Safety and feasibility of transcranial direct current stimulation stratified by corticospinal organization in children with hemiparesis.

Children with hemiparesis (CWH) due to stroke early in life face lifelong impairments in motor function. Transcranial direct current stimulation (tDCS) may be a safe and feasible adjuvant therapy to augment rehabilitation. Given the variability in outcomes following tDCS, tailored protocols of tDCS are required. We evaluated the safety, feasibility, and preliminary effects of a single session of targeted anodal tDCS based on individual corticospinal tract organization on corticospinal excitability. Fourteen CWH (age = 13.8 ± 3.63) were stratified into two corticospinal organization subgroups based on transcranial magnetic stimulation (TMS)-confirmed motor evoked potentials (MEP): ipsilesional MEP presence (MEPIL+) or absence (MEPIL-). Subgroups were randomized to real anodal or sham tDCS (1.5 mA, 20 min) applied to the ipsilesional (MEPIL + group) or contralesional (MEPIL- group) hemisphere combined with hand training. Safety was assessed with questionnaires and motor function evaluation, and corticospinal excitability was assessed at baseline and every 15 min for 1 h after tDCS. No serious adverse events occurred and anticipated minor side effects were reported and were self-limiting. Six of 14 participants had consistent ipsilesional MEPs (MEPIL + group). Paretic hand MEP amplitude increased in 5/8 participants who received real anodal tDCS to either the ipsilesional or contralesional hemisphere (+80% change). Application of tDCS based on individual corticospinal organization was safe and feasible with expected effects on excitability, indicating the potential for tailored tDCS protocols for CWH. Additional research involving expanded experimental designs is needed to confirm these effects and to determine if this approach can be translated into a clinically relevant intervention.

EMG breakthrough during cortical silent period in congenital hemiparesis: a descriptive case series.

BACKGROUND: The cortical silent period is a transient suppression of electromyographic activity after a transcranial magnetic stimulation pulse, attributed to spinal and supraspinal inhibitory mechanisms. Electromyographic breakthrough activity has been observed in healthy adults as a result of a spinal reflex response within the cortical silent period. OBJECTIVES: The objective of this case series is to report the ipsilesional and contralesional cortical silent period and the electromyographic breakthrough activity of 7 children with congenital hemiparesis. METHODS: TMS was delivered over the ipsilesional and contralesional primary motor cortices with resting motor threshold and cortical silent period measures recorded from first dorsal interosseous muscle. RESULTS: Seven children (13±2 years) were included. Ipsilesional and contralesional resting motor thresholds ranged from 49 to 80% and from 38 to 63% of maximum stimulator output, respectively. Ipsilesional (n=4) and contralesional (n=7) cortical silent period duration ranged from 49 to 206ms and 81 to 150ms, respectively. Electromyographic breakthrough activity was observed ipsilesionally in 3/4 (75%) and contralesionally in 3/7 (42.8%) participants. In the 3 children with ipsilesional breakthrough activity during the cortical silent period, all testing trials showed breakthrough. Contralesional breakthrough activity was observed in only one of the analyzable trials in each of those 3 participants. The mean peak amplitude of breakthrough activity ranged from 45 to 214µV (ipsilesional) and from 23 to 93µV (contralesional). CONCLUSION: Further research is warranted to understand the mechanisms and significance of electromyographic breakthrough activity within the cortical silent period in congenital hemiparesis. Understanding these mechanisms may lead to the design of tailored neuromodulation interventions for physical rehabilitation. TRIAL REGISTRATION: NCT02250092 (https://clinicaltrials.gov/ct2/show/NCT02250092).

Influence of Repetitive Transcranial Magnetic Stimulation on Human Neurochemistry and Functional Connectivity: A Pilot MRI/MRS Study at 7 T.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method commonly used in the disciplines of neuroscience, neurology, and neuropsychiatry to examine or modulate brain function. Low frequency rTMS (e.g., 1 Hz) is associated with a net suppression of cortical excitability, whereas higher frequencies (e.g., 5 Hz) purportedly increase excitability. Magnetic resonance spectroscopy (MRS) and resting-state functional MRI (rsfMRI) allow investigation of neurochemistry and functional connectivity, respectively, and can assess the influence of rTMS in these domains. This pilot study investigated the effects of rTMS on the primary motor cortex using pre and post MRS and rsfMRI assessments at 7 T. Seven right-handed males (age 27 ± 7 y.o.) underwent single-voxel MRS and rsfMRI before and about 30-min after rTMS was administered outside the scanner for 20-min over the primary motor cortex of the left (dominant) hemisphere. All participants received 1-Hz rTMS; one participant additionally received 5-Hz rTMS in a separate session. Concentrations of 17 neurochemicals were quantified in left and right motor cortices. Connectivity metrics included fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) of both motor cortices, strength of related brain networks, and inter-hemispheric connectivity. The group-analysis revealed few trends (i.e., uncorrected for multiple comparisons), including a mean increase in the concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) after the inhibitory rTMS protocol as compared to baseline in the stimulated (left) motor cortex (+8%, p = 0.043), along with a slight increase of total creatine (+2%, p = 0.018), and decrease of aspartate (-18%, p = 0.016). Additionally, GABA tended to decrease in the contralateral hemisphere (-6%, p = 0.033). No other changes of metabolite concentrations were found. Whereas functional connectivity outcomes did not exhibit trends of significant changes induced by rTMS, the percent changes of few connectivity metrics in both hemispheres were negatively correlated with GABA changes in the contralateral hemisphere. While studies in larger cohorts are needed to confirm these preliminary findings, our results indicate the safety and feasibility of detecting changes in key metabolites associated with neurotransmission after a single 1-Hz rTMS session, establishing the construct for future exploration of the neurochemical, and connectivity mechanisms of cortical responses to neuromodulation.

Determining Electrode Placement for Transcranial Direct Current Stimulation: A Comparison of EEG- Versus TMS-Guided Methods.

Transcranial direct current stimulation (tDCS) is increasingly researched as an adjuvant to motor rehabilitation for children with hemiparesis. The optimal method for the primary motor cortex (M1) somatotopic localization for tDCS electrode placement has not been established. The objective, therefore, was to determine the location of the M1 derived using the 10/20 electroencephalography (EEG) system and transcranial magnetic stimulation (TMS) in children with hemiparesis (CWH) and a comparison group of typically developing children (TDC). We hypothesized a difference in location for CWH but not for TDC. The 2 locations were evaluated in 47 children (21 CWH, 26 TDC). Distances between the locations were measured pending presence of a motor evoked potential. Distances between the EEG and TMS locations that exceeded the 2.5 cm × 2.5 cm rubber electrode area are reported in percentages [95% confidence interval] in CWH-nonlesioned hemisphere was 68.8% [41.3-89.0], lesioned: 85.7% [57.2-98.2]; TDC-dominant hemisphere 73.9% [51.6-89.8], nondominant: 82.6% [61.2-95.0]. Distances that exceeded the 3 × 5 cm electrode sponge area in CWH-nonlesioned was 25.0% [7.3-52.4], lesioned was 28.6% [8.4-58.1]; TDC-dominant was 52.2% [30.6-73.2], nondominant was 43.5 [23.2-65.5]). Distances that exceeded the 5 × 7 cm electrode sponge area in CWH-nonlesioned was 18.8% [4.0-45.6] and lesioned was 21.4% [4.7-50.8]; TDC-dominant was 21.7% [7.5-43.7] and nondominant was 26.1% [10.2-48.4]. Individual variability in brain somatotopic organization may influence surface scalp localization of underlying M1 in children regardless of neurologic impairment. Findings suggest further investigation of optimal tDCS electrode placement. EEG and TMS methods reveal variability in localizing M1 in children regardless of stroke diagnosis. This study was registered on clinicaltrials.gov NCT02015338.

Case report of vasovagal syncope associated with single pulse transcranial magnetic stimulation in a healthy adult participant.

BACKGROUND: Non-invasive brain stimulation-related seizures or syncopal events are rare. However, we report on a syncopal event in a healthy female during a transcranial magnetic stimulation single-pulse testing session. CASE PRESENTATION: A 47-year-old healthy female presented for a transcranial magnetic stimulation session involving single-pulse assessment of cortical excitability. During the session, the participant appeared to have a brief event involving fainting and myoclonic jerks of the upper extremities. Orthostatic assessment was performed after the event and physician evaluation determined that this was a vasovagal syncopal event. The ethical aspects of this neurophysiology testing protocol were reviewed by the University of Minnesota Institutional Review Board (IRB), and formal IRB approval was deemed unnecessary for single-pulse assessment of healthy control participants not directly involved in a research study. Informed consent was obtained by the participant, including review of potential adverse events. CONCLUSION: Although rare and rarely reported, vasovagal syncopal events surrounding non-invasive brain stimulation do occur. Thorough pre-screening should incorporate assessment of history of syncope and a plan for risk mitigation if such an event should occur. A complete assessment of the impact of stimulation on the autonomic nervous system is unknown. As such studies expand into patients with myriad neurologic diagnoses, further studies on this effect, in both healthy control and patient populations, are warranted. Such knowledge could contribute to identification of the optimal study participant, and improvements in techniques of stimulation administration.

American Association of Neuromuscular & Electrodiagnostic Medicine evidenced-based review: use of surface electromyography in the diagnosis and study of neuromuscular disorders.

Surface electromyography (sEMG) measures myoelectrical signals recorded from sensors placed on the skin surface. The non-invasive nature of sEMG makes it a potentially useful technology for studying diseases of muscle and nerve. Reviews published by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN), covering 1964-1994 and 1952-1998, respectively, concluded that sEMG adds no clinical utility over conventional needle EMG (nEMG) for the diagnosis of neuromuscular disease. The AANEM sEMG task force reevaluated the diagnostic utility and added value of this technology for the study of neuromuscular disease based on a contemporary review of relevant literature published between January 1994 and February 2006. The present review concludes that sEMG may be useful to detect the presence of neuromuscular disease (level C rating, class III data), but there are insufficient data to support its utility for distinguishing between neuropathic and myopathic conditions or for the diagnosis of specific neuromuscular diseases. sEMG may be useful for additional study of fatigue associated with post-poliomyelitis syndrome and electromechanical function in myotonic dystrophy (level C rating, class III data).

Drug therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of approximately 5 to 7 cases/100,000 population. Epidemiologic studies have identified some potential risk factors for developing ALS, including a high-fat, low-fiber diet; cigarette smoking; slimness and athleticism; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified. Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.

Axonal degeneration in the Trembler-j mouse demonstrated by stimulated single-fiber electromyography.

The Trembler-j (Tr-j) mouse is a naturally occurring mutant with a point mutation in the peripheral myelin protein-22 gene causing severe peripheral nerve demyelination. It is a genetically homologous murine model for Charcot-Marie-Tooth disease type 1A (CMT 1A). Our prior pilot studies using stimulated single-fiber needle electromyograpy (SSFEMG) showed increased jitter in 60-day-old Tr-j mice compared to age-matched, wildtype animals. The aim of this study was to better elucidate the etiology of increased jitter in Tr-j mice and test the following hypotheses: (1) the increased jitter in Tr-j mice is due to turnover of endplates secondary to axonal degeneration with reinnervation and not to conduction block secondary to demyelination of motor nerve axons; and (2) aging Tr-j mice demonstrate increased jitter and fiber density compared with younger mutant mice due to progressive motor axon loss. SSFEMG studies performed on 60- and 140-day-old mice indicated that average mean consecutive difference (MCD) and fiber density estimates (FDE) were significantly increased in Tr-j mice at both ages compared to age-matched wildtypes. FDE also increased substantially in older mutant mice. Intraperitoneal neostigmine injections produced significant reductions in average MCD in Tr-j mice, suggesting that impaired neuromuscular transmission is an early pathologic feature in these mice and likely reflects distal axonal degeneration. Our findings corroborate our prior pilot study, although in a much larger number of animals across a wider age span. Our study also indicates that SSFEMG, performed in a serial fashion, is a useful, noninvasive method of detecting progressive axon loss in this murine model of CMT 1A. This technique may be a valuable tool to study the affects of genetic or pharmaceutical interventions in murine models of peripheral neuropathy. Muscle Nerve, 2007.

Nerve conduction abnormalities in the trembler-j mouse: a model for Charcot-Marie-Tooth disease type 1A?

The trembler-j mouse is a spontaneously occurring, demyelinating mutant secondary to a point mutation involving a leucine for proline substitution in the first transmembrane domain of the peripheral-myelin protein-22 (PMP-22) gene. It is considered to be a model for Charcot-Marie-Tooth disease type 1A (CMT1A), largely based upon pathologic observations. However, functional studies demonstrating homology with CMT1A patients have not been documented. Sciatic nerve conduction was performed on 30 and 72-day-old wildtype and trembler-j mice in a blinded fashion. The findings in the mutants in both age groups were consistent with profound demyelination. Trembler-j mice appear to have a greater degree of motor nerve conduction slowing relative to human studies involving patients with PMP-22 gene duplication. Functionally, the trembler-j is a good murine model for CMT1A associated with an identical point mutation but may represent a more severe disease phenotype than CMT1A secondary to PMP-22 gene duplication.