement disorders also may be classified as
    • Focal or generalized
    • Unilateral or bilateral

Note: In unilateral movement disorders caused by focal lesions within the BG (e.g., caused by infarct, hemorrhage, abscess, tumor, or degeneration), the movement disorder is contralateral to the lesion of the basal ganglia

During sleep, most movement abnormalities cease, with the exception of palatal myoclonus and some tic disorders, but can occur on a milder basis which can result in sleep disturbances


Bradykinesia, Hypokinesia, Akinesia

  • Bradykinesia or “slowed movements” are often caused by increased inhibitory outflow from the BG to the thalamus
    • g., loss of function of DA nigrostriatal system, loss of inhibitory pathways from the striatum to the substantia nigra and internal pallidum, or loss of inhibitory projections from the external pallidum to the subthalamic nucleus
  • Hypokinesia or “decreased amount of movements”
    • Decreased spontaneous movements without coma may result from diffuse lesions of the frontal lobes, subcortical white matter, thalami, or brainstem reticular formation as well as the basal ganglia
  • Akinesia or “absence of movement”
    • These terms typically are used for dysfunction localized at levels higher than the upper motor neurons (i.e., corticospinal, corticobulbar, lower motor neuron, or muscular disorders)
    • Prominent disorders are associated with these movement abnormalities (e.g., Parkinson’s disease, abulia, akinetic mutism, & catatonia)
  • Rigidity
    • Increased resistance to passive movement of a limb, which is often present in disorders that cause bradykinesia or dystonia
    • Rigidity may be velocity-dependent, as in the clasp-knife rigidity of corticospinal disorders (the resistive tone initially increases as the muscles of the limb are stretched, and is then followed by a decrease in tone)
    • Rigidity characteristic of the BG disorders is more continuous throughout attempts to move the limb and is often described as plastic, waxy or lead pipe rigidity
    • In PD, the characteristic cogwheel rigidity is a form of plastic rigidity in which there are ratchet-like interruptions in tone that can be felt as the limb is bent
    • Paratonia or gegenhalten is a condition observed in patients with frontal lobe lesions in which there is active resistance of movement of their limbs. This has a more active, inconsistent, or quasi-voluntary quality
    • Dystonia: Patient assumes abnormal, distorted positions of the limbs, trunk or face that are more sustained or slower than in athetosis
      • Three forms of dystonia are:
  1. generalized,
  2. unilateral or
  3. focal
  • Focal dystonias believed to be due to BG dysfunction include:
    • Torticollis, which involves the muscles of the neck
    • Blepharospasm, which involves the facial muscles around the eyes
    • Spasmodic dysphonia, which involves the laryngeal muscles
    • Writer’s cramp
  • Treatment includes “botox” or botulinum toxin injections into the muscles, which are repeated every few months; Botox acts by interfering with presynaptic release of ACH at the neuromuscular junction
  • Primary idiopathic torsion dystonia (formerly known as dystonia musculorum deformans)
    • Uncommon hereditary disorder that causes generalized dystonia
  • Dystonia also may occur secondary to damage of the BG associated with tumors, abscesses, infarcts, carbon monoxide poisoning, Wilson’s disease, PD, and HD
  • Dystonias or faster dyskinesias (e.g., athetosis or chorea) may be seen with acute or chronic use of dopaminergic antagonists, such as antipsychotics or anti-emetics
  • Long-term use of DA antagonists may cause tardive dyskinesia with prominent oral and/or lingual choreic dyskinesias


Wilson’s disease

  • An autosomal recessive disorder of biliary copper excretion that causes progressive degeneration of the liver and BG
  • Typical neurologic manifestations of Wilson’s disease include:
    • Gradual onset dysarthria
    • Dystonia (facial dystonia causing a wry smile called risus sardonicus)
    • Rigidity
    • Tremor (e.g., “wing-beating” with arm abduction and elbow flexion)
    • Choreathetosis
    • Prominent psychiatric disturbances
    • Brownish outer corneal deposits of copper (i.e., Kayser-Fleischer rings)
  • Treatment for Wilson’s disease typically includes copper chelating agents (e.g., penicillamine) (which can arrest progress of the disorder)



  • Characterized by twisting movements of the limbs, face, and trunk that sometimes merge with faster choreic movements, hence the term choreoathetosis
  • May occur secondary to perinatal hypoxia, severe neonatal jaundice, Wilson’s disease, ataxia telangiectasia, HD, antipsychotic or anti-emetic medications, and levodopa in PD patients



  • Characterized by continuous involuntary movements that have a fluid or jerky, constantly varying quality
  • Ranges from mild “fidgeting’ to violent frantic “break dancing”
  • May involve proximal or distal extremities, the trunk, neck, face, and/or respiratory muscles
  • Huntington’s disease – major cause of chorea, which is an autosomal dominant neurodegenerative disorder
    • Characterized by chorea, severe neuropsychiatric disturbances, and ultimately inability to walk
    • Patients often die about 15 years after onset, usually from respiratory infections
  • Benign familial chorea – autosomal dominant inheritance, but nonprogressive form of chorea, without cognitive or emotional decline
  • Sydenham’s chorea (rheumatic chorea) – rare except in untreated streptococcal infections, with onset typically in adolescence and more often in females
    • The fidgetiness and emotional lability may be accompanied by impulsive or obsessive-compulsive behaviors
    • Believed to be caused by cross-reaction of antistreptococcal antibodies with striatal neurons
  • Systematic lupus erythematosus (SLE) – another cause of chorea in young females – Chorea may be the first manifestation of SLE
  • Chorea gravidarum – chorea occurring during pregnancy or while on oral contraceptives may represent an initial episode or recurrence of SLE or Sydenham’s chorea
  • Chorea can be a dyskinetic side effect of levodopa in PD or tardive side effect secondary to antipsychotics or anti-emetics
  • Numerous other conditions may cause chorea, such as perinatal anoxia; hyperthyroidism; hypoparathyroidism; electrolyte, amino acid or glucose abnormalities; drugs; Wilson’s disease; or Lesch-Nyham syndrome
  • Hemichorea – may occur contralateral to focal lesions of the BG


Ballismus (or ballism)

  • Movements of the proximal limb muscles with a large-amplitude, more rotatory or flinging quality
  • Hemiballismus – the most common type, in which there are unilateral flinging movement of the extremities contralateral to the lesion in the BG
  • Classically caused by a lacunar infarct of the subthalamic nucleus (sometimes striatum), with subsequent decreased pallidal inhibition of the thalamus
  • Typically disabling movements may be attenuated by haloperidol (DA antagonist)



  • A sudden brief action that is preceded by an urge to perform it and which is followed by a sense of relief
  • Motor tics – usually involve the face and neck (less often the extremities)
  • Vocal tics – brief grunts, coughing sounds, howling/barking, or elaborate vocalizations including coprolalia (obscenities)
  • May be observed as transient single motor or vocal tics of childhood or in the more pronounced Tourette’s syndrome
  • Tourette’s syndrome – four times more common in boys, with an apparent autosomal dominant inheritance pattern
    • Onset is usually in late childhood and may be accompanied by ADHD or obsessive-compulsive disorders
    • Symptoms wax and wane, and may remit partially during adolescence
    • Tics may occur as consequences of lesions such as encephalitis, infarcts, hemorrhage, or tumors
    • Treatment usually entails counseling and psychoeducation, but may include DA antagonists (e.g., haloperidol or pimozide) or clonidine (alpha-2-receptor antagonist)



  • A sudden rapid muscular jerk that can be focal, unilateral or bilateral, which is usually considered to be the fastest of all motor disorders
  • Numerous etiologies with many possible central locations of lesions (e.g., cortex, cerebellum, BG, brainstem or spinal cord (SC)
  • Common causes include anoxic brain injury, encephalitis, toxic or metabolic encephalopathies, paraneoplastic disorders (e.g., lung carcinoma, ovarian or breast carcinoma, & neuroblastoma)
  • Tics are not infrequent in epileptic cortical activity such as juvenile myoclonic epilepsy
  • Note: myoclonus also is prominent in cortical basal ganglionic degeneration and in prion-related diseases such as Creutzfeldt-Jakob disease, and in later stages of Lewy body disease or Alzheimer’s disease (AD)
  • Palatal myoclonus – markedly rhythmic and notably persistent during sleep, with movements of the palate occurring at a rate of 1 – 2 hertz and sometimes extending to the face or proximal upper extremities
    • Typically caused by lesions of the central tegmental tract
  • Asterixis (meaning “lack of fixed position”) – or flapping tremor
    • Often seen in metabolic or toxic encephalopathies, especially in hepatic failure in which it is known as “liver flap”
    • If the patient is asked to hold their arms in front of their chest, with palms facing forward from extended wrists, an intermittent flexion movement occurs at the wrists bilaterally
    • Not caused by muscle contractions but by brief interruptions in contractions of the wrist extensors



Rhythmic or semi-rhythmic oscillating movements, which differ from myoclonus and asterixis in that both agonist and antagonist muscles are activated, causing the bi-directional movements

  • Resting tremor – a frequency of 3 to 5 hertz, which is most prominent when the limbs are relaxed, with decreased or absent tremor when the patient moves the limbs
    • Important feature of PD and is often called parkinsonian tremor, which is often asymmetrical and usually involves the hands and upper extremities
    • Also known as pill-rolling tremor because pts appear to be rolling something between thumb and fingers
  • Postural tremor – a frequency of 5 to 8 hertz, most prominent when the patient’s limb actively held in position. Essential tremor is the most common type of postural tremor and may be the most common of all movement disorders
  • Also known as familial, benign, or senile tremor
  • Most commonly involves the hands or arms, but may affect the jaw, tongue, lips, head, or vocal cords
  • Usually bilateral, but may be asymmetrical
  • Increases with stress, but can be relieved by -adrenergic antagonists (e.g., propranolol), with advanced cases responsive to ventrolateral thalamotomy or thalamic stimulation
  • May be familial, with autosomal dominant inheritance
  • Onset from early adulthood to advanced age
  • Intention tremor (ataxic tremor) – with a frequency of 2 to 4 hertz, is usually a feature of appendicular ataxia associated with cerebellar disorders
    • Occurs as the patient attempts to move their limb toward a target, and is characterized by irregular, oscillating movements in multiple planes throughout the trajectory
  • Other Terms Related to Tremor
    • Action tremor – postural or intention tremor
    • Static tremor – resting or postural tremor
    • Kinetic tremor – intention tremor
    • Terminal tremor – tremor that increases toward the end of a mvmt (often the case w/ intention tremor)
  • Tremors Secondary to Cerebellar Lesions
    • Rubral tremor – most likely caused by lesions of the superior cerebellar peduncles or other cerebellar circuitry (not due to damage to the red nucleus), but also may be caused by multiple sclerosis (MS) or brainstem infarcts
      • Frequency of 2 to 4 hertz
      • Head and trunk titubation – secondary to lesions of the vermis
      • Palatal myoclonus – typically classified as a tremor rather than a myoclonus
    • Physiological tremor – frequency of 8 to 13 hertz, which is believed to be caused by enhancement of the normal tremor present in all individuals
      • Postural tremors may be caused by drugs, medications, metabolic derangements, alcohol withdrawal, intense fear, anxiety and other conditions


Parkinson’s Disease (PD) and Related Disorders – Key Clinical Concept

Parkinson’s Disease (PD)

Common idiopathic neurodegenerative condition caused by loss of DA neurons in the substantia nigra pars compacta

  • Characteristic Symptoms of PD include:
    • Asymmetrical resting tremor
    • Bradykinesia
    • Rigidity
    • Postural instability
  • PD usually responds well to treatment with levodopa
  • Note: parkinsonism and parkinsonian signs are general terms that refer to conditions with features similar to PD
  • Idiopathic Parkinson’s Disease [See Figure 16.10 for Pathologic Changes of PD]
    • A condition with unknown etiology and a common onset between the ages of 40 and 70
    • Generally no familial tendency
    • Loss of pigmented DA neurons in the substantia nigra pars compacta, which causes the characteristic pale appearance of this area
    • Remaining neurons often contain cytoplasmic inclusions or Lewy bodies (eosinophilic,
    • containing ubiquitin, & -synuclein and have a faint halo)
  • Classic Symptom Triad of PD. Diagnosis of idiopathic PD is based on clinical features, which typically include:
    • Resting tremor (“pill-rolling” tremor)
    • Bradykinesia
    • Rigidity (cogwheel)
  • These are accompanied typically by postural instability (plus stooped appearance and dystonic features) that causes an unsteady gait
  • Even severe forms typically remain asymmetrical and are responsive to levodopa
  • Progression is usually insidious, occurring over the course of 5 to 15 years
  • Other Clinical Features of Idiopathic PD
    • Masked facies or hypomimia – decrease in spontaneous blink rate and in facial expression
    • Hypophonic voice – hurried, muttering quality
    • Micrographia – small writing
    • Abnormal saccadic eye movements – slow and broken into catch-up saccades
    • Retropulsion – if the patient is pulled backward slightly, a series of several backward steps are taken to regain balance
    • Festinating gait – gait characterized by small, shuffling steps
    • Anteropulsion – appear to be continually falling and shuffling forward
    • En bloc turning – turns are executed without the normal twist of the torso
    • Myerson’s sign – inability to suppress blinking when the glabella (center of the brow) is tapped repeatedly
    • Dementia – not an early feature of PD, but may occur in 15 to 40% or more of the late-course PD patients, which may be coincident with Lewy body disease or AD
    • Bradyphrenia – responses are slowed, but typically are accurate when given sufficient time
    • Depression and anxiety – common in advanced PD
  • Treatment of PD
    • Levodopa – the most effective drug, with most formulations containing carbidopa, a decarboxylase inhibitor that cannot cross the blood-brain barrier (BBB)
    • Carbidopa inhibits the breakdown of levodopa to DA in peripheral tissues, thereby increasing the levodopa available for conversion to DA in the brain
    • “On-Off Phenomena”
      • “Wearing off” – seen in levodopa therapy and occurring toward the end of the time between doses
      • Patient may experience “freezing” and be unable to move, or fluctuate between this and dyskinesias
    • Other Treatments
      • Anticholinergic agents such as Cogentin (benztropine mesylate) or Artane (trihexyphenidyl)
      • Amantadine – increases DA release, as well as serving as an anticholinergic and antiglutaminergic agent
      • DA agonists – including pergolide, bromocriptine, ropinole, and pramipexole
      • Stereotactic surgery may also be used– pallidotomy, in which the lesion is placed within the globus pallidus, which can help with the “negative” symptoms, or thalamotomy, in which the lesion is placed in the ventral lateral thalamic nucleus, which can help with tremor (mnemonic: T for tremor)


Other Causes of Parkinsonism Symptoms

  • Dopaminergic antagonists
    • haloperidol (Haldol) or prochlorperazine (Compazine) may cause parkinsonian signs but usually the onset is abrupt and the symptoms are symmetrical
  • Neurodegenerative disease – or parkinsonism plus syndromes

Produce atypical parkinsonism, which is characterized by relatively symmetrical symptoms, absence of resting tremor, and lessened response to DA agents

  • Multisystem atrophy – neurodegenerative conditions which include striatonigral degeneration, Shy-Drager syndrome, and olivopontocerebellar atrophy
  • Progressive Supranuclear Palsy (PSP)
    • Also known as Steele-Richardson-Olszewski syndrome
    • Characterized by degeneration in multiple structures around the midbrain-diencephalic junction (e.g., superior colliculus, red nucleus, dentate nucleus, subthalamic nucleus, and globus pallidus)
    • Vertical eye movement – range is quite limited for both upward and downward saccades
    • Other features of PSP include waxy rigidity, bradykinesia, frequent falling, and a “wide-eyed stare”
  • Dementia with Lewy Bodies or Diffuse Lewy Body Disease
    • Lewy bodies are localized in the substantia nigra and throughout the cerebral cortex
    • Features include prominent psychiatric symptoms (visual hallucinations), with episodic exacerbations
  • Cortical Basal Ganglionic Degeneration – parkinsonism that resembles PD with marked cortical features including apraxia and corticospinal abnormalities
  • Huntington’s disease – also is a trinucleotide repeat disorder that can cause parkinsonism features – early onset can lead to Parkinson-type symptoms
  • Wilson’s disease – may cause tremor, rigidity and bradykinesia
  • MPTP – parkinsonism features secondary to this toxin ontained in a synthetic heroin-like meperidine analog
  • Dementia Pugilistica – characterized by parkinsonism and cognitive decline


Rule Outs for Parkinsonism:

  • Hydrocephalus
  • Frontal lobe lesions
  • Diffuse subcortical disorders and
  • Depression


Huntington’s Disease – Key Clinical Concepts

Autosomal dominant neurodegenerative disease, characterized by:

  • a progressive, typically choreiform, movement disorder
  • dementia
  • psychiatric disturbances
  • Prevalence: 4 – 5 cases per million (higher in those of northern European ancestry)
  • Onset: usually from 30 – 50 years of age
  • Initial symptoms: subtle chorea and behavioral disturbances
  • Median survival from onset of first symptoms is  15 years


  • Gene is located on chromosome 4 and is characterized by an abnormally high number of CAG repeats (i.e., trinucleotide sequence), with normal individuals usually having 30 or fewer and those with, or likely to develop, HD having over 40 (Note that a higher number leads to earlier onset)

HD gene encodes a protein called huntingtin Genetic testing permits identification of those likely to develop the disorder

Neuropathologic hallmark of HD:

  • Progressive atrophy of the striatum, especially the caudate nucleus
  • Atrophy occurs in the putamen and nucleus accumbens, with degeneration usually affecting the striatal neurons of the indirect pathway
  • Lateral ventricles may appear enlarged secondary to atrophy of the caudate and putamen

Clinical manifestations include abnormalities of:

  • Body movements
  • Eye movements
  • Emotions, and
  • Cognition
  • Early movement abnormalities include: clumsiness and subtle chorea (e.g., mild jerking & fidgety movements), tics, athetosis, and dystonic posturing
  • Eye movement abnormalities often include: slow saccades, impaired smooth pursuit, sluggish optokinetic nystagmus, and characteristic difficulty initiating saccades without moving the head or blinking

Common Psychiatric Symptoms of HD Include:

  • Affective disorders (e.g., depression & anxiety)
  • Obsessive-compulsive disorder
  • Impulsive or destructive manic-like behavior
  • Psychosis (occasionally)

Multiple cognitive impairments associated with HD include:

  • Decreased attention
  • Memory disorder (recent and remote)
  • Anomic aphasia
  • Impaired executive functions

Note: In advanced HD, profound dementia and loss of almost all purposeful movements occur


  • Primary goal is to alleviate symptoms, typically with anti-DA agents and control psychiatric manifestations with counseling and psychotropics


Brief Anatomical Study Guide/Review

  • Basal Ganglia provide complex feedback loops that influence descending motor pathways
  • Main components include:
    • Caudate nucleus
    • Putamen
    • Globus pallidus
    • Subthalamic nucleus
    • Substantia nigra
  • Striatum = caudate + putamen
  • Lentiform nucleus = putamen + globus pallidus
  • Internal capsule – forms a sideways V-shaped demarcation with the thalamus and the caudate nucleus lying medial to the internal capsule and the lentiform nucleus lying laterally

Input and Output

  • All input enters the BG via the striatum:
    • Input from the motor and premotor cortex
    • DA input from the substantia nigra pars compacta
    • Thalamic nuclei (intralaminar nuclei)
  • All output leaves via the internal segment of the globus pallidus and the substantia nigra pars reticulata
    • Thalamic ventral anterior (VA) and ventral lateral (VL)
    • Other thalamic nuclei
    • Brainstem reticular formation
    • Tectum

Hyperkinetic and Hypokinetic Movement Disorders

  • HD – hyperkinetic movement disorder
  • The inhibitory output from the BG to the thalamus is decreased, leading to a relative disinhibition of the descending motor systems
  • g., infarcts that destroy the subthalamic nucleus which cause hemiballismus or
  • Loss of inhibitory GABAergic neurons from the striatal neurons of the indirect pathway that causes HD
  • PD – hypokinetic movement disorder
  • The inhibitory output from the BG to the thalamus is increased, resulting in a paucity of movement
    • Typically degeneration of the DA neurons that project from the substantia nigra pars compacta to the striatum

Mediation of Four Parallel Channels by the Basal Ganglia

  • General motor functions with input primarily from the putamen
  • Eye movements with input from body of the caudate
  • Frontal executive functions with input from the head of the caudate
  • Limbic functions which involves ventral structures (e.g., nucleus accumbens & ventral pallidum)

Clinical manifestations of damage to the BG include prominent oculomotor, cognitive and psychiatric manifestations in addition to the pronounced motor disorders

Baddeley and Hitch Working Memory

Three components of Working Memory:

Central Executive System (CES)

  • Functions to coordinate and schedule different mental operations including the processing and immediate storage of info-controls the functioning of the 2 slave systems
  • Core feature of the CES is that the capacity of the system is limited, performance begins to break down as the demands on the CES increase-concept for CES grew out of results of dual-task experiments-any individual task requires cognitive processes that draw on the resources of the CES-placing two demanding tasks together is thought to exceed the capacity of the CES resulting in mutual interference between tasks with a subsequent decrement in performance


Phonological or articulatory loop system (ALS)

  • Repository for verbally encoded items combined with a rehearsal mechanism which recycles verbal material to refresh the memory trace-split into a phonological Short term store (PSS) and an articulatory rehearsal mechanism (ARM) which contribute to retaining verbally encodable material in STM

Visuospatial sketchpad (VSSP)

  • Retains visuospatial material in STM-split into separate visual and spatial storage mechanisms


Functional Neuroanatomy of WM

  • WM is complex multimodal system, therefore makes sense that physiological substrate would be distributed throughout the neocortex
  • Evidence that ALS is localized in the language dominant hemisphere-neuroimaging studies of pts with with selective auditory-verbal STM imps show pts tend to have lesions in the post portion of the left perisylivan region-Paulesu, et al 1993-PET study-localization of phonological input store in healthy normals-activation attributable to the phonological input store identified in the left supramarginal gyrus, whereas the subvocal rehearsal system of the articulatory loop was associated with activation in Broca’ s area of the left frontal cortex
  • Evidence for the localization of the VSSP is less direct, mainly because pts with selective imps in visuospatial WM haven’t been reported-electrophysiological evidence in nonhumand primates-Goldman-Rakic-neuroanatomical localiztion in the prefrontal cortex in the principal sulcus and arcuate regions of monkey and with the inferior convexity a region just inf to the PS
  • Proposed the CES is located in the prefrontal cortex


Long-term Memory or Secondary Memory

  • Organism’s ability to store info-organized on basis of meaning rather than sensory properties like in STM
  • Consolidation-process of storing info as LTM may occur quickly or continue for considerable lengths of time without requiring active involvement -initial acquisition of information is followed by 2 parallel events:gradual forgetting and gradually developing resistance to disruption of what remains