A few months ago I started reviewing the medical literature for reports that had used transcranial magnetic stimulation (TMS) with parameters similar to our  studies for treating children with neurodevelopmental conditions, emphasizing those with autism. I found many articles but the majority of them differed in one way or another from ours, e.g., site of stimulation, frequency, age range. Many of these have targeted the dorsolateral prefrontal cortex (DLPC) in order to alleviate symptoms of depression. Similar to the adult population, who suffer from refractory depression, many of the studies employed high frequency stimulation (e.g., 10 Hz).  In addition, there are many reports using rTMS stimulation as a treatment modality in children with ADHD, Tourette’s syndrome, myoclonus, progressive myoclonic epilepsy, bipolar disorder, and schizophrenia.  These studies have used either high frequencies or have preferentially targeted regions other than the DLPC, e.g., the motor cortex or the supplementary motor area.  In this blog, I will summarize the findings of those studies that have used low frequency rTMS (<1 Hz) over the DLPC in children/adolescents. References 1,3,5,8 were conducted at 0.5 Hz, all others at 1 Hz.

Studies that fulfilled our criteria are listed in the reference section (1-9). The total number of children/adolescents in these studies that received active rTMS is 163. The figure does not reflect those patients who were in the waitlist as controls and then selected to receive rTMS after the end of the study.

The reviewed literature shows that rTMS was well received by participating patients. In one study (5), sixteen children completed the 18 sessions required for the study. Two subjects (both boys) completed only 14 sessions and dropped out of the study due to familial exigencies (e.g., moving away). (Note: the two boys who withdrew are not counted in the total number reported of 163). Most studies described no side effects, those reported included an “itching” sensation around the nose, a tension-type headache, jaw twitching, and dizziness. These adverse effects were considered mild and transient.

Most of the studies used the same behavioral outcome measures: ABC, SRS, and RBS-R.  These behavioral evaluations post-TMS showed decreased irritability, hyperactivity, stereotyped behavior and compulsive behavior ratings. Other neuropsychological measures were meant to assess reaction time and response accuracy. In one study post rTMS reaction time to targets did not show any statistically significant difference but there was significant improvement in error percentage (3). In addition, several studies indirectly reported on the safety of rTMS based on autonomic dependent variables, i.e., R-R intervals, pNN50, NN50, SD R-R intervals, power of LF of HRV, LF/HF ratio and skin conductance level (1); and increased cardiac vagal control and reduced sympathetic arousal (considered as improvements) in ASD (5).

In regards to the effect of rTMS on executive functions several studies reported on improvements, never on adverse effects:

Reference #2: The study reported significant improvement in later stage ERP indices of selective attention. Selective attention is a component of working memory as it oversees decisions and regulates the ability to focus on task-relevant goals while excluding salient distracters.

Reference #3: Low-frequency rTMS minimized early cortical responses to irrelevant stimuli. Improved selectivity in early cortical responses led to better stimulus differentiation at later-stage responses as evident by P3b and P3a components.

Reference #4:  In this study the “focused attention” index showed a statistically significant linear increase over the 18 sessions of rTMS. There was a significant decrease of commission error rate in the TMS group. Note: Most pronounced improvements in ERP measures were observed closer to the site of stimulation, that is, at the frontal and fronto-central ROI (i.e., N100, P2d, N200, P3a components) as compared to posterior ROI (i.e., parietal and parieto-occipital P200, N200 and P3b).

Reference #7: This study reported on post rTMS improvements on error monitoring and correction function in autism.  The process of performance monitoring is an essential prerequisite for adaptively altering behavioral responses and making decisions for correction of behavior according to task demands. Executive function of behavioral performance monitoring comprises error detection and response conflict monitoring, functions that were measured in this study by their electrophysiological correlates.

Although not fulfilling the criteria for our review because of the age of the subjects, I should mention the study by Vanderhasselt et al. The influence of rTMS over the left dorsolateral prefrontal cortex on Stroop task performance. Exp Brain Res 169(2):279-82, 2006.  The study used twenty-eight right handed females (mean age 23 years, range 18-60) underwent high-frequency rTMS over the left dorsolateral prefrontal cortex on a Stroop task. The stimulation enhanced cognitive processing with decreased time noted on both the incongruent and congruent trials.

References

1. Wang Y, Hensley MK, Tasman A, Sears L, Casanova MF, Sokhadze EM. Heart rate variability and skin conductance during repetitive TMS course in children with autism. Applied Psychophysiology and Biofeedback 40(3): 2016 DOI 10.1007/s10484-015-9311-z Note: 33 children with autism (28 boys and 5 girls) mean age 12.88 years (range 7-21). 12 sessions at .5 Hz with a total of 160 pulses/session. Data from 3 patients (not included in our grand total) were discarded due to significant artifacts.
2. Casanova MF, Baruth JM, El-Baz A, Tasman A, Sears L, Sokhadze E. Repetitive transcranial magnetic stimulation (rTMS) modulates event-related potential (ERP) indices of attention in autism. Translational Neuroscience 3(2): 2012. DOI: 10.2478/s13380-012-0022-0 Note: 45 children (39 males and 6 females) with a mean age of 13.0 (age range 9 to 19 years). Only 25 were assigned to the active TMS group. Twelve weeks, 1 stimulation per week at 1Hz, 150 pulses per day.
3. Sokhadze E, Baruth J, Tasman A, Mansoor M, Ramaswamy R, Sears L, Mathai G, El-Baz A, Casanova MF. Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism. Appl Psychophysiol Biofeedback 35:147-161, 2010. DOI 10.1007/s10484-009-9121-2 Note: 13 participants, 12 males, 1 female, mean age 15.6 (age range 9-27 years) 0.5 Hz 150 pulses/day 2 times per week for 3 weeks
4. Sokhadze EM, El-Baz AS, Tasman A, Sears LL, Wang Y, Lamina EV, Casanova MF. Neuromodulation integrating rTMS and neurofeedback for the treatment of autism spectrum disorder: an exploratory study. Appl Psycophysiol Biofeedback 39:237-257, 2014. Note: 42 enrolled autistic patients, 34 males and 8 females with a mean age of 14.6 years (age range 10 to 21 years). Twenty of them were assigned to active 1.0 Hz TMS treatment (22 as waitlist controls). 180 pulses per day session, 1 session per week for 18 weeks. Mean age of subjects in the TMS group was 14.7 years.
5. Casanova MF, Hensley MK, Sokhadze EM, El-Baz AS, Wang Y, Li X, Sears L. Effects of weekly low-frequency rTMS on autonomic measures in children with autism spectrum disorders. Frontiers in Human Neuroscience 8(851), 2014 doi 10.3389/fnhum.2014.00851 Note: 18 children (14 boys and 4 girls) mean age 13.1 years. Stimulation was performed at 0.5 Hz with a total of 160 pulses per day, once per week for 18 weeks
6. Baruth J, Casanova MF, El-Baz A, Horrell T, Mathai G, Sears L, Sokhadze E. Low-frequency repetitive transcranial magnetic stimulation modulates evoked-gamma frequency oscillations in autism spectrum disorders. Journal of Neurotherapy 14:3, 179-194, 2010. Note: 25 ASD children, 21 male and 4 female with a mean age 13.8 years (age range 9-26 years) 1HZ with a total of 150 pulses per session, once per week for 12 weeks
7. Sokhadze EM, Baruth JM, Sears L, Sokhadze GF, El-Baz AS, Casanova MF. Prefrontal neuromodulation using rTMS improves error monitoring and correction function in autism. Appl Psychophysiol Biofeedback 37:91-102, 2012 DOI 10.1007/s10484-012-9182-5 Note: 20 participants enrolled in the rTMS treatment group, mean age 13.5 years (age range 10-19 years, 16 males and 4 females). TMS was administered once per week for 12 weeks I1Hz treatment, 150 pulses per day.
8. Sokhadze EM, El-Baz A, Baruth J, Mathai G, Sears L, Casanova MF. Effects of low frequency repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory figures in autism. J Autism Dev Disor 39:619-634, 2009. DOI 10.1007/s10803-008-0662-7 Note: 8 patients assigned to active TMS treatment, mean age 18.3 years, 0.5 Hz, 2 times per week for 3 weeks 150 pulses per day.
9. Cristancho, P., Akkineni, K., Constantino, J.N., Carter, A.R., & O’Reardon, J.P. (2014). Transcranial magnetic stimulation in a 15-year-old patient with autism and comorbid depression. Journal of ECT, 30(4), e46–e47. doi:10.1097/YCT. Note: Single case report of a 15 year old autistic with comorbid depression. Treated with rTMS 1 Hz frequency over the right and left DLPC.