Main Components of CNS and Their Pathophysiology

Neuro course - presentation

Topics

Arrangement of main components in the brain Pathways & circuitry, transmitters, function Dysfunction and pathophysiology Examples of clinical disorders: Cerebral palsy, Parkinson´s

disease, Huntington´s disease, Cerebellar syndrome Case reports Further information sources

Centers of Somatic Motor Control

Initiation and Control of Voluntary Movement

Motor Cortex DeficitsPrimary motor cortex (area 4) deficit paresis (paralysis), loss of fractionation (fine distal control of fingers)deficits are greatest in fine motor control of hand, mouth, feet, tongue, etc. spasticity most pronounced in anti-gravity muscles, usually arm flexors hold against gravity, the legs become spastic in extended position abnormal reflexes Babinski sign, extensor plantar response

Hemiplegia unilateral loss of voluntary movement changes in postural tone, changes in reflexes usually caused by vascular disease affecting middle cerebral artery which supplies motor areas and other (speech center, visual pathway, somatosensory pathway)

Apraxia described most thoroughly around 1900, belongs to the memory disorders inability to produce a movement that is not due to paresis (paralysis) - specific loss of skill various forms depending on site of damage (not complete agreement on designations and criteria) ideational apraxia - misuse of objects due to disturbance of identification (agnosia) ideomotor apraxia - simple movements can be executed, but complex movements cannot

Cortical DeficitsPremotor cortex lesioninterference with plan executionlesion is rare (usually not isolated to this region), deficits in sequences of movements (“limb kinetic apraxia”)e.g., the patient can brush their teeth, but ask him to pretend to brush their teeth and is becomes difficult - basically, he can’t plan that

Lesion of supplementar motor corteximpaired bimanual movements a difficulty in coordinating movement of two hands togetherthe patient will be unable to do independent things with each hand; instead, both hands will do the same thing

Prefrontal cortex lesiondeficits in delayed response tasks

Posterior parietal cortex (areas 5, 7) Gerstmann's syndrome - left parietal lesion (in normal right hand dominant) left-right confusion, finger agnosia, dysgraphia, dyscalculia, apraxia

Neglect syndromeright (nondominant) hemisphere damage constructional apraxia, left-sided agnosia

Cerebral Cortex Deficits

Main Components of Basal Ganglia System

Basal Ganglia FunctionTogether these nuclei are involved in modulating and regulating

activities, rather then in directly initiating or executing activities.

Motor : They work with other CNS regions to modulate movements both before they occur and during their execution. Via Motor loop and Oculomotor loop.

Cognitive effects : They seem to be involved in regulating such activities as attention and planning. Via Prefrontal loop.

Emotional effects : They may be involved in regulating emotional behaviors and motivation. Via Limbic loop.

Note that classically, these nuclei have been considered part of the motor system. It is only in more recent years that their role in non-motor activities has been recognized.

Basal Ganglia Loops

Initiation and Control of Voluntary Movement

Motor Deficits Resulting from Disease of the Basal Ganglia

dyskinesia -- abnormal involuntary movements

tremors (rhythmic, involuntary, oscillatory movements)

athetosis (slow, writhing movements of the fingers and

hands)

chorea (abrupt movements of the limbs and facial muscles)

ballismus (usually hemiballismus; violent, flailing

movements)

akinesia (literally means "no movement") or - abnormal

involuntary

postures

rigidity (cogwheel rigidity, ratchet rigidity or lead-pipe

rigidity)

dystonia (persistent posture of a body part which can result

in

grotesque movements and distorted positions of the body)

Clinical Units of the Basal Ganglia

Motor behavior is determined by the balance between direct/indirect striatal outputs

Hypokinetic disorders• insufficient direct pathway output• excess indirect pathway output

Hyperkinetic disorders• excess direct pathway output• insufficient indirect pathway output

Parkinson´s Disease

Degenerative disease in which the dopaminergic neurons in substantia nigra pars compacta die

Motor symptoms : Bradykinesia Rigidity

Normal Parkinson Normal Parkinson

The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormalaccumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation formsproteinaceous cytoplasmic inclusions called Lewy bodies.

Parkinson´s Disease – Hypothetic Explanation

Inhibition of GPe within the indirect pathway leads to disinhibition of the STN

Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.

This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.

Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

Hyperkinetic Disorders - Choreatic Syndromes

1. Huntington’s chorea

2. Dystonia

3. Tardive dyskinesia

4. DOPA-induced dyskinesia

5. Hemiballismus

6. Tourette’s syndrome

Causes:

Genetic (autosomal dominant)

Genetic or idiopathic

Chronic neuroleptic use

Parkinson’s therapy

Unilateral vascular accident, typically subthalamic nucleus

Excessive D2-subtypeDA receptor expression(?)

Huntington´s DiseaseInherited (AD) disease in which the neurons in caudate, putamen and neocortex die

Motor symptoms: Chorea

Other symptoms: Dementia

Atrophy of Caudate and Putamen:

Caused by unstable triplet (CAG) repeat in Huntingtin gene.

Huntington´s Disease – Hypothetic Explanation

• Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.

• Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.

Non-motor Functions of Basal Ganglia system

Basal ganglia are also involved in loops that modulate non-motor behaviors.

Maybe work the same way to suppress outputs.

• A prefrontal loop that modulates attention and planning.

• A limbic loop that may regulate emotional behavior and motivation.

• Schizophrenia, may be due to aberrant activity in multiple loops resulting in hallucinations etc.

Parkinson’s Disease: Sources Literature and images:Purvis:NeuroscienceMoore: The Developing HumanHaines: Fundamental NeurosciencePorth: PathophysiologyRobbins:Pathological Basis of DiseaseDigital AnatomistBlumenfeld: Neuroanatomy through Clinical Cases

Publications:Four Decades of Neurodegenerative Disease Research: How Far We Have Come! A. B.

Young (2009)J. Neurosci. 29, 12722-12728

The scientific and clinical basis for the treatment of Parkinson disease (2009). C. W. Olanow, M. B. Stern, and K. Sethi (2009)Neurology 72, S1-S136

Parkinson's disease: from monogenic forms to genetic susceptibility factors. S. Lesage and A. Brice (2009)Hum. Mol. Genet. 18, R48-R59

Genomic and proteomic biomarkers for Parkinson disease. T. Gasser (2009)Neurology 72, S27-S31

Structure and Function of Cerebellum

Function of Cerebelluminvolved in modulating and regulating activities, rather then

in directly initiating or executing activitiesipsilaterally organizedcoordination of movementmaintenance of posture and balancemaintenance of muscle toneerror detection and correction long term motor learning

The cerebellum does this by comparing the commands going to the muscle with the actual movements the muscles are making and then makes the appropriate adjustments.

Cerebellar Functions – LocalisationThe vestibulocerebellum 1)may be invaded by a tumor, typically a medulloblastoma occurring in childhood2)unsteady on the feet, walk on a wide base, and sway from side to side, loss of equilibrium and vertigo, a variety of eye movement difficulties (e.g., nystagmus) The spinocerebellumdecrease in tonic muscle tension - activity of gamma motor neurons is profoundly reduced. Thus, there is a reduction in background spindle afferent activity and reduction of input to motor cortex during movement (hypotonia).The cerebrocerebellum control of distal limb muscles - disturbances: 1)delay in initiation of movement 2)decreased muscle tone – hypotonia3)distortion of muscular coordination - ataxia

Disorders of the cerebellum, or of the fibers leading to and from, are difficult to interpret for several reasons: Lesions in patients typically are not localized to one particular portion of the cerebellum.Usually lesions or tumors that induce cerebellar damage involve other portions of the CNS. Cerebellar defects are compensated to a considerable extent by other mechanisms of the brain after sufficient time. Consequently symptoms are less severe in slowly progressing disease processes than in acute injuries of the cerebellum.

Cerebellar DisordersA. AtaxiaDisturbances of posture and gait may be pronounced. Lesions of the midline region of the cerebellum cause difficulty in maintaining an upright stance. Closing the eyes has very little worsening influence on this form of ataxia. The gait is staggering, not unlike that seen in drunkenness. A lesion located on one hemisphere of the cerebellum causes a tendency to fall toward the side of the lesion. Decomposition of movement. An action which requires the cooperative movement of several joints is not properly coordinated but is broken down into its component parts. For example, in bringing the hand to the mouth, the joints of the shoulder, elbow and wrist may be moved separately and not grouped together in one synchronized movement.B. Dysmetria is shown by the inability to stop a movement at the desired point. In reaching the hand toward an object, the patient either overshoots the goal or stops before it is reached. When the patient is asked to point a finger directly to the finger of the examiner, the patient may instead point consistently to one side, a phenomenon known as past-pointing.C Dysdiadochokinesia, is the inability to perform rapidly alternating movements, such as rapid pronation and supination of the hands, or rapid tapping with the fingers.D. Scanning speech is due to asynergy of the muscles used in speaking. The spacing of sounds is irregular with pauses in the wrong places.E. Hypotonia. The muscle tone is decreased which may be ascertained by palpation. The tendon reflexes are usually decreased on the side affected. A pendular knee jerk, in which the leg swings freely back and forth several times, is sometimes present.F. Tremor. The tremor of cerebellar dysfunction is usually an intention tremor. It is evident during powerful movements, but absent or diminished with rest (Contrast cerebellar tremor with disorders of basal ganglia). Lesions which are most apt to produce tremor are those that involve the efferent pathways of the superior cerebellar peduncle. The movements are coarse and arrhythmic.G. Nystagmus. This eye movement disorder is seen with lesions of the vestibulocerebellum.