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NeuroRegulation http://www.isnr.org
65 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
Neuromodulation Based on rTMS Affects Behavioral Measures
and Autonomic Nervous System Activity in Children with Autism
Guela E. Sokhadze1, Manuel F. Casanova1,2,3, Desmond P. Kelly2,3, Emily L. Casanova2,
Brook Russell4, and Estate M. Sokhadze1,2*
1University of Louisville, Louisville, Kentucky, USA
2University of South Carolina, School of Medicine, Greenville, South Carolina, USA
3Greenville Health System, Greenville, South Carolina, USA
4Clemson University, Clemson, South Carolina, USA
Abstract
Many children with autism spectrum disorder (ASD) exhibit symptoms associated with autonomic nervous system
(ANS) dysfunction indicative of low psychophysiological flexibility. It is suggested that ASD symptoms are
associated with generalized abnormalities in the central nervous system, including structures and networks
involved in the top-down regulation of the ANS. Repetitive transcranial magnetic stimulation (rTMS) has been
suggested as a possible therapy to target ANS regulation deficits in ASD. In the current study we used
neuromodulation based on rTMS over the dorsolateral prefrontal cortex (DLPFC) to reduce sympathetic arousal
and increase parasympathetic activity in children with ASD. In a study on 27 children with autism we
administered weekly 0.5 Hz rTMS bilaterally over the DLPFC with concurrent recording of autonomic activity.
Statistical analysis of time and frequency domain heart rate variability (HRV) indices and skin conductance level
(SCL) revealed a strong linear regression of most HRV and SCL measures. Several parental behavioral rating
scores improved post-TMS and showed a correlation with autonomic outcomes; in particular, parasympathetic
indices of HRV negatively correlated with repetitive and stereotyped behaviors, while sympathetic arousal indices
showed positive correlation with the same behaviors. The paper discusses potential neurobiological mechanisms
involved in post-TMS autonomic balance and aberrant behavior improvements.
Keywords: autism; rTMS; autonomic activity; repetitive and stereotype behaviors; prefrontal cortex
Citation: Sokhadze, G. E., Casanova, M. F., Kelly, D. P., Casanova, E. L., Russell, B., & Sokhadze, E. M. (2017). Neuromodulation based on
rTMS affects behavioral measures and autonomic nervous system activity in children with autism. NeuroRegulation, 4(2), 65–78.
http://dx.doi.org/10.15540/nr.4.2.65
*Address correspondence to: Dr. Estate Sokhadze, Department of
Biomedical Sciences, University of South Carolina School of
Medicine Greenville, GHS Pediatrics, 200 Patewood Dr., Ste A200,
Greenville, SC 29615, USA. Email: sokhadze@greenvillemed.sc.edu
Copyright: © 2017. Sokhadze et al. This is an Open Access article
distributed under the terms of the Creative Commons Attribution
License (CC-BY).
Edited by:
Rex L. Cannon, PhD, Knoxville Neurofeedback Group, Knoxville,
Tennessee, USA
Reviewed by:
Rex L. Cannon, PhD, Knoxville Neurofeedback Group, Knoxville,
Tennessee, USA
Randall Lyle, PhD, Mount Mercy University, Cedar Rapids, Iowa,
USA
Introduction
Autism spectrum disorder (ASD) is characterized by
deficits in social interaction and communication as
well as restricted, repetitive, and stereotyped
behavioral patterns (APA, 2013). A frequently
reported symptom of ASD is autonomic nervous
system (ANS) dysfunction observed during exposure
to sensory stimuli, engagement in social interaction,
and resting state. Children and adolescents with
ASD have been reported to have high sympathetic
tone and low parasympathetic tone compared to
controls (Benevides & Lane, 2015; Kushki, Brian,
Dupuis, & Anagnostou, 2014; Ming et al., 2011;
Ming, Julu, Brimacombe, Connor, & Daniels, 2005).
This abnormal autonomic balance is indicative of low
psychophysiological flexibility and rigid social
communication ability (Thayer & Lane, 2000). An
extensive body of literature suggests that ASD
symptoms are associated with generalized
abnormalities in the central nervous system,
including structures and networks involved in “top-
down” control of the ANS. For example, ASD has
been associated with pathological findings in
Sokhadze et al. NeuroRegulation
66 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
structures that play a crucial role in modulating the
ANS response, including the amygdala, anterior
cingulate cortex, and insula (Loveland, Bachevalier,
Pearson, & Lane, 2008). According to recent
studies, ASD may be associated with autonomic
arousal typical for anxiety that is most consistent
with sympathetic overarousal and parasympathetic
underarousal (Kushki et al., 2013). According to
some authors, anxiety in people diagnosed with
autism should be recognized for its direct links with
atypical autonomic control and excessive
sympathetic arousal (Gillott, Furniss, & Walter, 2001;
Helverschou & Martinsen, 2011). The ANS is
responsible for multiple physiological responses,
and dysfunction of this system is often hypothesized
as contributing to abnormal cognitive, affective, and
behavioral responses in children with autism
(Benevides & Lane, 2015; Smeekens, Didden, &
Verhoeven, 2015). Exploring the relationship
between ANS function and social competence is
important to gaining an understanding of how
dysregulation of autonomic activity may adversely
affect social functioning in individuals with ASD.
Transcranial magnetic stimulation (TMS)-based
neuromodulation
Repetitive transcranial magnetic stimulation (rTMS)
has been suggested by our group as a therapeutic
attempt at overcoming ANS regulation deficits
typically observed in individuals with ASD
(Casanova et al., 2014; Hensley, El-Baz, Casanova,
& Sokhadze, 2013; Hensley et al., 2012). In the
current study we propose using low-frequency rTMS
over the dorsolateral prefrontal cortex (DLPFC) to
reduce sympathetic arousal and increase
parasympathetic activity, thus improving autonomic
balance in children with ASD. The approach uses
rTMS to induce changes in ANS activity (shown in
our preliminary results, Casanova et al., 2014; Wang
et al., 2016) to lower aberrant behavior, stereotyped
and repetitive behaviors, and anxiety symptoms as
well as to improve social awareness and social
cognition children with ASD.
TMS operates based on Faraday’s law of
electromagnetic induction, which describes the
process by which a changing magnetic field induces
the flow of electric current in a nearby conductor,
preferentially one standing at a 90º angle to the
magnetic field. Studies have indicated that low-
frequency or ‘‘slow’’ rTMS (< 1 Hz) increases
inhibition of the stimulated cortex through activation
of inhibitory cortical circuits (Pascual-Leone, Walsh,
& Rothwell, 2000). The proposed mechanism of
post-TMS effects on autonomic arousal may include
improved normative tonic frontolimbic inhibitory
influences known to be deficient in autism
(Bachevalier & Loveland, 2006; Loveland et al.,
2008). We hypothesized that slow rTMS stimulation
applied to the DLPFC will lower sympathetic arousal
and normalize autonomic balance.
Theoretical rationale for the proposed intervention
was based on a “minicolumnar” neuropathological
model of autism (reviewed in Casanova, Sokhadze,
Opris, Wang, & Li, 2015). Prior studies from our
group suggest that supernumerary minicolumns and
reduced cell size of pyramidal cells biases cortico-
cortical connections in favor of short (i.e., arcuate)
projections at the expense of longer ones (i.e., long
association fibers). Furthermore, the abnormal width
of minicolumns in autism reflects primarily a loss of
the inhibitory tone of anatomical elements
surrounding this modular structure, resulting in a
reduced lateral inhibition effect (Casanova, 2005,
2006; Casanova, Buxhoeveden, & Brown, 2002;
Casanova et al., 2006). The minicolumnar
abnormalities are even more pronounced in the
prefrontal cortex (PFC), resulting in weakened
frontal control of other cortical and subcortical
networks, including those involved in regulating ANS
arousal (Casanova et al., 2014, 2015). We theorize
that contrary to other inhibitory cells (such as basket
cells and chandelier cells whose projections keep no
constant relation to the surface of the cortex), the
geometrically exact orientation of double-bouquet
cells and their location at the periphery of the
minicolumn (inhibitory surround) make them an
appropriate candidate for induction by a magnetic
field applied parallel to the PFC. Over a course of
treatment, slow rTMS may selectively depotentiate
enhanced synaptic weights associated with
pathological conditions, and in the case of ASD it
may lower the cortical excitation/inhibition ratio.
Review of autonomic dysfunctions in autism
Cardiac activity. In autism, ANS dysfunction
includes blunted cardiac responses to visual and
auditory social stimuli (Hirstein, Iversen, &
Ramachandran, 2001; Palkovitz & Wiesenfeld,
1980). These responses are important for
understanding social situations and awareness of
social context during communication (Jansen et al.,
2000). Developmental deficits in autonomic
regulation of the cardiac activity in children with
autism may result in a lower ability to engage in
social communication (Porges, 2003; Porges,
Doussard-Roosevelt, Portales, & Greenspan, 1996).
In addition to increased sympathetic tone, a
decrease in cardiac parasympathetic tone has been
often reported in ASD (Kushki et al., 2013, 2014;
Ming et al., 2005, 2011; Ming, Julu, Wark,
Sokhadze et al. NeuroRegulation
67 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
Apartopoulos, & Hansen, 2004). Julu et al. (2001)
reported reduced cardiac vagal tone, decreased
baroreflex sensitivity, and unstable respiratory
rhythm in individuals diagnosed with autism. The
respiratory dysrhythmia in children with ASD,
according to Ming, Patel, Kang, Chokroverty, and
Julu (2016), is a phenomenon associated with lower
cardiac vagal activity. Both respiratory and cardiac
vagal control hypofunction in ASD may suggest a
brainstem dysfunction or diminished top-down
control of the PFC over limbic and subcortical
structures (Bachevalier & Loveland, 2006; Loveland
et al., 2008). Low parasympathetic activity can help
explain chronic sensory hyperarousal and some of
the social communication difficulties in children with
ASD. This hypothesis is concordant with Porges’
“polyvagal theory” (Porges, 2003, 2011) that
emphasizes the important role of both efferents and
afferents of the vagus nerve in support of social
engagement and communication. The inhibitory
parasympathetic vagus nerve acts as a vagal
“brake” that slows heart rate (HR). Such modulation
of HR enables rapid engagement and
disengagement with objects and people, a skill
important for promoting social behaviors (Porges,
1995, 2003).
Time and frequency domain-based analysis of heart
rate variability (i.e., HRV) represents a measure
commonly used in psychopathology research for
assessment of cardiac autonomic control (Berntson
et al., 1997; Cohen, 2000; Thayer & Friedman,
2002). Attenuated spectral power of high frequency
(HF) component of HRV, frequently used as an
index of parasympathetic control, is an indicator of
limited psychophysiological flexibility (Berntson et
al., 1997; Cohen et al., 2000; Movius & Allen, 2005;
Thayer, Ahs, Fredrikson, Sollers, & Wager, 2012).
Children diagnosed with ASD have been found to
have deficits in suppression of HF component of
HRV during social tasks, compared to controls
(Althaus, Mulder, Mulder, Aarnoudse, & Minderaa,
1999; Hutt, Forrest, & Richer, 1975). Furthermore,
children with ASD demonstrate dampened HR
reactivity, unusually small deceleratory HR
responses, and generally low cardiac reactions to
auditory stimulation including socially relevant
speech, phrases, and tones (Corona, Dissanayake,
Arbelle, Wellington, & Sigman, 1998; Palkovitz &
Wiesenfeld, 1980; Zahn, Rumsey, & Van Kammen,
1987). Kleberg (2015) emphasized that atypical
autonomic arousal has been used to explain some
of the core symptoms of ASD. In effect, it has been
hypothesized that either elevated or attenuated tonic
arousal was a causal factor behind some of the core
autism symptoms, such as repetitive behaviors
(Hirstein et al., 2001; Toichi & Kamio, 2003; Toichi et
al., 1999) and avoidance of social interaction
(Rogers & Ozonoff, 2005). According to other
current theories, atypical regulation of arousal could
cause impairment in attention, another symptom
commonly associated with ASD (Orekhova &
Stroganova, 2014). A series of current studies of
autonomic dysfunctions in ASD were reported in the
literature showing drastically increased interest in
the investigation of autonomic system functioning
abnormalities in children with autism (Benevides &
Lane, 2015; Cohen, Masyn, Mastergeorge, & Hessl,
2015; Kleberg, 2015; Kushki et al., 2013, 2014;
Patriquin, Lorenzi, & Scarpa, 2013; Smeekens et al.,
2015). As noted by Rees (2014), there is an urgent
need to recognize the importance of the ANS in
pediatrics, not limited to neurodevelopmental
disorders.
Electrodermal activity. Electrodermal activity is a
commonly used measure in psychophysiology and
cognitive neuroscience research as it reflects
sympathetic neural responses independent of direct
parasympathetic control, or as its activity may reflect
effects of adrenaline (Boucsein, 2012; Williams et
al., 2004). Studies of skin conductance level (SCL)
in autism have demonstrated several manifestations
of abnormal sympathetic function (Ming et al., 2004,
2005, 2011, 2016). Classical psychophysiological
studies of skin conductance response (SCR) in
children with autism have shown a lack of the
normal habituation in the magnitudes of SCR to the
same stimulus presented over time, and they
demonstrate poor adaptation to a repeated stimulus
(Barry & James, 1988; van Engeland, 1984).
Furthermore, higher tonic electrodermal activity, as
well as larger SCRs to sounds, was observed in
autistic children compared to controls (Barry &
James, 1988). Palkovitz and Wiesenfeld (1980) did
not find differences in electrodermal reactivity to
auditory stimulation compared to controls, but
reported that the autistic group had a higher
baseline SCL. In addition, it has been reported that
children with autism had blunted autonomic arousal
to visual and auditory social stimuli (Hirstein et al.,
2001; Ming et al., 2016; Zahn et al., 1987). Several
of our own pilot studies reported excessive but less
differentiated SCR to affective sounds, visual, and
audio-visual stimuli in various affective stimulation
tests (Dombroski et al., 2014; Sokhadze et al.,
2012). Since SCL is controlled solely by
sympathetic inputs, the above effects are indications
of high sympathetic tone and at the same time
relatively low selectivity of ANS responses to
sensory stimuli in autism. High sympathetic
reactivity to sound may underlie the atypical
Sokhadze et al. NeuroRegulation
68 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
behavioral responses to sound often demonstrated
by children with ASD (Chang et al., 2012).
Liss, Saulnier, Fein, and Kinsbourne (2006)
suggested that the overfocused attentional style in
ASD may be the result of hyperarousal, while
Keehn, Müller, and Townsend (2013) hypothesized
that atypical behavioral arousal regulation in persons
with ASD results from early deficits in disengaging
attention. The term “arousal” was originally used to
describe both behavior and physiological activity,
including its cortical and autonomic components
(Lacey & Lacey, 1970). The most widely used
measures of autonomic arousal are the tonic SCL
and spontaneous and stimulus–related fluctuations
in electrodermal activity along with reduced HRV.
Schoen, Miller, Brett-Green, and Nielsen (2009)
have found that most children with autism had high
SCL (high tonic arousal) associated with higher than
normal SCR magnitudes, faster latencies, and
slower habituation.
Goals of the study
The aim of this case series study was to investigate
the effects of 18 weekly sessions of low-frequency
(0.5 Hz) rTMS over DLPFC on autonomic function
measures and on behavioral symptoms (based on
parental behavioral reports) in children with ASD.
We predicted that the course of rTMS would have
positive effects on behavioral rating scores similar to
those reported in our prior studies (Casanova et al.,
2014; Hensley et al., 2012, 2013; Wang et al.,
2016). In particular, based on our pilot studies, we
expected that the proposed rTMS therapy would
provide for improvements in irritability, hyperactivity,
and repetitive stereotyped behavior rating scales on
the Aberrant Behavior Checklist (ABC; Aman &
Singh, 1994) and Repetitive Behavior Scale (RBS-R;
Bodfish, Symons, & Lewis, 1999). In addition, we
used the Social Responsiveness Scale (SRS-2,
Constantino & Gruber, 2005) to assess changes in
social awareness, social cognition, and social
motivation. We hypothesized that the behavioral
improvement would also be manifested in autonomic
measures indicative of lower sympathetic arousal,
increased parasympathetic tone, and normalized
cardiac autonomic balance.
Methods
Subjects
In this study, we investigated the activity of the ANS
during rTMS treatment course in 27 children with
ASD (21 boys and 6 girls, mean age 12.52 ± 2.85
years). 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; LeCouteur, Lord, & Rutter, 2003) by a clinical
psychologist, who also did pre- and post-TMS
behavioral evaluations using ABC, RBS-R, and
SRS-2. Children with a history of a seizure disorder,
significant hearing or visual impairment, identified
brain abnormality, identified genetic disorder, or
comorbid severe psychopathology were excluded.
Subjects were excluded at the intake stage if they
were unable to tolerate TMS or autonomic
monitoring procedures such as placement of
adhesive electrodes and sensors on their skin.
Medication of enrolled subjects was monitored, but
subjects were not taken off prescribed medications.
All participants were high-functioning children with
ASD and with full-scale IQs > 80 assessed using the
Wechsler Intelligence Scale for Children, Fourth
Edition (WISC-IV; Wechsler, 2004). Twenty-nine
ASD subjects out of 32 enrolled in the study
completed all 18 sessions of rTMS. Two subjects
had excessive gross movements and artifacts
affecting autonomic activity recording and their data
were not entered into final analysis.
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 were
provided with full information about the study
including the purpose, requirements, responsibilities,
reimbursement, risks, benefits, alternatives, and the
role of the local IRB. The consent and assent forms
approved by the IRB were reviewed and explained
to all subjects who expressed interest in
participating. All questions were answered before
consent/assent signature was requested. If the
individual agreed to participate, both the child and
parent/guardian signed and dated the informed
consent/assent forms and received a copy
countersigned by the investigator who obtained
consent.
Sokhadze et al. NeuroRegulation
69 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
Low-frequency rTMS procedure
A trained electrophysiologist delivered rTMS using a
Magstim Rapid system (Magstim Co, Whitland, UK).
Participants were seated in a reclining chair and
fitted with a swimming cap. Motor threshold at the
first session was detected by mild supra-threshold
stimulations administered over the left motor cortex
to determine the optimal area for stimulation of the
abductor pollicis brevis muscle of the right hand.
The output of the machine was increased by 7%
each time until the least amount of machine power
that induced a 50-V deflection or a visible twitch
was identified in four out of five trials over the
cortical area controlling the contralateral abductor
pollicis brevis muscle. Surface electrodes were
attached over the abductor pollicis brevis and first
dorsal interossei areas. Electromyographic (EMG)
responses (motor-evoked potentials) were recorded
using the C2 J&J Engineering Inc. (Poulsbo, WA)
physiological data acquisition system with USE
software interfaced with Magstim TMS device.
Similar procedure was applied to determine motor
threshold for the right hemisphere. The TMS
treatment course was administered once per week
for 18 weeks over the DLPFC (six over the left, six
over right, and the last six sessions equally
distributed the number of pulses over the both left
and right hemispheres). The site for stimulation was
placed 5 cm anterior to and in a parasagittal plane to
the site of maximal abductor pollicis brevis
stimulation. The figure-eight coil, with a 70-mm wing
diameter, was kept flat over the scalp. Stimulation
was performed at 0.5 Hz and 90% of resting motor
threshold, with a total of 160 pulses per day (eight
trains of 20 pulses, with a 20-s interval between
trains; for additional details, see Casanova et al.,
2012, 2014; E. Sokhadze et al., 2009, 2016; G.
Sokhadze et al., 2012).
ANS monitoring
Physiological activity was monitored and recorded
from subjects during each rTMS session.
Additionally, several minutes of baseline and
postbaseline activity was recorded before and after
each TMS session. However, for data analysis in
this particular study we included only data recorded
during the administration of TMS. HRV measures
were calculated from 10-min segments derived from
an artifact-free electrocardiogram (ECG) recording
and mean SCL. Integrated EMG was used to detect
movement-related artifacts. ECG, EMG,
pneumogram, and electrodermal activity were
acquired (1024-Hz sampling rate for EMG and ECG,
128 Hz for pneumogram and electrodermal activity)
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, three Ag/AgCl
electrodes (EL-501 from Biopac) for EMG recording
from the right hand, and pneumogram was recorded
with a strain gauge transducer (J&J Engineering).
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 (RR), standard deviation of all
normal R-R intervals (SDNN), square root of the
mean of the squares of successive RR interval
differences (RMSSD, or the average change in
interval between beats); frequency domain HRV
measures such as power of high-frequency (HF),
low-frequency (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 were calculated as time
domain and frequency domain cardiac activity
measures (Kleiger, Stein, & Bigger, 2005). Artifact-
corrected ≥ 5-min-long recording epochs were
analyzed with fast Fourier transform (FFT) to assess
HRV. Integrals of the spectrum in 0.003–0.040 Hz
(VLF of HRV), 0.04–0.15 Hz (LF of HRV), and 0.15–
0.40 Hz (HF of HRV) bands were measured (in ms2).
All HRV data was analyzed offline using Kubios
HRV software version 2.0 (University of Kuopio,
Finland).
HRV interpretation was based on the following
concepts: (1) the HF component of HRV is often
referred to as respiratory sinus arrhythmia and is
assumed to be the noninvasive index of
parasympathetic influences on the heart (Berntson
et al., 1997; Sohn, Sokhadze, & Watanuki, 2001);
(2) the LF component of HRV has been linked to
sympathetic nervous system activity and sympatho-
vagal balance by numerous studies (Malliani,
Pagani, & Lombardi, 1994; Pagani et al., 1986).
Other studies have shown that the LF variability is
rather a reflection of both sympathetic and vagal
influences related to baroreflex mechanisms
(Berntson et al., 1997). It is thought that changes in
blood pressure amplitude may cause vagally-
mediated baroreflex responses as well as changes
in LF variability. Respiration rate on a 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.
Sokhadze et al. NeuroRegulation
70 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
Statistical analysis
The primary statistical analyses included linear
regression plot estimation of each autonomic
dependent variable (RR, SDNN, RMSS; VLF, LF,
and HF of HRV; LF/HF index) over 18 sessions of
rTMS course as well as paired sample student’s t-
test of pre- and post-TMS behavioral measures
(ABC, RBS-R, SRS-2). For each behavioral rating
score analyzed using paired sample student’s t-test,
normality of distribution test was performed to
ensure appropriateness for the t-test. To estimate
the power of the test for the linear regression
analysis, statistical results also included values of
observed power at = 0.05 and, when appropriate,
their comparisons to the desired power of 0.80.
Actual R, R2, and adjusted R2 values are reported for
each dependent variable in regression analysis. In
addition, we analyzed mean changes of autonomic
measures from the first to the last session of the
rTMS course. The changes of physiological
variables (time and frequency indices of HRV and
SCL) were entered in a correlation analysis
(Pearson correlation) with changes of behavioral
evaluation scores of ABC, RBS-R, and SRS-2.
SPSS and SigmaStat statistical software packages
were used for analysis.
Results
Behavioral evaluations post-TMS
As expected based on our prior studies, the ABC,
RBS-R, and SRS-2 parental behavioral checklists’
rating changes showed statistically significant
improvements in several domains. Lethargy/Social
Withdrawal subscale of the ABC (Aman & Singh,
1994) showed a significant score reduction, mean
decrease -2.21 ± 3.58, t(26) = -2.69, p = .015.
Hyperactivity score of the ABC also showed
reduction, -4.79 ± 7.34, t(26) = -2.84, p = .011.
Inappropriate Speech score decreased as
well, -1.63 ± 2.92, t(26) = 2.49, p = .028. Stereotypy
behavior scores had a marginal decrease that did
not reach a significant level, -2.26 ± 4.78, t(26)
= -2.06, p = .054.
We found a significant decrease in stereotypic,
repetitive, and restricted behavior patterns following
18 sessions of bilateral rTMS as measured by the
RBS-R (Bodfish et al., 1999). Total RBS-R score
decreased, -4.21 ± 5.59, t(26) = -3.28, p = .015.
Stereotypic Behavior subscale showed a significant
decrease, -0.95 ± 1.26, t(26) = -3.25, p = .004; and
Ritualistic/Sameness Behavior subscale scores
showed a decrease, -0.94 ± 1.74, t(26) = 2.36, p
= .03. Compulsive Behavior subscale also
demonstrated a significant decrease, -1.26 ± 2.46,
t(26) = -2.23, p = .039. Analysis of Social
Responsiveness Scale (SRS-2; Constantino &
Gruber, 2005) revealed changes in several subscale
rating scores. Social Awareness score of the SRS-2
improved post-TMS, -7.03 ± 7.96, t(26) = -4.51, p
< .001; along with Social Cognition, -8.19 ±7.22,
t(26) = -5.47, p = .001; and Social Motivation rating
scores, -6.73 ± 9.42, t(26) = -3.64, p = .001.
Autonomic activity measures
Time domain measures of HRV (RR intervals,
standard deviation of RR [SDNN], HR RMSSD).
Cardiointervals in ECG (RR intervals) showed a
statistically significant linear regression over
sessions of rTMS, R = .70, R2 = .50, adjusted R2
= .47, F = 15.11, p = .001, power of performed test
(hereafter referred as power) = 0.88 at = 0.05
(Figure 1). Standard deviation of RR (SDNN)
intervals showed a statistically significant linear
increase over rTMS course, R = .74, R2 = .54,
adjusted R2 = .52, F = 19.38, p < .001, power = 0.95
at = 0.05 (Figure 2). Paired sample t-test showed
that increase of SDNN from the first to the last
session of rTMS course was significant, 29.3 ± 56.4
ms, t(26) = 2.26, p = .036. Root mean square
standard deviation of RR (RMSSD) also showed
linear increase, R = .66, R2 = .44, F = 12.52, p
= .003, power = 0.87 at = 0.05. The t-test yielded
a significant increase of RMSSD, 27.78 ± 48.84
bpm, t(26) = 2.48, p = .023.
Figure 1. Mean RR intervals over 18 sessions of rTMS
in children with autism spectrum disorder.
R = .70, R2 = .49, F = 15.1, p < .001, power = 0.92.
Sokhadze et al. NeuroRegulation
71 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
Figure 2. Standard deviation of RR intervals over 18
sessions of rTMS in children with autism spectrum
disorder.
R = .74, R2 = .55, F = 19.3, p < .001, power = 0.95.
Frequency domain measures of HRV (VLF, LF
and HF of HRV, LF/HF ratio). The power of the
VLF component of HRV did not show any linear
regression trend, F = 0.14, p = .71. The power of
the LF component of HRV showed a marginal trend
towards linear regression, R = .50, R2 = .25, adjusted
R2 = .21, F = 5.43, p = .033, power = 0.57 at =
0.05, below desired power level of 0.80 (Figure 3).
The HF component of HRV showed a statistically
significant linear increase in power, R = .64, R2
= .41, adjusted R2 = .37, F = 11.25, p = .004, power
= 0.84 at = 0.05 (Figure 4). Increase of the HF
power was confirmed by paired sample t-test, 865 ±
1418 ms2, t(26) = 2.66, p = .016.
Figure 3. Power of low frequency (LF) of heart rate
variability (HRV) over 18 sessions of rTMS in children
with autism spectrum disorder.
R = .50, R2 = .25, F = 5.44, p = .033, power = 0.57.
Figure 4. Power of high frequency (HF) of heart rate
variability (HRV) over 18 sessions of rTMS in children
with autism spectrum disorder.
R = .64, R2 = .41, F = 11.2, p = .004, power = 0.84.
The LF/HF ratio of HRV (cardiac autonomic balance
index) showed a linear regression that was
statistically significant, R = .79, R2 = .62, adjusted R2
= .59, observed power = 0.97 at = 0.05 (Figure 5).
The LF/HR ratio of HRV tended to decrease from the
first to the last session of rTMS but failed to reach
statistical significance, -0.42 ± 1.07, t(26) = -1.72, p
= .103.
Skin conductance level (SCL). SCL showed
statistically significant linear regression over 18
sessions of rTMS, R = .63, R2 = .40, adjusted R2
= .36, F = 10.70, p = .004, power = 0.94 at = 0.05
(Figure 6).
Figure 5. Mean low frequency/high frequency (LF/HF)
ratio of heart rate variability (HRV) over 18 sessions of
rTMS in children with autism spectrum disorder.
R = .79, R2 = .62, F = 26.3, p < .001, power = 0.98.
Sokhadze et al. NeuroRegulation
72 | www.neuroregulation.org Vol. 4(2):65–78 2017 doi:10.15540/nr.4.2.65
Figure 6. Skin conductance level (SCL) over 18
sessions of rTMS in children with autism spectrum
disorder.
R = .63, R2 = .40, F = 10.7, p = .005, power = 0.93.
Correlation of changes in HRV and SCL
measures with behavioral score changes
Several time domain measures of HRV associated
with increased HRV showed significant negative
correlation with Stereotypy rating of the ABC (SDNN,
r = -0.73, p = < .001; RMSSD, r = -0.69, p = .001).
The LF component of HRV showed positive
correlation with Stereotypy rating changes (r = 0.76,
p < .001). In a similar manner, correlation of Total
Repetitive and Stereotyped Behaviors score
changes on the RBS-R questionnaire showed
negative correlation with time domain measure
(RMSSD of HR) changes (r = -0.51, p = .028), but
positive correlation with LF/HF ratio (r = 0.58, p
= .008). Skin conductance changes showed positive
correlation with the Total Repetitive and Stereotyped
Behavior of RBS-R (r = 0.56, p = .017). There were
no significant correlations found between individual
HRV and SCL measures and SRS-2 rating score
changes.
Discussion
The most notable result of the study is a replication
of the findings in our prior case series studies
(Casanova et al., 2014; Wang et al., 2016) reporting
improvements in aberrant, stereotyped, and
repetitive behaviors. In addition, we found
improvements in social awareness, social cognition,
and social motivation ratings of the SRS-2
questionnaire. Furthermore, there was a linear
increase of HR, as well as both time and frequency
domain measures of HRV. Our post-TMS HRV and
SCL outcomes point to a decrease of sympathetic
arousal and to an increase of parasympathetic
activity resulting in a trend of normalization of the
autonomic balance. The demonstration of
decreased sympathetic arousal, as indexed by
decrease of LF and LF/HF of HRV and decreased
electrodermal activity posttreatment, is also an
important finding. Considering that sympathetic
activation is often associated with autonomic
arousal, abnormalities of arousal regulation should
become one of the main aims of autism research
and treatment.
In a study by Hirstein et al. (2001) children with
autism mainly had higher than normal baseline SCL
and high-amplitude SCRs. In the majority of the
children, however, SCL and SCR magnitude
dropped below the values observed in normal
control groups as soon as they became involved in
self-stimulatory activities (such as putting their hands
in a bowl of dry beans). Stereotyped and repetitive
motor behaviors, one of the core features of autism,
has been proposed to be a coping response to
reduce hyperresponsive sympathetic activity
(Hirstein et al., 2001; Toichi & Kamio, 2003; Toichi et
al., 1999). Arousal dysregulation in autism may
manifest in two distinct modes of functioning. The
first mode is characterized by elevated tonic arousal,
anxiety, and difficulties in focusing attention. The
second mode is reflected in reduced tonic arousal,
self-stimulatory activities, and decreased awareness
of the surroundings. Our results showed a positive
correlation of LF of HRV with Stereotypy ratings on
ABC and a positive correlation of LF/HF index with
Total Repetitive and Stereotyped Behaviors scores
on RBS-R. At the same time we found negative
correlations of Stereotyped Behavior scores on both
ABC and RBS-R with such HRV measures as
SDNN, RMSSD, and standard deviation of HR.
These finding are supportive of hypotheses
proposing that stereotyped repetitive behaviors can
be considered as a coping mechanism for reducing
sympathetic overactivation and alleviating anxiety in
children with ASD.
How does prefrontal rTMS affect autonomic
functions? Only a few studies 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 (Czéh et al., 2002; Filippi,
Oliveri, Vernieri, Pasqualetti, & Rossini, 2000). It
has been reported that there might be neurohumoral
changes after treatment with rTMS (Beh-Shachar,
Belmaker, Grisaru, & Klein, 1997). There is also a
hypothesis suggesting that the anxiolytic effects of
rTMS may act through normalization of
hypothalamic-pituitary-adrenocortical (HPA) axis
(Holsboer, 2000). Chronic rTMS-induced changes in
Sokhadze et al. NeuroRegulation
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stress-related corticotropin and corticosterone levels
have been found in animal models providing support
for the suggestion that frontal brain exposure to
rTMS may attenuate the activity of the HPA system
(Hedges et al., 2002). It was shown that low-
frequency rTMS can influence autonomic balance
assessed using HRV (Yoshida et al., 2001). Udupa
et al. (2007) reported HRV measures indicating that
rTMS produced significant reduction in the cardiac
sympathetic/vagal ratio, suggesting improvement in
sympatho-vagal cardiac balance, an effect similar to
our findings. Lower post-TMS sympathetic activity
was reported in the study of Jenkins, Shajahan,
Lappin, and Ebmeier (2002).
We propose that it is possible that rTMS effects are
mediated through frontolimbic connections. The
limbic system is a complex network of structures
central to anxiety and mood regulation (Seminowicz
et al., 2004). Originally rTMS was investigated as a
potential antidepressant therapeutic device under
the assumption that magnetic stimulation of the PFC
would engage the connected limbic regions involved
in mood and anxiety regulation (George, Lisanby, &
Sackeim, 1999). The hypothesis is consistent with
PFC rTMS modulating the function of frontolimbic
circuits and subcortical structures controlling
autonomic activity.
The effects of rTMS on the ANS may also result
from a change of cortical excitation/inhibition
balance. Several studies outlined a disruption in the
cortical excitation/inhibition ratio in individuals with
autism (Casanova, 2006; Casanova et al., 2002;
Casanova, Buxhoeveden, & Gomez, 2003;
Rubenstein & Merzernich, 2003). One possible
explanation for an increase in the cortical
excitation/inhibition bias in ASD is the finding of
abnormalities in cortical minicolumns (Casanova,
2005). Double-bouquet cells in the peripheral
neuropil space of minicolumns impose a strong
vertically directed stream of inhibition surrounding
the minicolumnar core (Mountcastle, 2003). In ASD,
our preliminary studies indicate that cortical
minicolumns are reduced in size and increased in
number, especially within the PFC (Casanova, 2005,
2006; Casanova et al., 2002, 2006, 2012).
Disturbances in the ratio of cortical excitation to
inhibition may lead to an increase in cortical “noise”
which may influence functional cortical connectivity
and may hinder the binding of associated cortical
areas. It has been proposed that the effect of low-
frequency rTMS arises from increases in the
activation of inhibitory circuits (Casanova et al.,
2015; Sokhadze et al., 2014). Over a course of
treatment rTMS may selectively lower the ratio of
cortical excitation to cortical inhibition. Low-
frequency rTMS over DLPFC may therefore lead to
improvement in executive functions due to stronger
lateral inhibition and enhanced functional
connectivity that may lead to improvement in
frontolimbic functions, leading to restoration of the
normative inhibitory top-down control exerted by the
frontal structures.
In previous studies we have reported on the positive
effects of rTMS in autism using a large variety of
outcome measures (Baruth et al., 2010, 2011;
Casanova et al., 2012, 2015; Sokhadze et al., 2009,
2012, 2014, 2016; Wang et al., 2016). For better
understanding of potential mechanisms of TMS
neuromodulation effects on autonomic activity, it is
necessary to consider the interaction between the
central and autonomic nervous systems. The
Central autonomic network (CAN) model proposed
by Thayer and Lane (2000) describes how neural
structures involved in cognitive, affective, and
autonomic regulation are related to HRV and
cognitive performance. In this model, the
anatomical details of a CAN are described, linking
the nucleus of the solitary tract in the brainstem with
forebrain structures including the anterior cingulate
cortex, insula, ventromedial PFC, amygdala, and
hypothalamus through feedback and feed-forward
loops. Thayer et al. (2012) outlined connections
between the amygdala and medial prefrontal cortex
(mPFC), which evaluate stimuli in the context of
threat and safety and which regulate HRV through
their connections with the nucleus of the solitary
tract. Furthermore, the CAN model proposes that
vagally-mediated HRV is linked to prefrontal
executive functions and that HRV reflects the
functional capacity of the PFC to support emotional
and physiological self-regulation. It was
hypothesized that parasympathetically mediated
HRV is positively correlated with prefrontal cortical
performance; thus, when prefrontal cortical
functioning is decreased, HR increases and HRV
decreases. Prolonged prefrontal cortical inactivity
can lead to hypervigilance, defensiveness, and
social isolation (Thayer, Hansen, Saus-Rose, &
Johnsen, 2009). The CAN model predicts reduced
HRV and hypofunctional vagal activity in anxiety, as
it might be associated with abnormal ANS cardiac
control (Friedman, 2007). This approach challenges
the sympathetic overarousal model of anxiety that
overlooks the role of a hypofunctional
parasympathetic system. From this perspective,
disorders presenting with anxiety and dysregulated
autonomic control can involve varying degrees of
sympathetic overactivation and parasympathetic
underactivation. The main point is to account for
Sokhadze et al. NeuroRegulation
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both autonomic branches’ activation status in
research aimed at understanding the nature of
autonomic dysfunction.
The strategy for the selected intervention,
considering the CAN model, is that neuromodulation
of the DLPFC using low-frequency rTMS can
increase the PFC's ability to exercise top-down
control of emotional responses. Due to a cascading
effect caused by the anatomical and functional
connectivity of this integrative prefrontal brain
region, we expected the TMS-based intervention not
to be limited to the site of magnetic stimulation but
rather to generalize to other cortical and subcortical
areas including those directly involved in autonomic
arousal control. Biophysical foundations underlying
TMS effects are reviewed in Wagner, Rushmore,
Eden, and Valero-Cabre (2009), while effects of
TMS on connectivity of the cortical structures are
reviewed in Paus et al. (1997). Results of our pilot
studies (Sokhadze et al., 2009, 2016) showed
changes of event-related potentials and induced
electroencephalographic (EEG) gamma oscillations
that occurred not only in the frontal lobe but also in
distal cortical areas (e.g., parietal, parieto-occipital).
Effects of rTMS over DLPFC are possibly extended
to paralimbic and limbic structures as well and may
manifest themselves in ANS activity changes.
Brain functions involved in the generation and
representation of arousal state have been linked to
social cognition in typical development (Critchley,
2005), suggesting that they may be important to
disorders of social interaction such as ASD.
According to Critchley (2005), emotional and
cognitive processes evoke patterned changes in
profiles of physiological measures that may signal a
particular emotional state. The modulation of the
visceral state is mediated by the sympathetic and
parasympathetic divisions of the ANS. Moreover,
neural afferents support and convey representations
of the internal state of the body to the brain to further
influence emotion and cognition. Feedback from the
viscera is mapped in the brain to influence efferent
neural signals and, at the cortical level, to reinforce
affective responses and emotional states. The
discrete cortical substrates for these representations
include the anterior regions of the insula and
orbitofrontal cortex, areas that have direct
connections with the DLPFC. The misperception of
heightened arousal level (either over- or
underestimation of actual autonomic arousal level
status) may readily evoke significant changes in
emotional behavior. Cognitive processes such as
decision-making are guided by central feedback of
bodily arousal responses (Damasio, Everitt, &
Bishop, 1996). The influence of transient arousal
responses on aspects of affect and cognition is
embodied within Damasio's “Somatic Marker
Hypothesis” which proposes that emotional feelings
originate in mental representations within the
somatosensory cortices (Damasio et al., 1996).
Empirical studies have implicated the insular cortex
as the substrate for emotional states, supported by
activity within the amygdala, anterior cingulate
cortex, and orbital prefrontal regions—structures
which communicate directly with the DLPFC. The
anterior insula and ventromedial prefrontal cortex
contribute to the integration of visceral afferent
information. These observations also map into the
insula theory of anxiety of Paulus and Stein
(2006), who propose that feelings of anxiety emerge
through mismatched representation of anticipated
and perceived bodily states within the insular cortex.
The role of the heightened sympathetic arousal and
reduced vagal afferent activity biasing normal
autonomic/visceral state representations therefore
may negatively affect emotional reactivity in
individuals with ASD.
There are several limitations of this study that need
to be noted. The study was not controlled, as it was
not randomized and did not use a sham rTMS
group, and as such represents a continuation of our
case series studies. Furthermore, we measured
only tonic resting state autonomic activity during
rTMS procedure. Considering that the differences
between children with ASD and typically developing
children are reported not only in tonic basal
autonomic arousal level but also in phasic
autonomic responses to various stimuli, it would be
important to have a comparison in autonomic
reactivity as well. The age range in our cohort was
quite wide, even though our statistical analysis of
age-related factor yielded age differences only in
peaks of VLF and LF of HRV. Medication status of
all subjects was monitored but not included as a
confounding factor in statistical analysis. Ratio of
boys vs. girls was 3.5:1, which was probably the
reason why we could not find any gender-related
factor effects on rTMS course outcomes. Our future
studies will address limitations listed above by
adding sham-TMS group, stratified blinded
randomization of children with ASD into active and
sham-TMS groups, and a battery of
psychophysiological tests pre- and posttreatment.
We plan also to recruit subjects with more restricted
age eligibility range to rule out age-related factor
influences.
Sokhadze et al. NeuroRegulation
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Conclusion
In general, complementing rTMS treatment with
concurrent monitoring of autonomic functions may
advance neuromodulation approaches in other
psychiatric and neurological disorders as well,
especially in those where rTMS treatment has been
shown to be effective (e.g., major depression,
obsessive compulsive disorder, schizophrenia,
Parkinson disease).
The current theory-guided pilot study was based on
a hypothesis proposing that rTMS over the DLPFC
improves cortical excitation/inhibition ratio in autism
and enhances prefrontal functioning, including
enhancing normative prefrontal inhibitory influences
on the limbic system and subcortical centers
controlling level of autonomic arousal. We propose
that the application of rTMS has potential to be
considered as a novel, customizable
neurotherapeutic tool targeting autonomic balance
that may positively affect the social and behavior
deficits as well as the hyperactivity and anxiety
problems experienced by children and adolescents
with autism. In addition, this tool could serve as a
platform for the development of treatments of other
childhood anxiety disorders.
We believe that the application of neuromodulation
techniques to increase parasympathetic activity and
lower sympathetic activity is a potentially powerful
approach to treating some symptoms of autism. Our
underlying rationale for using rTMS in children with
autism links cardiac underreactivity in socially
engaging situations to dysfunctions in cardiac
autonomic regulation in autism which results in a
reduced attentional capacity to attend socially
relevant stimuli critical for effective communication
with peers. This hypothesis outlines an important
role of the ANS in emotional reactivity and social
behavior. Poor control of HR and vulnerability to
tachycardia is an important consequence of chronic
increased sympathetic activity and decreased vagal
tone (Berntson et al., 1997; Corona et al., 1998;
Friedman & Thayer, 1998; Thayer et al., 2012). The
baseline sympathetic arousal found in autism may
be a condition of disinhibition, resulting from
compromised baseline parasympathetic inhibition.
Reduced frontolimbic connectivity and poor
prefrontal tonic inhibitory control over the limbic
system might be one of the reasons for excessive
excitation of the sympathetic system in ASD. TMS
could be an effective technique for restoring
regulation of parasympathetic activity and for
improving sympatho-vagal cardiac balance in
autism. It may also result in restoration of normative
visceral representations thought to be distorted in
autism due to chronic sympathetic overarousal.
Future randomized clinical trials with blinding and
sham TMS control conditions may help in
establishing rTMS as a neuromodulatory treatment
aimed to regulate autonomic balance in children with
ASD. The current study is an early step aimed at
demonstrating the feasibility of this approach and a
call for further exploration and rigorous, controlled
clinical trials.
Author Notes
The study was partially supported by National
Institutes of Health Eureka R01 grant R01MH86784
and FERB graduate student grant.
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Received: March 10, 2017
Accepted: April 3, 2017
Published: June 30, 2017
