Parkinson's+Disease

**Overview**
The Basal Ganglia is an important group of structures in the Central Nervous System that function in the regulation and control of movement. These structures are nuclei that are interconnected with each other and with other cortical and subcortical structures. They use two separate pathways to send input received from the Sensorimotor Cortex through the various structures that make up the Basal Ganglia and back out to the Motor Cortex. They do this through the use of the neurotransmitters Glutamate, GABA, Enkephalin, Substance P, Acetylcholine, and Dopamine. The direct pathway results in a facilitation of a desired movement and the indirect pathway results in an inhibition of undesired movement. Dysfunction of these Basal Ganglia structures and pathways results in the movement disorder known as Parkinson's disease.

Functional Anatomical Review
The Basal Ganglia are a somatotopically organized grouping of nuclei located deep to the cortex that surround the Thalamus and are superior to the brainstem. They function in the processing of information in regards to the execution of movement. Its constituent parts are the Caudate, Putamen, Globus Pallidus, Subthalamic Nucleus (STN), and Substantia Nigra. The Caudate and Putamen make up the Striatum and are the main receptors for input to the Basal Ganglia from other areas. The Corpus Striatum is the same as the Striatum but it includes the Globus Pallidus, and the Lenticular Nucleus consists of the Putamen and Globus Pallidus. The Globus Pallidus has both an internal (GPi) and an external segment (GPe). The Substantia Nigra also has two parts -- the pars compacta (SNc) and pars reticulata (SNr). The GPe, STN, and SNc are involved in the internal processing within the Basal Ganglia pathways. The two main output nuclei are the SNr and GPi.

The Caudate is located most superior of the nuclei. It is also the largest forming the anterior portion of the Striatum and stretching back over and around the Lenticular Nucleus. Inferior and lateral to that is the Putamen, then the Globus Pallidus is internal to that. The Subthalamic Nucleus is located beneath the Thalamus as you probably inferred from its name. The Substantia Nigra is located in the Midbrain near the cerebral peduncles. There are two pathways within the Basal Ganglia -- the direct pathway and the indirect pathway. The direct pathway facilitates intended movement and the indirect pathway inhibits unintended movement.

Input and Output Pathways
The Basal Ganglia receives excitatory input through the neurotransmitter Glutamate to the Striatum from many cortical areas including the Primary Motor (M1), Supplementary Motor (SMA), Premotor (PM), and Primary Somatosensory (P1) cortices. It then processes this information through the direct and indirect pathways, and depending on the balance of direct versus indirect pathway usage, sends either inhibitory output through the neurotransmitter Gamma-aminobutyric Acid (GABA) from the internal segment of the Globus Pallidus or the Substantia Nigra pars reticulata to the Thalamus, which if uninhibited can send excitatory output back to the Motor Cortex, or sends no output at all. The Basal Ganglia also projects to the Superior Colliculi and the Pedunculopontine nucleus, which projects to the spinal cord. The balance of usage of the direct versus the indirect pathway is how the Basal Ganglia is involved in the control of movement. It is thought that the Basal Ganglia works as a gate in allowing the initiation of voluntary movements. These voluntary movements are viewed as motor programs that are stored in the Motor cortices. The Basal Ganglia facilitates the appropriate motor program for a task by exciting the cortex (through the Thalamus) using the direct pathway and inhibits other competing motor programs by inhibiting the cortex (again via the Thalamus) using the indirect pathway. There are four main loops that send input to the Basal Ganglia for processing and then receive its output. They are the Motor, Oculomotor, Prefrontal, and Limbic loops. Each loop is defined by what structures are sending input to the Striatum and where the Basal Ganglia output nuclei project to. The two loops of importance to movement are the Motor and Oculomotor loops, so those will be discussed in detail. The Motor loop sends cortical input from the Primary Motor, Premotor (lateral premotor and supplementary motor) and Somatosensory cortices to the Striatum, in particular the Putamen. This input is then processed and sent back to the Motor cortices via the Ventral Anterior (VA) and Ventral Lateral (VL) nuclei of the Thalamus. The Oculomotor loop sends cortical input from the Posterior Parietal cortex and Prefrontal cortex to the body of the Caudate in the Striatum. This information is processed and sent back to the Frontal Eye Fields and the Supplementary Eye Fields via the Mediodorsal and VA of the Thalamus. //The Direct Pathway// The direct pathway begins with the Striatum being excited by the Cortex. The Striatum then inhibits the internal segment of the Globus Pallidus and the Substantia Nigra pars reticulata using the neurotransmitters GABA or Substance P (Sub P). When these structures are inhibited they cannot inhibit the Thalamus rendering it free to fire and send excitatory input up to the Cortex, which facilitates movement. //The Indirect Pathway// The indirect pathway begins with the Striatum being excited by the Cortex (just like the direct pathway). Then Striatal neurons send inhibitory input to the external segment of the Globus Pallidus using the neurotransmitters GABA or Enkephalin (enk). The Globus Pallidus external segment usually sends inhibitory input to the Subthalamic Nucleus using GABA, but if it is inhibited by the Striatum then it is unable to inhibit the Subthalamic nucleus leaving it free to fire. The Subthalamic Nucleus being uninhibited sends the only purely excitatory input within the Basal Ganglia pathways to the Globus Pallidus internal segment and the Substantia Nigra pars reticulata. These structures then inhibit the VA and VL of the Thalamus making it unable to send excitatory input to the Cortex and thus indirectly inhibiting the Motor Cortices, which inhibits movement.

//The Substantia Nigra pars compacta// The Substantia Nigra pars compact plays a key role in the balance of direct versus indirect pathway. If functioning correctly the Substantia Nigra pars compacta has the overall effect of facilitating intended movement and inhibiting unintended movement. It does this by exciting the direct pathway and inhibiting the indirect pathway through release of the neurotransmitter Dopamine. Striatal neurons of the direct pathway have D1 receptors which are excited by Dopamine, whereas Striatal neurons of the indirect pathway have D2 receptors which are inhibited by Dopamine. The Substantia Nigra pars compacta also sends excitatory input directly to the Cortex again using Dopamine.

//Cholinergic (ACh) Striatal Interneurons// There are also cholinergic interneurons located within the Striatum that synapse on both the neurons of the direct and indirect pathways. These interneurons have the opposite affect of dopamine. Release of ACh causes the Striatal neurons of the direct pathway to be inhibited and the Striatal neurons of the indirect pathway to be excited. Thus these cholinergic interneurons add to the balance of control between the direct and indirect pathways.

//Note:// (In all cases of excitation and inhibition we must remember that there are individual neurons being depolarized or hyperpolarized by excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs) respectively, via chemically gated ion channels involving spatial and temporal summation. If a greater number of neurons reach threshold and then depolarize firing an action potential than do not then you will most likely see excitation of neurons in the next structure. We must also remember that whether a neuron is excited or inhibited by a chemically gated ion channel depends upon the neurotransmitters in the synaptic cleft and most importantly upon the receptors of the postsynaptic neuron.)

Parkinson's Disease
Parkinson's disease is a hypokinetic disorder that is the result of Basal Ganglia dysfunction. Patients with Parkinson's disease exhibit several key signs of motor dysfunction, these being difficulty initiating movement**,** bradykinesia, shuffling gait, flexed posture, impaired balance, muscular rigidity, and tremor. The disease usually develops later in life (typically in people 55 years or older) and as it progresses can lead to depression, anxiety, and eventually memory loss or dementia. The exact causes of Basal Ganglia dysfunction that results in Parkinson's disease are not well know but some possible effectors could be environmental, genetic, or brain injury. There are a few treatments for Parkinson's but no known cures. These treatments usually involve dopamine supplementation or imitation, or reducing the amount of Acetylcholine (ACh) in the striatum as well as surgical lesioning of the Subthalamic Nucleus or Globus Pallidus internus (both components of the Basal Ganglia).

The reasoning behind these treatments is because Parkinson's is a result of a disruption between the balance of the direct versus the indirect pathway. This balance is tipped more towards the indirect pathway resulting in less facilitation and more inhibition of movement. This disruption is caused by lesions of the Substantia Nigra pars compacta. This death of neurons in the pars compacta means that they can no longer release dopamine and excite the Striatal neurons in the direct pathway and inhibit the Striatal neurons in the indirect pathway. The pars compact also can no longer excite the Cortex directly.

Now due to the over-activity of the indirect pathway we see the signs of Parkinson's disease being exhibited. We understand why these are the symptoms because we know how the pathways within the Basal Ganglia function. All of the symptoms reflect the increase in inhibition of movement and the decrease in facilitation. Treatments of Parkinson's involving supplementation or imitation of Dopamine or lowering of Acetylcholine levels, as well as surgically lesioning the Subthalamic Nucleus or the internal segment of the Globus Pallidus aim to correct for the imbalance in pathway usage. By supplementing Dopamine or using Dopamine agonists the D1 receptors in the Striatum are excited and the D2 receptors are inhibited causing more facilitation of intended movement. By reducing the amount of ACh in the Striatum you reduce the amount of inhibition coming from the interneurons on the direct pathway and reduce the amount of excitation of the indirect pathway. By surgically lesioning the Subthalamic Nucleus you take away the excitatory input to the Globus Pallidus internus. Since it is no longer being excited it can't inhibit the VA and VL of the Thalamus so the Cortex is excited by Thalamic input. Surgical lesioning of the Globus Pallidus internus directly also frees up the Thalamus to fire and excite the Cortex.

Conclusion
An understanding of the Basal Ganglia was key in discovering the cause and some potential treatments of Parkinson's disease. A more complete understanding of neurophysiology as a whole -- the functions of all the various cortical and subcortical structures and there various interconnections and how they relate to each other -- is something that is extremely important to science and medicine. Parkinson's disease is one of the most common neurological disorders, second only to Alzheimer's disease, and therefore an understanding of the Basal Ganglia has given doctors a way to treat their patients who deal with Parkinson's disease. Despite the fact that the Basal Ganglia are only a grouping of nuclei in the brain, it is clear that it is extremely important in the regulation and control of human movement.

Glossary of Terms
__Cortex__ - general term referring to the outer layer of the Cerebrum __Thalamus__ - relays information to the Cortex __Caudate__ - 1 of 2 Basal Ganglia nuclei that receive input from the Cortex and other areas __Putamen__ - the other Basal Ganglia nucleus that receives input from the Cortex and other areas __Globus Pallidus__ - has both an internal segment, which is involved in output from the Basal Ganglia to the Thalamus, and an external segment, which is involved in the indirect pathway and synapses on the Subthalamic Nucleus __Subthalamic Nucleus__ - involved in the indirect pathway; sends the only excitatory input within the Basal Ganglia to the output nuclei __Substantia Nigra__ - located in the midbrain; has 2 parts, the pars reticulata is 1 of the output nuclei, the pars compacta sends dopaminergic projections to the Cortex and Striatum __Striatum__ - the input nuclei of the Basal Ganglia; consists of the Caudate and Putamen __Corpus Striatum__ - consists of the Caudate, Putamen, and Globus Pallidus __Lenticular Nucleus__ - consists of the Putamen and Globus Pallidus __Output Nuclei__ - GPi and SNr __Glutamate__ - a neurotransmitter used within the Basal Ganglia to send excitatory input __Gamma-aminobutyric acid (GABA)__ - a neurotransmitter used in inhibition __Dopamine__ - an important neurotransmitter used in both excitation and inhibition depending on the receptor type __Acetylcholine (ACh)__ - an important neurotransmitter used by interneurons in both excitation and inhibition __Substance P__ - a neurotransmitter used in the direct pathway to inhibit the GPi or SNr __Enkephalin__ - a neurotransmitter used in the indirect pathway to inhibit the GPe __Bradykinesia__ - slowness of movement __Muscular Rigidity__ - stiffness of the muscles around a joint caused by contraction of both agonist and antagonist muscle pairs __Tremor__ - shaking __Lesion__ - a region in an organ or tissue that has suffered cellular damage through injury or disease

Suggested Readings and Relevant Links
http://thalamus.wustl.edu/course/cerebell.html - gives a brief overview of the workings of the Basal Ganglia and the Cerebellum http://webspace.ship.edu/cgboer/basalganglia.html - another overview of the Basal Ganglia and the diseases that result from its dysfunction http://neuroscience.uth.tmc.edu/s3/chapter04.html - an in depth coverage of the Basal Ganglia (excellent source) http://emedicine.medscape.com/article/1831191-overview#a0101 - great coverage of Parkinson's disease from a medical perspective

Quiz Questions
__True/False__: 1. T/F - The Basal Ganglia directly controls for movement? 2. T/F - The Striatum consists of the input nuclei? 3. T/F - Parkinson's disease is a disorder of the Substantia Nigra pars reticulata? 4. T/F - A treatment of Parkinson's disease is to surgically lesion the Subthalamic Nucleus? 5. T/F - Onset of Parkinson's disease commonly occurs in people between the ages of 20 - 50?

__Multiple choice__: 6. Which of the following is the correctly ordered indirect pathway? A) Striatum, Cortex, GPi, GPe, STN, Thalamus, Cortex B) SNr, GPe, Cortex, Thalamus, STN, Striatum, Cortex C) Cortex, Striatum, GPe, STN, GPi, Thalamus, Cortex D) Cortex, Thalamus, GPe, STN, GPi, Striatum, Cortex

7. Which of the following are purely inhibitory neurotransmitters? A) GABA, Dopamine, Glutamate B) GABA, Enkephalin, Substance P C) GABA, Glutamate, Enkephalin D) Substance P, Enkephalin, Dopamine

8. What type of receptors do the Striatal neurons of the indirect pathway have? A) D1 B) cholinergic C) excitatory D) D2

9. What type of cells in the Basal Ganglia use Acetylcholine (ACh)? A) interneurons B) Dopaminergic C) inhibitory D) cortical

__Short answer__: 1. Differentiate between the direct and indirect pathway in the Basal Ganglia, and be able to describe the structures involved, the neurotransmitters used, and the synapses between structures for each pathway. 2. Describe how the disruption of the balance in the direct versus indirect pathway causes Parkinson's disease. 3. What are some common symptoms and treatments of Parkinson's disease?

//Answers:// 1. F 2. T 3. F 4. T 5. F 6. C 7. B 8. D 9. A