Introduction:

Huntington's Disease (or HD) is an inherited disorder characterized by degeneration of the neurons in the brain. Specifically, this is a loss or degeneration of the striatal projection neurons in the Basal Ganglia. The Basal Ganglia is a region of the brain just under the cortex, and it is a crucial component to both the control of movement as well as sensorimotor coordination (Shepherd 463). It also has some influence in emotional response as well. Because of its extensive responsibility in the neural control of movement, degeneration of this region of the brain leads to a variety of symptoms such as chorea, abnormal posture, impaired coordination, slurred speech, difficulty eating and swallowing, behavioral changes, and sometimes even dementia as well. The disease is known to progressively worsen over time, and is usually observed around the ages of 30-50, though some cases occur when the patient is under 20 years old (and this is called juvenile Huntington's Disease). Once symptoms start to show, the patient will usually have 10-15 years to live. Even though there is, as of now, no treatment to stall or slow the progression of the disease, there are various treatments that can be used to lessen the symptoms such that quality of life at the very least can be improved for the patient. (Frank).


Functional Anatomy of Basal Ganglia:

Overview/Components:
To understand HD better, it helps to start with the affected region. In this case, this is the region called the Basal Ganglia. The Basal Ganglia is, as aforementioned, an important player in neural control of movement. Located beneath the cortex, the Basal Ganglia isn't actually one structure, but rather a collection of structures. Grouped within this collective are the Striatum, the Globus Pallidus, the Substantia Nigra and the Subthalamic Nucleus (STN). The striatum actually contains two nuclei -- the Caudate and Putamen. These two nuclei are the main receptive nuclei of the basal ganglia and receive inputs from the cortex, thalamus, and substantia nigra. The globus pallidus also has two parts to it, these are the externa (GPe) and interna (GPi). The substantia nigra also contains two parts - the pars reticulata (SNr) and the pars compacta (SNc). The GPi and the SNr are both the main output nuclei for the basal ganglia. All these structures together make up what is known as the basal ganglia. The function of the basal ganglia in motor control is not understood in great detail. What we do know about its function is that it appears to be involved in the enabling of practiced motor acts and in gating the initiation of voluntary movements by modulating motor programs stored in the motor cortex and elsewhere in the motor hierarchy (Neuroscience Online).

Image 1:
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http://scienceblogs.com/purepedantry/wp-content/blogs.dir/454/files/2012/04/i-05b9f20e65a3464654059e6249f4e016-basal-ganglia.jpg


Inputs/Outputs:
The basal ganglia receives input from cortex, the thalamus, and the substantia nigra, and its projections go mainly to the Thalamus. To go into more detail, the afferent inputs arise from the entire cerebral cortex and from the intralaminar nuclei of the thalamus, projecting mostly to the striatum of the basal ganglia. There is a fair amount of segregation as to which part of the striatum receives which input. From the cortex, the frontal lobe projects predominantly to the caudate head and the putamen; the parietal and occipital lobes project to the caudate body; and the temporal lobe projects to the caudate tail. The primary motor cortex and the primary somatosensory cortex project mainly to the putamen, while premotor cortex and supplementary motor areas project to the caudate head (Neuroscience Online). The two main efferent nuclei of the Basal Ganglia are the SNr and the GPi. These two receive inputs from other sections of the Basal Ganglia and give GABAergic inhibitory input to the Thalamus. There are many connections between the various nuclei of the basal ganglia as well. These connections give rise to the two main pathways it uses to control movement.

Image 2:
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https://kin450-neurophysiology.wikispaces.com/file/view/basal_ganglia1.jpg/393621000/basal_ganglia1.jpg


Pathways:
Within the Basal Ganglia there are two main pathways in which inputs travel. These pathways are simply called the Direct and Indirect pathways. These work in tandem to control the movements we make and to ensure that a motor task is carried out correctly and efficiently. The Direct Pathway ensures that a desired movement is achieved and performed. It all starts when we have a movement we want to carry out. To begin, neurons from the Cortex release glutamate (an excitatory neurotransmitter) to the neurons in the striatum. These neurons, now excited, inhibit the GPi by releasing GABA (an inhibitory neurotransmitter) and Substance P. With the GPi now inhibited, there is less inhibition on the thalamus, enabling it to communicate with the nuclei in the cortex, thereby enabling us to carry out a given movement. While the direct pathway enables the performance of a desired movement, the indirect pathway has a different role in ensuring that any extra unwanted movements are inhibited, so that the only movement being performed is the one we want to perform. This starts again with the striatum. In the indirect pathway, the striatum, once excited by the cortex, also releases GABA (as well as enkephalin) to the GPe, inhibiting its activity. Normally the GPe has an inhibitory connection to the STN, (as seen in image 3), so when the GPe is inhibited, there is less inhibition on the STN, causing it the release Glutamate to the GPi. This excitation of the GPi increases its inhibition of the Thalamus, effectively stopping it from communicating the unwanted movement with the Cortex. In addition to these two main pathways, there is a third that ensures their harmonious interworking. This third pathway is called the Nigrostriatal Pathway, and it is a dopaminergic pathway between the SNc and the striatum. The Direct pathway striatal neurons have D1 dopamine receptors. These receptors depolarize the cell in response to dopamine. Indirect pathway striatal neurons have D2 dopamine receptors. These receptors hyperpolarize the cell in response to dopamine. The nigrostriatal pathway works to excite the direct pathway while simultaneously inhibiting the indirect pathway. Because of this, excitation of the nigrostriatal pathway has the net effect of exciting the cortex by two routes; first, by exciting the direct pathway (which itself has a net excitatory effect on cortex) and inhibiting the indirect pathway (thereby disinhibiting the net inhibitory effect of the indirect pathway on cortex). Normally, these systems provide a fine balance in which dopamine activity modulates glutamate-induced excitation in the basal ganglia and cortex. (Andre).

Image 3:
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https://kin450-neurophysiology.wikispaces.com/file/view/Untitled.gif/393620976/Untitled.gif


History of HD:

Huntington's Disease was first discovered by George Huntington (whom it is named for) in 1872. Before this, the first noted observation of the symptoms was during the epidemic of "dancing mania" in 1374 (Zuccato). Later, Paracelcus (who lived during the 15th/16th centuries), was the first to give these abnormal movements a name, and he termed it "chorea" (Zuccato). There had been numerous cases throughout history documenting some of the symptoms, most notably chorea as this is the most prevalent symptom, but it wasn't until Huntington started looking into it that a more detailed view of the disease came to be. He had first noticed it through a group of patients from certain families that he, his father, and his grandfather had observed over several generations in East Hampton, New York. What they first observed was that there were three very important characteristics to this, until then, unknown affliction: (1) It was heritable, (2) Chorea was present, and (3) there was observed dementia as well. The trait of heredity was further confirmed when it was shown that almost all patients with the disease could be traced back to a few ancestors who had immigrated to the U.S years before. In one case in particular, there was a family whose line had been traced back 12 generations, and each was shown to have had traits consistent with the disease (Kandel 355-356). From there research and understanding of the disease only began to increase.

Neuropathology:

Huntington's disease is an autosomal dominant neurodegenerative disorder, meaning that it is passed down from generation to generation. It is characterized by choreiform movements, cognitive decline, and personality disturbance. It is passed down from generation to generation. The disease is caused by a CAG (glutamine) trinucleotide expansion in exon 1 of the huntingtin (htt) gene, which is located at chromosome 4 (Reiner). This mutation causes the degeneration of striatal neurons. the important part, however, is that the specific neurons damaged are striatal neurons along the indirect pathway. Because of this specific degeneration, the indirect pathway loses its influence on the thalamus. The loss of striatal neuron input to the GPe means that the GPe is no longer inhibited, which leads to inhibition of the STN. This inhibition causes there to be less glutamate release by the STN to the GPi, which in turn stops inhibiting the Thalamus. With this decrease in inhibition, there will be an overcommunication of the Thalamus with the cortex. This will lead to random and often inappropriate firing of the Thalamus, leading to many unwanted movements being performed that the patient will have no control over. (Neuroscience Online). HD cases into five different severity grades (0–4). Grade 0 appears indistinguishable from normal brains after gross examination. However, 30–40% neuronal loss can be detected in the head of the caudate nucleus upon histological examination. Grade 1 shows atrophy, neuronal loss, and astrogliosis in the tail and, in some cases, the body of the caudate nucleus. Grades 2 and 3 are characterized by a progressive severe gross striatal atrophy. Grade 4 includes the most severe HD cases with atrophy of the striatum and up to 95% neuronal loss (Zuccato). Again, the main manifestation of this disease is seen thorugh symptoms such as chorea, although there are many other symptoms that are possible to observe including emotional changes, dementia, slurred speech, and a lack of coordination.

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Treatments:

As far as treatments go, there is no cure for Huntington's disease. The disease will run its course, and as of now not much can be done about that. As of now, prognosis is one of the most important facets of treatment, because if one's parents or a direct relation has the disease, there is a chance that it may show up in that person as well. Also, because the disease normally does not show itself until middle age, sometimes people won't even know until it hits them. To this day, as people continue to research treatments for this disease, there still continues to be a need for symptomatic agents, and no agent has been proven to change the course (Frank). Treatments that we have now include treatments to ease the symptoms and help people learn learn to live with their disease. Many treatments involve drugs to be taken in order to treat symptoms. For example, Tetrabenazine is prescribed for treating Huntington’s-associated chorea, and is the only drug approved by the U.S. Food and Drug Administration specifically for use against HD. Antipsychotic drugs also may help with chorea and may also be used to help control hallucinations, delusions, and violent outbursts. Drugs may be prescribed to treat depression and anxiety as well. In addition, there are drugs that can be used to lessen dopamine release, thus lowering the activity of the cortex. For now, these are the most effective treatments for Huntington's disease, but new research is being done every day to attempt to find new ways of combatting it.

Summary:

HD is an inherited disease that affects people's ability to control movement. It affects the striatal neurons in the basal ganglia, cutting off the effects of the inhibitory pathway, leading to overactivity in the cortex, manifested in random, unwanted movements being performed without control from the patient. It progresses slowly over 10-15 years, ultimately leading to the death of the patient. There is still no cure for HD, but research is being done constantly to determine new ways with which to combat it in a way where we can try to, at the very least, slow the proression; at best, stop or reverse its effects. Until then, drugs can be used to lessen the physical symptoms and to treat the emotional symptoms as well, helping patients with the disease in their learning to adapt to living with it.


Further Reading
  • Nicholls JG, Fuchs PA, Martin AR, Martin RA, Wallace BG. From neuron to brain: Cellular approach to the function of the nervous system. 4th ed. Sunderland, MA: Sinauer Associates Inc.,U.S.; February 8, 2001.
  • Siegel GJ, Agranoff BW, Albers WR, Molinoff PB. Basic neurochemistry: Molecular, cellular, and medical aspects. 4th ed. New York: Raven Press; December 1, 1989.



Glossary of Terms:
Basal Ganglia: A group of structures linked to the thalamus in the base of the brain. Involved in the coordination of movement.
Caudate: The upper of the two gray nuclei of the corpus striatum in the cerebrum of the brain
Putamen: A round structure located at the base of the forebrain. Forms the striatum along with the caudate.
Globus Pallidus: A sub-cortical sturcture of the brain. Major component of the basal ganglia.
Substantia Nigra: Structure located in the midbrain. Plays an imporntat role in reward and movement.
Subthalamic Nucleus: A small, lens-shpaed nucleus in the brain where it is, from a fucntional point of view, part of the basal ganglia.
Cortex: The outer layer of the cerebrum. Composed of folded gray matter.
Thalamus: Either of two masses of gray matter lying between the cerebral hemispheres on either side of the third ventricle, relaying sensory information and acting as a center for pain perception.
Dopamine: An important chemical of the catecholamine family. In the brain, acts as a neurotransmitter. Plays a role in reward-motivated behavior.
Glutamate: Most abundant neurotransmitter in the body. Has an excitatory effect.
GABA: The chief inhibitory neurotransmitter in the nervous system.


Quiz:

I. Multiple Choice

1. Which of the following is NOT a possible symptom of HD?
a. Chorea
b. Trouble Swallowing
c. Dementia
d. Lack of coordination
e. These are all symptoms of HD

2. Around what age do symptoms for HD normally appear?
a. Noticeable at birth
b. 5-8
c. 30-50
d. None of the above
e. All of the above

3. Neurons from which structure are damaged in HD?
a. Primary Motor Cortex
b. Striatum
c. Thalamus
d. SNr
e. STN

4. Which regions does the striatum NOT receive input from?
a. Thalamus
b. Cortex
c. STN
d. Substantia Nigra
e. It receives input from all of these

5. Which neurotransmitter is released by the striatum to the GPi in the direct pathway?
a. GABA
b. Glutamate
c. Dopamine
d. Glutamine
e. Enkephalin

II. T/F
1. HD affects the direct pathway of the basal ganglia
2. The GPi normally has an inhibitory effect on the STN
3. Glutamate release from the cortex excites the striatum

III. Short Answer
1. Briefly describe the direct/indirect pathways of the basal ganglia
2. What happens in the basal ganglia as a result of the presence of HD?
3. Describe the treatment options afforded to people suffering with HD


References:

Journal Articles:
  • André VM, Cepeda C, Levine MS. Dopamine and Glutamate in Huntington’s Disease: A Balancing Act. CNS neuroscience & therapeutics. 2010;16(3):163-178. doi:10.1111/j.1755-5949.2010.00134.x.
  • Frank S. Treatment of Huntington’s Disease. Neurotherapeutics. 2014;11(1):153-160. doi:10.1007/s13311-013-0244-z.
  • Long J, Langbehn, Tabrizi S, et al. Validation of a prognostic index for Huntington’s disease. Movement disorders : official journal of the Movement Disorder Society. November 2016. https://www.ncbi.nlm.nih.gov/pubmed/27892614. Accessed November 30, 2016.
  • Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB. Differential loss of striatal projection neurons in Huntington disease. Proceedings of the National Academy of Sciences. 1988;85(15):5733–5737. http://www.pnas.org/content/85/15/5733.short. Accessed November 30, 2016.
  • Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential Therapeutical targets in Huntington’s disease. American Physiological Society. 2010;90(3):905–981. doi:10.1152/physrev.00041.2009. http://physrev.physiology.org/content/90/3/905.full.pdf+html. Accessed December 1, 2016.


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Image/Video Sources:

Quiz Answers:

I. MC
1. e
2. c
3. b
4. c
5. a
II. T/F
1. F
2. F
3. T