The following story details some of my frustrations during the early history of transcranial magnetic stimulation (TMS) and autism. For those not cognizant of what TMS is, over the years I have posted several blogs detailing different aspects of this therapy (you can use the search function at corticalchauvinism.com to find them). Basically TMS induces electrical current through anatomical elements of the brain (for example axons) by subjecting the same to a rapidly expanding magnetic field. The machine itself uses the discharge of a very high current over a coiled wire (called an inductor) to create a strong magnetic field, that is, one of the same order of magnitude as an MRI scanner. Although the current is high and the magnetic field quite strong, there are few side effects to the same and TMS is one of the safest techniques available in psychiatry.
I should clarify that TMS works on a different principle than electroshock therapy (ECT). The latter uses a high current passing through the brain in order to induce a generalized convulsion. In the initial years of its implementation ECT had many side effects, most important of which were memory loss and bone fractures -the latter stemming from the thrashing around movements caused by the convulsions and the strong muscle contractions. At present patients are anesthetized and the high current is delivered in pulses in areas outside those that dictate memory. These innovations have made ECT safer and have minimized the side effects. At present ECT is a useful therapeutic intervention for select patients with either major depression or schizophrenia.
I first had my Eureka moment for using TMS in autism in 2001 when we discovered salient microscopic findings in the brains of autistic individuals. Our article appeared in print in 2002. Knowing that the significance of any findings is based on their explanatory and predictive powers I decided to expand on these in some publications and congress presentations. It was evident that the presence of a minicolumnopathy could explain an excitatory/inhibitory bias in the brain, seizures and sensory abnormalities in autism. The interesting part was when I tried to predict findings in autism that weren’t known back then. In this regard I predicted that, for autism, the presence of a minicolumnopathy would entail a change in the blueprint of connectivity of the white matter, abnormalities of gamma oscillations (brain waves associated with how we “bind together” different aspects of cognition), and that TMS would be a potential therapeutic modality. Although I tried to pursue all of my predictions through different means, the one related to TMS was the hardest one to accomplish.
From 2002 through 2004 I gave several lectures including Grand Rounds trying to entice TMS experts to pursue this therapeutic modality in autism. I went twice to MUSC and talked to Mark George, whom I considered the world leader in TMS. MUSC didn’t have an autism clinic back then and their TMS efforts focused on adults with major depression. With little else to go on I decided to push forwards by myself, buy the equipment, and initiate the trials. Given our postmortem studies, we already knew some important parameters for the trials, i.e., the place and frequency of stimulation. With the help of my good friend and colleague Dr. Estate Sokhadze, it took us 2 years (2004-05) to collect data on our first clinical trial. Little did I know that this was the beginning of a long uphill battle to get our results published.
In 2008 we finally managed to have our results published electronically (Epub ahead of print by JAAD) and then one more year before they appeared in print. The article per se went through a number of revisions with reviewers asking for more and more information. A short introduction section transformed from a few paragraphs to several pages. Other studies would pick up on our trail and publish on TMS and autism but only years later.
Given our positive results and the fact that the technique could make a dent on the pathology of autism, I thought that our efforts would be well received in the literature as well as by funding agencies. Till then most of our initial endeavors were funded out of my own pocket. Some interest came from Columbia University, NY when an investigator asked me for a copy of our protocol. I sent the individual a copy of a recently rejected federal grant detailing our protocol. Little did I know that they meant to paraphrase our grant and submit to the National Alliance for Autism Research (NAAR) for funding at the same time we did. I was told that both grants were heavily discussed but the NY group received funding because the committee thought they had more experience using TMS. In the end the funded NY group never carried forth any significant amount of research while my group had to proceed forward without funding.
Some time later I participated in a discussion on possible therapeutic endeavors for neurodevelopmental disorders hosted by the NIH. It was a closed group with representatives from Stanford, Harvard and myself from, by comparison, lowly Louisville. I was the only person who presented at the meeting results of a clinical trial and more so one on TMS and autism. The result of the meeting was a request for proposal for clinical trials in neurodevelopmental disorders. The group from Harvard asked me to join in this endeavor and write a conjoint grant on TMS and autism. I gladly agreed and sent them a copy of our grant and preliminary results (they didn’t have any of their own back then). One day or so before the grant submission deadline the Harvard group emailed me saying that they would be submitting alone. As for a reason, they said that the scientific officer at NIH in-charge of the request for proposal preferred for them to have an individual endeavor. It was too late for me to submit my own grant individually, that is, to have it processed and collect all of the necessary signatures. As it happened, I had trained with the scientific officer who drafted the request for proposal and called her. Harvard had never called and she would have preferred a conjoint proposal. Again, we missed a funding opportunity that was practically made for us.
Most recently we had a grant proposal to the NIMH detailing the possible synergism between neurofeedback and TMS. The grant was discussed and given a low score primarily because our group had presumably little experience in clinical trials based on TMS in autism. Curiously over half of the reported clinical trials to date from all over the world belong to my group. We have seen and treated more patients than all other groups around the world combined. We have won multiple citation awards from different congress and even a EUREKA award from the NIMH, -all for our clinical trials. It is a pity that the federal government can often base funding considerations on personal biases rather than on scientific criteria.
I found these initial experiences unsettling as ours was a «mom and pop» operation with no financial backing. Instead of fancy computers to help localize a returning site of stimulation we used an individual swimming cap for each patient detailing with a magic marker our stimulation site. Instead of using a fancy and expensive arm to hold the magnet we used graduate students. Even our furniture was made of thrown away pieces that we had retrieved from a Goodwill center.
We never charged anything to the hundred of patients we helped through our trials. More often than not we gave them money to help pay with gasoline and/or parking expenses. Others took advantage of our initial results and offered off-label TMS treatment for autism at a steep price. I never took a patent on the method with the idea that eventually it would be available to anybody who needed it at the lowest possible price . Now entrepreneurs are taking money from desperate parents- the very same thing I was trying to avoid. As a grandparent of an autistic child the whole experience is like a dagger through my heart.
Hopefully funding agencies will see TMS as a viable technique for autism treatment sometime in the near future. We have continued forwards with little or no funding for our research in TMS, only being able to advance by baby steps. Since many outcome measurements rely on behavioral screening techniques that may offer a subjective bias, we have introduced unbiased electrophysiological techniques in our trials. Our group was the first to examine how TMS improves higher cognitive functions and even the so-called binding of perceptions in autistic individuals. We have also employed other treatment modalities (neurofeedback) along with TMS to examine for possible synergism. At present we have also developed biomarkers that will allow us to foretell at baseline the result of a TMS intervention. Still, it will be baby steps. We would like to institute a trial with enough patients for it to be considered by the FDA, a longitudinal follow-up to see what are the long terms benefits of the same, and even examine the age range over which treatment may be most appropriate. Time will tell if we will be able to achieve these goals.
Below are some of the publications, congress presentations, and book chapters of our group detailing our clinical trials with participating ASD individuals. There are more accepted for publication or pending presentation in future congresses.
- Sokhadze, E.M., El-Baz, A., Baruth, J., Mathai, G., Sears, L., and Casanova M.F.: Effect of a 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. Disord. 39(4):619-634, 2009.
- Sokhadze, E., Baruth, J., and Casanova, M.: Neuropathological theories and EEG gamma oscillation abnormalities in autism. Neuroconnections, Fall: 34-37, 2009.
- Sokhadze, E., Baruth, J., Tasman, A., Mansoor, M., Ramaswamy, R., Sears, L., Mathai, G., El -Baz, A., and Casanova, M.F.: Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism. App. Psychophysiol. Biofeedback 35(2):147-161, 2010.
- Baruth, J., Casanova, M., El-Baz, A., Horrell, T., Mathai, G., Sears, L., and Sokhadze, E.: Low-frequency repetitive transcranial magnetic stimulation modulates evoked-gamma frequency oscillations in autism spectrum disorders. J. Neurother. 14(3):179-194, 2010
- Baruth, J., Williams, E., Sokhadze, E., El-Baz, A., Sears, L., and Casanova, M.F.: Repetitive transcranial stimulation (rTMS) improves electroencephalographic and behavioral outcome measures in autism spectrum disorders (ASD). Autism Science Digest 1(1):52-57, 2011.
- Sokhadze, E.M., Baruth, J.M., Sears, L., Sokhadze, G.E., El-Baz, A.S., and Casanova, M.F.: Prefrontal neuromodulation using rTMS improves error monitoring and correction functions in autism. Appl. Psychophysiol. Biofeedback 37(2):91-102, 2012.
- Sokhadze, E., Sokhadze, G., and Casanova, M.F.: Neuromodulation using transcranial DC stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) as a translational neuroscience approach to treat autism. Neuroconnections Newsletter, Summer:16-18, 2012.
- Casanova, M., Baruth, J., El-Baz, A., Tasman, A., Sears, L., and Sokhadze, E.: Repetitive transcranial magnetic stimulation (rTMS) modulates event-related potential (ERP) indices of attention in autism. Transl. Neurosci. 3(2):170-180, 2012.
- Sokhadze, E.M., El-Baz, A.S., Sears, L.L., Opris, I., and Casanova, M.F.: rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism. Front. Syst. Neurosci. 8:134, 2014.
- Sokhadze, E.M., El-Baz, A.S., Tasman, A., Sears, L.L., Wang, Y., Lamina, E.V., and Casanova, M.F.: Neuromodulation integrating rTMS and neurofeedback for the treatment of autism spectrum disorder: An exploratory study. Appl. Psychophysiol. Biofeedback 39 (3-4):237-257, 2014.
- Casanova, M.F., Hensley, M.K., Sokhadze, E.M., El-Baz, A.S., Wang, Y., Li, X., and Sears, L.: Effects of weekly low-frequency rTMS on autonomic measures in children with autism spectrum disorder. Front. Hum. Neurosci. 8:851, 2014. doi: 10.3389/fnhum.2014.00851
- Casanova, M.F., Sokhadze, E., Opris, I., Wang, Y., and Li, X.: Autism spectrum disorders: Linking neuropathological findings to treatment with transcranial magnetic stimulation. Acta Pediatr., 2015, 104:346-355. doi: 10.1111/apa
- Wang, Y., Li, X., Sears, L., Casanova, M., Tasman, A., and Sokhadze, E.: A study of relative power of specific EEG bands and their ratios during neurofeedback training in children with autism spectrum disorder. Fron Hum Neurosci 9:723, 2016 doi 10.3389/fnhum2015.
- 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. Appl Psychophysiol Biofeedback 41(1):47-60, 2016.
- Casanova., M.F., Sokhadze, E., El-Baz, A., Baruth, J., Mathai, G., and Sears L.: Research at the University of Louisville Autism Center. In Siri, K., and Lyons, T. (Eds.); Cutting-Edge Therapies for Autism. New York, Skyhorse Publishing, 2010, pp. 410-413.
- Baruth, J., Sokhadze, E., El-Baz, A., Mathai ,G., Sears, L., and Casanova, M.F.: Transcaranial magnetic stimulation as a treatment for autism. In Siri, K., and Lyons, T. (Eds.); Cutting-Edge Therapies for Autism. New York, Skyhorse Publishing, 2010, pp. 388-397.
- Casanova., M F., Sokhadze, E., El-Baz, A., Baruth, J., Mathai, G., and Sears L.: Research at the University of Louisville Autism Center. In Siri, K., and Lyons, T. (Eds.); Cutting-Edge Therapies for Autism. New York, Skyhorse Publishing, 2011, pp. 425-429.
- Baruth, J., Sokhadze, E., El-Baz, A., Mathai ,G., Sears, L., and Casanova, M.F.: Transcranial magnetic stimulation as a treatment for autism. In Siri, K., and Lyons, T. (Eds.); Cutting-Edge Therapies for Autism. New York, Skyhorse Publishing, 2011, pp. 402-411.
- Pennington, R.C., Welch, K.C., Sokhadze, E., El-Baz, A., Farag, A., Williams, P.G., and Casanova, M.F.: Crossing the divide: Collaborative efforts towards innovative treatments at the University of Louisville Autism Center. In Siri, K., and Lyons, T. (Eds.); Cutting-Edge Therapies for Autism. New York: Skyhorse Publishing, 2012, pp.161-164.
- Sokhadze, E.M., Casanova, M.F., and Baruth, J.: Transcranial magnetic stimulation in autism spectrum disorders. In Alba-Ferrara, L. (Ed.); Transcranial Magnetic Stimulation: Methods, Clinical Uses and Effects on the Brain. New York, NOVA Science Publishers, Inc., 2013, pp. 219-231.
- Baruth, J.M., Sokhadze, E.M., El-Baz, A.S., Sears, L., and Casanova, M.F.: Transcranial magnetic stimulation for the treatment of autism. In Siri, K., and Lyons, T. (Eds.); Cutting-Edge Therapies for Autism, Fourth Edition. New York, NY, Skyhorse Publishing, 2014, pp.120-137.
- Casanova, M.F., and Sokhadze, E.M.: Transcranial magnetic stimulation: Application in autism treatment. In Hu, V.W. (Ed.); Frontiers in Autism Research: New Horizons for Diagnosis and Treatment. Hackensack, NJ, World Scientific Publishing Co, 2014, pp. 583-606.
- Sokhadze, E., Sears, L., El-Baz, A., Tasman, A., and Casanova, M. Clinical applications of electrophysiological approaches based on cortical modularity. In.: M.F.Casanova and I.Opris.(Eds) Recent Advances on the Modular Organization of the Cortex. Springer, New York Chapter 14, 2015 .
- Sokhadze, E., Baruth, J., El-Baz, A., Ramaswamy, R., Sears, L., and Casanova, M.: Transcranial magnetic stimulation study of gamma frequency induction in response to illusory figures in patients with autism spectrum disorders. J. Neurother. 13(4):271-272, 2009.
- Sokhadze, E., Sokhadze, G., and Sears, L.: Neurofeedback training to improve attention and control alertness in ADHD. J. Neurother. 14(4):367-368, 2010.
- Baruth, J., Casanova, M., Sokhadze, G., Sears, L., and Sokhadze, E.: Transcranial magnetic stimulation modulates cognitive potentials in autism. Appl. Psychophysiol. Biofeedback 36:224, 2011.
- Hensley, M.K., Sokhadze, E.M., Casanova, M.F., Gross, E., and El-Baz, A.: Development of method for the analysis of EEG gamma coherence in children with autism enrolled in TMS treatment. Psychophysiol. 48: S32, 2011.
- Baruth, J., Casanova, M. F., Sears, L., and Sokhadze, E.: Transcranial magnetic stimulation (rTMS) modulates selective attention and executive functioning in autism. J. Neurother. 15(4):431-432, 2011.
- Sokhadze, E., Baruth, J., Sears, L., Sokhadze, G.E., El-Baz, A.S., Hensley, M., Gross, E., Tasman, A., and Casanova, M.F.: Neuromodulation using rTMS improves error monitoring and correction function in autism spectrum disorders. J. Neurother. 15(4):445-447, 2011.
- Hensley, M., El-Baz, A., Sokhadze, G., Sears, L., Casanova, M.F., and Sokhadze, E.M.: TMS effects on cardiac autonomic control in children with autism. Psychophysiol. 49:S40, 2012.
- Sokhadze, G., El-Baz, A., Sokhadze, E., Sears, L., and Casanova, M.: Effects of TMS on autonomic nervous system in children with autism. Appl. Psychophysiol. Biofeedback 37:S302, 2012.
- Sokhadze, E., Baruth, J., El-Baz, A., Gross, E., Sears, L., and Casanova, M.: Repetitive transcranial magnetic stimulation (rTMS) modulates event-related potential indices of attention and executive functioning in autism. Appl. Psychophysiol. Biofeedback 37:S303, 2012.
- Sears, L., Sokhadze, E., Baruth, J., and Casanova, M.F.: Combination of TMS and EEG biofeedback in autism: A single case study. Appl. Psychophysiol. Biofeedback 37:S303, 2012.
- Hensley, M., El-Baz, A., Casanova, M., and Sokhadze, T.: Heart rate variability and cardiac autonomic measures changes during rTMS course in autism. Appl. Psychophysiol. Biofeedback 38(3):238, 2013.
- Sokhadze, E., Sears, L., El-Baz, A.S., Wang, Y., Hensley, M., and Casanova, M.F.: Repetitive TMS course improves measures of information processing and behavioral performance in autism. Appl. Psychophysiol. Biofeedback 39:301-302, 2014.
- Sokhadze, E., Sears, L., Sokhadze, G., Edelson, S.M., Tasman, A., and Casanova, M.F.: Motor response preparation deficits in a cued spatial attention task in autism. Psychophysiol. 51:S16, 2014.
- Hensley, M., El-Baz, A.S., Sokhadze, E., Sears, L., and Casanova, M.F.: Effects of 18 session TMS therapy on gamma coherence in autism. Psychophysiol. 51:S16, 2014.
- Sokhadze, E., El-Baz, A.S., Sears, L., and Casanova, M.F.: Neuromodulation based on 18 Session rTMS course improves functional measures of information processing and behavioral responses in autism spectrum disorder. NeuroRegulation 1(3-4):307-308, 2014.
Manny, you know how I feel. You are indeed the «renaissance man» of TMS. You have a lot of crazy ideas, which is one reason I like you. And some of those ideas are paying off, as your own research is showing.
So keep going!
And one more thing . . . .you complain about «sour grapes» because you are in a comparatively backwater university. What about the autistics like me that could not even make it out of high school? The university that employed you in no way diminishes my regard for your ideas.
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Thanks. I always hold your opinion in high regards. I should clarify that I am proud of the accomplishments of my group (usually 2 people) in different institutions that lack support or research infrastructure. However, considering all the possible paths that we could have opened in autism, the lack of support and the slow pace has been depressing. Thanks again for your comments.
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I’m still academically interested in TMS though my knowledge of it is limited and hard for me to concentrate and read the publications and trying to do other things too. From what I know there are problems that make research on TMS efficacy difficult, such as the fact that you can’t really use sham TMS as an effective control as the controls would know they are not getting the real mcCoy. Using wait lists as controls may not be as effective as a true sham TMS protocol could be. Also, in one of your studies that I read (I think the one where you used neurofeedback) it is unclear if the persons who evaluated the subjects were blinded as to who got the therapy and the purpose of the experiment.
Another thing I’m wondering about is the fact that autism may involve some sort of glial pathology. I seem to remember there is some evidence of that in autism and that recent research on glial cells is starting to show that they do a lot more than just provide supportive functions to neurons and assist in the reuptake of neurotransmitters and they may have a much greater role in brain function than once thought. If autism involved some sort of glial pathology, using TMS could be problematic as glial cells don’t have action potentials and can’t be stimulated by TMS the way neurons can be. Of course, it is possible that by stimulating neurons, you can indirectly influence glial cells as well and enhanced brain functioning, in the same manner that stimulating the dorsolateral prefrontal cortex has a cascading effect since the brain is interconnected.
I also wonder if indirectly stimulating limbic structures through the cascading effects of cortical structures would be the same thing if you could directly stimulate deep nuclei such as amygdala and hippocampus which I don’t think is possible given the current state of the art.
You’re also probably familiar with yuri danilov’s research where they can put electrodes on some cranial nerves on the tongue which connect to the brainstem and pons and can stimulate the entire brain, I guess through connections with the reticular formation. I wonder if this is a more effective technique of neuromodulation than TMS. Danilov was interested in doing a research study on autism and inquired about the possibility of my being a subject, but never got back to me. I wonder if this could be used to complement TMS as well as neurofeedback did in your studies.
Maybe someday I will try to read all the studies and learn more about it, so I could ask better questions, but i’m curious about all these things.
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I am not sure that I will be able to answer everything but let me try. We have a sham coil from Magstim that has proven useless since the beginning. Families meet with each other outside the laboratory and discuss the side effects of their treatment or read about them from the literature. The sham coil won’t make your scalp contract or give you a headache.
In terms of outcome measures we have included in our trials electrophysiological techniques like event related potentials and autonomic measures. In this regard the computer making the testing and calculation is unbiased and does not care as to whether you are in the sham or active group.
Glia may be involved in the pathology of autism. They may have to do with synaptic remodeling rather than an inflammatory response. The main pathology thus far reported however is in neurons. The pathology suggests a migratory defect of neuronal precursors to the developing cerebral cortex.
Your comment about retrogradely stimulating the brain from a peripheral nerve is well known and has had several decades of research to back the same. You may look up vagal nerve stimulation (VNS) which is now being used primarily for epilepsy. I am not sure the same has been applied in autism. VNS and TMS each have their own particular strengths and weaknesses as well as indications.
Hope your book is coming along well. I am sure it will be well received.
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