The neuromuscular junction (NMJ), for most extremity and axial skeletal muscle fibers, with the exception of extraocular, middle ear, and some facial and pharyngeal muscles, is a “slave” synapse that ...is designed to activate the muscle fiber every time the nerve terminal is activated. The fidelity of the NMJ hinges upon the electrical depolarization produced by activation of acetylcholine receptors (AChRs), called the endplate potential (EPP), being larger than is needed to trigger an action potential (AP) in the skeletal muscle fiber. The safety factor (SF) is a measure of how much larger the EPP is than the depolarization needed to trigger an AP (EAP). The SF depends on the amount of transmitter released, AChR density, EAP, and the effectiveness of the EPP in stimulating the Na+ channels that trigger the AP. This study focuses on the postsynaptic factors that influence the SF and how the SF is altered in myasthenia gravis. Muscle Nerve, 2011
For neurorehabilitation to advance from art to science, it must become evidence-based. Historically, there has been a dearth of evidence from which to construct rehabilitation interventions that are ...properly framed, accurately targeted, and credibly measured. In many instances, evidence of treatment response has not been sufficiently robust to demonstrate a change in function that is clinically, statistically, and economically important. Research evidence of activity-dependent central nervous system (CNS) plasticity and the requisite motor learning principles can be used to construct an efficacious motor recovery intervention. Brain plasticity after stroke refers to the regeneration of brain neuronal structures and/or reorganization of the function of neurons. Not only can CNS structure and function change in response to injury, but also, the changes may be modified by "activity". For gait training or upper limb functional training for stroke survivors, the "activity" is motor behavior, including coordination and strengthening exercise and functional training that comprise motor learning. Critical principles of motor learning required for CNS activity-dependent plasticity include: close-to-normal movements, muscle activation driving practice of movement; focused attention, repetition of desired movements, and training specificity. The ultimate goal of rehabilitation is to restore function so that a satisfying quality of life can be experienced. Accurate measurement of dysfunction and its underlying impairments are critical to the development of accurately targeted interventions that are sufficiently robust to produce gains, not only in function, but also in quality of life. The Classification of Functioning, Disability, and Health Model (ICF) model of disablement, put forth by the World Health Organization, can provide not only some guidance in measurement level selection, but also can serve as a guide to incorporate function and quality of life enhancement as the ultimate goals of rehabilitation interventions. Based on the evidence and principles of activity-dependent plasticity and motor learning, we developed gait training and upper limb functional training protocols. Guided by the ICF model, we selected and developed measures with characteristics rendering them most likely to capture change in the targeted aspects of intervention, as well as measures having membership not only in the impairment, but also in the functional or life role participation levels contained in the ICF model. We measured response to innovative gait training using a knee flexion coordination measure, coefficient of coordination consistency (ACC) of relative hip/knee (H/K) movement across multiple steps (H/K ACC), and milestones of participation in life role activities. We measured response to upper limb functional training according to measures designed to quantify functional gains in response to treatment targeted at wrist/hand or shoulder elbow training (Arm Motor Ability Test for wrist/hand (AMAT W/H) or shoulder/elbow (AMAT S/E)). We found that there was a statistically significant advantage for adding FES-IM gait training to an otherwise comparable and comprehensive gait training, according to the following measures: H/K ACC, the measure of consistently executed hip/knee coordination during walking; a specific measure of isolated joint knee flexion coordination; and a measure of multiple coordinated gait components. Further, enhanced gains in gait component coordination were robust enough to result in achievement of milestones in participation in life role activities. In the upper limb functional training study, we found that robotics + motor learning (ROB ML; shoulder/elbow robotics practice plus motor learning) produced a statistically significant gain in AMAT S/E; whereas functional electrical stimulation + motor learning (FES ML) did not. We found that FES ML (wrist/hand FES plus motor learning) produced a statistically significant gain in AMAT W/H; whereas ROB ML did not. These results together, support the phenomenon of training specificity in that the most practiced joint movements improved in comparison to joint movements that were practiced at a lesser intensity and frequency. Both ROB ML and FES ML protocols addressed an array of impairments thought to underlie dysfunction. If we are willing to adhere to the ICF model, we accept the challenge that the goal of rehabilitation is life role participation, with functional improvement as in important intermediary step. The ICF model suggests that we intervene at multiple lower levels (e.g., pathology and impairment) in order to improve the higher levels of function and life role participation. The ICF model also suggests that we measure at each level. Not only can we then understand response to treatment at each level, but also, we can begin to understand relationships between levels (e.g., impairment and function). With the ICF model proffering the challenge of restoring life role participation, it then becomes important to design and test interventions that result in impairment gains sufficiently robust to be reflected in functional activities and further, in life role participation. Fortunately, CNS plasticity and associated motor learning principles can serve well as the basis for generating such interventions. These principles were useful in generating both efficacious gait training and efficacious upper limb functional training interventions. These principles led to the use of therapeutic agents (FES and robotics) so that close-to-normal movements could be practiced. These principles supported the use of specific therapeutic agents (BWSTT, FES, and robotics) so that sufficient movement repetition could be provided. These principles also supported incorporation of functional task practice and the demand of attention to task practice within the intervention. The ICF model provided the challenge to restore function and life role participation. The means to that end was provided by principles of CNS plasticity and motor learning.
The failure of axons in the central nervous system (CNS) to regenerate has been considered the main factor limiting recovery from spinal cord injury (SCI). Impressive gains in identification of ...growth‐inhibitory molecules in the CNS led to expectations that their neutralization would lead to functional regeneration. However, results of therapeutic approaches based on this assumption have been mixed. Recent data suggest that neurons differ in their ability to regenerate through similar extracellular environments, and moreover, they undergo a developmental loss of intrinsic regenerative ability. Factors mediating these intrinsic regenerative abilities include expression of (1) receptors for inhibitory molecules such as the myelin‐associated growth inhibitors and developmental guidance molecules, (2) surface molecules that permit axon adhesion to cells in the path of growth, (3) cytoskeletal proteins that mediate the mechanics of axon growth, and (4) molecules in the intracellular signaling cascades that mediate responses to chemoattractive and chemorepulsive cues. In contrast to axon development, regeneration might involve internal protrusive forces generated by microtubules, either through their own elongation or by transporting other cytoskeletal elements such as neurofilaments into the axon tip. Because of the complexity of the regenerative program, one approach will probably be insufficient to achieve functional restoration of neuronal circuits. Combination treatments will be increasingly prominent. SCI is a debilitating and costly condition that compromises pursuit of activities usually associated with an independent and productive lifestyle. This article discusses recent advances in neurorehabilitation that can improve the life quality of individuals with SCI.
Abstract Myasthenia gravis (MG), the most common of autoimmune myasthenic syndromes, is characterized by antibodies directed against the skeletal muscle acetylcholine receptors (AChRs). Endplate Na+ ...channels ensure the efficiency of neuromuscular transmission by reducing the threshold depolarization needed to trigger an action potential. Postsynaptic AChRs and voltage-gated Na+ channels are both lost from the neuromuscular junction in MG. This study examined the impact of postsynaptic voltage-gated Na+ channel loss on the safety factor for neuromuscular transmission. In intercostal nerve–muscle preparations from MG patients, we found that endplate AChR loss decreases the size of the endplate potential, and endplate Na+ channel loss increases the threshold depolarization needed to produce a muscle action potential. To evaluate whether AChR-specific antibody impairs the function of Na+ channels, we tested omohyoid nerve–muscle preparations from rats injected with monoclonal myasthenogenic IgG (passive transfer model of MG PTMG). The AChR antibody that produces PTMG did not alter the function of Na+ channels. We conclude that loss of endplate Na+ channels in MG is due to complement-mediated loss of endplate membrane rather than a direct effect of myasthenogenic antibodies on endplate Na+ channels.
This article reviews possible ways that traumatic brain injury (TBI) can induce migraine-type post-traumatic headaches (PTHs) in children, adults, civilians, and military personnel. Several cerebral ...alterations resulting from TBI can foster the development of PTH, including neuroinflammation that can activate neural systems associated with migraine. TBI can also compromise the intrinsic pain modulation system and this would increase the level of perceived pain associated with PTH. Depression and anxiety disorders, especially post-traumatic stress disorder (PTSD), are associated with TBI and these psychological conditions can directly intensify PTH. Additionally, depression and PTSD alter sleep and this will increase headache severity and foster the genesis of PTH. This article also reviews the anatomic loci of injury associated with TBI and notes the overlap between areas of injury associated with TBI and PTSD.
Background. Stroke survivors can exhibit abnormally elevated oxygen consumption during walking. Therapeutic interventions can improve gait deficits and oxygen consumption. A practical measure of ...oxygen cost is not available. This study tested the usefulness of an indirect index of oxygen cost, the Physiological Cost Index, and the ability of this index to discriminate between healthy adults and stroke survivors. Methods. The authors studied 17 subjects with stroke and 10 healthy control participants. Participants walked 10 minutes at their chosen comfortable speed on a treadmill. Oxygen consumption and heart rate data were collected. Primary measures were oxygen cost and the Physiological Cost Index. Secondary measures were age and gait speed. Results. The Physiological Cost Index and oxygen cost had a good to excellent correlation (r = .83, P < .001) for subjects with stroke. Both oxygen cost and the Physiological Cost Index were comparable in detecting a significantly abnormal elevation for stroke survivors versus healthy adults (P = .003 and .002, respectively). Age was not correlated with oxygen cost, the Physiological Cost Index, or chosen gait speed. A moderate correlation of gait speed to both the Physiological Cost Index and oxygen cost was found. Conclusions. The Physiological Cost Index can be used as a proxy index for the oxygen cost of walking in subjects after stroke because it is correlated with oxygen cost and is comparable to oxygen cost in its capability to discriminate between healthy controls and subjects with stroke. The Physiological Cost Index can be performed inexpensively on a routine basis in a clinical environment.
OBJECTIVETo assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for ...up to 18 months.
METHODSOf 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28–79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life.
RESULTSOver subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use.
CONCLUSIONThe Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used.
Departments of Neurology and Neuroscience, Case Western Reserve
University School of Medicine, Louis Stokes Cleveland Veterans
Affairs Medical Center, University Hospitals of Cleveland,
Cleveland, ...Ohio 44106
Patch-clamp
studies of mammalian skeletal muscle
Na + channels are commonly done at
subphysiological temperatures, usually room temperature. However, at
subphysiological temperatures, most
Na + channels are inactivated at
the cell resting potential. This study examined the effects of
temperature on fast and slow inactivation of
Na + channels to determine if
temperature changed the fraction of Na + channels that were excitable
at resting potential. The loose patch voltage clamp recorded
Na + currents
( I Na ) in vitro
at 19, 25, 31, and 37°C from the sarcolemma of rat type IIb
fast-twitch omohyoid skeletal muscle fibers. Temperature affected the
fraction of Na + channels that were
excitable at the resting potential. At 19°C, only 30% of channels
were excitable at the resting potential. In contrast, at 37°C, 93%
of Na + channels were excitable at
the resting potential. Temperature did not alter the resting potential
or the voltage dependencies of activation or fast inactivation.
I Na available at
the resting potential increased with temperature because the
steady-state voltage dependence of slow inactivation shifted in a
depolarizing direction with increasing temperature. The membrane
potential at which half of the Na +
channels were in the slow inactivated state was shifted by +16 mV at
37°C compared with 19°C. Consequently, the low availability of
excitable Na + channels at
subphysiological temperatures resulted from channels being in the slow,
inactivated state at the resting potential.
mammalian skeletal muscle; sodium channel; sodium current; fast
inactivation; slow inactivation; paramyotonia congenita; hyperkalemic
periodic paralysis
Post‐traumatic headache (PTH) is the most frequent symptom after traumatic brain injury (TBI). We review the epidemiology and characterization of PTH in military and civilian settings. PTH appears to ...be more likely to develop following mild TBI (concussion) compared with moderate or severe TBI. PTH often clinically resembles primary headache disorders, usually migraine. For migraine‐like PTH, individuals who had the most severe headache pain had the highest headache frequencies. Based on studies to date in both civilian and military settings, we recommend changes to the current definition of PTH. Anxiety disorders such as post‐traumatic stress disorder (PTSD) are frequently associated with TBI, especially in military populations and in combat settings. PTSD can complicate treatment of PTH as a comorbid condition of post‐concussion syndrome. PTH should not be treated as an isolated condition. Comorbid conditions such as PTSD and sleep disturbances also need to be treated. Double‐blind placebo‐controlled trials in PTH population are necessary to see whether similar phenotypes in the primary headache disorders and PTH will respond similarly to treatment. Until blinded treatment trials are completed, we suggest that, when possible, PTH be treated as one would treat the primary headache disorder(s) that the PTH most closely resembles.
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