Low frequency rTMS in Children with Autism

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.

 

 

 

 

 

9 responses to “Low frequency rTMS in Children with Autism

  1. Disculpe por hacer el comentario en español cuando la entrada del blog está en inglés, pero tengo unas cuantas preguntas sobre la EMT que me gustaría que me aclarara… ¿Cual es la fuerza de inducción del campo magnético (medida en Teslas o Gauss) que usan habitualmente? ¿Usan una fuerza de campo magnético fija, o variable según los casos?

    ¿Cual ha sido en su opinión profesional la ratio de sesiones semanales, frecuencias y nº de pulsaciones más adecuada para tratar los síntomas de stress o ansiedad como pueden ser las estereotipias, la sobrecarga emocional (o excitabilidad, que creo que sería similar) o la focalización en la atención?

    Hay un centro en mi ciudad donde se aplica terapia de EMT para múltiples patologías, y me gustaría saber si en general se mantienen las mismas condiciones tanto técnicas como de tratamiento en el autismo específicamente, o si debería comprobarlas por si acaso.
    Me llama la atención que en la web de este centro se afirma, además, que se puede tratar el autismo con esta técnica en la medida en que la EMT es capaz de reducir la hiperplasticidad del cerebro para mejorar los síntomas de esta patología ¿Es esto correcto?

    Disculpe todas por todas estas dudas, un cordial saludo

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    • La fuerfa magnetica es de cerca de 1 Tesla. Uno puede usar un pulso o varios. Respuestas fisiologicas duraderas tan solo se notan con pulsos repetidos. En el caso del autismo bajas frequencias sonmejores ya que aumentan la inhibicion del cerebro. Tambien se enfoca el EMT sobre la corteza frontal. El tratamiento sigue siendo experimental.

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  2. Gracias por la respuesta. Me parece que todavía queda bastante por estudiar con respecto a esta técnica, mientras que en la publicidad del centro que le comentaba la “venden” como si fuera ya una solución eficaz y contrastada. Lo cual no me inspira mucha confianza.

    De todas formas le agradecería que me contestara -si hay datos al respecto- una cuestión específica. Al hablar de la respuesta inhibitoria del cerebro con respecto a a la EMT, quisiera saber si esta atenuación neurológica tiene alguna correlación con respecto a la presencia de un cierto nivel de bloqueo o embotamiento emocional similar al que se produce con el uso de ciertos ansiolíticos o neurolépticos. (por mis circunstancias, este aspecto me resulta fundamental).

    Por otra parte, no estoy muy seguro de que -tal y como anuncia esta empresa que le decía- la EMT es capaz de reducir la hiperplasticidad del cerebro con autismo. En un artículo suyo sobre la EMT da a entender, o a mi me parece entender, que esta hiperplasticidad representa en todo caso una limitación con respecto a la efectividad de esta técnica. Me interesaría que me aclarara también este extremo si es posible.

    Un saludo

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    • La atencuaion es una respuesta en las neuronas que las inhibe. El mecanismo no se sabe. Esto ocurre a bajas frequencias como de 1 HZ o menos. A altas frequencias la respuesta es excitatoria. Estas respuestas no necesariamente se traducen al comportamiento. Hasta la fecha han habido un sinumerode articulos sobre plasticidad y TMS. La mayor parte de ellos provienen de Harvard. Creo que estrapolan demasiado. En ultima instancia si pudieramos decir que hay cambios cronicos que se pueden producir con la tecnica.

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      • Bueno, la verdad es que yo barajaba las dos opciones clásicas de mecanismos de respuestas frente al estrés a nivel psicológico:
        Por una parte está la posibilidad de que se produzca un “aplanamiento” emocional en el cual se inhibe completamente la reacción emocional generándose respuestas nulas o neutras frente a los estímulos externos.
        Por otra parte está la posibilidad de ir fortaleciendo las reacciones frente a estos estímulos de tal modo que se vaya incrementando progresivamente la tolerancia con respecto a los mismos, o dicho de otro modo, que se mejore la asimilación en general de la carga sensorial que soporta el individuo.

        Por la forma en que actúa la EMT (en la que se van obteniendo en primera instancia unos resultados más bien modestos o moderados, que estos resultados se producen de forma progresiva y que finalmente se debe prolongar su uso a lo largo del tiempo para mantener sus efectos), personalmente vería esta técnica más compatible con la segunda opción -más preferible- de reforzamiento del proceso de percepción sensorial en su conjunto. Es sólo una hipótesis, y por eso preguntaba si había evidencias con respecto a la otra opción.
        Lo cierto es que los medicamentos utilizados en psiquiatría que mencionaba en mi comentario anterior, y que se basan en el mecanismo de embotamiento emocional, tienen una forma de actuar muy rápida y sus resultados en cuanto a la anulación del estrés y la ansiedad son bastante más “espectaculares”. A un alto coste, claro está.

        Como decía, creo que esperaré a ver cómo evolucionan los estudios sobre la EMT. De todas formas, no creo que existan formas rápidas ni sencillas de solucionar estas problemáticas, dado que en el autismo el estrés se ve acentuado por la particular forma en que filtramos el conjunto de datos que recogen nuestro sentidos.

        Un cordial saludo, y muchas gracias de nuevo

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  3. I have a question, the predisposition genes for autism and schizophrenia, like many of their symptoms, do overlap, yet autism is increasing, so is schizophrenia but at a much slower and steadier rate. Why would enviromental triggers favor one over the other?

    Why is autism in particular increasing quicker and more rapidly than schizophrenia is? And why is the gender gap smaller in schizophrenia if their is such a strong connection to the factors of autism?

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    • The question is not an easy one to answer and in the end I can only speculate. One possibility is that an environmental exigency is affecting the brain during development more often than before. This environmental influence would presumably steer the outcome more towards autism than schizophrenia. You can probably take prenatal ultrasound as an example. It increases cell migration and errors related to the same (which have been seen more commonly in autism but not in schizophrenia). However, this is all speculation.

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      • Neural migration and abnormalities have been seen in schizophrenia too and so has abnormal brain weight, but usually the symptoms kick in during puberty or early adulthood when the brain is not growing but sculpting itself, scientists have watched videos of people with schizophrenia from their childhood before the onset and have noticed abnormal stiff movement and irritability. There is evidence of it also being neurodevelopmental too but requiring more time to kick in like autistic regression sometimes happening at the age of 2-3 instead of starting directly from birth, instead it is a different kind of regression at the ages of 16-25.

        Perhaps the enviromental influences directly during a woman’s pregnancy now do favor an earlier striking of malfunction leading to autism and the increase in non-pregnancy related enviromental factors explains why schizophrenia is rising, but much more steadily while autism is booming out of control. So autism is the addition of direct pregancy related enviromental problems to non-pregnancy enviromental problems.

        Some factors may also favor one over the other are in autism’s favor now. Older paternal age and obesity in fathers is increasing across the world which favors autism, schizophrenia often is favored by very immature age and being underweight in mothers which is uncommon in the west but still common in 3rd world countries which have higher schizophrenia rates and slightly less autism than the USA.

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