Alcohol+&+Cerebellum

__**Overview **__
The cerebellum influences movements primarily by modifying the activity patterns of the upper motor neurons. Its primary function is to detect the difference, or "motor error," between an intended movement and the actual movement (6). One factor that can disrupt this function is the introduction of alcohol into the blood. When alcohol is consumed at a rate faster than it can be metabolized by the body, the function of most major brain structures is altered (4). The effect of alcohol on the cerebellum presents primarily as a loss of coordinated movement and balance along with an ataxic gait (1,4). It has been proposed that one of the main mechanisms by which alcohol affects the cerebellum is via increased GABAergic inhibition of cerebellar granule cells resulting from increased output of the neurotransmitter GABA from the Golgi cells (8, 9). Chronic alcohol consumption can leave long term effects on the cerebellum. These effects are mainly secondary to cerebellar degeneration, which can result in permanent gait ataxia and memory loss (4, 5). Further research on the effect of alcohol during the development of the cerebellum can be seen in children who have fetal alcohol syndrome. Consumption during pregnancy has been shown to lead to reduced size of the cerebellum causing poor coordination of movement.

__**Functions of the Cerebellum: **__

 * 1) **//Maintenance of balance and posture://** The is important for making postural adjustments in order to maintain balance (2).
 * 2) //**Coordination of voluntary movements:**// coordinates the timing and force of the different muscles groups used during limb or body movement (2).
 * 3) **//Motor Learning://** role in adapting and fine-tuning motor programs to make accurate movements through a trial-and- error process (2).
 * 4) //**Cognitive functions:**// involved in certain cognitive functions such as language (2).

__**Structure of the Cerebellum: **__
__Cerebellar cortex__: tissue that encase the deep nuclei and contain almost all of the neurons in the cerebellum (2).

//**Output from cerebellum****:**// Cerebellar deep nuclei: sole output for the cerebellum
 * __Fastigial nucleus__: receives input from the vermis and vestibular and projects to the vestibular nuclei and reticular formation (2).[[image:kin450-neurophysiology/Picture 4.png align="right" caption="Figure 2. (6)"]]
 * __Interposed nuclei__: receives input from the intermediate zone and projects to the red nucleus (2).
 * __Dentate nucleus__: receives input from the lateral hemisphere and projects to the contralateral red nucleus and ventrolateral thalamic nucleus (2).
 * __Vestibular nuclei:__ receive input from the and vestibular labyrinth and project to motor nuclei (2).

//**Cerebellar peduncles:**// fiber bundles that carry the input and output of the cerebellum.
 * __Inferior__: contains fibers from the medulla, as well as efferents to the vestibular nuclei (2).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Middle__: contains afferents form the pontine nuclei (2).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Superior__: contains afferent from the cerebellar nuclei, as well as some from the spinocerebellar tract.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;"> //**<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Subdivisions: **// > and is involved in vestibular reflexes and postural maintenance (2).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Vestibulocerebellum: comprises the flocculonodular lobe and connects with the lateral vestibular nuclei
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Spinocerebellum: comprises the vermis and the intermediate zone as well as the fastigial and interposed nuclei. Involved in the integration of sensory input with motor commands to produce adaptive motor coordination (2).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Cerebrocerebellum: comprises the lateral hemispheres and the denate nuclei. Involved in the planning and timing of movements and cognitive functions (2).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">//**Input into cerebellum:**// afferent information enters via mossy fibers or climbing fibers and act on cerebellar cortical Purkinje cells (3).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;"> //**<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Neural Circuitry: **// <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Input from the cerebral cortex to the Purkinje cells is indirect. Neurons in the pontine nuclei receive a massive projection from the cerebral cortex and relay the information to the contralateral cerebellar cortex (6). The axons from the pontine nuclei are the mossy fibers, which synapse on neurons in the deep cerebellar nuclei and on granule cells in the granule cell layer of the cerebellar cortex (6).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Granule cells then give rise to parallel fibers that ascend to the molecular layer of the cerebellar cortex. They bifurcate in the molecular layer to form branches that relay information via excitatory synapses onto the dendritic spines of Purkinje cells (6).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">The Purkinje cells also receive direct modulatory input on their dendritic shafts from the climbing fibers that arise form the inferior olive. Each Purkinje cells receives numerous synaptic contacts from a single climbing fiber. They provide a “training” signal that modulates the effectiveness of the mossy-parallel fiber connection with the Purkinje cells (6).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Purkinje cells then project to the deep cerebellar nuclei and since they are GABAergic, the output of the cerebellar cortex as a whole is inhibitory. Neurons in the deep cerebellar nuclei receive excitatory input from the collaterals of the mossy and climbing fibers. The inhibitory projections of Purkinje cells serve to shape the discharge patterns that deep nuclei neurons generate in response to this direct mossy and climbing fiber input (Figure 4) (6).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">The deep excitatory loop consists of the mossy and climbing fibers collateral drives that activate the neurons in the deep cerebellar nuclei. This is where input signals converge on the output stage of cerebellar processing (6).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">The cortical inhibitory loop involve the Purkinje cells which modify the activity of the deep cerebellar nuclei by a descending inhibitory input driven by both mossy and climbing fibers as well. The Purkinje cells integrate these principal inputs by responding to an excitatory drive and inhibitory output (Figure 4) (6).

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Other cells such as the Golgi, stellate, and basket all control the flow of information through the cerebellar cortex. The Golgi cells form an inhibitory feedback circuit that control the gain of the granule cell input to the Purkinje cells, whereas the basket cells provide lateral inhibition that may focus the spatial distribution of Purkinje cell activity (6).

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<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">The first signs of intoxication in non-alcoholic persons begin when blood levels reach approximately 60 mg/dL, and extreme signs of intoxication occur at levels of 120 to 150 mg/dL. In alcoholics, signs of intoxication may not present until blood levels are as high as 150 mg/dL.4 Signs of intoxication include varying degrees of euphoria, exhilaration, excitement, loss of restraint, irregular behavior, slurred speech, incoordination of movement, gait ataxia, irritability and combativeness, and the effect alcohol has on the cerebellum is responsible for many of these symptoms (4). At higher blood levels, brain functions deteriorate and other signs, such as lethargy, stupor and coma, suggest that high levels produce inhibition of brain activity (4). =====

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Order in which alcohol affects the brain centers is:
 * 1) <span style="font-family: 'Times New Roman',Times,serif;">Cerebral Cortex: cortex processes information from your senses, does your "thought" processing and consciousness (in combination with a structure called the basal ganglia), initiates most voluntary muscle movements and influences lower-order brain centers (1).
 * 2) <span style="font-family: 'Times New Roman',Times,serif;">Depresses the behavioral inhibitory centers: more talkative, self-confident and less socially inhibited (1).
 * 3) <span style="font-family: 'Times New Roman',Times,serif;">Slows down the processing of information from the senses (1).
 * 4) <span style="font-family: 'Times New Roman',Times,serif;">Inhibits thought processes so there is clouded judgment (1)
 * 5) <span style="font-family: 'Times New Roman',Times,serif;">Limbic system: exaggerated states of emotion and memory loss (1).
 * 6) <span style="font-family: 'Times New Roman',Times,serif;">Cerebellum: movements become uncoordinated and loss of balance (1).
 * 7) <span style="font-family: 'Times New Roman',Times,serif;">Hypothalamus and pituitary gland: depresses nerve centers in the hypothalamus so there is an increase in sexual behavior, and also inhibits the pituitary secretion of anti-diuretic hormone causing lack of absorption of water increasing production of urine (1).
 * 8) <span style="font-family: 'Times New Roman',Times,serif;">Medulla (brain stem): effect on the reticular formation causes sleepiness and potentially unconsciousness. Conditions can become fatal when effects of alcohol reach this level of the brain (1).

__**<span style="font-family: 'Times New Roman',Times,serif;">GABA Inhibition **__
<span style="font-family: 'Times New Roman',Times,serif;">Recent studies have shown that alcohol impairs motor coordination by enhancing the tonic inhibition of granule cells, mediated by a specific subtype of extrasynaptic GABA A receptor (8). The excitability of the granule cells is partly modulated by the GABAergic output of the Golgi cells. Granule cells receive this GABAergic input in the form of both phasic and tonic currents that are mediated by synaptic and extrasynaptic receptors, respectively (9). This inhibitory input is important for filtering mossy fiber input on the granule cells, which profoundly modulates cerebellar information and storage capacity (9). The specific <span style="font-family: 'Times New Roman',Times,serif;"> <span style="font-family: 'Times New Roman',Times,serif;"> combination of α-6 and δ subunits in a GABA A receptor is only found in cerebellar granule cells. These extrasynaptic GABA receptors generate a tonic inhibitory potential that exerts strong control over granule cell firing patterns (8). Studies have demonstrated that alcohol indirectly enhances GABAergic transmission to the cerebellar granule cells via an increase in GABA release from the Golgi cells (9). Concentrations of alcohol in the blood high enough to produce behavioral changes have been shown to enhance the tonic inhibition of cerebellar granule cells mediated by the extrasynaptic GABA receptors (8). The greatest effect of this increased GABA inhibition is impaired motor coordination (8). Different polymorphisms of these GABA receptors are one factor that can increase or decrease a person’s sensitivity to alcohol, and persons with low sensitivity are more likely to develop alcoholism (8, 9).

__**<span style="font-family: 'Times New Roman',Times,serif;">Fetal Alcohol Syndrome **__
<span style="font-family: 'Times New Roman',Times,serif;">This is a condition that results from alcohol exposure during pregnancy that leads to physical deformities, mental retardation, learning disorders, vision difficulties and behavioral problems (13). Early alcohol exposure can cause gross reduction in brain size and alter a number of brain regions. The cerebellum is one area that is vulnerable to alcohol. Figure 5 shows a view through the vermis of the cerebellum for a control rat (A) and a rat exposed to alcohol (B) during brain growth (12). Alcohol treatment during the brain growth significantly reduces granule cell number and Purkinje cell number in the cerebellum (12). There is also effects on the glutamate receptors and GABA receptors involved within cortical loops of the cerebellum (14). Figure 6 to the left shows the obvious difference in the size of the brain of a fetal alcohol affected child. <span style="font-family: 'Times New Roman',Times,serif;">The brain on the left being the affected one is much smaller than the normal brain on the right (10). Also looking at Figure 7 to the left, a study done on FAS children shows again the change in brain size. The cerebellum looks to be about 82% of the control brain.

<span style="font-family: 'Times New Roman',Times,serif;">

<span style="font-family: 'Times New Roman',Times,serif;">Higher doses of alcohol the greater the likelihood the child will exhibit fetal alcohol effects. Binge drinking is found to be more damaging to the fetus producing high blood alcohol levels compared to chronic alcohol exposure that produces lower blood alcohol levels. Developmental timing of alcohol exposure may influence the outcome. The facial features appear to be related to alcohol exposure during the first trimester. The brain undergoes a very prolonged developmental course and therefore may be susceptible to fetal alcohol effects throughout gestation.

__<span style="font-family: 'Times New Roman',Times,serif;">**Long Term Effects** __
<span style="font-family: 'Times New Roman',Times,serif;">One of the primary long-term effects of chronic alcoholism is cerebellar degeneration. A prominent symptom of cerebellar degeneration is a slowly progressive gait ataxia characterized by a wide-based stance and an unsteady, short-stepped, lurching gait pattern. MRI studies indicate that long-term alcohol consumption results in atrophy of the superior cerebellar vermis. Pathology studies demonstrate the loss of cerebellar and Purkinje cells, as well as other neurons, primarily in the superior vermis as well as the vestibular nuclei (4). It has been shown that Purkinje cells in the vermis can be reduced on average by 43%, <span style="font-family: 'Times New Roman',Times,serif;"> and this degeneration is correlated with the presence of ataxia and unsteadiness (5). Some studies have also associated the loss of Purkinje cells in the lateral lobes of the cerebellum with the presentation of “mental signs” such as memory loss. This may be related to recent speculation that the cerebellum plays an important role in the organization of higher cerebral functions (5). Currently, there are no known treatments that can reverse gait ataxia.4 Other studies have shown that the volume of white matter in the cerebellum is reduced in alcoholics, which can lead to disturbances in the cerebellum’s executive function as well as the cerebellar-cerebral loops (5). The mechanism for this loss of cerebellar white matter is not fully understood, but it appears to be related to changes in both myelination and axonal integrity (5).

__**<span style="font-family: 'Times New Roman',Times,serif;">Wernicke’s Encephalopathy and Korsakoff Psychosis Syndrome **__
<span style="font-family: 'Times New Roman',Times,serif;">WKS is a long-term side effect associated with alcoholism which affects the cerebellum. People with chronic alcoholism can obtain as high as 50% of their daily caloric intake from alcohol, resulting in serious nutritional deficiencies (4). WKS results from a deficiency in thiamine (vitamin B1), which is common in many alcoholics (7). Neuropathological findings indicate that this deficiency primarily affects the gray matter regions of the cerebellum, particularly the Purkinje and granule cells of the anterior-superior vermis, as well as other regions such as the thalamus, pons and medulla (4).This disorder is characterized by a horizontal and vertical nystagmus, paralysis of the external rectus muscles of the eyes, gait ataxia and persistent learning and memory problems (4, 7).

__**<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">Test Your Knowledge **__

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">1. What structure of the brain is last to respond to a high level of alcohol?
 * 1) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Cerebellum
 * 2) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Hypothalmus
 * 3) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Brainstem
 * 4) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Medulla

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">2. T / F : The neurotransmitter GABA has an excitatory effect on granule cells.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">3. T / F: Mossy fibers originate from the inferior olive and synapse directly onto granule cells and the deep cerebellar nuclei.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">4. Which subdivision of the cerebellar is involved in the planning and timing of movement?
 * 1) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Vestibulocerebellum
 * 2) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Spinocerebellum
 * 3) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Cerebrocerebellum
 * 4) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Flocculocerebellum

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">5. The deficiency of which vitamin is responsible for the cerebellar disturbances caused by WKS?
 * 1) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">B12
 * 2) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">A
 * 3) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">B1
 * 4) <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">K

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">6. T / F: High levels of alcohol due to binge drinking is not as damaging as chronic consumption.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Short Answer Questions

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">1. Describe the signs of gait ataxia.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">2. Describe the difference between mossy and climbing fibers and their involvement within the neural circuitry of the cerebellum.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">3. Describe three functions of the cerebellum.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">4. What produces the uncoordinated movement when alcohol is consumed by an individual?

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">//Answers:// 1) 4 2) F 3) F 4) 3 5) 3 6) F

__**<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">Glossary **__
<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Mossy fibers__: make excitatory projections onto the cerebellar nuclei and onto granule cells in the cerebellar cortex. <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Climbing fibers__: axons that originate in the inferior olive, ascend through the inferior cerebellar peduncle, and make terminal arborizations that invest the dendritic tree of Purkinje cells. <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Pontine nuclei__: receives input from the cerebellar cortex and sends their axons across the mid-line to the cerebellar cortex via the middle cerebellar peduncle. <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Ataxic gait__: wide-based stance and an unsteady, short-stepped, lurching gait pattern <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__GABA__: inhibitory neurotransmitter common in the brain and spinal cord, most commonly found in cerebellar Purkinje cells <span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">__Vermis__: is associated with bodily posture and locomotion. The vermis is included within the spinocerebellum and receives somatic sensory input from the head and proximal body parts via ascending spinal pathways.

__**<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">Recommended Links **__
<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px;">Example of ataxic gait:[]

__**<span style="font-family: 'Times New Roman',Times,serif; font-size: 16px;">References **__
<span style="font-family: 'Times New Roman',Times,serif;">1. Freudenrich, C. (2012). How the Body Responds to Alcohol. http://science.howstuffworks.com/alcohol6.htm

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<span style="font-family: 'Times New Roman',Times,serif;">4. Davis, L. E. et. al. (2005). Fundamentals of Neurologic Disease: Neurological Complications of Alcoholism. New York: Demos Medical Publishing. =====

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<span style="font-family: 'Times New Roman',Times,serif;">5. Harper, C. (2009). The Neuropathology of Alcohol-Related Brain Damage. Alcohol & Alcoholism, 44 (2). []. ===== <span style="font-family: 'Times New Roman',Times,serif;">6. Purves, D. (2008). Neuroscience. Sunderland: Sinauer Associates, INC. <span style="font-family: 'Times New Roman',Times,serif;">7. U.S. Department of Health and Human Services: NIAA. (2004). Alcohol’s Damaging Effects on the Brain. Rockville: NIAAA Publications. http://pubs.niaaa.nih.gov/publications/aa63/aa63.htm <span style="font-family: 'Times New Roman',Times,serif;">8. Hanchar, H.J. et. al. (2005). Alcohol-induced motor impairment caused by increased extrasynaptic GABA A Receptor Activity. Nature Neuroscience. 8(3). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854077/ <span style="font-family: 'Times New Roman',Times,serif;">9. Carta, M. et. al. (2004). Alcohol Enhances GABAergic Transmission to Cerebellar Granule Cells via an Increase in Golgi Cell Excitability. The Journal of Neuroscience. 24(15). []. <span style="font-family: 'Times New Roman',Times,serif;">10. Clarren, S. K. (1986). Neuropathology in fetal alcohol syndrome. In J. R. West (Ed.), Alcohol and Brain Development (pp. 158-166). New York: Oxford University Press. <span style="font-family: 'Times New Roman',Times,serif;">11. Mattson, S. N., Jernigan, T. L., & Riley, E. P. (1994a). MRI and prenatal alcohol exposure. Alcohol Health & Research World, 18(1), 49-52. <span style="font-family: 'Times New Roman',Times,serif;">12. West, J.R., Chen, W-J. A., & Pantazis, N.J. (1994) Fetal alcohol syndrome: The vulnerability of the developing brain and possible mechanisms of damage. Metabolic Brain Disease, 9, 291-322. <span style="font-family: 'Times New Roman',Times,serif;">13. CNN Health. (2011). Fetal alcohol syndrome. http://www.cnn.com/HEALTH/library/fetal-alcohol-syndrome/DS00184.html <span style="font-family: 'Times New Roman',Times,serif;">14. West, J.R., Chen, W-J. A., & Pantazis, N.J. (1994) Fetal alcohol syndrome: The vulnerability of the developing brain and possible mechanisms of damage. Metabolic Brain Disease, 9, 291-322.