Effects of TMS on Autonomic Nervous System in Children with Autism.

Introduction & Background

Theoretical Rationale to Use rTMS in Autism

Methods: repetitive TMS

Detection of Motor

Threshold for TMS

using EMG

Summary of Results

.

According to the irritability subscale of the

Aberrant Behavior Checklist (ABC) (Aman &

Singh, 1994), there was a significant

reduction in irritability as a result of

bilateral rTMS (F=5.608, P=0.022).

Results: Autonomic Changes post 12 rTMS sessions

Results: Autonomic measures Post-TMS

Heart rate and Heart Rate Variability components changes following TMS

Results: Baseline Autonomic Group Differences

(Autism vs. Controls): Pilot Study

Post-TMS Behavioral Clinical Evaluations

Autonomic control of Cardiac Activity

Guela Sokhadze1., Ayman El-Baz2, Tato Sokhadze3, Lonnie Sears4 & Manuel Casanova 3

1Undergraduate Student, Department of Arts, Sciences, 2Department of Bioengineering, 3Department of Psychiatry & Behavioral Sciences, 4Department of Pediatrics.

During 12 session long rTMS course regression analysis show significant decrease of

Heart Rate and LF component of Heart Rate Variability in children with autism

Autism is a pervasive developmental disorder (prevalence is 1 in 150)

marked by difficulty in social interaction, impairments or lack of

communication , and restricted range of interests. Many children with

autism exhibit symptoms associated with autonomic dysfunction, which

is abnormalities in regulation of blood pressure, temperature, heart rate,

and all other body functions by the autonomic nervous system (ANS).

The main findings of autonomic abnormalities studies in Autistic

Spectrum Disorders (ASD) point at reduced baseline parasympathetic

activity in association with evidence of increased baseline sympathetic

tone resulting in autonomic disbalance which affects physiological

functions and manifests in different physiological measures.

Aims of the study was to investigate differences in physiological

measures reflecting autonomic nervous system (ANS) activity in children

with autism and in typically developing children. Another aim of the

study was to investigate effects of low frequency repetitive Transcranial

Magnetic Stimulation (rTMS) on ANS measure in children with autism.

Hypotheses to be tested in the study were (1) low frequency (0.5 Hz)

rTMS of frontal cortex may lower ANS hyper- activation in children with

autism through activation of frontal inhibitory tone controlling ANS, and

(2) lower ANS arousal post-TMS will be manifested in decrease of skin

conductance level (SCL), heart rate (HR), and increased HR variability. .

In this study, we investigated the activity of the autonomic nervous

system in 19 children with ASD (mean age 12.9 years, SD=1.8) and 21

control subjects (16.8 years, SD= 5.2).

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) (LeCouteur et al. 2003)

by Dr Sears, who also did pre- and post-TMS clinical evaluations.

All participants were high-functioning children with ASD with full-

scale IQs >80 assessed using the Wechsler Intelligence Scale for

Children, Fourth Edition (WISC-IV; Wechsler 2003).

Participating subjects and their parents (or legal guardians) were

provided with all information regarding the study, and the consent and

assent forms approved by the IRB were reviewed and signed.

Sixteen ASD subjects out of 19 participated in 18 session rTMS trial.

Control children were recruited by ads and did only ANS assessment.

Acquisition of physiological data

Physiological activity measures such as EMG, skin conductance level (SCL),

heart rate (HR), Heart Rate variability (HRV), and skin temperature (SKT) were

recorded during resting state with a C-2 J&J Engineering Inc. (WA)

psychophysiological monitor. Sampling rate in both devices was set at 1024 Hz.

Analysis of HRV was conducted using Kubios (Helsinki, Finland) software.

Methods: ANS Activity Measurements

.

Subjects

We investigated autonomic nervous system activity in 19 children with Autism

(ASD) and 21 typically developing subjects. Physiological activity measures such as

skin conductance level (SCL), heart rate (HR), HR variability (HRV), and skin

temperature (SKT) were recorded during resting state with a C-2 J&J Engineering Inc

and Nexus-10 Mind Media B.V. monitors.

Analysis of autonomic measures during 5-10 min long resting baseline revealed

higher HR (93.5 beats/min in ASD vs. 80.4 beats/min in controls, F=5.95, p=0.019),

higher SCL (7.3 mS [microSiemens] vs. 4.4 mS in controls, F=4.74, p=0.036), and a

tendency (F=3.93, p=0.056) to reduced respiratory sinus arrhythmia reflected in lower

power of high frequency (HF) component of HRV in autism.

High basal tonic electrodermal activity (SCL) and accelerated HR in association

with lower HRV index found in children with autism are indicators of excessive

sympathetic and reduced parasympathetic activation in ASD resulting in a limited

psychophysiological flexibility.

We investigated changes in autonomic activity during 12 and 18 repetitive

magnetic transcranial stimulation (rTMS) course in the same children with autism. Post-

12 rTMS measurements showed a decrease of LF component of HRV (linear regression,

F=5.26, p=0.024) with statistical changes in HR regression (F=4.52, p=0.036) , without

any significant changes in HF of HRV, SCL, or SKT.

Post 18 session rTMS outcomes showed slower heart rate accompanied by decrease

of LF, increase of HF of HRV, and lower LF/HF ratio.

Our findings show reduced sympathetic activation after TMS course resulting in

lower HR predominantly through withdrawal of sympathetic tone (LF of HRV) rather

than increase of parasympathetic (vagus) cardiac neural control activity post 12 rTMS

sessions, but higher HF after 18 sessions.

Low frequency rTMS activates inhibitory tone of the frontal cortex resulting in a

lower excitation of the autonomic nervous system probably through the inhibitory

fronto-limbic circuits. C-2 J&J Engineering Inc. physiological monitor.

Procedure of rTMS

using concurrent

autonomic recording

C-2 J&J Eng. Inc. device ANS recording layout

The modular arrangement of the cortex is based on the cell minicolumn: a self-contained

ecosystem of neurons (cortical unit) and their afferent, efferent, and inter-neuronal connections.

Our preliminary studies (Casanova et al., 2006; Sokhadze et al., 2009) indicate that

minicolumns in the brains of autistic patients are narrower, with an altered internal

organization resulting in a disruption of the normal excitation/inhibition balance. Frontal

cortex has lower functional connectivity, and inhibitory frontal influences on the limbic system

and ANS are reduced.

Heart rate is controlled by excitatory sympathetic

and inhibitory parasympathetic ANS inputs:

Sympathetic influences are reflected in VLF and LF

components of HRV, while parasympathetic in HF.

Autonomic control of Electrodermal

Activity (Skin Conductance)

Skin conductance is controlled solely by

sympathetic inputs: Skin Conductance

Level (SCL) and Responses (SCR) are

used as sympathetic indices

Children with autism had higher HR and SCL, lower HF as compared to typical children

Administration of repetitive TMS in children with autism

During each session, patients were seated in a comfortable chair and

wore a swim cap and ear plugs while a trained electrophysiologist

delivered rTMS using a Magstim Model 220 instrument (Magstim Corp.,

England) using a 70-mm wing span figure-eight coil. Motor threshold

(MT) was determined by administering mild supra-threshold

stimulations administered over the left motor cortex to determine the

optimal area for stimulation of the abductor pollicis brevis (APB)

muscle. The output of the machine was decreased by 2 % each time until

the least amount of machine power that induces a 50-μV deflection, or a

visible twitch, is identified in 5 out of 10 trials over the cortical area

controlling the contralateral APB. Surface electrodes were attached over

the first dorsal interossi (FDI) areas. The TMS treatment course was

administered once per week for 18 weeks (a total of eighteen 0.5 Hz

rTMS treatments) over the left DLPFC. The site for stimulation was

placed 5 cm anterior to the site of maximal FDI stimulation, in a

parasagittal plane. The figure-eight coil, with a 70 mm wing diameter

was kept flat over the scalp. Stimulation was done at 0.5 Hz and 90 %

MT, for a total of 150 pulses per day (ten 0.5 Hz pulse trains with a

20 sec. interval between the trains).

Va

Low-frequency rTMS of dorsolateral

prefrontal cortex (DLPFC) may result in

an alteration of cortical inhibition through

the activation of inhibitory GABAergic

interneurons leading to an improvement

in the excitatory /inhibitory balance.

Poor spatial contrast across

minicolumns is not capable of adequate

inhibition of surrounding columns for

optimal spatial contrast.

TMS activation of intracortical

inhibitory neurons within minicolumn

leads to an enhanced surround inhibition

and a better spatial contrast. This leads to

improved capability and functioning of

the cortical unit (so called “minicolumn”).

Post-rTMS measurements showed a decrease of LF component of HRV (linear

regression r=0.54, F=5.26, p=0.024) with changes in HR(F=4.52, p=0.036), and linear

regression of SCL across 12 sessions of rTMS.

This suggests a reduced sympathetic tone after TMS course resulting in a lower HR

predominantly through withdrawal of sympathetic arousal. However, effects of

rTMS on parasympathetic tone cannot be excluded either as during 8 min of rTMS

session (12 rTMS sessions) HF of HRV showed statistical increase.

According to the Repetitive Behavior

Scale (RBS) (Bodfish et al., 1999),

there was a significant reduction in

repetitive behavior as a result of

bilateral rTMS (F=6.273, P=0.016).

Results: Autonomic Changes post 18 rTMS sessions