Basal ganglia


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Basal ganglia

  2. 2. INTRODUCTION A collection of subcortical nuclei that have captured the fascination of clinicians for well over a century because of the remarkable range of behavioral dysfunction associated with basal ganglia disease. Movement control deficits are among the key signs, ranging from the tremor and rigidity of Parkinson disease and the writhing movements of Huntington disease to the bizarre tics of Tourette syndrome. In addition to producing movement control deficits, basal ganglia disease can also impair intellectual capacity, suggesting an important role in cognition. The basal ganglia have also been linked with emotional function, playing a role in aspects of drug addiction and psychiatric disease.
  5. 5. SEPARATE COMPONENTS OF THEBASAL GANGLIA PROCESS INCOMINGINFORMATION AND MEDIATE THEOUTPUT On the basis of their connections, the components of the basal ganglia can be divided into three categories: input nuclei, output nuclei, and intrinsic nuclei. The input nuclei receive afferent connections from brain regions other than the basal ganglia and in turn project to the intrinsic and output nuclei. The output nuclei project to regions of the diencephalon and brain stem that are not part of the basal ganglia. The connections of the intrinsic nuclei are largely restricted to the basal ganglia.
  6. 6.  The striatum is the input nucleus of the basal ganglia, receiving afferent projections from the cerebral cortex. Three subnuclei comprise the striatum:1. The caudate nucleus, which participates in eye movement control and cognition;2. The putamen, which participates in control of limb and trunk movements; and3.The nucleus accumbens, which participates in emotions.
  7. 7.  There are three nuclei on the output side of the basal ganglia: the internal segment of the globus pallidus, the substantia nigra pars reticulata, and the ventral pallidum. The axons of output nuclei project to thalamic nuclei, which project to different areas of the frontal lobe. These thalamic nuclei include the ventrolateral nucleus (a part distinct from the one receiving cerebellar input), the ventral anterior nucleus, and the medial dorsal nucleus. The output nuclei also project to the pedunculopontine nucleus at the junction of the midbrain and pons, which is implicated in limb and trunk control during locomotion, and to the superior colliculus, which controls saccadic eye movements
  8. 8.  The basal ganglia have four intrinsic nuclei: the external segment of the globus pallidus, the subthalamic nucleus, the substantia nigra pars compacta, and the ventral tegmental area. Their connections are closely related to the input and output nuclei. The external segment of the globus pallidus and the subthalamic nucleus are part of a basal ganglia circuit that receives input from other basal ganglia nuclei and in turn projects back. The substantia nigra pars compacta and the ventral tegmental area contain dopaminergic neurons that project to the striatum.
  9. 9.  The striatum has a complex shape . The caudate nucleus has a C-shape, with three components: head, body, and tail. The putamen, when viewed from its lateral surface, is shaped like a disk. The nucleus accumbens is contiguous with the ventromedial portions of the caudate nucleus and the putamen.
  10. 10. The Anterior Limb of the Internal Capsule Separates the Head of the Caudate Nucleus From the Putamen Three main segments of the internal capsule are the anterior limb; the posterior limb; and the genu The anterior limb separates the head of the caudate nucleus from the putamen. This limb contains axons projecting to and from the prefrontal association cortex and the various premotor cortical areas. The posterior limb separates the putamen and the globus pallidus (lenticular nucleus) from the thalamus and body and tail of the caudate nucleus. The posterior limb contains the corticospinal tract as well as the projections to and from the somatic sensory areas in the parietal lobe. The genu contains the corticobulbar tract
  11. 11. Cell Bridges Link the Caudate Nucleusand the Putamen Although the internal capsule courses between the caudate nucleus and the putamen, striatal cell bridges link the two structures. These cell bridges are a reminder that, in the developing brain, axons coursing to and from the cortex incompletely divide the group developing neurons in the floor of the lateral ventricle that give rise to the striatum. The nucleus accumbens, together with the ventromedial portions of the caudate nucleus and putamen comprise the ventral striatum, the striatal component of the limbic loop. (The olfactory tubercle is sometimes included within the ventral striatum)
  12. 12. The Striatum Has aCompartmental Organization Histochemical staining, however, also reveals a striking lack of homogeneity in which neurotransmitters and neuromodulators have a nonuniform distribution within local regions of the components of the striatum. For acetylcholinesterase, a matrix of tissue that contains a higher concentration surrounds patches, also called striasomes, of low concentration. Enkephalin, as well as numerous other neuroactive substances present in the striatum, also has a patchy distribution. The functional significance of striatal compartmentalization has remained elusive and is among the most important of the many unresolved questions concerning basal ganglia organization. Recent experimental findings have shown that neurons in the matrix and striasomal compartments have different connections. The striasomes receive their major cortical input from the limbic
  13. 13. THE HEAD OF THE CAUDATENUCLEUS IS A RADIOLOGICALLANDMARK The head of the caudate nucleus bulges into the anterior horn of the lateral ventricle. This can be seen on a magnetic resonance imaging (MRI) scan of a normal individual. Patients with Huntington disease exhibit a loss of medium spiny neurons. This cell loss begins in the caudate nucleus and dorsal putamen. Because these neurons constitute more than three quarters of striatal neurons, in patients with Huntington disease the characteristic bulge of the head of the caudate nucleus into the lateral ventricle is absent.
  14. 14. THE EXTERNAL SEGMENT OF THEGLOBUS PALLIDUS AND THE VENTRALPALLIDUM ARE SEPARATED BY THEANTERIOR COMMISSURE The ventral pallidum is the output nucleus for the limbic loop. The external segment of the globus pallidus and the ventral pallidum are separated by the anterior commissure. This commissure, like the corpus callosum, interconnects regions of the cerebral cortex of either hemisphere. the anterior commissure interconnects specific regions: anterior temporal lobes, the amygdaloid nuclear complex, and several olfactory structures.
  15. 15. The Ansa Lenticularis and the LenticularFasciculus Are Output Paths of the InternalSegment of the Globus Pallidus Two major laminae separate components of the basal ganglia. The lateral medullary lamina separates the external segment of the globus pallidus from the putamen, and the medial medullary lamina separates the internal and external segments of the globus pallidus Neurons of the internal segment of the globus pallidus project their axons to the thalamus. These axons course in two anatomically separate pathways: the lenticular fasciculus and the ansa lenticularis. The axons of the lenticular fasciculus course directly through the internal capsule, but these axons are not clearly visualized until they collect medial to the internal capsule The internal capsule appears to be a barrier for fibers of the ansa lenticularis; these fibers course around it to reach the thalamus.
  16. 16.  The three major thalamic targets of the output nuclei of the basal ganglia are: the medial dorsal nucleus, the ventrolateral nucleus, and the ventral anterior nucleus. Two intralaminar thalamic nuclei, the centromedian and parafascicular nuclei, are anatomically closely related to the basal ganglia because they provide a major direct input to the striatum. These thalamic nuclei also project to the frontal lobe, which is the cortical target of the basal ganglia. Because the intralaminar nuclei have widespread cortical projections, they are diffuse-projecting thalamic nuclei and not relay nuclei.
  17. 17. Lesion of the Subthalamic Region Produces Hemiballism Two major nuclei in this poorly understood brain region are the subthalamic nucleus and zona incerta. A lesion of the subthalamic nucleus produces hemiballism, characterized by ballistic movements of the contralateral limbs. The connections of the subthalamic nucleus are complex. Receiving input from the external segment of the globus pallidus as well as from the motor cortex, the subthalamic nucleus projects back to the external and internal segments of the globus pallidus. The subthalamic nucleus is also a target of brain electrical stimulation, where activation of its excitatory output circuitry can have beneficial effects in Parkinson disease. The subthalamic nucleus is also reciprocally connected with the ventral pallidum.
  18. 18. The Substantia Nigra ContainsTwo Anatomical Divisions The substantia nigra pars reticulata, which is adjacent to the basis pedunculi, contains GABA. The substantia nigra pars reticulata, like the internal segment of the globus pallidus, also projects to the thalamus and pedunculopontine nucleus . In addition, the substantia nigra projects to the superior colliculus , which is important in controlling saccadic eye movements.
  19. 19.  The substantia nigra pars compacta, which consists of neurons containing dopamine. The projection of these neurons to the striatum forms the nigrostriatal tract. The dendrites of dopaminergic neurons irrespective of their location within the substantia nigra pars compacta extend into the substantia nigra pars reticulata. This arrangement is thought to be functionally important for integrating information between the various parallel loops. The substantia nigra pars compacta is not the only midbrain region that contains dopamine. The ventral tegmental area is dorsomedial to the substantia nigra, beneath the floor of the interpeduncular fossa. Dopaminergic neurons in the ventral tegmental area send their axons to the striatum via the medial forebrain bundle as well as to the frontal
  20. 20.  Two other brain stem nuclei are closely associated with the basal ganglia, the pedunculopontine nucleus, found at the junction of the pons and midbrain in the reticular formation, and the dorsal raphe nucleus, located in the caudal midbrain. The output nuclei of the basal ganglia project to the pedunculopontine nucleus. This is the descending projection of the basal ganglia, and it is thought to play an important behavioral role. The pedunculopontine nucleus has diverse functions, including regulating arousal (through diffuse ascending projections to the thalamus and cortex) and movement control (through reticular formation connections and direct reticulospinal projections). Many of the neurons in this nucleus are cholinergic, including those projecting to the thalamus. The dorsal raphe nucleus gives rise to an ascending serotonergic projection to the striatum. In addition to projecting to the striatum, the dorsal raphe nucleus has extensive projections to most of the cerebral cortex and to other forebrain nuclei.
  21. 21. The Vascular Supply of the Basal Ganglia IsProvided by the Middle Cerebral Artery Most of the striatum is supplied by perforating branches of the middle cerebral artery; however, rostromedial regions are supplied by perforating branches of the anterior cerebral artery. Collectively these penetrating branches of the anterior and middle cerebral arteries are termed the lenticulostriate arteries. Most of the globus pallidus is supplied by the anterior choroidal artery, which is a branch of the internal carotid artery.
  22. 22. FUNCTIONAL ANATOMY There are two important pathways through which striatal information reaches GP(internal) - the direct pathway and the indirect pathway. These two pathways have opposite effects on motor activity and help explain many clinical symptoms of basal ganglia diseases. In the direct pathway, striatal cells project directly to GP(internal). The consequence of this pathway is to increase the excitatory drive from thalamus to cortex.
  23. 23. DIRECT PATHWAY In the direct pathway, striatal cells project directly to GP(internal). The consequence of this pathway is to increase the excitatory drive from thalamus to cortex. The cortical projections to the striatum use the excitatory transmitter glutamate. When they are activated, these cortical projections excite striatal neurons. This striatal cell uses the inhibitory transmitter GABA and its axon passes to, and inhibits, a cell in GP(internal). The cells in GP(internal) that project to VA/VL also use GABA. So, the cortical signal excites striatal neurons, which results in MORE inhibition from striatum to GP(internal). More inhibition of GP(internal) means LESS inhibition of motor thalamus (VA/VL). Since the motor thalamus receives LESS inhibition, the VA/VL cells will INCREASE their firing. This decrease in inhibition is called dis-inhibition.
  24. 24. Indirect Pathway Instead of projecting to GP(internal), the striatal neurons of the indirect pathway project to GP(external). Cells in GP(external) project to the subthalamic nucleus. Cells in the subthalamic nucleus then project to GP(internal), which in turn projects to VA/VL. In the indirect pathway, cortical fibers excite striatal neurons that project to GP(external).
  25. 25.  The GABAergic cells in GP(external) inhibit cells in the subthalamic nucleus, so the decrease in activity in GP(external) results in less inhibition of cells in the subthalamic nucleus. That is, subthalmic neurons are dis-inhibited and increase their activity. The “return” projection from the subthalamic nucleus to GP(internal) is excitatory, so the increased activity in the subthalamic nucleus results in more excitation to cells in GP(internal).
  26. 26.  Thus, the end result of actions of the indirect loop is an increase in activity of the GABAergic cells in GP(internal) that project to VA/VL or an INCREASE in INHIBITION of the thalamic neurons. The Indirect Pathway turns DOWN the motor thalamus and, in turn, motor cortex. Thus, it TURNS DOWN motor activity.
  27. 27. DOPAMINERGIC and CHOLINERGICModulation of Direct and Indirect Pathways Nigrostriatal axon terminals release dopamine into the striatum. Dopamine has an EXCITATORY effect upon cells in the striatum that are part of the Direct Pathway. This is via D1 receptors. Dopamine has an INHIBITORY effect upon striatal cells associated with the Indirect Pathway.This is via D2 receptors.
  28. 28.  In other words, the direct pathway (which turns up motor activity) is excited by dopamine while the indirect pathway (which turns down motor activity) is inhibited. Both of these effects lead to increased motor activity. THE EFFECT OF THE DOPAMINERGIC NIGROSTRIATAL PROJECTION IS TO INCREASE MOTOR ACTIVITY.
  29. 29.  There is a population of cholinergic (ACh) neurons in the striatum whose axons do not leave the striatum (called interneurons or local circuit neurons). These cholinergic interneurons synapse on the GABAergic striatal neurons that project to GP(internal) and on the striatal neurons that project to GP(external). The cholinergic actions INHIBIT striatal cells of the Direct pathway and EXCITE striatal cells of the Indirect pathway. THE EFFECT OF THE CHOLINERGIC STRIATAL INTERNEURONS IS TO DECREASE MOTOR ACTIVITY.
  30. 30. Parallel Circuits Course Throughthe Basal Ganglia Each of the loops originates from multiple cortical regions that have similar general functions. Each loop passes through different basal ganglia and thalamic nuclei, or separate portions of the same nucleus. The cortical targets of the loops are separate portions of the frontal lobe
  31. 31.  Four such loops:1.the skeletomotor,2.oculomotor,3.prefrental cortex, and4.limbic loops.
  32. 32.  The skeletomotor loop plays important roles in the control of facial, limb, and trunk musculature . Inputs originate from the primary somatic sensory and frontal motor areas and project back to the frontal motor areas . The oculomotor loop plays a role in the control of saccadic eye movements. Key inputs derive from the frontal eye field, which is important in the production of rapid conjugate eye movements through brain stem projections, and the posterior parietal association cortex, which processes visual information for controlling the speed and direction of eye movements. The output of this loop is to the frontal eye movement control centers .
  33. 33. The Basal Ganglia Also Have a Role in Cognition, Mood, and Nonmotor Behavior Function The dorsolateral prefrontal circuit :it originates in Brodmanns areas 9 and 10 and projects to the head of the caudate nucleus, which then projects directly and indirectly to the dorsomedial portion of the internal pallidal segment and the rostral substantia nigra pars reticulata. Projections from these regions terminate in the ventral anterior and medial dorsal thalamic nuclei, which in turn project back upon the dorsolateral prefrontal area. The dorsolateral prefrontal circuit has been implicated broadly in so- called “executive functions”. These include cognitive tasks such as organizing behavioral responses and using verbal skills in problem solving. Damage to the dorsolateral prefrontal cortex or subcortical portions of the circuit is associated with a variety of behavioral abnormalities
  34. 34.  The lateral orbitofrontal circuit:it arises in the lateral prefrontal cortex and projects to the ventromedial caudate nucleus. The pathway from the caudate nucleus follows that of the dorsolateral circuit and returns to the orbitofrontal cortex. The lateral orbitofrontal cortex appears to play a major role in mediating empathetic and socially appropriate responses. Damage to this area is associated with irritability, emotional lability, failure to respond to social cues, and lack of empathy. A neuro-psychiatric disorder thought to be associated with disturbances in the lateral orbitofrontal cortex and circuit is obsessive-compulsive disorder.
  35. 35.  The anterior cingulate circuit:it arises in the anterior cingulate gyrus and projects to the ventral striatum. The ventral striatum also receives “limbic” input from the hippocampus, amygdala, and entorhinal cortices. The projections of the ventral striatum are directed to the ventral and rostromedial pallidum and the rostrodorsal substantia nigra pars reticulata. From there the pathway continues to neurons in the paramedian portion of the medial dorsal nucleus of the thalamus, which in turn project back upon the anterior cingulate cortex. The anterior cingulate circuit appears to play an important role in motivated behavior, and it may convey reinforcing stimuli to diffuse areas of the basal ganglia and cortex via inputs through the ventral tegmental areas and the substantia nigra pars compacta. These inputs may play a major role in procedural learning
  36. 36.  Integration across the numerous parallel basal ganglia circuits must take place. Two mechanisms are important. First, the dendrites of striatal neurons can extend beyond their own loops into adjacent loops, thereby receiving information from more diverse cortical areas. Second, striatal neurons in all of the loops project back to the substantia nigra pars compacta. The terminals of axons comprising the different loops may converge on nigral dopaminergic neurons and interneurons and, thus, be sites for integration.
  37. 37. Disorders of the BasalGanglia:Hypokinesia The most well known hypokinetic syndrome is Parkinson’s disease, and it generally affects the elderly population. While hypokinesia (reduced movement) is the hallmark of Parkinson’s disease, three other signs (rigidity, tremor and loss of postural reflexes) accompany this decrease in movement. It is difficult to explain all these symptoms with the knowledge that we currently have, but we can certainly account for the hypokinesia.
  38. 38.  dopaminergic neurons in substantia nigra pars compacta are lost in Parkinson’s disease. The degenerating nigral dopaminergic cells accumulate deposits of protein called Lewy Bodies. This is a histological hallmark of the disease. The SN lesion takes away the dopaminergic drive on the direct pathway-activity in the direct pathway goes down, and motor activity goes down. Compounding this reduction in dopamine facilitation, Ach interneurons are still inhibiting the striatal cells at the head of the direct pathway. Again, the end result is MORE inhibition reaching the VA/VL.
  39. 39.  Take away the dopamine inhibition and the indirect pathway increases its activity. The loss of dopaminergic inhibition to the indirect pathway is compounded by the now un-opposed excitatory actions of the cholinergic interneurons that drive the indirect pathway. The results of losing dopamine on both the Direct and Indirect Pathways is a reduction in the activity of VA/VL and, in turn, motor cortical neurons. This results in hypokinetic symptoms such as akinesia (no movement) or bradykinesia (slow movement)
  40. 40.  Since the hypokinetic (Parkinson’s) patients have decreased levels of dopamine in the striatum and substantia nigra pars compacta, they can be treated symptomatically with dopaminergic agonists, such as L- dopa. Parkinson’s patients can also be treated with drugs that decrease the level of acetylcholine in the striatum. some of the symptoms of Parkinson’s disease can be reduced or alleviated by placing stimulating electrodes in the thalamus, subthalamic nucleus, or pallidum Thalamic stimulators seem to be effective in reducing tremor, but do little for akinesia.Pallidal stimulation seems to have a more all- encompassing therapeutic effect
  41. 41. Disorders of the Basal Ganglia: Hyperkinesia Two classic hyperkinetic disorders are hemiballism and Huntington’s chorea. Hemiballism is characterized by wild, flinging movements of the body, and it results from lesion in the subthalamic nucleus The excitatory input to GP(internal) is lost following such lesions. The result is LESS inhibition reaching the VA/VL (the subthalamic nucleus normally increases the inhibition in the pallidal-VA/VL projection). Thus, the VA/VL is turned up, as is motor cortex, and there is uncontrollable hyperactivity of the motor system.
  42. 42.  Huntington’s chorea is characterized by involuntary choreiform movements which show up as rapid, involuntary and purposeless jerks of irregular and variable location on the body. There is memory loss and attention deficit The initial cause of these uncontrollable movements is the loss of GABAergic cells in the striatum that project only to GP(external), the head of the indirect pathway. The loss of this inhibition on the head of the indirect pathway (which turns down motor activity) means that VA/VL is turned up, as is the motor cortex, and there is uncontrollable hyperactivity of the motor system. In addition to the loss of striatal GABAergic cells of the indirect pathway, the striatal cholinergic cells also begin to die.
  43. 43. TREATMENT The hyperkinesia can be reduced by bringing the contributions of the direct and indirect pathways more into balance. One approach is to replace the lost cholinergic input to the striatum. ACh turns DOWN motor activity by inhibiting the direct pathway. If there are any surviving striatal-GP(external) neurons, ACh would excite them and thus increase activity in the indirect pathway, also leading to a decrease in motor activity. As an alternative, you could also decrease activity in the direct pathway by reducing its activation from dopamine with a dopaminergic antagonist.
  44. 44. Pathophysiological model ofparkinsonism Clinically, parkinsonism is characterized by the tetrad of akinesia, bradykinesia, rigidity and tremor. The study of degeneration of nigrostratal fibres in parkinsons disease has been greatly facilitated by the introduction of an animal model, i.e the primate treated with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP).
  45. 45. AKINESIA, BRADYKINESIA ANDRIGIDITY Akinesia, the earliest sign of parkinsonism in MPTP treated primates, is seen after doses of neurotoxin small enough to damage almost exclusively the dopamine supply to the striatum. Although pathophysiological changes in basal ganglia discharge underlying akinesia, bradykinesia and rigidity are thought to be the same i.e changes of basal ganglia output, the expression of these signs may depend on abnormalities in different motor sub circuits. Akinesia may be related to abnormal discharge in the sub circuit eminating from the SMA and mesial cortical motor areas.
  46. 46.  In contrast, bradykinesia and rigidity may result from abnormalities in the sub circuit arising from motor cortex. Abnormalities of neuronal activity in the basal ganglia and cortex will eventually lead to abnormal activity in the spinal cord. One of the main consequences of these down stream effects appears to be increased alpha motor neuron excitability. In support of this concept, dorsal root section abolishes parkinsonian rigidity. Possible explanation is altered basal ganglia output mediated via the pontine nucleus and dorsal longitudinal fasciculus of the reticulo spinal projection may lead to increased inhibition of 1b interneurons which intern disinhibit alpha motor neurons.
  47. 47. TREMOR Although tremor in parkinson’s disease has been largely considered as a result of thalamic auscillatory discharge, it has more recently been linked to abnormal discharge in the basal ganglia. This may be explained by increased tonic basal ganglia output to the thalamus may promote oscillatory activity through increased hyperpolarisation in the nucleus. Oscillations generated in the motor areas of basal ganglia output nuclei or thalamus will eventually lead to rhythmic activity in thalamocortical cells which inturn lead to auscillations in corticospinal projection neurons.
  48. 48.  THANK YOU