Steve W. Wu

Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia

Summary Background Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca’s area for chronic aphasia treatment. Material/Methods We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca’s area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca’s. Results 6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS. Conclusions FMRI-guided, excitatory rTMS applied to the affected Broca’s area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.

Effects of 30 Hz Theta Burst Transcranial Magnetic Stimulation on the primary motor cortex

Theta Burst Stimulation (TBS) is a relatively new form of repetitive Transcranial Magnetic Stimulation (TMS) used to probe neuroplasticity in the human cortex. Thirty-Hz TBS, a variation of the originally described 50Hz TBS, has been shown to induce cortical changes in several nonmotor regions. However, its effects over the primary motor cortex have not been examined. Due to TMS device mechanical properties, 30Hz TBS is advantageous over 50Hz TBS in that it can be delivered at higher stimulation intensities. The goal of this pilot study is to examine the neurophysiologic effects of 30Hz TBS on the primary motor cortex (M1) of healthy adults. Eighteen right-handed adults (33±9.0 years; M:F=8:10) completed intermittent TBS (iTBS) or continuous TBS (cTBS) over left M1. TBS was performed with Magstim® SuperRapid2 with stimulation bursts (3 pulses at 30Hz) repeating every 200ms. For iTBS, each 2-s stimulation train was separated by 8s but there was no pause between trains for cTBS. Each TBS consisted of a total of 600 pulses delivered at an intensity of 90%*Resting Motor Threshold. Motor-Evoked Potentials (MEP) in the right first dorsal interosseous muscle were measured before, and one and ten minutes after TBS. Pre/post-TBS MEP amplitudes were compared using repeated-measures ANOVA. MEP amplitudes increased after 30Hz iTBS and decreased after 30Hz cTBS (TBS-Type*Time effect p=0.009). In conclusion, 30Hz TBS induced similar neurophysiologic effects over M1 as conventional 50Hz TBS.

Safety and tolerability of theta-burst transcranial magnetic stimulation in children.

Aim  Theta‐burst stimulation (TBS) is a lower intensity, high‐frequency repetitive transcranial magnetic stimulation technique developed recently for quantifying and modulating cerebral cortical function. Nearly all published studies have involved adults. The aim of this study was to obtain safety data as a basis for evaluating potential risks versus benefits of TBS research in children.

CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: Clinical, histopathologic, and biochemical findings

A Caucasian male with Gaucher disease type 3, treated with continuous enzyme therapy (ET) for 11 years, experienced progressive mesenteric and retroperitoneal lymphadenopathy, lung disease, and neurological involvement leading to death at an age of 12.5 years. Autopsy showed significant pathology of the brain, lymph nodes, and lungs. Liver and spleen glucosylceramide (GluCer) and glucosylsphingosine (GluS) levels were nearly normal and storage cells were cleared. Clusters of macrophages and very elevated GluCer and GluS levels were in the lungs, and brain parenchymal and perivascular regions. Compared to normal brain GluCer (GC 18:0), GluCer species with long fatty acid acyl chains were increased in the patients brain. This profile was similar to that in the patients lungs, suggesting that these lipids were present in brain perivascular macrophages. In the patients brain, generalized astrogliosis, and enhanced LC3, ubiquitin, and Tau signals were identified in the regions surrounding macrophage clusters, indicating proinflammation, altered autophagy, and neurodegeneration. These findings highlight the altered phenotypes resulting from increased longevity due to ET, as well as those in poorly accessible compartments of brain and lung, which manifested progressive disease involvement despite ET.

Relationship between reaction time variability and motor skill development in ADHD.

Slower and more variable reaction times to computerized tasks have been documented in children diagnosed with attention deficit/hyperactivity disorder (ADHD). Recent research supports a role for attentional lapses in generating abnormally variable and slow responses. However, given the association between ADHD and impairments in motor control, we hypothesized that slower or more variable reaction times might also correlate with motor development. The aim of this case-control study was to explore the relationship between motor function, reaction speed and variability, and ADHD. After comprehensive educational and clinical assessments, motor skill development was evaluated in 35 children ages 9 to 14 (19 with ADHD) using the Physical and Neurological Examination for Subtle Signs (PANESS) test battery. Finger-sequencing speed and variability were quantified with goniometers. Reaction times were measured with 20 trials each of computerized simple and choice (binary) tasks. Compared to healthy controls, children with ADHD had slower and more variable reaction times, and these findings correlated with impaired motor development (PANESS) and slow and variable finger sequencing (goniometers). Further studies of motor development in ADHD may identify factors influencing speed and variability of reaction times.

Functional MRI-navigated Repetitive Transcranial Magnetic Stimulation Over Supplementary Motor Area in Chronic Tic Disorders

BACKGROUND Open label studies have shown repetitive transcranial magnetic stimulation to be effective in reducing tics. OBJECTIVES To determine whether 8 sessions of continuous theta burst stimulation (cTBS) over supplementary motor area (SMA) given over 2 days may reduce tics and motor cortical network activity in Tourette syndrome/chronic tic disorders. METHODS This was a randomized (1:1), double-blind, sham-controlled trial of functional MRI (fMRI)-navigated, 30 Hz cTBS at 90% of resting motor threshold (RMT) over SMA in 12 patients ages 10-22 years. Comorbid ADHD (n = 8), OCD (n = 8), and stable concurrent medications (n = 9) were permitted. Neuro-navigation utilized each individuals event-related fMRI signal. Primary clinical and cortical outcomes were: 1) Yale Global Tic Severity Scale (YGTSS) at one week; 2) fMRI event-related signal in SMA and primary motor cortex (M1) during a finger-tapping motor task. RESULT Baseline characteristics were not statistically different between groups (age, current tic/OCD/ADHD severities, tic-years, number of prior medication trials, RMT). Mean YGTSS scores decreased in both active (27.5 ± 7.4 to 23.2 ± 9.8) and sham (26.8 ± 4.8 to 21.7 ± 7.7) groups. However, no significant difference in video-based tic severity rating was detected between the two groups. Two-day post-treatment fMRI activation during finger tapping decreased significantly in active vs. sham groups for SMA (P = 0.02), left M1 (P = 0.0004), and right M1 (P < 0.0001). No serious adverse events occurred. CONCLUSION Active, fMRI-navigated cTBS administered in 8 sessions over 2 days to the SMA induced significant inhibition in the motor network (SMA, bilateral M1). However, both groups on average experienced tic reduction at 7 days. Larger sample size and protocol modifications may be needed to produce clinically significant tic reduction beyond placebo effect.

Altered neurophysiologic response to intermittent theta burst stimulation in Tourette syndrome

BACKGROUND The motor system in Tourette syndrome has been found to be abnormal in previous fine-motor and neurophysiologic studies. OBJECTIVE This novel pilot study uses repetitive transcranial magnetic stimulation as a method to characterize the neurophysiology of the motor system in Tourette syndrome. METHOD We investigated the modulation of cortical excitability in adult Tourette syndrome patients by measuring motor-evoked potential amplitudes before and after applying intermittent theta burst transcranial magnetic stimulation. RESULTS Motor-evoked potential amplitude changes over 1 and 10 minutes after intermittent theta burst transcranial magnetic stimulation were greater in 11 healthy controls than 10 adult patients with Tourette syndrome (P = 0.004). CONCLUSIONS This altered neurophysiologic response to intermittent theta burst stimulation may contribute to the understanding of motor cortical mechanisms in Tourette syndrome.

Clinical and positron emission tomography findings of chorea associated with primary antiphospholipid antibody syndrome

A fourteen‐year‐old right‐handed male with a history of attention deficit hyperactivity disorder (ADHD) presented with alternating hemichorea. Laboratory findings included elevated anticardiolipin IgG and anti‐β2‐glycoprotein I IgG, which were consistent with primary antiphospholipid antibody syndrome. Positron emission tomography (PET) imaging revealed altered striatal metabolism in his left putamen while he was exhibiting right‐sided hemichorea. His symptoms resolved on prednisone; however, his antiphospholipid antibody profile remained markedly abnormal despite being symptom‐free for 26 months.

Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia

BackgroundRecently, heterozygous mutations in PRRT2 (Chr 16p11.2) have been identified in Han Chinese, Japanese and Caucasians with paroxysmal kinesigenic dyskinesia. In previous work, a paroxysmal kinesigenic dyskinesia locus was mapped to Chr 16p11.2 - q11.2 in a multiplex African-American family.MethodsSanger sequencing was used to analyze all four PRRT2 exons for sequence variants in 13 probands (9 Caucasian, 1 Caucasian-Thai, 1 Vietnamese and 2 African-American) with some form of paroxysmal dyskinesia.ResultsOne patient of mixed Caucasian-Thai background and one African-American family harbored the previously described hotspot mutation in PRRT2 (c.649dupC, p.R217Pfs*8). Another African-American family was found to have a novel mutation (c.776dupG, p.E260*). Both of these variants are likely to cause loss-of-function via nonsense-mediated decay of mutant PRRT2 transcripts. All affected individuals had classic paroxysmal kinesigenic dyskinesia phenotypes.ConclusionsHeterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects.

Background: Although single- and paired-pulse (sp/pp) transcranial magnetic stimulation (TMS) studies are considered minimal risk in adults and children, the safety profile for theta-burst TMS (TBS) is unknown. Objective: In this comparative analysis, we explored the rate, severity, and specific symptoms of TMS-related adverse effects (AEs) between sp/ppTMS and TBS in subjects between ages 6 and 18 years. Method: Data from 165 participants from 2009 to 2014 were analyzed. Assessment of AEs was performed based on baseline and post-TMS administration of a symptom-based questionnaire that rated AEs on a 5-level ordinal scale (minimal, mild, moderate, marked, severe). AE rates and severity were compared using Chi Square or Fisher’s Exact Test depending on data characteristics. Result: Overall, no seizures or severe-rated AEs were reported by 165 pediatric participants. The rate of AE in all TBS sessions was 10.5% (n = 76, 95% CI: 4.7–19.7%), whereas the rate of AE in all sp/ppTMS sessions was 12.4% (n = 89, 95% CI: 6.3–21.0%). There was no statistical difference in AE rates between TBS and sp/ppTMS (p = 0.71). In all sp/ppTMS and TBS sessions, 20 subjects reported a total of 35 AEs, among these 31 (~88.6%) were rated as “minimal” or “mild”. There was no difference in the severity of AE between TBS and sp/ppTMS (p = 1.0). Only one of 76 TBS participants reported an AE rated as more than minimal/mild. Conclusion: Our comparative analysis showed that TBS appears to be as safe as sp/ppTMS in terms of AE rate and severity. This report supports further investigation of TBS in children.