My last clinical trial in autism

I retired last July from academics but still have a backlog of publications and data that seem to pop-up now and then in the medical literature. Hopefully, I will complete my bucket list and publish a pending book about brain augmentation with Springer. The same was a joint effort with Ioan Opris, who unfortunately died last year. I have tried to fill the shoes of my friend Ioan and make his last effort come to fruition. I will keep the readers informed of that venture. In the meanwhile, I have worked with ASCOPAS from Costa Rica in translating into Spanish a lot of practical autism related information that I had originally written in English. I hope that this book, Autismo Actualizado, will fill a knowledge gap for the Hispanic speaking community.

My last clinical trial on transcranial magnetic stimulation (TMS) is now available online. It may be the last article that I write as first author for the medical literature. Many of the reader of this blog know of my love for electronics. Doing neuromodulation as part of my medical career has therefore been an exhilarating hobby for me. In this particular article I had the idea of analyzing brainwaves the same way we do in electronic communications. I loved the results and sometimes read and reread the paragraphs trying to relive my euphoria for the findings. The full article is available by clicking this link. At the top of the page you will find a tab for the “full-text available”.

Noteworthy points are the following:

In addition to the normal metrics of event-related gamma potentials, our study is the first to quantitate the envelope and settling time of gamma oscillations. Measurements of the ringing decay were significantly different when comparing autistics and neurotypical controls. In autism, baseline levels of gamma oscillations showed a shortened period of ringing decay. Short ringing times implies a system with lower sensitivity (Silver & Tiede-mann, 1978); one that makes synchronization and integration of information among different neuronal networks imprecise or inefficient. The inhibitory deficit evidenced in neuropathological studies of ASD thus translates into a low sensitivity system seemingly overwhelmed by the background level of noise. In a previous study, modeling such a system gave rise to stochastic resonance; a phenomenon where a neural network embedded in a noisy back-ground acquired, counterintuitively, enhanced sensitivity (Casanova et al., 2014). The phenomenon serves to explain the autistic emphasis for sameness (i.e., an adaptation to an optimal noise level) and the sensory peculiarities (hypo- and hypersensitivity) characteristic of the condition.

In modeling the activity of excitable membranes, resonance is achieved by the combined action of inductive and capacitive reactance (Gutfreund et al., 1995). These are intrinsic properties of passive elements within the membrane that serve to oppose the flow of current. The interaction of capacitance and inductance allows the membrane to act as an electrical resonator, one that preferentially oscillates at the circuit’s resonant frequency. In biological systems, a resonant peak in the frequency domain implies a dampened oscillation in the time domain (Gutfreund et al., 1995). Some systems may have multiple, distinct resonance frequencies. The greatest response or amplitude is achieved for the least amount of dampening. Following an excitatory phase, wherein the system is stimulated into resonance, a free ring-ing decay ensues which provides a measure of impedance (Brewer, 2012). For brainwave forms, interneurons provide the resistive element necessary to elicit gamma oscillations. Detailed computational models of cortical circuitry have shown how downregulation of PV cells disinhibit networks and alter gamma oscillations in response to stimulation (Volman et al., 2011). Indeed, optogenetically inhibiting the action of PV cells suppresses gamma oscillations in vivo while activating these interneurons generates gamma oscillations (Sohal et al., 2009). In the end, excitation and inhibition of appropriate power alternate in order to establish the cyclic behavior of brainwave oscillations (Buzsáki & Wang, 2012). During this cyclic behavior excitation and amplification mark the time period to peak amplitude while inhibition characterizes the settling pace of the ensuing decay curve.—In essence we described a biomarker for the level of excitation and for inhibition in the brain that can be used as outcome measure when following patients!
(PDF) Ringing Decay of Gamma Oscillations and Transcranial Magnetic Stimulation Therapy in Autism Spectrum Disorder. Available from: https://www.researchgate.net/publication/351008295_Ringing_Decay_of_Gamma_Oscillations_and_Transcranial_Magnetic_Stimulation_Therapy_in_Autism_Spectrum_Disorder#fullTextFileContent [accessed Apr 22 2021].

The complete abstract of the article reads as follows:

Research suggest that in autism spectrum disorder (ASD) a disturbance in the coordinated interactions of neurons within local networks gives rise to abnormal patterns of brainwave activity in the gamma bandwidth. Low frequency transcranial magnetic stimulation (TMS) over the dorsolateral prefrontal cortex (DLPFC) has been proven to normalize gamma oscillation abnormalities, executive functions, and repetitive behaviors in high functioning ASD individuals. In this study, gamma frequency oscillations in response to a visual classification task (Kanizsa figures) were analyzed and compared in 19 ASD (ADI-R diagnosed, 14.2 ± 3.61 years old, 5 girls) and 19 (14.8 ± 3.67 years old, 5 girls) age/gender matched neurotypical individuals. The ASD group was treated with low frequency TMS (1.0 Hz, 90% motor threshold, 18 weekly sessions) targeting the DLPFC. In autistic subjects, as compared to neurotypicals, significant differences in event-related gamma oscillations were evident in amplitude (higher) pre-TMS. In addition, recordings after TMS treatment in our autistic subjects revealed a significant reduction in the time period to reach peak amplitude and an increase in the decay phase (settling time). The use of a novel metric for gamma oscillations. i.e., envelope analysis, and measurements of its ringing decay allowed us to characterize the impedance of the originating neuronal circuit. The ringing decay or dampening of gamma oscillations is dependent on the inhibitory tone generated by networks of interneurons. The results suggest that the ringing decay of gamma oscillations may provide a biomarker reflective of the excitatory/inhibitory balance of the cortex and a putative outcome measure for interventions in autism.

I am enthused by the reported findings and hope that the medical community pursues the practical aspects of our research. My best regards to all of my collaborators over the years. Loved all of our conjoint efforts and discussions which kept me young at heart. I will always be indebted to all of you.

9 responses to “My last clinical trial in autism

  1. I do electronics too. Mostly based on radio receivers of the 1940s and 1950s. However, turning my theoretical knowledge of obscure physics to practical application proves to be challenging. People such as myself tend to shine more in the maths and physics area. However, lately I am doing a lot more construction.
    Otherwise I remain a source of obscure information but no application to the modern sphere. The days of AA5s have long since passed.

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  2. How long do you think the benefits of TMS last for? is it something that a patient would have to do regularly for life or a short few weeks every year / few years? Are greater benefits seen in younger patients?

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  3. Using our protocol benefits lasted 6 months to 1 year. Booster treatments were necessary, but after each treatment, they spread apart. So after a booster shot, you may not need another treatment for 2-5 years and afterwards maybe never. This is a personal opinion. The proper follow-up studies have not been made. We twice lost a large patient cohort that we were following in order to answer this question.

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  4. Sorry, I forgot to answer part of your question. Yes, younger individuals seem to have a better response. Again, the studies have not been made as clinical trials have usually involved children aged 8 and older. Researcher find that older aged individuals are more likely to comply with testing protocols.

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  5. I just learned of your research and TMS from your participation with the Autism Research Institute. I have several questions regarding this therapy for my kid with ASD in the area of speech. How can I get more information where this therapy is offered? Thank you in advance.

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    • TMS in autism remains experimental at present. You can go to clinicaltrials.gov and use its search function with key words (TMS/autism) to see if there is anything near to you. You can also examine the website of tertiary medical centers in your state and their Department of Psychiatry to see if they have a TMS unit. Also, you may approach the Clinical Transcranial Magnetic Stimulation Society to see if they know of somebody in your area. Wishing you well in your search. Best regards

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  6. Lots of tms centers have popped up around the nation and people are paying out of pocket for autism therapy off label.
    Our closest center does treatment just for depression on one part of the brain. But they do have autism patients who see benefits.

    There are other centers out west using qEEG to map the brain for areas that specifically need treatment and then TMS treatment is based on that individual. So, more than one area of the brain is stimulated.

    We have a young adult with HFA as well as depression, insomnia and other things. Is it worthwhile to go to one of the centers using qEEG with TMS? Or will the “one size fits all” treatment be as likely to help as the other?

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    • It is not a “one size fit all”, Many of these centers were established for financial reasons. They do not report their results in the literature which makes it difficult to judge their efficacy. These centers are set up to collect a few and can not judge their results against series of controls. Overall, I do not recommend the same.

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