This week Science Over a Cuppa hosts our first guest scientist, Dr. Manuel F. Casanova. Manuel has his M.D. in Neurology, with extensive additional training and experience in neuropathology, especially of childhood conditions. From Manuel’s early training in childhood neuropathology, he developed a keen interest in autism spectrum conditions and has been hooked ever since. While he has had much clinical experience, he is no longer practicing and instead devotes his time fully to research. He is one of the preeminent researchers in the study of autism and has made notable contributions to the field, such as the study of minicolumnopathy in the condition, as well as the treatment of some of the symptoms of autism with low-frequency repetitive transcranial magnetic stimulation (rTMS), the subject of the following post [1, 2, 3]. He has a number of new exciting experiments in the works so stay tuned to his blog, Cortical Chauvinism, for further updates.
And now I give you my partner, Dr. Manuel Casanova, providing a general review of clinical rTMS and its use in the treatment of autism.
Transcranial Magnetic Stimulation (TMS) is a way of altering brain activity in awake patients. Whenever a changing magnetic field is applied to the cortex, the same induces the flow of electric current in conductors (in this case neurons) situated directly underneath. The magnetic fields, in the range of 1 Tesla, are powerful enough to induce neuronal depolarization. TMS can be applied as a single pulse or repetively (rTMS). Usually rTMS is used to alter the excitability of targeted areas of the cerebral cortex. Low (or slow) frequency rTMS, defined as <1Hz, increases inhibition whereas higher frequencies increase excitation. In the case of autism, only low-frequency rTMS is applied.
The figure illustrates the mechanism of action of TMS.
The procedure itself is quite simple and lasts some 30 minutes while the patient is seated on a reclining chair. Before an experiment/study begins the intensity of a pulse over the motor cortex needed to cause a motor response in a hand muscle is determined (motor threshold). The intensity of the stimulation will be adjusted subject to the pulse intensity of the motor threshold. In other words, the threshold for motor activity is used as a base so that instrumentation can be fine-tuned for each individual.
The technique itself is regarded as safe and has no lasting side effects. Some patients report tension-type headaches or complain about the noise due to the sound of the pulses. Sometimes earplugs are recommended to prevent discomfort. There is a very small risk for inducing a seizure and because of this patients with epilepsy or a family history of the same are usually excluded. To my knowledge seizures have only been reported with high frequency rTMS.
rTMS has been applied to a variety of psychiatric and neurological conditions including ADHD, major depression, bipolar depression, chronic pain, posttraumatic stress disorder, obsessive compulsive disorder, migraines, stroke, and Parkinson’s disease. It has been reported that rTMS may improve the mood of depressed patients after repeated stimulation of their frontal lobes [4]. In 2008, the FDA approved rTMS for the treatment of adult patients with Major Depression who had failed to achieve improvement with antidepressant medications [5].
In recent years, and probably due to the popularity gained by TMS, a different technique using transcranial direct current stimulation (tDCS) has surfaced. The technique uses battery power to supply the flow of low direct current between a pair of electrodes. tDCS works to increase or decrease neuronal excitability in targeted sites by changing the direction of current flow. Although the equipment is cheaper and easier to operate than rTMS, its effects are also smaller and experience in autism is quite limited.
In autism, our studies have shown that modular units of the cortex called minicolumns are abnormal. Minicolumns in autism lack a “buffer zone” that surrounds the same and isolates them from neighboring modules. The lack of buffer zone could affect the functional distinctiveness of minicolumnar activation and result in isolated islands of coordinated excitatory activity, e.g., seizures. This autonomous cortical activity may hinder the binding of associated cortical areas, arguably promoting the focus on “details” as opposed to “general features”.
The geometric orientation of inhibitory cells at the periphery of minicolumns makes it possible to modulate their activity by applying a variable magnetic field to the cortex. Furthermore, benefits of the therapy can be followed by using gamma frequencies (30-80 Hz) as the latter depends on the integrity of networks of inhibitory neurons. Our initial trials have shown significant improvements in gamma oscillations after as little as 12 sessions when slow rTMS is applied to the prefrontal cortex. We have also shown significant improvements in repetitive and restricted behavior patterns associated with autism.
In other studies by our group, slow rTMS minimizes a subject’s response to irrelevant stimuli and increases those to relevant ones, indicating increased selectivity and better stimulus differentiation (i.e., improved attention). In addition, we have been able to demonstrate a significant reduction in the percentage of errors in motor responses to target stimuli. Improvement in error detection and restricted behavior patterns appears to be mediated by increased coordination (or coherence) between different regions of the brain (see 6). The fact that rTMS-treated autistic patients show significant improvement in error detection and correction suggests improved executive functioning and behavioral performance.
Overall, our results with rTMS in autism suggest that it may be a promising therapy which can target the core symptoms of autism. Contrary to other therapeutic interventions that focus on accessory symptoms, rTMS has the potential of being curative and with little in terms of side effects. It’s especially comforting that we have gotten overwhelmingly positive feedback from families as well as the patients themselves, many who request to continue the therapy beyond the period allotted for the study.
Science Over a Cuppa 
Hi Manual Casanova –
Do you have any data, or wild guesses, on the mechanism by which a persistent behavioral effect of rTMS is achieved? If I understand correctly (a big if!), the minicolumn structure is set and locked in prenatally; so the only option I can speculate on would involve a change would be a sort of re-programming of the threshold of (de)polarization.
As a related question, do we have any data (or guesses) on neurochemical changes as a result of rTMS? Your data and some papers on neurofeedback are the only ones that I’ve seen that seem to focus on electrical change. I’m not sure if this is a function of a relative paucity of data or my own failings at pubmed-foo. Do we have animal models or anything else that gives us insight into the chemical modifications as a result of rTMS? I hope these questions aren’t too simplistic.
Thank you for working on autism.
– pD
My question echoes that of the previous comment, above,—that is, concerning the theory according to which the therapy is supposed to be effective. I wonder if the answer is to be found in your description here:
Is this essentially the reasoning on which the therapy is founded? If so, could you translate that into more familiar laymen’s terms or, if this isn’t the basis for the therapy’s effectiveness, I’m interested in a brief and simpflified word (if possible) on how this rTMS is thought to stimulate the desired effects. Thanks.
Hi pD,
Thank you for commenting on the blog. The effects of TMS are not persistent and rely on the plasticity of the brain to provide adaptive changes. It has been our experience that treated patients may need another course of TMS after about 6 months of the initial therapy. We hypothesize that the inhibitory elements surrounding the minicolumn are not working correctly and that slow frequency TMS may give them a boost. We have explained this at length in one of our publications in JADD 39(4):619-34, 2009. You can access the publication from pubmed or our web page: http://minicolumn.org/people/casanova/.
I do not have data on neurochemical changes propitiated by TMS. However, TMS has been used extensively in animals and some suggestions have been made in regards to the involvement of certain pathways (glutamate for high frequency stimulation see J Neurosci Res 90(5):1085-95, 2012, and antioxidant pathways for low-frequency stimulation see Brain Stimul 6(1):85-6, 2013). A useful review of animal models and how TMS can modulate cortical inhibition is provided by Funke K and Benali A. J Physiol 589(pt 18):4423-35, 2011.
Let me know if I can be of any additional help.
Best regards,
Manuel
Hi,
I have tried explaining the basis of the therapy in several publications. A simplistic explanation is provided in my blog site: http://corticalchauvinism.wordpress.com/. In terms of an analogy I would say that the cerebral cortex is made of modules called minicolumns. The function of these modules is to transmit information. You may think of them as pieces of insulated copper wire within an electrical circuit. The insulation surrounding the copper wire prevents electricity from jumping from one wire to another and providing a short circuit. The insulation of minicolumns is provided by inhibitory elements which appear to be abnormal in autism. In this condition information is no longer kept within individual minicolumns, but is allowed to jump to adjacent ones thus distorting the information they were carrying. Overall, abnormal insulation (or an inhibitory surround to minicolumns) translates into an amplification cascade, that is, a hyperexcitable cortex. This phenomenon may help explain the presence of sensory abnormalities and seizures in autistic individuals.
Let me know if I may be of any additional help.
Best regards,
Manuel
Hi Dr. Casanova:
I have a 13yo son with Autism, do you recommend TMS on young patients? He’s never had seizures, will TMS cause him to have seizures? Does TMS also work on language, one of this deficients is language although he can speak, his language is not at an age appropriate level. Look forward to your reply.
Take care,
Jeanne & Charles
We have had fairly young patients, starting at around 5 or 6 years of age. We have noticed the better results in the younger patients. The frequency of stimulation we use is very low and is meant to increase the inhibitory tone of the cortex. Seizures, to my knowledge, have only been reported with high frequencies. There have been few side effects, e.g. headaches and complains about noise during therapy. I have not observed changes in language. I have not seen a non-verbal individual regain language after therapy. On the other hand I have heard of improvements in this area from other providers.
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Thank you for your study-blogging. Keeps overwhelmed parents from wading through scientific jargon.: ) I read your comment about repeat therapy 6 months after initial treatment. And then? Would that be it, or would the 6-month intervals continue?
Also, is there a standard in terms of training to use the TMS equipment? If TMS becomes available locally–how would I know to trust the practitioner? Considering the brain’s plasticity, it seems some wild aberrations could occur if the practitioner was not genuinely skilled.
Thank you,
Cynthia
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Will rTMS work on an individual on the spectrum in his early 20s, or is it too late at that point?