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9.5: Impact of Disease States and Neural Damage on Motor Control

  • Page ID
    116201
  • This page is a draft and under active development. Please forward any questions, comments, and/or feedback to the ASCCC OERI (oeri@asccc.org).

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    Learning Objectives
    • Describe the general symptoms of the major motor disorders of the nervous system
    • Categorize motor disorders based on their underlying neuroantomical or neurochemical mechanisms
    • Explain some of the treatments for some of the major disorders

    Motor Disorders and Their Neuroanatomical/Neurochemical Mechanisms

    Given that motor control involves such an extensive collection of structures and circuits throughout both the central and peripheral nervous systems, it is amazing how well and, often effortlessly, these systems function every second of our lives. However, the comprehensive nature of motor systems also allows for multiple avenues of potential damage or degeneration which can lead to profound consequences in one's ability to move or even survive.

    Damage or disease can occur in regions of the forebrain associated with Upper Motor Neurons in the cortex or the basal ganglia, and/or Lower Motor Neuron regions of the medulla or spinal cord. These anatomical distinctions can be critical in the diagnosis and treatment of specific motor disorders.

    Multiple Sclerosis

    Multiple sclerosis (MS) is a progressive motor disease that attacks neurons in both the central and peripheral nervous systems. The main mode of this attack is the destruction of the myelin coating around the axon which ultimately will slow down action potential conductance. As axons are demyelinated, inflammatory patches called lesions are formed. As the disease progresses, the myelin-producing oligodendrocytes and, ultimately, the axons themselves are destroyed. There is compelling evidence that the destruction is caused by selective activation of the cellular immune system and inflammatory molecules, thus supporting the idea that MS is an autoimmune disease.

    Findings from MRI studies indicate that an individual with MS may have abnormalities around sites like the lateral ventricle, optic nerve, brainstem, spinal cord, cerebellum and other areas (see Figure \(\PageIndex{1}\) below).

    MRI images showing white hyperintensities in different areas of the brain of an individual experiencing symptoms of multiple sclerosis.
    Figure \(\PageIndex{1}\): MRI images showing white hyperintensities in different areas of the brain of an individual experiencing symptoms of multiple sclerosis. (A) A coronal slice showing a lesion in peripheral white matter. (B) A sagittal slice showing large periventricular lesions. (C) An axial slice showing both periventricular and peripheral white matter lesions. (D) A case where severe atrophy caused midline false positives to not be removed, as they were further from midline than expected. Image from National Library of Medicine.  License: CC BY 4.0.
     

    Symptoms of MS

    Multiple sclerosis also presents itself differently in acute and chronic phases. During the acute phase, the condition is associated with intermittent symptoms, whereas the chronic phase is associated with progressive forms of the disease and increased severity of symptoms.

    Most people experience their first symptoms of MS between the ages of 20 and 40 with initial blurred or double vision, red-green color distortion, or even blindness in one eye. Most MS patients also experience muscle weakness in their extremities and difficulty with coordination and balance. These symptoms may be severe enough to impair walking or even standing. In the worst cases, MS can produce partial or complete paralysis.

    Most people with MS also exhibit paresthesias, transitory abnormal sensory feelings such as numbness, prickling, or "pins and needles" sensations. Some may also experience pain. Speech impediments, tremors, and dizziness are other frequent complaints. Occasionally, people with MS have hearing loss. Approximately half of all people with MS experience cognitive impairments such as difficulties with concentration, attention, memory, and poor judgment, but such symptoms are usually mild and are frequently overlooked. Depression is another common feature of MS.

    Potential Causes of MS

    Currently, there is no known cause for MS although many different hypotheses have been put forward. Surprisingly, there are no known associative genes that have been implicated in causing MS, and scientists believe there might be a complex interaction between genes and environmental factors that produce demyelination. The most common theories about the cause(s) of multiple sclerosis include:

    1. Viral infection resulting in an autoimmune reaction
    2. Genetic factors: inherited predisposition possibly through the immune system, although a mutation in a gene has not been discovered
    3. Environmental factor(s) which might work with genetics such as low vitamin D levels or smoking.

    Although this is a well-characterized disorder, we still don’t know much about its causes.

    Parkinson’s Disease

    Parkinson's disease (PD) belongs to a group of conditions called motor system disorders, which cause unintended or uncontrollable movements of the body. The precise cause of PD is unknown, but some cases are hereditary while others are thought to occur from a combination of genetics and environmental factors that trigger the disease. In PD, brain cells become damaged or die in the substantia nigra which produces the neurotransmitter dopamine--a chemical needed to produce smooth, purposeful movement.

    Symptoms of PD

    The four primary symptoms of PD are:

    • tremor--shaking that has a characteristic rhythmic back and forth motion
    • rigidity--muscle stiffness or a resistance to movement, where muscles remain constantly tense and contracted
    • bradykinesia--slowing of spontaneous and automatic movement that can make it difficult to perform simple tasks or rapidly perform routine movements
    • postural instability--impaired balance and changes in posture that can increase the risk of falls.

    Other symptoms may include difficulty swallowing, chewing, or speaking; emotional changes; urinary problems or constipation; dementia or other cognitive problems; fatigue; and problems sleeping.

    PD usually affects people around the age of 70 years but can occur earlier. PD affects men more than women. Currently there are no specific tests that diagnose sporadic PD.

    Potential causes of PD

    The current model for most neurodegenerative conditions is that neurons die via apoptosis, a programmed form of cell death. Although this type of cell death occurs during normal development, neurodegenerative diseases such as Parkinson’s Disease and Alzheimer’s Disease are believed to use apoptotic pathways. This suggests that there is a component protein that is aberrantly folded to produce apoptosis. This has very important clinical implications as turning on or turning off specific genes/proteins is a method to stop or possibly reverse neurodegeneration.

    Most cases of this disorder appear to be sporadic (i.e. non-genetic in origin) although a very few cases seem to have a genetic origin. Parkinson’s Disease is most often associated with the loss of “pigmented” nuclei in the brain and typically involves the loss of a group of neurons found in the substantia nigra (see Figure \(\PageIndex{2}\)). The substantia nigra neurons are dopaminergic and are pigmented because they contain the protein melanin.

    Loss of the pigmented dopaminergic neurons within the Substantia Nigra of individuals with Parkinson’s Disease.
    Figure \(\PageIndex{2}\): Loss of the pigmented dopaminergic neurons within the Substantia Nigra of individuals with Parkinson’s Disease.

    Loss of the substantia nigra cells affects the processing and execution of voluntary movement in individuals with Parkinson’s Disease. Similar to MS, once diagnosed, the symptoms become continuous and progressive – i.e. the symptoms worsen over time. Again, there are many similarities with MS, and there is no known cure for Parkinson’s Disease. The disease remains idiopathic although there are some known causes of Parkinson’s Disease including loss of movement following cerebral atherosclerosis, viral encephalitis, and as the result of side effects from drugs such as phenothiazides and reserpine.

    Alpha-synuclein is a naturally occurring protein within neurons. Mutations in the PARK1 and PARK4 genes which normally encodes for alpha-synuclein have been associated with Parkinson’s Disease. As such, many animal models of Parkinson’s Disease look for the production of the fibrillary form of alpha-synuclein as it misfolds and then accumulates within the substantia nigral neurons known as Lewy bodies (see Figure \(\PageIndex{3}\)). The misfolding and accumulation of alpha-synuclein has been hypothesized to be the reason that neurons undergo apoptosis, although the exact mechanism for how this occurs remains to be elucidated.

    Lewy bodies and alpha-synuclein – hallmark features of Parkinson’s Disease
    Misfolding and subsequent accumulation of alpha-synuclein.
     
    Figure \(\PageIndex{3}\):Misfolding and subsequent accumulation of alpha-synuclein.

    Treatment of PD

    At present, there is no cure for PD, but a variety of medications provide dramatic relief from the symptoms. Usually, affected individuals are given levodopa (l-dopa) combined with carbidopa. Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. Although levodopa helps most people with PD, not everyone responds equally to the drug. The symptoms of bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all.

    There are a large variety of other drugs that affect the dopamine system and treat symptoms of PD. Some mimic the role of dopamine in the brain, causing the nerve cells to react as they would to dopamine, while others prolong the effects of levodopa by preventing the breakdown of dopamine in the brain. In addition to these dopaminergic drugs, anticholinergic drugs have been shown to help control symptoms of tremor and rigidity.

    In some cases, surgery may be appropriate if the disease doesn't respond to drugs. One option is deep brain stimulation (DBS), in which electrodes are implanted into the brain and connected to a small electrical device called a pulse generator to painlessly stimulate the brain to block signals that cause many of the motor symptoms of PD. DBS is generally appropriate for people with levodopa-responsive PD who have developed dyskinesias or other disabling "off" symptoms despite drug therapy. However, DBS does not stop PD from progressing and some problems may gradually return.

    Huntingtons Disease

    Huntington's disease (HD) is an inherited disorder which causes the death of select populations of neurons. The affected neurons are located in various areas of the brain, including those in the basal ganglia which help to control voluntary (intentional) movement.

    Symptoms of HD

    Symptoms of the disease, which gets progressively worse, include uncontrolled movements (chorea), abnormal body postures, and changes in behavior, emotion, judgment, and cognition. People with HD also develop impaired coordination, slurred speech, and difficulty feeding and swallowing.

    HD typically begins between ages 30 and 50. An earlier onset form called juvenile HD occurs under age 20. Its symptoms differ somewhat from adult onset HD and include rigidity, slowness, difficulty at school, rapid involuntary muscle jerks called myoclonus, and seizures. More than 30,000 Americans have HD.

    Huntington’s disease causes disability that gets worse over time. Currently no treatment is available to slow, stop, or reverse the course of HD. People with HD usually die within 10 to 30 years following symptom onset, most commonly from infections (most often pneumonia) and injuries related to falls.

    Causes of HD

    Huntington’s disease is caused by a mutation in the gene for a protein called huntingtin. The mutated gene includes an increased number of repeats of a select portion of it's normal genetic code. How these increased repeats lead to the disorder is still unclear. Each child of a parent with HD has a 50-50 chance of inheriting the mutated gene. A child who does not inherit the HD gene will not develop the disease and cannot pass it to subsequent generations. Since this is an autosomal dominant trait, a person who inherits the HD gene will eventually develop the disease. HD is generally diagnosed based on a genetic test, medical history, brain imaging, and neurological and laboratory tests.

    Treatment of HD

    There is no treatment that can stop or reverse the course of HD. The drugs, tetrabenazine and deuterabenazine can treat chorea associated with HD. Antipsychotic drugs may ease chorea and help to control hallucinations, delusions, and violent outbursts. Drugs may be prescribed to treat depression and anxiety. Side effects of drugs used to treat the symptoms of HD may include fatigue, sedation, decreased concentration, restlessness, or hyperexcitability, and should only be used when symptoms create problems for the individual.

    Amyotrophic lateral sclerosis (Formally known as Lou Gehrig's Disease)

    Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that primarily affects the neurons responsible for controlling voluntary muscle movement. Voluntary muscles produce movements like chewing, walking, and talking. The disease is progressive, meaning the symptoms get worse over time. Currently, there is no cure for ALS and no effective treatment to halt or reverse the progression of the disease.

    ALS belongs to a wider group of disorders known as motor neuron diseases, which are caused by gradual deterioration (degeneration) and death of motor neurons. As motor neurons degenerate, they stop sending messages to the muscles and the muscles gradually weaken, start to twitch, and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements.

    Early symptoms of ALS usually include muscle weakness or stiffness. Gradually all voluntary muscles are affected, and individuals lose their strength and the ability to speak, eat, move, and even breathe. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear. However, about 10 percent of people with ALS survive for 10 or more years.

    Because people with ALS usually can perform higher mental processes such as reasoning, remembering, understanding, and problem solving, they are aware of their progressive loss of function and may become anxious and depressed. A small percentage of individuals may experience problems with language or decision-making, and there is growing evidence that some may even develop a form of dementia over time.

    Possible Causes of ALS

    The cause of ALS is not known, and scientists do not yet know why ALS strikes some people and not others.

    Motor neuronal hyperexcitability potentially contributes to motor neuron death in ALS. Many previous studies support this hypothesis, including clinical trials of riluzole, a glutamate antagonist that delays ALS progression (Miller et al., 2012).

    In addition to the possible role of motor neuron dysfunction, scientific evidence suggests that both genetics and environment play a role in motor neuron degeneration and the development of ALS.

    In 1993, scientists supported by the National Institute of Neurological Disorders and Stroke (NINDS) discovered that mutations in the SOD1 gene were associated with some cases of familial ALS. Since then, more than a dozen additional genetic mutations have been identified, many through NINDS-supported research.

    Research on certain gene mutations suggests that changes in the processing of RNA molecules may lead to ALS-related motor neuron degeneration. RNA molecules are involved with the production of molecules in the cell and with gene activity.

    Other gene mutations indicate there may be defects in protein recycling—a naturally occurring process in which malfunctioning proteins are broken down and used to build new working ones. Still others point to possible defects in the structure and shape of motor neurons, as well as increased susceptibility to environmental toxins.

    Researchers are studying the impact of environmental factors, such as exposure to toxic or infectious agents, viruses, physical trauma, diet, and behavioral and occupational factors. For example, exposure to toxins during warfare, or strenuous physical activity, are possible reasons for why some veterans and athletes may be at increased risk of developing ALS. Ongoing research may show that some factors are involved in the development or progression of the disease.

    Attributions:

    Selections of Parkinsons Disease and Multiple Sclerosis sections adapted from Neuroscience Canadian, 2nd EditionLicense: CC-BY 4.0.

    Amyotrophic Lateral Sclerosis section adapted from National Institute of Neurological Disorders and Stroke (NINDS)License: Public Domain: No Known Copyright

    Miller RG, Mitchell JD, Moore DH. (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev., Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3.

    This page titled 9.5: Impact of Disease States and Neural Damage on Motor Control is shared under a mixed license and was authored, remixed, and/or curated by Multiple Authors (ASCCC Open Educational Resources Initiative (OERI)) .