cool new study by manuel casanova's group with TMS and neurofeedback

Those familiar with my novel, "The Mu Rhythm Bluff", know that I wrote a fictional account of a high-functioning individual with autism who undergoes a study involving neurofeedback (training to control certain types of brainwaves) and transcranial magnetic stimulation, a technique in which specific areas of the brain can be stimulated magnetically to induce or suppress the firing of neurons in the targeted area.  Recently non-fiction has imitated my art in a study  published by Manuel Casanova's research group. 

As I wrote in my novel (and in a blog post)  about how Mu rhythms are abnormal in autistic people and how they can be trained via neurofeedback and enabling autistic people to have improved functioning, at least according to one controlled study.  Gamma is another type of brain wave that has been found to be aberrant in autistic people in various studies.  Casanova's group has done studies showing brain abnormalities (particularly in a structure called the minicolumn) in the area of the dorsolateral prefrontal cortex of the brain.  They've attempted to treat this by applying TMS to this area. 

This current study is unique in that it is probably the first study of its kind that combines both neurofeedback and TMS to attempt to mitigate autistic symptomatology in a group of experimental subjects.  The study used 42 autistic subjects.  20 of them were put into an experimental group that used combined neurofeedback therapy to improve gamma wave abnormalities accentuated by transcranial magnetic stimulation to the dorsolateral prefrontal cortex.  The remaining subjects were placed in a waitlist control group.  The subjects all had IQs greater than 80, so people with severe intellectual disability were excluded.  Participants with a history of seizure disorder, genetic conditions, etc. were also excluded which I guess is common in a lot of studies like these.  One of the interesting thing about the research subject pool is that it consisted of 34 males and 8 females which mirrors the male to female ratio of those on the spectrum in the general population of autistic people. More interestingly, the male to female ratio is probably even greater in a high-functioning group such as this where most of the participants have a normal or at least a near normal intelligence as measured by IQ test.  So, if anything, there was a high preponderance of females in the study.  This is in contrast with many studies such as this where nearly all or sometimes even all of the subjects are males. 

The subjects in the treatment group had regular sessions of both TMS and neurofeedback.  On evaluations using portions of the aberrant behavior checklist and Repetitive Behavior Scale, the treatment subjects improved far more than the waitlist controls.  Also their gamma function was improved over the controls as well as responses to various event related potential tests. 

Though interesting, the study seemed to have a few problems and limitations.  The group was rated on these measures both by caretakers and a trained psychologist.  The authors neglected to mention whether the raters were blinded to the identities of who was in the treatment group and who was in the waitlist group.  I emailed Dr. C asking him about this and he told me that the psychologist who did the ratings was blind to the purpose of the experiment, but I'm not sure if that means whether or not he knew there was an experiment and knew who was in the waitlist group and the treatment group.  I'm not sure if the caretakers knew whether or not their charge was in the control group or the waitlist group.  I neglected to ask Dr. Casanova about this and it is unclear to me.  I'm not sure how reliable caretaker and parental ratings are as they are often subjective and biased and seem to want to believe their child is improving when that is not necessarily the case. 

Another problem is that assignment to the experimental and control groups were not really randomized as there were factors and treatment choices that influenced whether a subject went into a waitlist group or treatment group. I'm not sure how much if at all this affected the outcome of the study, but Casanova and company admitted to this and stated they hoped to do a more randomized trial at some point.

Ideally, subjects would be placed in treatment and control groups at random with the control group using a sham treatment and the experimental group receiving the real treatment.  This is how I had them do it in "The Mu Rhythm Bluff".  In the real world, however, there are practical limitations in that sham TMS  treatment has been easily identified by persons in control groups and has not really been practical.  I'm not sure if sham neurofeedback is feasible.  Also, there may be ethical considerations in randomizing people in a study where controls would arbitrarily be deprived of a beneficial treatment.

Another problem that the group acknowledged was that the TMS was more limited than in other treatment protocols such as those with adults being treated for depression with TMS.  The group was comprised largely of children (ranging in age from 10 to 21 years old with the average age being about 14-1/2), so they thought that the children might be more vulnerable to an intense treatment.

Another issue I'm curious about is that not only has Casanova found minicolumn abnormalities in the frontal and temporal areas of the brain, but also in the anterior cingulate area.  I'm not sure if TMS of this area was used or not and whether that would factor into the results or if an experiment might need to be modified to account for this.  Not only have Casanova et. al. chosen the dorsolateral prefontal cortex to stimulate with TMS because of the minicolumn abnormalities found there, but also because it has rich interconnections to other brain areas that will help with the so-called cascading effect that TMS has so other areas of the brain will be influenced.  I write a bit more about this below.  

I also wonder if there will be any long term follow-up of these kids into adulthood where we can really assess the benefits of this treatment.  We will see if they can complete college, find a good job, get married, etc.  (In other words, do a lot of things normal adults do that the majority of persons on the spectrum won't be able to do without treatment).  Logistically, it may be hard to follow people into adult years.  This may have been the problem in Lovaas (1987) where attempts were made to follow the children into adulthood and funding granted for this purpose and informal presentations made at conferences but no actual studies reported on what happened to the kids as adults and if they maintained the so-called normal functioning.

Another issue I'm curious about is whether other structures of the brain besides the dorsolateral prefrontal cortex will be influenced.  Though TMS is very specific for what areas of the brain can be stimulated, the magnet only covers a couple of inches within the cerebral cortex and won't go to deep layers of the brain where areas of the limbic system such as the amygdala and hippocampus are located.  Of course, Dr. C has written about a so-called cascading effect of TMS where various parts of the brain are interconnected and can influence each other so that this treatment might influence the structures that are deeper within the brain and not just on the surface of the cerebral cortex.  I didn't write to Dr. C about this, but on a side note, I did ask him a question about whether the pyramidal cells in the prefrontal cortex thought to be involved in autism were connected to the nucleus accumbens which is an area of the brain involved in pleasurable activities such as drug use.  I knew that some of those were connected to the NA and thought that perhaps they were inhibitory cells that contained GABA as a neurotransmitter which had been found to be deficient in the minicolumns that Casanova had found to be abnormal.  I thought that perhaps this could explain my twiddling (self-stimulatory behavior) in that there was some hidden motor pleasure center that was inhibited by GABA in typical people whose prefrontal cells were connected to the nucleus accumbens.  He told me that the pyramidal cells did in fact have connections to the nucleus accumbens but they were excitatory cells that did not use GABA as a neurotransmitter.  So, I guess that's one straw I've been gasping at to find out what is wrong with myself that did not work out.

And, of course, another limitation was the use of higher functioning autistics.  We have to wonder how persons with IQs below 80 would respond to paradigms such as this one.  This is a problem rampant in autism research and not just particular to this study.  There are compliance issues with people on the lower end of the spectrum and other problems that would make them unsuitable as research subjects given the current state of the art.  

For years, I've wondered why I have these symptoms.  If, in fact, it is due to some sort of dysfunction in the brain, how is my brain different.  Why do I have to twiddle, have motor coordination problems, social problems impairing my ability to relate to people and a fear of birds and dogs I am not familiar with? Also, is it possible some sort of neuromodulation of the type that the Casanova group is experimenting with that could help these problems in me and also people like myself.  I have to ponder all this, thinking I've come upon some new thing that will enable me to understand myself and help me and everytime I seem to come to a dead end.  I don't know if research in neuromodulation such as this will help, but I find it very intriguing and I hope to be able to follow it and understand as much of it as possible, even given the limitations my disability puts upon me.