Treating Autism Spectrum Disorders (ASDs)

Autism in DSM5 is characterized as one of the so-called pervasive developmental disorders (PDD) which also includes Asperger’s disorder and other pervasive developmental disorders not hereto specified.

These groups of disorders are collectively called autism spectrum disorders (ASD). ASDs are characterized by impairments in social skills, repetitive behavior, and the communicative use of verbal and nonverbal language.

Children with restricted and repetitive behavior share features such as intricacies of behavior and the inability to grasp concepts. ASD affects about 1 in 60 children, but there are currently no pharmaceutical treatments that can target the core networks implicated in ASD.

Recent evidence shows that repetitive transcranial magnetic stimulation (rTMS) holds high potential to alleviate the main symptoms of individuals with ASD.

Individuals with autism have a Unique Brain Complexity

The primary symptoms caused by social and executive function (EF) deficits in ASD have been treated by standard rTMS by using theta-burst stimulation to prefrontal regions, including the right inferior frontal gyrus1. In other words, standard rTMS treatments of ASD have shown significant alleviation of clinical symptoms in ASD. EF deficits in ASD cause poor adaptive functioning in socialization and communication in childhood, adolescence and adulthood.

Therefore, EF deficits have been the target of interventions to improve function and independence in children and young adults with ASD. In the treatment of EF deficits, standard rTMS has been applied to the dorsolateral prefrontal cortex (DLPFC) with favorable results.

There is strong evidence that rTMS improves symptoms in young people with ASD. Our experience indicates that rTMS applied to DLPFC has efficacy as a novel intervention for EF deficits in ASD.

By leveraging our rsFC MRI technology we give TMS the capability to directly treat malfunctioning regions and acquire pre-/post-treatment neuroimaging measures, to document the effect of treatment on brain structures that are essential for EF performance.

This capability allows us to examine the neural mechanisms for rTMS treatment efficacy. We also use a longitudinal follow-up that enables us to assess the need for ongoing intervention to maintain treatment effects.

How we use rTMS in ASDs

As in depression, the standard rTMS in ASD uses the site of treatment based upon fixed location relative to the motor cortex. For depression, it has been shown that differences in the clinical efficacy of different left dorsolateral prefrontal cortex (DLPFC) stimulation sites are related to differences in the connectivity of these sites to deeper limbic regions, especially the subgenual cingulate (sgACC).

Target sites in the left DLPFC with the best rTMS antidepressant efficacy showed the strongest anticorrelated resting-state functional connectivity (rsFC) with the sgACC.

Since autism is a disorder of the association cortex, and in particular, a disorder of connectivity that primarily involves intra-hemispheric connectivity, for treating ASD a connectivity-based targeting strategy for TMS would be to identify optimal TMS target coordinates in the bilateral DLPFC. We—uniquely—have such capability.

Treatment Based on Networks

Our prior experience suggests that in ASD with a predominance of social-cognitive malfunctions, our technology enables us to:

(i) measure changes in resting-state functional connectivity (rsFC) between nodes of involved networks, e.g., Theory of Mind (ToM) network of prefrontal cortex, orbitofrontal cortex, supplementary areas, anterior cingulate cortex, posterior cingulate, superior temporal cortex, superior/middle temporal gyrus and inferior parietal lobe regions, with the culprit deep nuclei regions, e.g., ventral anterior nucleus of the thalamus. Such comparisons yield correlations that mediate treatment response and,

(ii) we use a connectivity-based targeting approach applied at the single-subject level to identify optimized bilateral targets in the prefrontal cortex for TMS to individualize therapy. We, therefore, offer a novel, innovative approach with enhanced efficacy TMS guided by rsFC MRI.

This approach is fundamentally different from traditional approaches that target without looking into your brain or understanding differences in brain organization. Indeed, our approach stimulates the brain based on the individual brain’s rsFC pattern.

Our emphasis is on the network architecture of the human brain and as such we use rsFC MRI to construct the networks implicated in each disorder.

Concerning ASD, evidence such as the generalized dysfunction of the association cortex with sparing of primary sensory and motor cortex and white matter, combined with the absence of clinical signs of focal brain dysfunction, common in children with hypoxic-ischemic injury and cerebral palsy, such as visuospatial deficits, points to a distributed neural systems abnormality.

Significant Clinical Improvement

Decreased connectivity within/between superior temporal sulcus and inferior frontal gyrus in a patient with autism prior to treatment

This is why our treatment is based on networks. Others have used EEG-based functional connectivity to guide their TMS treatment of ASD. They reported a significant clinical improvement in their ASD group, not only in repetitive and restricted behavior patterns and irritability domains but also in social aspects and communication. They also reported that the effects persisted into the sixth month after completion of treatment.

These results are very important findings because, in comparison, our results indicate that patients under an anatomically precise technique would experience longer-lasting clinical improvements. Of course, rsFC MRI is capable of achieving more long-term outcomes.

Normal connectivity within/between superior temporal sulcus and inferior frontal gyrus in healthy volunteers matching age/sex

Our results reproduce similar neuromodulatory effects to those reported previously by two other research groups who used the same target (DLPFC), applying either rTMS or tDCS2,3. The use of therapeutic TMS in autism, even for one weekly application, produces a significant reduction in repetitive and restricted behavior patterns and irritability.

In our practice, rsFC MRI is guiding target’s selection based on the individual pattern of brain activity and connectivity for treatments to produce considerably higher efficacy. This is in correspondence with our observation of the efficacy of rsFC MRI guided TMS in other disorders such as depression, obsessive-compulsive, chronic pain, etc., in order to obtain a sustained effect.


References

1. Stephanie H. Ameis, Zafiris J. Daskalakis, Daniel M. Blumberger, Pushpal Desarkar, Irene Drmic, Donald J. Mabbott, Meng-Chuan Lai, Paul E. Croarkin, Peter Szatmari. Repetitive Transcranial Magnetic Stimulation for the Treatment of Executive Function Deficits in Autism Spectrum Disorder: Clinical Trial Approach. J Child Adolesc Psychopharmacol. 2017 Jun 1; 27(5): 413–421.

2. Oberman, L. M., Enticott, P. G., Casanova, M. F., Rotenberg, A., Pascual-Leone, A., McCracken, J. T., & TMS in ASD Consensus Group (2016). Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. Autism Res. 2016 Feb; 9(2): 184–203.

3. Hameed, M. Q., Dhamne, S. C., Gersner, R., Kaye, H. L., Oberman, L. M., Pascual-Leone, A., & Rotenberg, A. Transcranial Magnetic and Direct Current Stimulation in Children. Curr Neurol Neurosci Rep. 2017 Feb;17(2):11.

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Neurotherapeutix is the leading clinic for functional imaging guided transcranial magnetic stimulation (TMS), a safe, innovative, and non-invasive methodology for treating a wide range of acute and chronic mental disorders and brain injuries. Our advanced fMRI technology allows us to map the brain for the... Learn More »

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