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1.  Reduced Short Interval Cortical Inhibition Correlates with Atomoxetine Response in Children with ADHD 
Journal of child neurology  2014;29(12):1672-1679.
Clinical trials in children with Attention Deficit Hyperactivity Disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX). The objective of this study was to determine whether Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (SICI) might be a biomarker predicting, or correlating with, clinical ATX response. At baseline and after 4 weeks of ATX treatment in 7–12 year old children with ADHD, TMS-SICI was measured, blinded to clinical improvement. Primary analysis was by multivariate ANCOVA. Baseline SICI did not predict clinical responses. However, paradoxically, after 4 weeks of ATX, mean SICI was reduced 31.9% in responders and increased 6.1% in non-responders (ANCOVA t41=2.88; p = .0063). Percent reductions in SICI correlated with reductions in ADHD-Rating Scale (ADHDRS) (r = .50; p = .0005). In children ages 7–12 years with ADHD treated with ATX, improvements in clinical symptoms are correlated with reductions in motor cortex SICI.
doi:10.1177/0883073813513333
PMCID: PMC4092054  PMID: 24413361
Clinical Pharmacology / Clinical Trials; Psychopharmacology; Neuropharmacology; Biological Psychiatry; Attention Deficit Hyperactivity Disorder; Transcranial Magnetic Stimulation; Atomoxetine; Short Interval Cortical Inhibition
2.  Abnormal Cortical Plasticity in Youth with Autism Spectrum Disorder: A Transcranial Magnetic Stimulation Case–Control Pilot Study 
Abstract
Objective: This case–control study investigated the use of a low-intensity repetitive transcranial magnetic stimulation (rTMS) protocol to measure motor cortex (M1) plasticity in youth with autism spectrum disorder (ASD) compared with typically developing children (TDC). We hypothesized that impairments in long-term potentiation-like properties represent a neurophysiological biomarker of abnormal cortical function in ASD.
Methods: We studied youth with ASD aged 11–18 years and matched controls (TDC). Intermittent theta burst stimulation (iTBS) was delivered to the dominant M1 at an intensity of 70% of resting motor threshold. Suprathreshold single-pulse TMS was performed to compare amplitudes of motor-evoked potentials (MEP) measured from surface electromyography electrodes on a target muscle before (20 pulses) and after (10 pulses/time point) iTBS at predefined timepoints (up to 30 minutes) to measure any potentiation effects. A linear mixed model was used to examine group differences in MEP amplitudes over time following iTBS.
Results: Nine youth with ASD (mean age 15.6; 7 males; 6 right-hand dominant) and 9 TDC (mean age 14.5; 5 males; 9 right-hand dominant) participated. All subjects tolerated the procedure well. Both groups had a mean increase in excitability after iTBS for 30 minutes; however, the time course of excitability changes differed (F9,144 = 2.05; p = 0.038). Post-hoc testing identified a significant decrease in amplitude of the ASD group at 20 minutes following iTBS compared with the TDC after correcting for multiple comparisons.
Conclusion: In this study, we demonstrate early evidence for a potential physiological biomarker of cortical plasticity in youth with ASD using a rapid low-intensity rTMS protocol with a discriminate measure at 20 minutes following stimulation. The procedure was well tolerated by all 18 participants. Future work will include modification of the protocol to improve the ability to distinguish subtypes of ASD based on behavioral and cognitive testing.
doi:10.1089/cap.2015.0183
PMCID: PMC5035833  PMID: 27007257
3.  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.
doi:10.3389/fnhum.2015.00029
PMCID: PMC4316715  PMID: 25698958
children; youth; transcranial magnetic stimulation; repetitive transcranial magnetic stimulation; theta burst stimulation; safety
4.  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.
doi:10.1080/09297049.2011.625356
PMCID: PMC3461120  PMID: 22111593
Reaction Time Variability; Motor Development; Children; Attention Deficit Hyperactivity Disorder; Goniometer; PANES
5.  CNS, Lung, and Lymph Node involvement in Gaucher disease type 3 after 11 years of therapy: Clinical, Histopathologic, and Biochemical Findings 
Molecular genetics and metabolism  2014;114(2):233-241.
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 age 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 patient’s brain. This profile was similar to that in the patient’s lungs, suggesting these lipids were present in brain perivascular macrophages. In the patient’s 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.
doi:10.1016/j.ymgme.2014.08.011
PMCID: PMC4312736  PMID: 25219293
Gaucher Disease; Lysosomal Storage Disease; Enzyme Replacement Therapy; lymphadenopathy; Pathology
6.  Transcranial Magnetic Stimulation Measures in Attention-Deficit/Hyperactivity Disorder 
Pediatric neurology  2012;47(3):177-185.
Children affected by Attention-Deficit/Hyperactivity Disorder have diminished intra-hemispheric inhibition (Short Interval Cortical Inhibition) as measured by Transcranial Magnetic Stimulation. This study’s objective is to determine whether inter-hemispheric inhibition (Ipsilateral Silent Period Latency) correlates with clinical behavioral rating and motor control deficits of affected children. In 114 8–12 year old, right-handed children (age/sex-matched, 50 affected, 64 controls), we performed comprehensive assessments of behavior, motor skills and cognition. Using Transcranial Magnetic Stimulation, we reliably elicited Ipsilateral Silent Period in 54 children (23 affected) - all were on average older than those who had unobtainable measures. Mean Ipsilateral Silent Period latency was 5 milliseconds longer in the affected group (p=0.007). Longer latencies correlated with more severe behavioral symptom scores (r=0.38, p=0.007), particularly hyperactivity (r=0.39, p=0.006), as well as with worse motor ratings on the Physical and Neurological Examination for Soft Signs (r=0.27, p=0.05). Longer latency also correlated with Short Interval Cortical Inhibition (r=0.36, p=0.008). In conclusion, longer Ipsilateral Silent Period latencies suggest interhemispheric inhibitory signaling is slower in affected children. The deficit in this inhibitory measure may underlie developmental, behavioral and motor impairments in children with Attention-Deficit/Hyperactivity Disorder.
doi:10.1016/j.pediatrneurol.2012.06.003
PMCID: PMC3418513  PMID: 22883282
7.  Effects of 30 Hz Theta Burst Transcranial Magnetic Stimulation on the Primary Motor Cortex 
Journal of Neuroscience Methods  2012;208(2):161-164.
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 50 Hz 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, 30 Hz TBS is advantageous over 50 Hz TBS in that it can be delivered at higher stimulation intensities. The goal of this pilot study is to examine the neurophysiologic effects of 30 Hz 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 30 Hz) repeating every 200 milliseconds. For iTBS, each 2-second stimulation train was separated by 8 seconds 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 30 Hz iTBS and decreased after 30 Hz cTBS (TBS-Type*Time effect p=0.009). In conclusion, 30 Hz TBS induced similar neurophysiologic effects over M1 as conventional 50 Hz TBS.
doi:10.1016/j.jneumeth.2012.05.014
PMCID: PMC3398243  PMID: 22627376
Repetitive Transcranial Magnetic Stimulation; Theta Burst Stimulation; Neuroplasticity; Motor Cortex
8.  Effect of 30 Hz theta burst transcranial magnetic stimulation on the primary motor cortex in children and adolescents 
Fourteen healthy children (13.8 ± 2.2 years, range 10–16; M:F = 5:9) received 30 Hz intermittent theta burst transcranial magnetic stimulation (iTBS) with a stimulation intensity of 70% of resting motor threshold (RMT) with a total of 300 (iTBS300) pulses. All volunteers were free of neurologic, psychiatric and serious medical illnesses, not taking any neuropsychiatric medications, and did not have any contraindications to transcranial magnetic stimulation. Changes in the mean amplitudes of motor-evoked potentials from baseline following iTBS were expressed as a ratio and assessed from 1 to 10 min (BLOCK1) and 1–30 min (BLOCK2) using repeated-measures analysis of variance. All 14 subjects completed iTBS300 over the dominant primary motor cortex (M1) without any clinically reported adverse events. ITBS300 produced significant M1 facilitation [F(5, 65) = 3.165, p = 0.01] at BLOCK1 and trend level M1 facilitation at BLOCK2 [F(10, 129) = 1.69, p = 0.089]. Although iTBS300 (stimulation duration of 92 s at 70% RMT) delivered over M1 in typically developed children was well-tolerated and produced on average significant facilitatory changes in cortical excitability, the post-iTBS300 neurophysiologic response was variable in our small sample. ITBS300-induced changes may represent a potential neuroplastic biomarker in healthy children and those with neuro-genetic or neuro-psychiatric disorders. However, a larger sample size is needed to address safety and concerns of response variability.
doi:10.3389/fnhum.2015.00091
PMCID: PMC4340218  PMID: 25762919
repetitive transcranial magnetic stimulation; theta burst stimulation; long-term potentiation; pediatric; neuroplasticity
9.  Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia 
BMC Neurology  2012;12:93.
Background
Recently, 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.
Methods
Sanger 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.
Results
One 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.
Conclusions
Heterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.
doi:10.1186/1471-2377-12-93
PMCID: PMC3460747  PMID: 22985072
PKD; PRRT2; African-American; ICCA; Hotspot mutation
10.  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.
PMCID: PMC3057942  PMID: 21358599
aphasia; language; fMRI; rTMS; rehabilitation; stroke
11.  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.
doi:10.12659/MSM.881446
PMCID: PMC3057942  PMID: 21358599
aphasia; language; fMRI; rTMS; rehabilitation; stroke

Results 1-11 (11)