Neuroscience: Basal Ganglia

Subthalamic Nucleus

(diencephalon) The STN lies ventral to the thalamus, medial to the internal capsule. Neurotransmitter: glutamate (excitatory). STN is involved in the indirect circuit

Spastic internal capsule

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Basal Ganglia Role in Motor Control

1. Flexible motor set selection and shifting Selecting context specific movement set and inhibiting competing movement programs Shifting or changing motor sets as the task demand changes 2. Basal Ganglia is an important "gate" for processing of sensory information and how it will be used in motor control Important in selecting relevant sensory information and suppressing irrelevant information prior to executing an action Ongoing evaluation of environmental cues 3. BG are particularly important in internally generated movements vs. cerebellum which is more active with visually triggered and guided movements 4. Cognitive-related functions: Focus attention on primary task Maintain safe mobility during multiple ongoing motor and cognitive tasks

Key Clinical Features of PD

1. resting pill rolling tremor (4-6 Hz). Decreases with intentional movement. 2. bradykinesia and poverty of movement -loss of facial expression -difficulty initiating movements -increased latency to onset of voluntary movement -loss of reciprocal movement -decreased amplitude and speed of movements -micrographia 3. cog-wheel rigidity 4. loss of equilibrium and postural reflexes (usually seen later in primary PD, rather than early on) To receive diagnosis of clinical PD, must have 2 of the 1st 3 key clinical features listed above and a consistent response to L-Dopa replacement therapy

Cerebral Palsy

A group of disorders with common factors 1. abnormality in motor control 2. early onset 3. absence of recognized underlying progressive disease Common associated features: Seizures, cognitive impairment, visual and visuo-motor abnormalities, deafness, speech and learning impairments

Hyperkinetic MD

Chorea Athetosis Ballism Dystonia

Parkinson's Plus Syndromes

Differential Dx of PD vs. other degenerative disorders. Early on these degenerative disorders may present with one or more PD-related signs like tremor or bradykinesia These diseases are not DA responsive and progress more rapidly than PD Multiple System Atrophy (MSA) Progressive Supranuclear Palsy (PSP) Corticobasal Degeneration Lewy Body Dementia Olivopontocerebellar Atrophy

BG Direct and Indirect Circuits

Direct Circuit: Cortex excites striatum Striatum inhibits the GPi which allows disinhibition of the thalamus Net effect: Thalamus and Cortical excitation i.e. activation of specific motor program Indirect Circuit: Cortex excites striatum Striatum inhibits the inhibitory effect of the GPe on the STN, so STN is activated and excites GPi neurons which then further inhibit the thalamus Net Effect: Thalamus and Cortical inhibition (inhibits competing or unwanted programs) The functional combined effect of these 2 circuits is related to the role of the BG in activating a desired motor program (direct circuit) while inhibiting a competing program (indirect).

PD Medical Management

Dopamine agonist (Mirapex) L-Dopa replacement therapy (Sinemet) Delay drug treatment as long as possible. Why? Side effects develop over time with treatment Dyskinesias On/Off Deep brain stimulation (DBS) can have dramatic effects Most common site for DBS is subthalamic nucleus

Huntington's Chorea

Etiology/Pathology Autosomal dominant genetic disorder - 50% chance of inheritance Huntington's allele located on chromosome 4 Genetic testing is available Consists of extended CAG trinucleotide repeat >40 repeats causes Huntington's disease Profound loss of interneurons (spiny neurons) in caudate and putamen Reactive gliosis in striatum Other neuron loss in cortex and cerebellum Enlarged ventricles Cell death thought to be due to accumulation of oxygen free radicals or failure of mitochondrial energy metabolism Epidemiology Rare prevalence 6.5/100,000. All races Mean age onset 35-42 (small percentage in young and old age) Symptoms Often initially present with cognitive changes Depression, irritability Slowing of cognition, decreased ability to problem solve Subtle changes in coordination, choreoathetotic movements in fingers Chorea advances proximally Ataxic gait with chorea Choreoathetotic movements of face and tongue Depression and dementia Diagnostic testing Genetic testing MRI/CT - reduced volume in striatum PET scan - reduced D1 and D2 binding SPECT - reduced blood flow caudate>putamen

Globus Pallidus

Forms the medial portion of the lentiform nucleus. Neurotransmitter: GABA GP is one of the 2 "outflow" nuclei of the basal ganglia The globus pallidus is divided into external (Gpe) and internal (Gpi) segments. GPi- Tonic (baseline) inhibitory effect on the thalamus GPe- Tonic (baseline) inhibitory effect on the subthalamic nucleus (STN)

Substantia nigra pars reticulate functions

Functions in: 1. Walking: Mesencephalic Locomotor Region (MLR) Drive central pattern generator in spinal cord for locomotion MLR affect rhythmic stepping, initiation and termination of locomotion 2. Muscle Tone: Reticular Formation Projects to area of reticular formation that controls muscle tone Without normal BG influence, muscle tone increases (rigidity) 3. Eye Movements: Superior colliculus Generates saccadic eye movements

Athetosis

Greek word for "without position". A type of dyskinesia Damage to: the striatum. Symptoms: -slow writhing movements, snakelike. Involves more of limbs than chorea.

Chorea

Greek word for dance. A type of dyskinesia Damage to: the striatum Symptoms: -series of continuous rapid movements of the face, tongue and limbs, especially fingers and toes. The movements usually resemble fragments of functional movements but are involuntary.

Hemiballismus

Greek word meaning "jumping about". A type of dyskinesia Damage to: subthalamic nucleus. May result from stroke involving small branch of posterior cerebral artery. Symptoms: -Violent flailing movements of usually one arm or one leg.

Choreoathetosis

Intermediate form between chorea and athetosis.

Dystonia

Involuntary muscle contractions causing abnormal twisting movements or postures Affects any part of the body including neck, face eyelids Contractions can be sustained, intermittent, rhythmic or tremulous Symptoms vary with activity or posture. May be task specific Often worsened by stress and fatigue Cortical disinhibition Indirect BG circuit does not inhibit surround Sensory gating affected - abnormal links between sensory input and motor output Abnormal body schema representations in cortex Classification: Age of onset Infantile < 2yrs Childhood 2-26 yrs Adult >26 yrs Etiology Primary - no other disease - genetic Secondary - to meds tumor, stroke, trauma, can occurs with CRPS Primary Plus - dystonia plus other neuro signs Part of another degenerative disorder like Huntington's Disease Distribution Focal - e.g. bletherospasm, torticollis, writer's cramp) Segmental Generalized Clinical Presentation Mobile or fixed Treatment Some, not all, dystonias are sensitive to DA replacement Botox injections DBS not as reliably effective as in PD DO NOT STRETCH Maintain mobility and fitness. Carefully evaluate the benefit of bracing as a way to alter sensory input

Striatum: Role, Neurotransmitter, Components

Is the "receiving" area of the BG. Receives inputs from all areas of cortex and thalamus Projection neurons neurotransmitter: GABA When excited by the cortex, the striatum inhibits the globus pallidus (allowing disinhibition of the thalamus) Made up of: Nucleus accumbens (limbic, ventral) Caudate nucleus Putamen

Clinical Correlates

Lesions in different areas of the basal ganglia produce various syndromes of movement disorders. These appear contralateral to the lesion due to the crossing of the corticospinal tract through which the deficits are manifested.

Parkinson's disease: Etiology and Pathology

Loss of dopaminergic cells of the SN pars compacta (70-80% before see symptoms, severely impaired patients have lost >90% of striatal dopamine). Degeneration may be due to a number of reasons Most likely etiology is a combination of accelerated aging, genetic predisposition, exposure to toxins and abnormality in oxidative mechanisms. Oxygen free radical damage results in accumulation of Lewy bodies in DA neurons in SNc

Movement Disorders

Movement Disorders are a class of neurological disorders that are all related to basal ganglia dysfunction. The resulting movement disorder is either hyperkinetic or hypokinetic.

Nucleus Accumbens

Nucleus Accumbens is the ventral part of striatum - related to limbic system Related to things like addiction, OCD

Parkinson's Disease Epidemiology

Onset 40-70 yoa Infrequent before 30 (15% under the age of 50) Slightly more men than women All socioeconomic classes Black 1/4 that of whites North America: Prevelance 1 million; 1% of population over 65 Incidence 60,000 new cases/year

Hypokinetic MD

Parkinson's Disease Parkinson's Plus Syndromes

Substantia Nigra (midbrain): Location and role of the pars compacta and the pars reticulata

Pars compacta (SNc) Pars Reticulata (SNr) Substantia Nigra pars compacta (SNc): is the dorsal part of the substantia nigra. The neurons in this region contain the pigment neuromelanin, which gives the substantia nigra its name. Neurotransmitter: dopamine. SNc projects to striatum and sets the background level of excitability in the striatum The pars reticulata (SNr) is the ventral part of the substantia nigra, adjacent to the crus cerebri. Neurotransmitter: GABA (inhibitory) Also has tonic inhibitory effect on targets (thalamus and brainstem areas) Is the other "outflow" nucleus for the basal ganglia

Lentiform Nucleus

Putamen + GP

PD Signs/Sxs

Rigidity Results in flexed posture, decreased trunk rotation Festinating gait - Difficulty terminating gait Difficulty with sensory organization and in selecting sensory information useful for postural control Formal testing show only subtle losses but research shows PD patients inability to use proprioception in useful ways Can't filter information from the environment Results in decreased perception of movement (contributing to bradykinesia) over-reliance on vision Worsened with DA medications Freezing Related to difficulty switching motor programs. Inflexible program selection (not improved by DA replacement) Movement hesitation resulting in a delay or complete inability to initiate step Major contributor to falls (PD has the highest fall rate of any common neurological disorder) Occurs more often when person negotiating a complex environment, narrow doorway (both related to difficulty processing sensory information), with secondary task (challenge with divided attention), making a turn (changing motor set) Weakness from decreased central cortical drive of muscles Weakness is not a muscular issue early on as demonstrated by artificial stimulation of muscles Abnormal activation of agonist in bursts As disease progresses muscle do become weak Postural Control affected by (increased fall risk) Rigidity of trunk (limits scale of responses) Bradykinesia (not improved with DA medication) Impaired anticipatory postural responses prior to rising on toes or step initiation Reduced voluntary and reactive limits of stability especially in backward direction Lack of appropriate or effective postural response in response to perturbation - Co-contraction, increased trunk activation, decreased hip Eye Movements Hypometric saccades Breakdown of smooth pursuit More dependent on external cues, rather than internal cues, to initiate and maintain movements. Music therapy Visual cues Cognitive/limbic issues (not helped by DA meds) Difficulty in divided attention situations (may freeze or become unsteady) Concurrent depression and/or dementia as disease progresses Secondary impairments (contractures, decreased respiratory excursion) may contribute to mobility difficulties Later in disease autonomic (orthostasis, decreased bowel motility, urinary frequency) and sleep disturbances (periodic leg movements, no muscle relaxation, sleep apnea)

Functional Roles of the Basal Ganglia

Selecting context-specific movement set and inhibiting competing movement plans Shifting or changing motor sets as the task demand changes Basal Ganglia function is essential for sensorimotor agility Involved in motor learning and establishing motor plan

Subclassifications of Cerebral Palsy

Spastic UMN with hyperreflexia Abnormal postural reflexes Sustained clonus, adductor tome Dominant tonic neck reflexes Further subclassified by topography (related to damage to cortex or internal capsule; correlates to area damaged) Hemiplegia Spastic diplegia (most common; due to damage of medial portion of internal capsule) Spastic quadriplegia Monoplegia Triplegia Extrapyramidal (related to basal ganglia damage) Athetosis, chorea, choreo-athetotic Hypotonic Mixed and atypical types Etiologies CP in low birth weight infants Spastic diplegia most common

"Outflow" nuclei for BG

Substantia nigra Globus pallidus

Substantia nigra pars reticulate: role in BG and connections

Substantia nigra pars reticulate (SNr) is the other outflow nucleus of the BG and has significant brainstem connections (in addition to projecting to thalamus)

Non-motor Functions of the Basal Ganglia

Switching attention between tasks Caudate - Compulsive behavior as in Obsessive Compulsive Disorder Ventral striatum (nucleus accumbens) - Reward-based behaviors related to addiction, perhaps associated with schizophrenia also

Caudate: Origin, location and growth pattern

The caudate and putamen are from the same embryological origin Located lateral to lateral ventricle As the caudate develops it grows around in the wall of the lateral ventricle.

Putamen

The putamen forms the outer most part of the lentiform nucleus (i.e. putamen + globus pallidus)

The Role of Dopamine

The role of dopamine is complex because there are 5 different types of dopamine receptors. -Sets tonic background level of excitation in striatum DA in Motor Learning and Adaptive Plasticity -Dopamine bursts interacts with the cortical input to striatal neurons during learning and promotes long term potentiation of cortical inputs Major role in implicit or procedural learning DA may act to focus attention Too little dopamine results in akinesia; too much dopamine results in dyskinesias.

Anatomy of the Basal Ganglia

The term "basal ganglia" refers to subcortical grey matter. Includes striatum and globus pallidus. Functionally it also includes the substantia nigra and subthalamic nucleus

Factors predisposing to both CP and prematurity/low birth weight

There may be factors predisposing to both CP and prematurity/low birth weight e.g. some congenital malformation CP in sick, term infants May have infection Majority (80%) do not have serious perinatal asphyxia CP without obvious postnatal insult in term infants who were well as newborns About 1/3 have cortical dysgenesis with abnormal neuronal migration Hyperbilirubinemia with athetotic CP Exposure to toxins In utero infection Perinatal maternal infection/fever

Anatomy of the Basal Ganglia: Picture

also look at slides 8-9 in BG lecture