Development of Non-Invasive Brain Stimulation Techniques

Objectives

Noninvasive brain stimulation (NIBS) using magnetic and electrical means, through the use of
transcranial magnetic stimulation (TMS) and transcranial direct and alternating current
stimulation (tDCS and tACS respectively), has proven to be a versatile tool in the
investigation of cortical organization and function, and has shown great potential as a means
to diagnose and treat psychiatric and neurological illness. Unfortunately, this research has
been slowed due to two fundamental problems that directly impact the usefulness of NIBS.
First, the space of parameters used to produce NIBS is immensely large and has barely been
explored. Such parameters include intensity of stimulation, pulse wave form and duration,
number and timing of pulses (which in turn can involve trains of pulses: their frequency,
duration, number, and intertrain intervals), the shape of the magnetic or electric field
produced (for TMS, meaning type of coil used, its position, and its orientation (with three
degrees of freedom for a figure eight coil), and for tDCS and tACS, the numbers, sizes and
placements of electrodes), and, for creating long-lasting effects, the number and timing of
NIBS sessions. Differences- often even very small differences- in the particular values of
any of these parameters have been shown to have significant impact on the size and duration
of NIBS effects, and yet little is known. Parametric exploration has only been addressed in a
limited way in the field, and primarily only in motor cortex. Second, the interaction of any
set of NIBS parameters with any individual brain is poorly understood, and this has led to
unpredictable efficacy and a large amount of inter-individual variability in NIBS studies.
The human brain is always in a complex, dynamic state of change, and it has become
increasingly clear that the state of a cortical region and its associated network connections
when NIBS is applied strongly influences its effects There are now a great many
demonstrations of how the state of the cortical region being stimulated plays a large role in
determining what specific NIBS effect occurs. Not knowing the particular state of a brain
when stimulating it has led to wide variability and unpredictability in NIBS effects. Thus
while the variable state of the target region in each subject is likely an important source
of the large amount of inter-individual variability found in TMS and tDCS studies, little
research has been performed as yet. This poses a huge challenge to the effectiveness of NIBS
therapeutic interventions on an individual and precision medicine basis, to the design and
implementation of brain stimulation studies and to the test-retest reliability of the
neurophysiological and behavioral measures used (and their optimization).

The purpose of this technical development protocol is to address these two fundamental
deficiencies in NIBS research. To do so, we would like to 1) explore, within safe ranges as
established by international consensus, the effects of different sets of NIBS stimulation
parameters on behavioral and cortical function, as measured by behavioral performance,
electroencephalography (EEG), electromyography (EMG), eye movements, and MRI. and, 2) to
develop the methodologies and analytic techniques behind those behavioral and physiological
measures in order to increase their usefulness in interpreting NIBS effects. In addition,
this protocol will be used to train new fellows coming to the Non-invasive Neuromodulation
Unit (NNU) in the use of TMS techniques. The NNU is exceptionally well-situated, both in
terms of expertise and resources, to perform this protocol. We expect that information
emerging from these studies will allow us to 1) optimize NIBS effects across ranges of
stimulation parameters and brain states, within individual subjects, and in terms test-retest
reliability, 2) to collect pilot data in healthy volunteers to establish feasibility and for
power analysis for future patient-oriented hypothesis-driven protocols, and 3) to train new
fellows in the use of these different methods.

We specifically propose to begin this development protocol with five substudies that span the
NIBS areas in need of further research, examining stimulus intensity, stimulus timing and
frequency, stimulus targeting, and methods for controlling brain state. These explorations
will provide a useful initial foray into NIBS parameter space, and will in addition help
develop means to more effectively dose TMS outside of motor cortex and reduce variability in
TMS effects, to test new methods of targeting TMS, to develop the usefulness of EEG in TMS,
and to understand the relationship of TMS timing and endogenous oscillations.

The protocol consists of the below substudies:

Substudy 1 (Using TMS-evoked potential (TEP) to dose TMS outside of the motor cortex)

This study aims to begin an exploration of the feasibility of using EEG to evaluate the
response to single pulses of TMS over differing cortical brain areas, as a novel method of
individualizing the dose of TMS in a site-specific fashion. The local cortical response
represents an evoked wave of neuronal activity in the immediate vicinity of the stimulating
coil and could provide a useful dosing measure outside the motor cortex. In this first step,
at two cortical locations (motor cortex and occipital visual cortex) we explore the
relationship of TMS evoked potentials with functional evoked responses (MEPs from motor
cortex, visual discrimination in visual cortex) and with fMRI BOLD response to TMS at
different intensities applied to both cortical locations.

Substudy 2 (The value of electric field modeling in TMS localization)

The study question for this substudy is as follows: Does inclusion of electric field modeling
to TMS targeting increase the efficacy of TMS?

The overall goal is to compare an electric field guided coil placement method with
(f)MRI-guided and scalp-guided NIBS targeting approaches. Including the latter condition
additionally allows for the substudy to address the only study that compared scalp-based and
fMRI-based targeting (Sack et al., 2009). The Sack et al. study was designed as between
groups, using very small Ns (of 5): the NIBS field would greatly benefit from a replication
with a larger group and a within-subjects design. In this first substudy, we will test the
efficacy of three E-field modeling approaches to TMS targeting, with the intention of using
the best method in a subsequent substudy to compare TMS targeting methods.

Substudy 3 (Controlling ongoing cortical state during NIBS with neurofeedback)

The study question for this substudy is as follows: Does controlling brain states using
neurofeedback result in greater intra- and inter-individual variability in responses to TMS?

This study aims to explore the use of neurofeedback to control brain state, using EEG to
evaluate the cortical response to single pulses of TMS while subjects are controlling the
electrophysiological state of their brain.

Substudy 4 (Using cTMS EEG to understand mechanism and to optimize theta-burst stimulation
(TBS))

The study question for this substudy is as follows: What are the effects of TBS on EMG across
different waveforms of TMS pulses?

In this substudy, we aim to parametrically examine the effects of intertrial interval on TBS
response, and to harness the flexible control of pulse parameters using the cTMS device
(Rogue Research Inc., Canada) to investigate the effects of TBS.

Substudy 5 (using TMS as a probe of the fronto-striatal network, a key circuit implicated in
reward processing)

We seek to establish whether TMS can reach, in a dose-dependent way, a targeted subcortical
region transynaptically which is too distant for effective stimulation directly.
Specifically, we will test whether TMS, delivered to the dorsolateral prefrontal cortex
(DLPFC) or the pre-supplementary motor area (pre-SMA), results in changes in activation of
the striatum, in a dose-dependent fashion. This hypothesis will be tested with the
perturbation-imaging procedure of TMS/fMRI interleaving, i.e. while participants receive TMS
during both resting state and task based fMRI.

Study Population

Up to 180 healthy volunteers, age 18 and older. The number is the sum of requested
participants (N=25) in the 4 substudies, with an additional 25 given an anticipated 20%
drop-out rate.

Design

Healthy adult volunteers will participate typically using repeated measures design, given the
goals of exploring parametric NIBS effects and to establish reliability in those effects,
although between groups designs might be required in some cases (e.g., when learning is
involved). Experiments will be carried out in two phases: with Phase I involving screening
and baseline procedures and Phase II being the experimental NIBS sessions. Phase I will
include consenting and screening. It will generally include an MRI session due to the need
for at least a structural MRI to be used for neuronavigation in NIBS targetingPhase I may
also include introduction and training in some behavioral task or tasks, as well as baseline
measures of, EEG, and EMG, as needed. In Phase II the experimental NIBS sessions will be
performed with each participant. The number of sessions will be variable, in general between
1 and 4, lasting about 1-3 hours each, depending on the exploratory question. NIBS may be
given in conjunction with EEG, EMG, and/or fMRI, either simultaneously or in a pre-post
manner. The NIBS stimulation parameters will never exceed safe ranges, as established in
international consensus safety reports. Experimental control comparisons may be between sham
and active NIBS, and/or in the latter case being NIBS to different scalp locations or at
different times, or in the case of parametric studies, differing values of the parameter in
question.

The experience in the NIBS field over the past three decades provides no evidence that there
is an upper limit on the number of NIBS sessions an individual can safely participate in.
This conclusion is primarily based on the many thousands of individuals who have received TMS
treatment for depression according to the FDA-cleared labeling, in which six weeks of daily
weekday treatment (30 sessions involving 3000 pulses of rTMS per session) are provided, with
no new, unexpected adverse events reported. Thus, the amount of participation will only be
limited in two ways: first, subjects participate in one experimental session per day. A
single session, which generally lasts between 1-3 hours, may last no longer than 8 hours to
allow for the initial testing paradigm followed by retests or performing other components of
the same substudy later in the day, with appropriate rest breaks and meal breaks during long
sessions. Second, subjects can participate in only one substudy at a time.

Outcome measures:

Substudy 1: MEP and TEP amplitudes and latencies; fMRI BOLD changes; visual discrimination
threshold

Substudy 2: Pre-post change in behavioral performance (RT and accuracy) and in parietal fMRI
BOLD response across conditions.

Substudy 3: Individual and group averaged amplitudes and latencies of TEPs.

Substudy 4: Amplitude and latency of MEP.

Substudy 5: change in fMRI BOLD response in the striatum as the result of surface cortical
TMS.

- INCLUSION CRITERIA (for all substudies):

Male and female subjects between 18 and 65 years of age.

Subjects must be able to give written informed consent prior to participation in this
study.

All subjects must have undergone a screening assessment under protocol 01-M-0254, The
Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers .

For cognitive experiments utilizing language stimuli only native English speakers will be
enrolled.

EXCLUSION CRITERIA (for all substudies):

Women who are pregnant or breastfeeding.

History of any Axis I DSM-IV disorder, except alcohol abuse outside of one year.

History of seizure (childhood febrile seizures are acceptable and these subjects may be
included in the study), history of epilepsy in self or first degree relatives, stroke,
brain surgery, head injury, known structural brain lesion.

Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), or currently taking
medication that lowers the seizure threshold. Excluded medications and substances include:
imipramine, amitriptyline, doxepine, nortriptyline, maprotiline, chlorpromazine, clozapine,
foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, (MDMA, ecstasy), phencyclidine
(PCP, angel s dust), ketamine, gamma-hydroxybutyrate (GHB), alcohol, theophylline.

A history of drug or alcohol abuse within 1 year or a lifetime history of drug or alcohol
dependence (DSM-IV criteria).

Presence of ferromagnetic metal in the body, for example metallic (ferromagnetic) implants
(e.g, heart pacemaker, aneurysm clip).

Subjects with an unstable or serious medical or neurological disorder.

No concurrent medications, such as psychotropic drugs, that affect brain function.

Presence of any medical illness likely to alter brain morphology and/or physiology (e.g.,
hypertension, diabetes) even if controlled by medications.

Positive test for HIV.

Subjects who have hearing loss that has been clinically evaluated and diagnosed.

Participants who are uncomfortable in small closed spaces (have claustrophobia), unable to
lie comfortably supine for up to 60 minutes, and would feel uncomfortable in the MRI
machine (for subjects doing imaging component of the study only).

A current NIMH employee or staff or their immediate family member.

Participant is concurrently participating in another substudy in this protocol, or in any
other study involving NIBS.