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.

Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD).

Clinical trials in children with attention-deficit hyperactivity disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine. The objective of this study was to determine whether transcranial magnetic stimulation-evoked short interval cortical inhibition might be a biomarker predicting, or correlating with, clinical atomoxetine response. At baseline and after 4 weeks of atomoxetine treatment in 7- to 12-year-old children with ADHD, transcranial magnetic stimulation short interval cortical inhibition was measured, blinded to clinical improvement. Primary analysis was by multivariate analysis of covariance. Baseline short interval cortical inhibition did not predict clinical responses. However, paradoxically, after 4 weeks of atomoxetine, mean short interval cortical inhibition was reduced 31.9% in responders and increased 6.1% in nonresponders (analysis of covariance t 41 = 2.88; P = .0063). Percentage reductions in short interval cortical inhibition correlated with reductions in the ADHD Rating Scale (r = 0.50; P = .0005). In children ages 7 to 12 years with ADHD treated with atomoxetine, improvements in clinical symptoms are correlated with reductions in motor cortex short interval cortical inhibition.

Tourette syndrome.

This chapter addresses research applications of transcranial magnetic stimulation (TMS) in Tourette syndrome (TS). TS is a primary, idiopathic, neurological disorder characterized by multiple motor and vocal tics of childhood onset, with duration greater than 1 year, and associated in the majority of cases with attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and/or other psychiatric disorders. The majority of the chapter is a critical synopsis of case-control studies applying basic single- and paired-pulse TMS techniques to "resting" motor cortex. Newer applications of theta-burst stimulation are also analyzed. A number of intriguing findings have emerged, which may reflect abnormalities in several disrupted inhibitory or modulatory pathways that may underlie the tendency to manifest tics as well as commonly co-occurring problems such as ADHD and OCD. Chapter sections are organized by type of TMS measurement, with each section describing briefly the technique, the pitfalls of the technique with regard to the above-described challenges, the findings in TS using that technique, and the possible implications for those findings in furthering our understanding of TS. Possible future applications for TMS in studying TS are also discussed.

Transcranial magnetic stimulation measures in attention-deficit/hyperactivity disorder.

Children affected by attention-deficit/hyperactivity disorder demonstrate diminished intrahemispheric inhibition (short interval cortical inhibition), as measured by transcranial magnetic stimulation. This study determined whether interhemispheric inhibition (ipsilateral silent period latency) correlates with clinical behavioral rating and motor control deficits of affected children. In 114 right-handed children (aged 8-12 years; age/sex-matched; 50 affected, 64 controls), we performed comprehensive assessments of behavior, motor skills, and cognition. Transcranial magnetic stimulation reliably elicited ipsilateral silent periods in 54 children (23 affected); all were on average older than those with 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), and 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). 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.

Effects of 30Hz θ 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. METHOD: Forty participants under 18 years: 16 with Tourette syndrome (five females, 11 males; mean age 12y, SD 2y 10mo) and 24 typically developing children (12 females, 12 males; mean age 12y 11mo, SD 2y 10mo) underwent intermittent or continuous TBS over the left motor cortex. Open questions, a structured 16-question review of systems, and visual analog mood scale (VAMS) were administered before and after TBS. A Wilcoxon signed-rank sum test was used to analyze differences in VAMS scores before and after TBS. RESULTS: There were no serious adverse events. Five of the 40 children reported mild, self-limited adverse events: a subjective sensation of finger twitching (n=1), neck stiffness (n=1), and mild headache (n=3). The total adverse event rate was 11.6%. There was no significant change in VAMS score in either group after one session of TBS. INTERPRETATION: A single session of TBS in children appears to be safe and well tolerated.

Neurochemical alteration in the caudate: implications for the pathophysiology of bipolar disorder.

Several lines of evidence suggest that the neuropathophysiology of bipolar disorder is marked by structural and functional abnormalities in the caudate. We used magnetic resonance spectroscopy imaging (MRSI) to examine potential neurochemical changes in the caudate of adult bipolar patients (BP). 2D-MRSI scans including the caudate were obtained from 25 BP and 9 healthy subjects (HS). BP patients were further divided into medicated (n=14) and unmedicated (n=11) groups; the majority of medicated patients received atypical antipsychotics (AAP). Ratios of Cr/Cho, Cho/NAA and Cr/NAA in the caudate were compared between groups, controlling for age, gender and gray/white ratio. BP and HS did not significantly differ on any ratios. The Cr/Cho ratio, however, was significantly greater in medicated BP compared to HS. Conversely, the Cho/NAA ratio was non-significantly lower in medicated BP vs. HS. Medicated BP also showed significantly greater Cr/Cho and significantly smaller Cho/NAA ratios than unmedicated BP. Although we did not observe significant overall differences between BP and HS, our findings suggest the presence of reduced choline levels in the caudate of medicated BP receiving AAP. While speculative, these results suggest that AAP do not cause oxidative injury to neuronal membranes.