Edited by: Lindsay M. Oberman, Brown University, USA
Reviewed by: Marco Iacoboni, University of California Los Angeles, USA; Paul Croarkin, Mayo Clinic, USA
*Correspondence: Manuel Fernando Casanova, Department of Psychiatry and Behavioral Sciences, University of Louisville, 500 South Preston Street, Louisville, 40202 KY, USA e-mail:
This article was submitted to the journal Frontiers in Human Neuroscience.
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The term autism spectrum disorder (ASD) describes a range of conditions characterized by impairments in social interactions, communication, and by restricted and repetitive behaviors. Autism spectrum disorder may also present with symptoms suggestive of autonomic nervous system (ANS) dysfunction. The objective of this study was to determine the effect of 18 sessions of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) on autonomic function in children with ASD by recording electrocardiogram (ECG) and electrodermal activity (EDA) pre- post- and during each rTMS session. The autonomic measures of interest in this study were R-R cardiointervals in EKG (R-R), time and frequency domain measures of heart rate variability (HRV) and skin conductance level (SCL). Heart rate variability measures such as R-R intervals, standard deviation of cardiac intervals, pNN50 (percentage of cardiointervals >50 ms different from preceding interval), power of high frequency (HF) and LF components of HRV spectrum, LF/HF ratio, were then derived from the recorded EKG. We expected that the course of 18 weekly inhibitory LF rTMS applied to the dorsolateral prefrontal cortex (DLPFC) would enhance autonomic balance by facilitating frontal inhibition of limbic activity thus resulting in decreased overall heart rate (HR), increased HRV (in a form of increased HF power), decreased LF power (resulting in decreased LF/HF ratio), and decreased SCL. Behavioral evaluations post-18 TMS showed decreased irritability, hyperactivity, stereotype behavior and compulsive behavior ratings while autonomic measures indicated a significant increase in cardiac interval variability and a decrease of tonic SCL. The results suggest that 18 sessions of LF rTMS in ASD results in increased cardiac vagal control and reduced sympathetic arousal.
Autism spectrum disorder (ASD) is characterized by difficulties in social interactions communication, and restricted and repetitive patterns of behaviors. In 2014, it was estimated by the Centers for Disease Control and Prevention (CDC) that ASD affects approximately 1 in 68 children (CDC’s Morbidity and Mortality Weekly Report,
Several types of autonomic dysfunctions have been reported in autism, including increased basal sympathetic tone (Hirstein et al.,
Poor control of HR and vulnerability to tachycardia is an important consequence of chronic increased sympathetic activity and decreased vagal tone (Berntson et al.,
Studies of the ANS in autism have demonstrated several manifestations of abnormal sympathetic functions (Ming et al.,
Recently there has been considerable interest on the effects of repetitive transcranial magnetic stimulation (rTMS) on cortical excitability. Biophysical foundations underlying TMS effects are reviewed in Wagner et al. (
Transcranial magnetic stimulation has already shown to be an effective neuromodulatory tool capable of altering ANS functions. In a paper by Udupa et al. (
The dorsolateral prefrontal cortex (DLPFC) was selected as a target for stimulation in our rTMS studies based on the topographical analysis of minicolumnar morphometry in cortices varying in cytoarchitectural differentiation: paralimbic, high-order (heteromodal) association, modality specific (unimodal) association, and idiotypic areas (Casanova et al.,
It is doubtful whether a pervasive neurodevelopmental disorder such as ASD could be explained in terms of pathology within a single brain area, i.e., DLPC. However, “normalizing” an area like the DLPFC whose physiology depends on distributed networks may provide beneficial cascading effects at secondary sites (Walsh and Pascual-Leone,
We hypothesized that rTMS stimulation applied bilaterally to the DLPFC would improve autonomic measures, more specifically, it was predicted that it would lower sympathetic arousal and normalize autonomic balance. Heart rate variability and SCL measurements were used to track changes in autonomic balance caused by rTMS. We chose to use HRV and SCL as indicators of the effectiveness of rTMS treatment because they are largely controlled by the ANS. The first measure, HRV, allowed us to observe differences in cardiac autonomic control, while the second measure, SCL, is controlled solely by sympathetic inputs and is therefore an excellent indicator of sympathetic nervous system activity. The expected outcomes were an increase in average R-R intervals in ECG, an increase in standard deviation of R-R intervals, an increase in the HF component of HRV, a decrease in the LF component of HRV, a decrease in the LF/HF ratio, increase in pNN50, as well as a decrease of SCL. We also predicted that the proposed intervention would provide for improvements in irritability, hyperactivity and repetitive behavior rating scales on the Aberrant Behavior Checklist (ABC; Aman and Singh,
In this study, we investigated the activity of the ANS during rTMS treatment in 18 children with ASD (14 boys and 4 girls, mean age 13.1 years, SD = 2.2). Participants with ASD were recruited through the University of Louisville Weisskopf Child Evaluation Center (WCEC). Diagnosis was made according to the DSM-IV-TR and further ascertained with the Autism Diagnostic Interview-Revised (ADI-R; Le Couteur et al.,
The study complied with all relevant national regulations and institutional policies and has been approved by the local Institutional Review Board (IRB). Participating subjects and their parents (or legal guardians) were provided with full information about the study including the purpose, requirements, responsibilities, reimbursement, risks, benefits, alternatives, and role of the local IRB. The consent and assent forms approved by the IRB were reviewed and explained to all subjects who expressed interest to participate. All questions were answered before consent signature was requested. If the individual agreed to participate, both she/he and parent/guardian signed and dated the consent or assent form and received a copy countersigned by the investigator who obtained consent.
A trained electrophysiologist delivered rTMS using a Magstim Rapid 220 system (Magstim Co, Whitland, UK). Patients were seated in a leather chair and fitted with a swimming head cap. Motor threshold (MT) was determined in the following manner: mild supra-threshold stimulations was administered over the left motor cortex to determine the optimal area for stimulation of the
For 3–5 min before rTMS, during ~10–12 min rTMS session, and immediately after the completion of the TMS for another 3–5 min the subjects had their physiological activity monitored and recorded. Therefore, all autonomic measures were recorded during each rTMS session in every participant for several minutes preceding TMS administration, then during TMS procedure, and also for several minutes after TMS session. For data analysis in this particular study were included only data during administration of TMS. We used approximately 10 min long period to calculate HRV variability measures (RR intervals, SDRR, LF and HF of HRV) derived from an artifact free ECG recording and mean SCL. In our other pilot studies (Hensley et al.,
The monitoring of ANS activity was conducted using C2 J&J Engineering Inc. (Poulsbo, WA) device with specialist USE-3 software application. The procedure of autonomic monitoring includes presentation of HRV measures in a form of cascading HRV spectrum, individual HRV components and SCL (both tonic and phasic changes) with visual and auditory feedback for experimenter. All physiological measures were analyzed both on- and off-line. Schematic presentation of the procedure is depicted at the Figure
Electrocardiogram, electromyogram (EMG), pneumogram (PNG), and EDA were acquired (1024 Hz sampling rate for EMG and ECG, 128 Hz for PNG and EDA) by a C-2 J&J Engineering Inc. physiological monitoring system with USE-3 software (Physiodata, Poulsbo, WA). Three Ag/AgCl electrodes (El-503, Biopac Systems, Inc., CA) were attached for measurement of Lead II ECG, 3 Ag/AgCl electrodes (EL-501 from Biopac) for EMG recording from the right hand, and PNG was recorded with a strain gauge transducer. Electrodermal activity was recorded by Ag/AgCl electrodes (EL-507 by Biopac with Unibase isotonic gel) attached to the distal phalanx of index and middle fingers to measure SCL.
Average R-R intervals in ECG (R-R), standard deviation of all normal R-R (NN) intervals (SDNN), Square root of the mean of the squares of successive NN interval differences (or the average change in interval between beats)— RMSSD, the percentage of intervals >50 ms different from preceding interval (pNN50); frequency domain HRV measures such as power of HF, LF, very low frequency (VLF) components, and the ratio of the LF over the HF (LF/HF ratio is used as an indirect autonomic balance index) of HRV are calculated as time domain and frequency domain cardiac activity measures (Kleiger et al.,
Respiration rate on per minute basis and peak respiration frequency were calculated. These measures were used to control HF peak in HRV related to respiratory frequencies in HRV and were not used as dependent measures.
Skin conductance level (in µS) and amplitude of the SCR, defined as fluctuation with more than 0.02 µS increment (Boucsein,
For the evaluation of social and behavioral functioning we utilized caregiver reports and clinician ratings of improvement. Every participant was evaluated before TMS course and within 2 weeks following TMS treatment. Aberrant Behavior Checklist (Aman and Singh,
The primary statistical analyses included linear regression estimation of each autonomic dependent variable over 18 sessions of rTMS course, paired sample
Cardiointervals in ECG (R-R intervals) showed a statistically significant linear regression over 18 sessions of rTMS (
Power of HF component of HRV showed a strong statistically significant linear increase (
Skin conductance level showed statistically significant liner regression over 18 sessions of rTMS (
The ABC and RBS behavioral checklists showed significant improvements in several areas. We found a significant decrease in stereotype repetitive and restricted behavior patterns following 18 sessions of bilateral rTMS as measured by the RBS-R (Bodfish et al.,
Results of the HRV analysis show several measures with significant differences between pre- and post-TMS therapy. Table
Measure | Units | R2 | Regression equation | Power at |
|||
---|---|---|---|---|---|---|---|
ms | 3.52 | 0.003 | 0.661 | 0.437 | 0.868 | ||
ms | 3.38 | 0.004 | 0.645 | 0.417 | 0.844 | ||
ms2 | 2.15 | 0.047 | 0.473 | 0.224 | 0.512 | ||
ms2 | −1.02 | 0.323 | 0.247 | 0.061 | 0.163 | ||
ms2 | 5.12 | <0.001 | 0.788 | 0.621 | 0.985 | ||
N/A | −3.83 | 0.001 | 0.691 | 0.478 | 0.913 | ||
µS | −3.71 | 0.002 | 0.681 | 0.464 | 0.948 |
Regression analysis was completed to observe trends during the entire 18 session TMS course. Table
Pairs | Paired differences | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Units | Mean | Std. Dev. | 95% CI | df | ||||||||
Lower | Upper | |||||||||||
ms | 39.08 | 53.61 | 70.04 | 8.13 | 2.73 | 13 | 0.017 | |||||
ms | 39.09 | 66.78 | 77.65 | 0.54 | 2.19 | 13 | 0.047 | |||||
ms2 | 1249.3 | 1556.1 | 2147.8 | 350.8 | 3.00 | 13 | 0.010 | |||||
N/A | −0.48 | 0.81 | −0.01 | −0.95 | −2.23 | 13 | 0.044 | |||||
µS | −4.37 | 5.65 | −1.11 | −7.64 | −2.89 | 13 | 0.013 |
All novel studies involving neuromodulation techniques in children should proceed with caution. Transcranial magnetic stimulation is a non-invasive intervention, which could be a potential strategy for early intervention for autism; however, the dose, duration, and type of rTMS stimulation for such intervention in children as well as effects on vital functions need to be carefully investigated and documented. This need requires proof of concept studies when testing the feasibility of using rTMS in order to modulate autonomic activity in ASD.
Results of our study indicate that HRV and EDA are noninvasive and effective ways of gathering information about ANS functioning during rTMS therapy in autism. Accelerated HR in association with lower HRV indexed by high LF/HF ratio and low SDNN along with high electrodermal activity (SCL) found in children with ASD at the pre-treatment stage are indicators of excessive sympathetic and reduced parasympathetic activation in ASD resulting in limited psychophysiological flexibility and behavioral rigidity. We investigated changes in autonomic activity during 18 rTMS sessions in the same children with ASD. Our hypothesis was that children with ASD would show improved HRV measures (decreased overall HR indexed by longer R-R intervals, increased STDRR, higher pNN50 index, increased HF power, decreased LF power, decreased LF/HF ratio, increased pNN50) and lower SCL measures. Our results showed that, except for a reduction in LF power and pNN50, all dependent HRV variables changed in the predicted way, as indexed by statistically significant liner regression coefficients over TMS sessions and statistically significant pre-
Time-domain HRV results showed that the most significant changes from TMS treatment were an increase in R-R cardiointerval length and a higher standard deviation of R-R intervals. Frequency-domain HRV results showed increase of HF power in HRV, and decreased LF/HF ratio. Electrodermal activity also showed a decrease in the form of lower tonic SCL. The increased standard deviation in cardiointervals along with higher power of HF of HRV and decreased LF/HF ratio are promising because this suggests more prominent parasympathetic activity and more flexibility in HR overall. Significant change was also observed in mean R-R interval lengths, which means a lower HR. Outcomes within the frequency-domain of HRV showed increased HF component of HRV, which is also of importance as it suggests enhancement of the parasympathetic tone. As we did not observe a statistical change in the LF component, it can be inferred that restoration of autonomic balance was achieved mainly through an increased HF component of HRV, which correlates to parasympathetic (vagus) cardiac neural control. However, while the change in the LF component was not significant, we did observe a decrease in SCL over the 18 sessions. This result suggests a withdrawal of sympathetic tone as SCL is controlled by sympathetic inputs. It should be noted that cardiac sympathetic influences are predominantly mediated through beta-adrenergic drives, while peripheral sympathetic control of sweat glands is exerted through alpha-adrenergic drives.
The question remains as to how does prefrontal rTMS affect autonomic functions? Only a few papers have looked at the effects of rTMS on the autonomic system, despite the fact that many frontal cortical areas are directly implicated in ANS control (Filippi et al.,
Low frequency rTMS can influence autonomic balance when using HRV (Yoshida et al.,
Another important question is how TMS affects cortical E/I balance. Several studies have outlined a disruption in the ratio between cortical excitation and inhibition in ASD (Casanova et al.,
By convention, rTMS in 0.3–1 Hz frequency range is referred to as “slow,” whereas “fast” rTMS refers to stimulation greater than 5 Hz. Hoffman and Cavus (
Some potential implications of TMS based neuromodulation could be considered in the context of other stimulation approaches and comorbidities proper to ASD. Excessive sympathetic arousal is often associated with anxiety. For children with ASD, especially during adolescence, anxiety is one of the most common presenting problems in clinical settings. Several research groups have reported that over 55% of sampled children with ASD meet criteria for at least one anxiety disorder (de Bruin et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The study was partially supported by National Institutes of Health Eureka R01 grant MH86784 to Manuel Fernando Casanova, M.D.