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CHAPTER 12 Delving into Motor Systems Disorders 221
Toxin therapy is limited because toxins need to be injected, but their rapid and
potent eects make toxins promising for treating spasticity and pain.
Looking At Damage to Motor Neurons
Damage to motor neurons can occur through diseases, strokes, or injuries that
lead to either paralysis or spasticity. Damage can occur to lower alpha motor neu-
rons or upper motor neurons originating in the motor cortex or brainstem (refer
to Chapters7 and8). Damage to sensory neurons can also lead to paralysis by
eliminating feedback to the spinal cord and brain about limb position and force.
The following addresses some of the common disorders.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease) is a debili-
tating adult-onset motor neuron disease characterized by loss of motor neurons
in the central nervous system (CNS). Symptoms include limb weakness, and dif-
culty swallowing, speaking, and breathing. ALS can run in families with familial
ALS accounting for 10 to 20 percent of all cases; the other 80 to 90 percent of cases
are called sporadic ALS.
Both familial and sporadic ALS involve genetic components. Mutations in the
C9ORF72gene are present in 25 to 50 percent of familial ALS and 7 to 10 percent
of sporadic ALS.The protein encoded by this gene regulates autophagy, the deg-
radation of cellular components, and vesicular tracking. Variants in the super-
oxide dismutase (SOD) gene are present in 10 to 20 percent of familial ALS and
1 to 2 percent of sporadic ALS.SOD catalyzes the breakdown of the superoxide
radical (O2-), which is an important antioxidant function. Other genes identied
in both familial and sporadic ALS are TARDBP, FUS, and TBK1.
Environmental and lifestyle factors contribute to ALS risk and include exposure to
chemicals, trauma, military service, smoking, and exercise. FDA-approved drugs
to treat ALS include riluzole, which inhibits glutamate release. Excess glutamate
can cause glutamate excitotoxicity, where prolonged excitation of neurons leads
to increased calcium, oxidative stress, membrane damage, and cell death.
ALS is the most common of the motor neuron diseases. Other motor neuron dis-
eases include primary lateral sclerosis, progressive muscular atrophy, progressive
bulbar palsy, and pseudobulbar palsy.
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222 PART 2 Controlling Muscles, Movement, and Survival
Multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disorder that leads to destruction of mye-
lin membrane sheaths that surround axons in the brain and spinal cord.
Myelin is provided by oligodendrocytes in the CNS and Schwann cells in the periph-
eral nervous system. Myelination enables rapid and reliable conduction of action
potentials along axons. MS is characterized by the presence of autoantibodies to
myelin proteins in CNS axons.
MS occurs more frequently in women than in men, and its onset is typically in
early adulthood. In the US, MS occurs in about 1in every 1,000 people. Symptoms
begin with limb weakness, and vision and coordination problems. Symptoms can
occur either intermittently in attacks that mitigate somewhat afterward or in a
progressive form. In late stages of MS, degeneration of axons and motor neurons
and cognitive dysfunction can occur.
Studies have implicated the Epstein-Barr virus (EBV), the virus that causes infec-
tious mononucleosis, in triggering MS in genetically susceptible individuals. One
study examined data records from millions of military personnel and discovered
that high levels of specic antibodies to EBV were associated with a 36-fold
increased risk for developing MS.
Treatments for MS include immunosuppressant drugs and biologics including
interferon beta and monoclonal antibodies (mAbs).
Viral infections
Some viruses can cross the blood-brain barrier, and others gain access via the
choroid plexus or olfactory or motor neurons. Synaptic vesicles fuse with the pre-
synaptic membrane to release neurotransmitters. This is balanced by endocytosis,
where the plasma membrane pinches inside small vesicles called endocytic vesicles.
Polio and rabies viruses enter motor neuron axon terminals using endocytosis.
Polio
Polio (poliomyelitis) is an infectious viral disease. After entering motor neurons,
the virus destroys them, causing muscle weakness and paralysis. Physical therapy
can stimulate the remaining motor neurons to sprout new axon terminals to
recover some function. The loss of motor neurons during aging is particularly
disabling in individuals with polio because each motor neuron that dies was doing
a larger share of controlling muscle contraction.
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CHAPTER 12 Delving into Motor Systems Disorders 223
Rabies
Rabies is a viral infection that aects the nervous system, typically leading to
brain damage and death within days. Transmitted by an infected animal bite,
rabies virus gets to the brain through peripheral nerve axons. Rabies virus is typi-
cally fatal unless the infected animal or person receives a vaccine.
Examining Disorders of Movement
Movement disorders can involve dysfunction in the control of upper motor neu-
rons in diseases such as Parkinson’s, Huntington’s, and Creutzfeldt-Jakob dis-
ease, as we discuss all three here. Movement can also be signicantly aected by
damage to motor neurons and their control systems following strokes and injuries
to the brain and spinal cord.
Parkinson’s disease
Parkinson’s disease (PD) is named after Dr. James Parkinson who published a
description of it in 1817. PD involves the loss of dopaminergic neurons in the sub-
stantia nigra. Early symptoms of PD include rigidity, tremor, slow movement, and
diculty initiating movement. In later stages of PD, cognitive compromise and
dementia may occur. The onset of PD typically occurs after age 50. The incidence
of PD is about 1.5 cases per 1,000 individuals. Men are twice as likely to develop PD
than women, but women often experience more severe symptoms.
Age, gender, and some insecticides (such as rotenone) are associated with
increased risk of PD, while cigarette smoking is associated with reduced risk.
Research also implicates metabolic processes in the gastrointestinal tract in the
development of PD.PD-like symptoms can be produced by MPTP, a side product
of illegal opioid drug synthesis. MPTP is metabolized to MPP
+
, which destroys
dopaminergic neurons.
PD is characterized by inclusions called Lewy bodies in dopaminergic neurons.
These contain aggregates of the protein alpha-synuclein with other proteins
including ubiquitin and Tau. Alpha synuclein may function in the movement of
vesicles in neurons. Mutations or variants in the alpha synuclein gene SNCA, and
the genes PINK1, LRRK2, GBA, PARK2, PARK7, and PRKN have been identied in PD.
Dopamine is released by neurons in the substantia nigra and amplies activity in
the basal ganglia direct pathway to increase activation of motor pathways that will
be executed. In the indirect pathway, dopamine enhances inhibition of nonse-
lected pathways. Decreased dopamine release in Parkinson’s disease reduces the
ability to control movement via both direct and indirect pathways.
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Oral dopamine can’t cross the blood-brain barrier. A metabolic precursor in
dopamine synthesis, L-DOPA (levodopa), crosses this barrier. When taken with
carbidopa, which prevents levodopa metabolism, it can relieve symptoms for a
period of years. As PD progresses, dopaminergic neurons become depleted so
supplying dopamine precursors is no longer eective.
Other drugs used for PD include dopamine-receptor agonists and inhibitors of
monoamine oxidase. Deep brain stimulation (DBS) is used successfully for treat-
ing uncontrolled movement in PD.DBS involves implanting electrodes in the brain
and a control generator in the chest, which work to provide stimulation to nuclei
in the basal ganglia.
In later stages, PD can cause mood problems including depression, anxiety, and
poor impulse control. These can lead to medication overuse that causes other
psychiatric disturbances and motor complications. Some PD symptoms may be
related to treatments that increase dopamine levels rather than primarily from PD
itself. Risks of dementia increase in the later stages of PD.
Huntington’s disease
Huntington’s disease (HD) is a neurodegenerative genetic disorder that initially
aects neurons in the striatum, producing an eect that is in some ways the
opposite of PD.In the United States, the incidence of HD is about 1 case per 12,000
people. The major symptom of HD is involuntary writhing movements called
chorea, often with atypical facial expression and diculties swallowing and speak-
ing. Late stage HD symptoms include loss of muscle coordination, cognitive
impairment, and psychiatric problems.
HD is caused by an autosomal dominant abnormality in the huntingtin gene, with
expansion in the gene that adds many glutamine repeats. These repeats cause neu-
rodegeneration. The function of the huntingtin protein is unknown, but it interacts
with many other proteins. Treatment of HD includes the use of monoamine-
depleting drugs to treat chorea and antipsychotic drugs that may ease chorea,
hallucinations, and delusions.
Geneticists can now determine if a person has the genetic abnormality that will
develop into HD in childhood. Ethical debates about testing exist because the
disease has no cure, though HD symptoms can be partly relieved through phar-
macological treatment.
Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease with
onset occurring around age 60. Early symptoms include cognitive decline and
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CHAPTER 12 Delving into Motor Systems Disorders 225
poor coordination, and later symptoms include dementia. CJD is caused by mis-
folding of the prion protein, encoded by the PRNP gene. In CJD the misfolded prion
proteins are toxic and induce the refolding of normal prion protein. The toxic
prion proteins causes neuronal cell death.
About 85 percent of cases of CJD are sporadic, while about 7.5 percent of cases
involve inherited mutations in the PRNP gene. Rare exposure to tissue from an
infected person may result in infection. Most agents used to destroy infectious
pathogens aren’t eective against toxic prions. No specic treatment for CJD has
been developed.
Neuropathies: motor-sensory dysfunction
Peripheral neuropathy is a dysfunction of the peripheral nerves, either motor neu-
rons that innervate the muscles from the spinal cord or brainstem, or sensory
neurons that convey touch, temperature, pain, and position information to the
spinal cord or brain. Neuropathies may also involve autonomic innervation of
organs and blood vessels. Peripheral neuropathies may be caused by systemic ill-
ness, infection, or trauma to the nerve.
Symptoms of neuropathy depend on which motor or sensory nerves are aected.
Motor neuropathies can produce muscle weakness, spasms, and loss of balance or
coordination. Sensory neuropathy can manifest as insensitivity to pain, numb-
ness, tingling, or burning sensations. Autonomic neuropathy is associated with
involuntary function problems such as high or low heart rate and blood pressure
and bladder and sexual dysfunction.
Peripheral neuropathies are often classied in the following two ways:
»
Mononeuropathy (only one nerve involved): Common mononeuropathies
resulting from nerve compression include carpal tunnel syndrome.
Mononeuritis multiplex involves several noncontiguous nerves, often as a
result of diabetes mellitus.
»
Polyneuropathy (many nerves involved): This term is often synonymous
with peripheral neuropathy. Its most frequent cause is diabetic neuropathy.
Other causes include Lyme disease, toxins, vitamin deciencies, and side
eects of some prescribed drugs.
Peripheral nerve dysfunction is called neuritis, a term for nerve inammation.
Neuritis can develop from physical or chemical injury, radiation, overuse, or from
infections such as herpes simplex virus, shingles, and Lyme disease.
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Bell’s palsy
Bell’s palsy, also called acute peripheral facial palsy, is a mononeuropathy that causes
sudden weakness in the muscles on one side of the face. The causes of Bell’s palsy
are unknown, but it involves inammation of the facial nerve that controls the
muscles on one side of the face. More than likely a viral infection triggers it.
Symptoms typically begin to improve within a few weeks, with complete recovery
after about six months.
Paralysis can result from sensory peripheral neuropathy. Aerent sensory nerves
convey information about limb position to the spine and brain (refer to Chapter7).
Diseases such as diabetes can cause peripheral neuropathies that aect sensory
nerves. In these cases, as in strokes, patients refuse to use the limbs for which
they did not receive sensory feedback, even though the motor systems are intact.
Therapies such as constraint-induced (CI) therapy are often successful in allow-
ing patients to regain function of sensory deaerented limbs— by restraining the
non-aected limb.
Focusing on Strokes and Injuries
Strokes are vascular incidents that have neurological eects via a cascade of
events that lead to neuronal cell death. Here we describe the types, causes, eects,
and treatments of strokes.
Experiencing a stroke
A stroke (also called a cerebrovascular accident) involves the loss of brain function
from a disturbance in the brain’s blood supply. Strokes are the second leading
cause of death worldwide. Stroke can cause permanent neurological damage and
death. Age, high blood pressure, diabetes, atherosclerosis, and atrial brillation
are risk factors for stroke.
The two major types of stroke are as follows:
»
Ischemic strokes: Ischemic strokes are caused by a lack of blood ow
produced by blockage, such as thrombosis (a blood clot), embolism (an
embolus or clot arriving from elsewhere), or systemic hypoperfusion (loss of
adequate blood supply, such as during shock). Strokes deprive brain tissue of
adequate oxygen and glucose for metabolism.
»
Hemorrhagic strokes: Hemorrhagic strokes involve bleeding in the brain,
which leads to ischemic eects and toxic alteration of the regulated
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CHAPTER 12 Delving into Motor Systems Disorders 227
concentrations of ions and other substances in the extracellular space.
Hemorrhagic strokes are often associated with the loss of consciousness
and vomiting due to increased intracranial pressure.
Stroke symptoms typically have a sudden onset, asymmetry in symptoms, and
depend on the area of the brain aected. A stroke on the left side of the brain will
aect the right side of the body and vice versa. Strokes on the left side of the brain
often produce aphasia (speech diculties) along with right-side paresis or paral-
ysis. Visual eld defects are typically associated with occipital lobe damage, while
memory decits occur with strokes that aect the temporal lobe. Parietal lobe
stokes, particularly on the right side, produce left visual eld hemi-neglect. Fron-
tal lobe strokes impair cognitive function and produce confusion and incoherent
thinking.
Treating strokes
A physical exam and CT scan are typically used to determine the type of stroke. For
an ischemic stroke, if treatment can begin within three hours of symptom onset,
the main treatment istissue plasminogen activator(tPA), which breaks up the
blood clot blocking blood ow. A physician can deliver tPA directly within the
artery using an endovascular procedure. For a hemorrhagic stroke, surgery is used
to control the bleeding, reduce intracranial pressure, and repair damaged arteries.
Patients are subsequently prescribed drugs and therapies to treat the underlying
causes of the stroke.
Injuring the brain
Brain injuries can cause damage to brain tissue that produce eects and symp-
toms similar to strokes. Brain injury from external forces is typically called a trau-
matic brain injury (TBI). The most common causes of adult TBI are violence, injuries
from motorcycle, auto, and construction accidents, and sports. Worldwide, TBI is
a major cause of disability.
STROKE WITHOUT SYMPTOMS
The phenomenon called “silent strokes” has been recognized via neuroimaging such
as MRI.Patients lack outward symptoms and are typically unaware they’ve suered a
stroke. However, a silent stroke can still damage the brain since a sequence of silent
strokes eventually accumulates damage that crosses a threshold for neural dysfunction.
They also tend to precede major strokes.
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228 PART 2 Controlling Muscles, Movement, and Survival
Imaging techniques have enhanced the ability to detect brain injuries that weren’t
evident using early imaging modalities, including edema (swelling) and diuse
axonal injury to cortical white matter.
Brain areas that are particularly susceptible to injury include the orbitofrontal
cortex and anterior temporal lobes. Damage to the prefrontal cortex can compro-
mise decision making, social behavior, and emotional regulation. Damage to
motor control areas can produce hemiparesis (partial paralysis on one side), while
damage to the left side of the brain can produce aphasia.
Damage to the brain from physical force is also often accompanied by a hematoma
(bleeding into the brain), with similar eects as from hemorrhagic strokes. A
common symptom of TBI is unequal pupil size. Moderate or severe TBIs may pro-
duce persistent headaches, vomiting, convulsions, slurred speech, and aphasia,
among other symptoms.
Sports studies show that any brain injury that is associated with even momentary
loss of consciousness carries a signicant risk of brain damage. In healthy chil-
dren and young adults, the brain may compensate well for injuries, but eects
may accumulate past a threshold that exceeds the brain’s ability to compensate.
Repeatedly heading a soccer ball is statistically associated with neural loss, even
without concussion.
Severity of TBI is assessed by a CT scan and physical exam with the Glasgow Coma
Scale. Care for moderate to severe TBI ensures the patient has sucient oxygen
and blood supplies, stable blood pressure, and no further injury. Surgery can
remove blood clots and repair damaged skull fractures or blood vessels. Patients
with severe TBI may be placed in an induced coma. Medications for TBI include
antiseizure and anti-inammatory drugs. Individuals with severe TBI typically
require rehabilitation through physical, occupation, and cognitive therapies.
Injuring the spinal cord
Injury is the cause of most spinal cord dysfunction. Eects of the injury depend on
the extent of trauma and level of the spinal cord at which it occurs. The most com-
mon causes of these are motor vehicle accidents, falls, sports, and violence. More
than 80 percent of spinal cord injuries occur in men.
The eects of such injuries are death of neurons and glia within the spinal cord
segment, and transection, a tear within the cord that damages or severs sensory
and motor axons. Death of neurons at the level of the injury aects innervation of
skin and muscles at that segment. Transection of axon tracts at a segment also
interrupts sensory information transmitted from below that segment and motor
commands transmitted down through that segment.
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CHAPTER 12 Delving into Motor Systems Disorders 229
In severe spinal injury, termed complete, a person loses all sensory and motor
function below the injured area. Incomplete injuries have less total eect in the
same regions. In sacral sparing, some sensation remains in sacral skin areas, even
though sensation is lost in thoracic and lumbar skin areas. In sacral sparing,
axons may resist compression injury through protection by the lamination of
sacral axons within the spinal cord.
Thoracic spinal-level injuries typically result in paraplegia of the legs, but hand,
arm, neck, and breathing functions are retained. Lumbosacral injuries decrease
control of the legs, urinary system, and anus. Sacral spinal segment injuries com-
promise sexual function.
Severe injuries to high cervical segments can produce quadriplegia and loss of
respiratory control. Lower cervical injuries or incomplete high injuries may allow
some respiratory control and limited hand and arm use. Cervical injuries are also
associated with poor autonomic regulation.
A persistent mystery about mammalian axonal injuries is that axons in the periph-
eral nervous system axons, which are myelinated by Schwann cells, can regener-
ate. In contrast, axons in the CNS, which are myelinated by oligodendrocytes,
typically can’t regenerate.
Experimental treatments for spinal cord injuries involve transplanting Schwann
or stem cells into damaged spinal cord, or suppression of inammation or excito-
toxicity that oer hope for rehabilitation. For CNS injuries there are also bioengi-
neering prosthetic approaches.
Substituting Machines: Neuroprostheses
One current goal of neuroprosthesis is to restore motor function via electrical
stimulation to overcome the loss of damaged neural components. Some studies
have made progress in the development of neuroprosthesis to improve muscle
strength and restore limb movement following spinal cord injury. Consider the
following ways that motor neuroprostheses is being used:
»
Functional electrical stimulation (FES): FES electrode microarrays are used
to stimulate the eerent axons of motor neurons innervating specic muscles
to produce movement. FES can be used to reduce impairment or in rehabilita-
tion to build up muscle strength.
»
Spinal cord stimulation (SES): Controlled electrode stimulation leads to
activation of motor neuron pools at specic spinal cord segments, which send
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230 PART 2 Controlling Muscles, Movement, and Survival
action potentials out to target muscles. Studies in 2018 demonstrated that
combining SES with intensive rehabilitation enabled independent overground
walking in six subjects with spinal cord injuries.
»
Brain computer interface (BCI): Brain-controlled neuroprosthesis, BCI
involves implanting recording electrodes in primary motor cortex. Activity in
the motor cortex is relayed through wires to lower motor neurons or muscles
to control movement. Activity in the motor cortex can be recorded by EEG,
electrocorticographic (ECoG) grids, or by intracranial electrodes.
•
In recent studies with subjects with spinal cord injuries, the BCI motor
cortex signals were transmitted past the spinal cord transection and
directly to the spinal cord segment (as in SES) to control motor neuron
output and muscle contraction. This has been successful in restoring upper
limb movements and walking in a few individuals with spinal cord injury.
•
In another type of BCI called BrainGate2, research participants with
tetraplegia had microelectrode arrays implanted in their motor cortex.
Participants used this intracortical BCI to control a commercial tablet
computer to communicate with others via email, browse the web, play
music using an app, and shop online.
»
Neuroprostheses for speech: Development of speech neuroprosthesis for
paralyses patients that can’t speak is underway. It works by detecting speech-
related brain signals that control the vocal cords. This requires the patient to
wear an electrode array to capture and record activity from the speech motor
cortex. In initial studies, up to 18 words per minute were translated with
93 percent accuracy.
An additional outcome of neuroprosthesis is its potential benecial eect
to the motor system. In many incomplete spinal injuries, intact sensory and
motor axons may remain, but their activity is below the threshold to allow
the person to move their limb. Articial limb movements may induce neuro-
plasticity, similar to what occurs in rehabilitation. Neuroplasticity can induce
remaining pathways to restore enough activity to permit movement without
the articial aid. Without the neuroprosthesis-producing activity and move-
ment, the entire motor neuron system can degenerate from lack of activity.
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