Strick Lecture 4 March 29, 2006 Page 1

Strick Lecture 4 March 29, 2006 Page 1 Basal Ganglia OUTLINE- I. Structures included in the basal ganglia II. III. IV. Skeleton diagram of Basal Ganglia Loops with cortex Similarity with Cerebellar Loops Movement disorders associated with basal ganglia dysfunction EMG basis of rigidity Segmental and Long Loop Circuits Why are the basal ganglia so easily damaged? V. Chemical-Anatomy model of basal ganglia dysfunction VI. Proposals about normal function of the basal ganglia Elemental and Complex deficits associated with step-tracking New words used during the lecture: dystonia musculoram deformans MPTP Kernicterus jaundice bilirubin tardive dyskinesia lecithin

Strick Lecture 4 March 29, 2006 Page 2 I. Structures included in the Basal Ganglia (Figure 1) The Basal Ganglia consist of 4 major subcortical structures 1. neostriatum = caudate and putamen (input nuclei) 2. substantia nigra = 2 subdivisions: pars compacta and pars reticulata 3. subthalamic nucleus 4. globus pallidus = 2 subdivisions: external segment and internal segment (Note: internal segment and pars reticulata = output nuclei) Functionally the pars reticulata of the substantia nigra appears equivalent to the internal segment of the globus pallidus. However, like the caudate and putamen, a fiber bundle separates these two nuclei. II. Skeleton diagram of Basal Ganglia Loops with the Cerebral Cortex (Figure 2) A- a set of cortical areas project to a localized region of the neostriatum (e.g., prefrontal cortical regions tend to innervate the caudate; primary motor and somatic sensory tend to innervate the putamen) B- localized regions of the neostriatum have topographic projections upon the output nuclei (e.g., parts of the caudate tend to innervate the pars reticulata; parts of the putamen tend to innervate the internal segment of the globus pallidus) C- each of the output nuclei have topographic projections upon selected thalamic nuclei (e.g., parts of GPi project upon subdivisions of VL thalamus; parts of the pars reticulata project upon VA and MD) g primary motor cortex -> putamen ->GPi -> VL -> motor cortex prefrontal -> caudate -> pars reticulata -> VA/MD -> prefrontal D- each thalamic nucleus innervates a distinct cortical area. Multiple cortical areas may contribute to the cortico-basal ganglia loop, but only selected cortical areas receive the effects of basal ganglia processing There are at least 5 different functional loops that connect the Basal Ganglia with the Cerebral Cortex: (examine the open and closed loop components) 1. Motor Loops (including the primary motor cortex and SMA) 2. Oculomotor (Frontal Eye Fields) 3. Prefrontal 4. Orbital frontal 5. Anterior cingulate 6. Inferotemporal (recently described) Note: Basal Ganglia loops with Cerebral Cortex are in many respects similar to the Cerebellar loops with Cerebral Cortex (Figures 3&4). There are multiple functional loops that connect the cerebellum with areas of cerebral cortex: 1. Motor Loops (including the primary motor and lateral premotor cortex) 2. Oculomotor (Frontal Eye Fields) 3. Prefrontal 4. Posterior Parietal (under investigation) Note: Features Common to Basal Ganglia and Cerebellar Loops

Strick Lecture 4 March 29, 2006 Page 3 1. Both cerebellar and basal ganglia circuits have an input that does not change in a moment by moment fashion with behavior (i.e., climbing fiber input to cerebellar cortex, and SNpc input to neostriatum) 2. The cerebellar and basal ganglia loops that are concerned with the control of limb movement are somatotopically organized (body maps exist in the nuclei of both subcortical systems) 3. These loops perform some operation on information from multiple cortical areas. 4. What ever this operation is, it is useful not only for the control of arm movements, but also for the control of eye movements Major Unresolved Issue: What is the unitary operation performed by basal ganglia and cerebellar loops? III. Basal Ganglia Movement Disorders (Figure 5) The basal ganglia are particularly notable because bizarre movement disorders are associated with damage to these nuclei. There are 3 major classes of dysfunction: Akinesia Alterations in muscle tone Involuntary movements 1. AKINESIA is said to be the cardinal deficit of basal ganglia dysfunction. Akinesia means a disinclination to use the affected body part in a normal manner. For example, some patients with basal ganglia disorders will sit motionless. They will show little facial expression and have a "mask-like" stare. These patients will initiate few movements on their own. When they walk, they will show a loss of associated movements. The lack of movement initiation is not due to muscle paralysis or changes in muscle tone. Although some patients with Parkinson's disease will have both rigidity and akinesia, other patients will only be akinetic and show little rigidity. Also, it is possible to abolish rigidity in some patients by making a stereotaxic lesion in the rostral part of the VL thalamus. The akinesia will still be present even in those cases where surgery decreases rigidity. In fact, thalamic surgery may increase the patients akinesia. The most profound akinesia is said to be associated with damage to the pars compacta of the substantia nigra. Forms of akinesia are also seen after lesions of the globus pallidus (psychic akinesia). Bradykinesia is often associated with (and confused with) akinesia. Akinesia refers to the failure to initiate movement or movement that is slow to be initiated. In contrast, Bradykinesia refers to a movement that, once initiated, is performed slowly (later in the lecture I will present the potential physiological basis of bradykinesia).

Strick Lecture 4 March 29, 2006 Page 4 2. ALTERATIONS IN MUSCLE TONE are the second major class of movement disorder associated with basal ganglia dysfunction. The most common change in muscle tone is an increase. e.g., Rigidity - is an abnormal increase in tone. a- tonic activity is increased in opposing muscles b- muscles are active even when the subject attempts to relax c- because of the increased muscle activity, passive movements in any direction meet resistance d- rigidity is often most pronounced at proximal joints where there are large muscle masses e- rigidity is commonly seen in Parkinson's disease Neurophysiological Basis of Rigidity= abnormal long loop reflexes (Figs. 6&7) Record the activity of a wrist muscle after it is rapidly stretched. The subject is given the prior instruction to relax and told not to respond to the stretch. Normal subjects will show multiple phases of muscle activity: 1. The first phase (onset at 28-32 msec) = a segmental response 2. Two later phases (onset at 58-62 msec and 85-95 msec) = these later phases are termed "long loop" responses Parkinson subjects with rigidity: 1. have abnormally large "long loop" responses to stretch (i.e., large responses beginning approx. 58 msec after the onset of the stretch). 2. do not have any changes in their earliest response to stretch, i.e., the segmental response between 28 and 58 msec.). Thus, segmental mechanisms are unaffected by Parkinson's disease. On the other hand, the enlarged "long loop" responses indicate a central malfunction. Hypotonia- Some basal ganglia disorders show abnormal decreases in muscle tone. Hypotonia is commonly seen in patients with Huntington's disease. With hypotonia subjects show pendular tendon jerks. (This is said to be due to the lack of activity in antagonist muscles. On the other hand, it could be due to a reduction in the long loop responses to stretch. (Rigid subjects do not have pendular tendon jerks.) 3. INVOLUNTARY MOVEMENTS are the third major class of basal ganglia motor dysfunction. These are movements over which the patient has no control. Four types of involuntary movements are seen in patients with basal ganglia dysfunction: Chorea Athetosis Torsion spasm (dystonia) Tremor A- Chorea = rapid, somewhat spasmodic movements. These abnormal movements can involve one limb, one side of the body or all parts of the body. They can appear like "fragments of a purposeful act", but more often look entirely meaningless. Sometimes these abnormal movements will flow into one another to produce an "elaborate sequence of

Strick Lecture 4 March 29, 2006 Page 5 meaningless acts." Patients with choreiform movements are capable of normal movements, but often these movements will have choreic features grafted on to them. Choreiform movements are characteristic of Huntington's disease which has lesions in the neostriatum. B- Athetosis = slow, spreading contractions of closely related muscle groups. These are sinuous, writhing movements most commonly observed in the extremities. C- Torsion spasm = (torsion dystonia) powerful tonic contraction of axial and proximal body musculature. Torsion spasm will lead to grotesque postures that are uncontrollable (and at times quite painful). Spasm can appear at the onset of movement and disappear at complete rest. All 3 of these types of voluntary movements are said to require cortical mechanisms for their expression. Cortical or capsular lesions which cause paralysis can abolish these involuntary movements. D- Tremor = alternating to and fro movements caused by alternating contractions in opposing muscles. The rate of many basal ganglia tremors is 3-6/sec. A resting tremor is characteristic of Parkinson's disease. This type of tremor is usually abolished at the start of a voluntary movement. For example, a Park. patient holding a newspaper will have a marked tremor while reading a page of the paper. However, when the patient goes to turn the page, the tremor is abolished. IV. Why are the Basal Ganglia so easily damaged- (Figure 8) What is it about the Basal Ganglia that makes them so susceptible to dysfunction? Four properties of these nuclei may endow them with a special vulnerability: 1) High oxidative metabolism 2) High concentrations of selected neurotransmitters 3) High concentrations of heavy metals 4) Selective affinity for some neurotoxins 1- Oxidative metabolism: The basal ganglia appear to have particularly high metabolic requirements. The caudate and putamen (along with the cerebral and cerebellar cortex) have the highest utilization of oxygen in the brain. This requirement for oxygen may account for these regions being particularly vulnerable to hypoxia. For example, human subjects who have had a bout of hypoxia have a high incidence of Athetosis (a basal ganglia disorder), mental retardation (of cerebral cortex origin), and show cerebellar signs. 2- Neurotransmitters: The basal ganglia have particularly high concentrations of selected neurotransmitters. For example, Dopamine- is most concentrated in the caudate-putamen. Dopamine is located largely in the synaptic terminals. These terminals originate from neurons whose cell bodies lie in the pars compacta of the substantia nigra.

Strick Lecture 4 March 29, 2006 Page 6 GABA- is most concentrated in the globus pallidus and parts of the substantia nigra. Acetylcholine- is found in high concentrations in the caudate-putamen. Serotonin- one of the highest concentrations of serotonin in the brain is found in the substantia nigra. These neurotransmitters are found at multiple sites throughout the nervous system. However, some of their peak concentrations are found in the basal ganglia. Any "chemical pathology", i.e., any dysfunction in the synthesis, storage, metabolism or release of these transmitters could have profound consequences on basal ganglia function. 3- Heavy Metals: Normally, the basal ganglia have the highest concentration of 3 heavy metals- copper, iron and manganese. Why these metals should be attracted to the basal ganglia is unclear. However, exposure to high levels of these heavy metals results in toxic accumulations of them in the basal ganglia and characteristic movement disorders. For example- IRON - is most concentrated in the globus pallidus and the pars reticulata of the substantia nigra. Exposure to high levels of iron results in a disorder termed Hallervorden - Spatz disease. Patients suffering from this disorder have dystonic postures. MANGANESE - In manganese intoxication, high levels of this heavy metal are found in the globus pallidus and subthalamic nucleus. Patients suffering from this disorder have a Parkinson-like syndrome. 4- Selective affinity for damage: MPTP Story (a neurotoxin) MPTP = a contaminant of homemade heroin. After short term use of a homemade form of heroin that was contaminated with MPTP, patients developed an acute syndrome which in many respects was indistinguishable from Parkinson's disease (profound akinesia and rigidity). Other users initially did not show any symptoms. However, after careful examination, many of these subjects were found to have one of the earliest symptoms of Parkinson's disease- micrographia. Later, some of these subjects developed the full blown Parkinson syndrome. Injecting monkeys with MPTP generates a realistic animal model of Parkinson's disease. Analysis of the brains of monkeys and humans exposed to MPTP shows that this treatment results in a loss of dopaminergic neurons which is particularly severe in the pars compacta of the substantia nigra. VII. Chemical-Anatomy Model of Basal Ganglia dysfunction (Figures 9&10) 3 Fundamental Assumptions of the Model: 1- increase pallidal output -> decreases VL thalamic activity -> decreases motor cortex activity = akinesia 2- decrease pallidal output -> increases VL thalamic activity -> increases motor cortex activity = hyperkinesia or involuntary movements

Strick Lecture 4 March 29, 2006 Page 7 3- Dopamine and ACh have opposite effects on striatal output Examples- Subthalamic dyskinesia model- 1- Subthalamic nucleus normally excites GPi neurons. 2- Removal of this excitation, results in a net decrease in pallidal output 3- A decrease in pallidal output leads to decreased inhibition of thalamic neurons and an increase in VL activity 4- Increase VL activity -> increase in motor cortex activity = involuntary movements Parkinson - MPTP model- 1- SNpc DOPA normally excites specific sets of striatal neurons 2- Removal of this excitation, results in a decrease in the activity of striatal neurons that directly inhibit GPi neurons and a net increase in GPi output 3- An increase in pallidal output leads to increased inhibition of thalamic neurons and an decrease in VL activity 4- Decrease VL activity -> decrease in motor cortex activity = akinesia Note: recent evidence suggests that monkeys treated with MPTP have increased GPi activity when they are akinetic. A subthalamic lesion in these animals results in a net decrease in GPi activity (to a more normal level) and less akinesia. What about L-DOPA toxicity? 3 Significant Problems with the model: 1- How can you explain the rigidity seen in Parkinson's disease as a decrease in VL-Motor Cortex activity? 2- If decreases in pallidal output are thought to lead to increases in thalamic input to the motor cortex and hyperkinesia, why doesn't a pallidal lesion produce abnormal movements? 3- Patients vary in their symptoms. Some Parkinson patients have all 3 cardinal symptoms; others display only one of the 3. This feature of the disease is not explained by the model, nor is the finding that lesions in different parts of VL thalamus can differentially affect tremor and rigidity. Anterior lesions in VL tend to reduce rigidity and more posterior lesions in VL tend to affect tremor.

Strick Lecture 4 March 29, 2006 Page 8 VIII. Proposals about normal function of the Basal Ganglia- Conceptual issue: Most of what we know about the normal function of the basal ganglia is derived from studying the deficits seen in patients with Parkinson's or Huntington's disease. However, can we learn about the normal function of a system from studying it when it is not functioning properly? Logical question: If you cause tremors when you lesion the cerebellum, does that mean that the function of the cerebellum is to prevent tremor? Tracking Task: "Elemental" and "Complex" deficits seen in Parkinson patients. Elemental deficit (grading agonist burst amplitude): Figures 11&12 Complex deficit (generating movement based on an internal model): Figures 13&14 Figure 1

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