Huntington's+Disease

The basal ganglia is a structure in the brain that contributes to the initiation of movement as well as the control of movement. Through intrinsic pathways it sends signals to the motor cortex to begin motor pathways. However, it controls movement by inhibiting certain muscles by suppressing output through the thalamus. Damage to the basal ganglia leads to a set of symptoms very different from symptoms that arise from damage to descending motor pathways. Two diseases are traced back to disrupted pathways within the basal ganglia, Parkinson’s disease and Huntington’s disease. Huntington’s disease is a hereditary disorder that leads to symptoms such as choreic movement (brief, purposeless and involuntary). The official cause is unknown, but it is hypothesized that the indirect pathway within the basal ganglia is disrupted because of a loss of striatal neurons. 




 * Functional Anatomy **

The striatum consists of the putamen and the caudate. The caudate has a head, body and tail. The Corpus striatum is the caudate, putamen and the globus pallidus. The globus pallidus has an internal segment (GPi) and an external segment (GPe). The Lenticular nucleus consists of the caudate and the globus pallidus. Other parts of the BG include the subthalamic nucleus and the substantia nigra which consists of two parts: pars compacta (SNc) and pars reticulata (SNr). The BG receives input from the cerebral cortex, the intralaminar nucleus of the thalamus and the substantia nigra compacta. Most of the information goes to the striatum. The projections are segregated based on the area it is sent from. The frontal lobe projects to the caudate head and putamen. The parietal and occipital lobe project to the caudate body. The temporal lobe projects to the caudate tail. The primary motor cortex and primary somatosensory cortex project to the putamen. The premotor cortex and supplementary motor cortex project to the caudate head. The output structures in the basal ganglia are the GPi and the SNr. The GPi sends output to the thalamus with neurotransmitter GABA. It sends sensorimotor information and neocortical information. The SNr also uses GABA, but projects to the superior colliculus; this projection relays information about eye movement.  
 * Input: **
 * Output: **
 * Pathways: **
 * Direct pathway disinhibits the thalamus to excite the cortex for initiation of movement.
 * o The direct pathway begins with an excitatory signal from the sensorimotor cortex to the striatum with the neurotransmitter Glutamate. The striatum sends inhibitory signals through GABA and substance P to the SNr and GPi which then inhibits the thalamus or disinhibits the thalamus so that it can send excitatory glutamate to the cortex to allow for the initiation of movement.
 * The indirect pathway inhibits the thalamus therefore inhibiting the cortex to suppress unwanted movement during action.
 * o The indirect pathway also begins with glutamate projections from the cortex to the striatum. Inhibitory GABA is then projected to the GPe. The GPe sends GABA inhibitory signals to the subthalamic nucleus which then sends excitatory glutamate to the SNr and GPi. When the output structures are excited they send inhibitory GABA to the thalamus, but unlike the direct pathway this further inhibits the thalamus instead of dis-inhibiting it. With the thalamus having a stronger inhibition it sends GABA to the cortex therefore preventing movement from occurring.
 * Nigrostriatal projection excites the direct pathway while simultaneously inhibiting the indirect pathway. The outcome of this dual action is excitation of the cortex. This projection occurs with the release of dopamine from the SNc that affects the striatal neuron receptors differently. Striatal neurons are medium spiny neurons. There are D1 and D2 receptors in the striatum that react to the dopamine neurotransmitter differently. Dopamine excites D1 receptors therefore exciting the direct pathway. Dopamine inhibits D2 receptors therefore inhibiting the indirect pathway. Both of these responses lead to excitation of the cortex.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Facts about Huntington’s disease
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">4-8/100,000 people are diagnosed with HD
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">25,000 cases in the US
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">25% of people with HD have late onset (symptoms after 50 years old)
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">No cure

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Huntington’s disease stems from a disruption in the balance of the direct and indirect pathways. Therefore actions such as random, involuntary movement occur; these are known as choreic movement. Choreiform movements can be continuous, but uncontrolled and occur specifically in the extremities and the face. They also occur without behavior significance. Other symptoms include: <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">The official cause of HD is unknown. However, there are observed effects that have been seen in patients with HD. There is atrophy of the striatum in the basal ganglia and loss of small and medium striatal neurons. Atrophy of the putamen is connected to the neurologic symptoms as well. There is white matter degeneration in the frontal cortex. There is a decrease in production of glial cells that inhibit neural transmission and lead to cortex and cerebellar changes. In the early and middle stages of the disease the neurons projecting from the striatum to the subthalamic nucleus are depleted therefore a reduction of GABA, Ach and metenkephalin. Therefore there are higher concentrations of dopamine and norepinephrine. The balance of inhibition and excitation response in the thalamus is disrupted because the balance of the indirect and direct pathway is off. There is excessive excitation of the thalamocortical pathway which leads to excessive abnormal involuntary movements. The neurons fire randomly and inappropriately which causes the motor cortex to execute motor programs with no conscious control. The later stages involve loss of direct inhibitory substance that causes more inhibition of the thalmocortical output. It also leads to rigidity and bradykinesia.
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Inability to maintain tongue protrusion or hand grip.
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Initially muscle tone is unaffected, but rigidity will become part of the disease.
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Eye movement abnormalities
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Saccadic movement is disrupted
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Decrease in velocity of movement
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Undershooting of a target
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Latency in initiation of movement
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Gaze fixation abnormalities
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Interrupted smooth pursuit of eyes
 * o <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Inability to suppress reflex saccades to a visual stimulus
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Pathology **

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">There is no cure for HD, but there is treatment to help symptoms and for people to learn to live with the disease. There is psychological therapy for both patients with HD and their families. It can be a difficult change to someone’s lifestyle; many support groups have been created for people to learn to accept the change. Medical treatment involves anticonvulsant drugs to relieve chorea symptoms. There are also antipsychotic agents that block dopamine neurotransmission to help reduce the amount of excitation to the motor cortex. Surgical procedures are also available, but not highly responsive. The internal globus pallidus can be removed or adrenal medullary grafts can be implanted into the brain.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">HD is a hereditary disease that stems from disruptions in the basal ganglia. There are two pathways within the basal ganglia: the direct and the indirect pathways. The direct pathway sends signals to the motor cortex to initiate movement and the indirect pathway sends inhibitory signals to the motor cortex to prevent movement at rest or control certain muscles during specific movements. When the striatal neurons are depleted within the basal ganglia both pathways are disrupted and the direct pathway is favorited leading to uncontrolled choreic movement. Although the official cause of HD is unknown, there have been many attributes of the basal ganglia that are reoccurring in patients. Through brain images it is clear that the striatal neurons deplete over time in HD patients. The biggest treatment is therapy (both physical and psychological) to learn to live with the changes in movement. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">i. Caudate body <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">ii. Putamen <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">iii. Caudate tail <span style="font-family: 'Times New Roman',serif; font-size: 8pt;">Answers: F, T, F, C, B, D, a-ii, b-i, c-iii
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Summary **
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Vocabulary **
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Ach- inhibitory neurotransmitter
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Atrophy- decrease in size or wasting away
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Bradykinesia- slow movement
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Caudate – anatomical structure of basal ganglia, specifically the striatum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Choreic movement- brief, involuntary movement
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Descending motor pathway- information is sent from higher brain centers through the spinal cord to the muscles
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Dopamine- neurotransmitter that is part of nigrostriatal pathway, sent from SNc to striatum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">GABA- inhibitory neurotransmitter
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Glial cells- cells that inhibit neural transmission and are found in the cortex and cerebellum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Globus pallidus- anatomical structure in the basal ganglia that consists of an internal and external component, it is also part of the Corpus striatum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Glutamate- an excitatory neurotransmitter
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Intrinsic pathways- projections of neurotransmitters within the basal ganglia
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Metenkephalin- inhibitory neurotransmitter
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Motor cortex- part of the cerebral cortex in brain where intentional movement in initiated, sends input to basal ganglia
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Nigrostriatal projections- when dopamine is released from SNc to striatum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Putamen- anatomical structure of basal ganglia and part of striatum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Saccadic movement- rapid movement of the eye
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Somatosensory cortex- part of cerebral cortex in brain that receives sensory information and sends input to the basal ganglia
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Striatal neurons- neurons in the striatum
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Striatum- anatomical structure of the basal ganglia composed of the putamen and caudate.
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Substance P- inhibitory neurotransmitter
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Substantia nigra- anatomical structure of the basal ganglia consisting of two parts, reticula which sends output from basal ganglia and compacta which sends input to the basal ganglia.
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Subthalamic nucleus- anatomical structure of basal ganglia important in the indirect pathway
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Superior colliculus- receives output information from the basal ganglia
 * <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Thalamus- receives output information from the basal ganglia and projects to the cortex.
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Quiz **
 * 1) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">1. The GPi and GPe send output from the basal ganglia. (T/F)
 * 2) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">2. GABA is the main inhibitory neurotransmitter. (T/F)
 * 3) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">3. The direct pathway initiates movement because the thalamus is excited. (T/F)
 * 4) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">4. Which of the following is not a symptom of HD?
 * 5) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">a. Choreic movement
 * 6) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">b. Random movement
 * 7) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">c. Tremors/shaking
 * 8) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">d. Disrupted saccadic movement
 * 9) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">5. What neurotransmitter has a higher concentration with HD?
 * 10) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">a. Ach
 * 11) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">b. Dopamine
 * 12) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">c. GABA
 * 13) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">d. Metakephaline
 * 14) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">6. With part of the basal ganglia is atrophied with HD?
 * 15) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">a. Subthalamic nucleus
 * 16) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">b. Substantia nigra
 * 17) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">c. Globus pallidus
 * 18) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">d. Striatum
 * 19) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">7. Match the following area of the brain to the part of the basal ganglia it innervates:
 * 20) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">a. Frontal lobe
 * 21) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">b. Parietal/occipital lobe
 * 22) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">c. Temporal lobe
 * 1) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">8. Draw the direct pathway of the basal ganglia.
 * 2) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">9. Draw the indirect pathway of the basal ganglia.
 * 3) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">10. Describe how the balance of the pathways is disrupted in patients who have HD.

<span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[] <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">: overview of the basal ganglia and brief description of HD <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Progenitor Cells and Adult Neurogenesis in Neurodegenerative Diseases and Injuries of the Basal Ganglia:// [|http://web.ebscohost.com/ehost/detail?vid=3&hid=122&sid=d3374831-c0a5-4b73a03f1ce3a5747b99%40sessionmgr114&bdata=JkF1dGhUeXBlPWlwJnNpdGU9ZWhvc3QtbGl2ZSZzY29wZT1zaXRl#db=aph&AN=24488333] //: the response of the forebrain to the degeneration of the striatum in the basal ganglia and how it affects HD. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Impact of **Huntington's** across the entire **disease** spectrum: the phases and stages of **disease** from the patient perspective.: // [|http://web.ebscohost.com/ehost/detail?vid=4&hid=122&sid=d3374831-c0a54b73a03f1ce3a5747b99%40sessionmgr114&bdata=JkF1dGhUeXBlPWlwJnNpdGU9ZWhvc3QtbGl2ZSZzY29wZT1zaXRl#db=aph&AN=64122733] :// An article based on interviews with HD patients and how the disease has effected everyday life physically, emotionally and socially. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Variation within the **Huntington's****Disease** Gene Influences Normal Brain Structure. //<span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[|http://web.ebscohost.com/ehost/detail?vid=4&hid=122&sid=d3374831-c0a5-4b73-a03f-1ce3a5747b99%40sessionmgr114&bdata=JkF1dGhUeXBlPWlwJnNpdGU9ZWhvc3QtbGl2ZSZzY29wZT1zaXRl#db=aph&AN=79911123] ////<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">. //<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> This article discusses how the genetic make-up of HD affects the brain structure and how it compares to normal brain structure. <span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[] <span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[] <span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[] <span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[] <span style="color: windowtext; font-family: 'Times New Roman',serif; font-size: 12pt;">[] Goodman, Catherine C., MBA, PT, Kenda S. Fuller, PT, NCS, and William G. Boissonnault, MS, PT. //Pathology Implications for the Physical Therapist//. Second Edition ed. Philadelphia: Saunders, 2003. Print. "Basal Ganglia (Section 3, Chapter 4) " //Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston//. The University of Texas Health Science Center at Houston (UTHealth)., 1997. Web. 03 Dec. 2012. <http://neuroscience.uth.tmc.edu/s3/chapter04.html>.
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Further Reading **
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Picture References ( ****<span style="font-family: 'Times New Roman',serif; font-size: 10pt;">in order that they appear ****<span style="font-family: 'Times New Roman',serif; font-size: 14pt;">) **
 * <span style="font-family: 'Times New Roman',serif; font-size: 14pt;">Book Sources **