ANALYSIS & PERSPECTIVE

Clinical Implementation of Noninvasive Brain Stimulation in an

Outpatient Neurorehabilitation Program
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Rajani Sebastian, PhD, CCC-SLP, Kendra M. Cherry-Allen, PT, DPT, PhD, April Pruski, MD, MBA,
Jake Sinkowitz, BS, Joan Stilling, MD, MSc, Manuel A. Anaya, MD,
Gabriela Cantarero, PhD, and Pablo A. Celnik, MD
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Abstract: Motor, speech, and cognitive impairments are the most traumatic brain injury, and other neurological disorders. Several
common consequences of neurological disorders. There has been an efforts have focused on the development of new approaches to
increasing interest in the use of noninvasive brain stimulation tech- improve neurorehabilitation outcomes. In particular, noninva-
niques such as transcranial direct current stimulation and transcranial sive brain stimulation (NIBS) techniques, such as transcranial
magnetic stimulation to augment the effects of neurorehabilitation. magnetic stimulation (TMS) and transcranial direct current
Numerous research studies have shown that transcranial direct current stimulation, have been recognized in numerous research
stimulation and transcranial magnetic stimulation are highly promis- studies as promising adjuvants for treating motor, speech, and
ing neuromodulation tools that can work as adjuvants to standard language deficits.2–7
neurorehabilitation services, including physical therapy, occupational Transcranial direct current stimulation is a noninvasive
therapy, and speech-language pathology. However, to date, there are stimulation technique used to modulate cortical activity.8
vast differences in methodology in studies including noninvasive brain Transcranial direct current stimulation delivers low intensity
stimulation parameters, patient characteristics, time point of interven- electrical current (1–2 mA) to modulate neuronal activity.
tion after injury, and outcome measures, making it difficult to translate Transcranial direct current stimulation works by applying a
and implement transcranial direct current stimulation and transcranial positive (anodal) or negative (cathodal) current via electrodes
magnetic stimulation in the clinical setting. Despite this, a series of attached to the scalp. Transcranial direct current stimulation
principles are thought to underlie the effectiveness of noninvasive can increase or decrease cortical excitability due to a shift of
brain stimulation techniques. We developed a noninvasive brain stim- the resting membrane potential of the nerve cells in the brain.9
ulation rehabilitation program using these principles to provide best Human and animal studies suggest that the neuromodulatory ef-
practices for applying transcranial direct current stimulation and/or fects of tDCS are mediated by multiple molecular mechanisms in-
transcranial magnetic stimulation as rehabilitation adjuvants in the cluding changes in calcium-dependent mechanisms,10 N-methyl-
11
clinical setting to help improve neurorehabilitation outcomes. This ar- D-aspartate receptor–dependent processes, brain-derived neuro-
ticle outlines our approach, philosophy, and experience. trophic factors and tyrosine receptor kinase B receptors,12,13 and
γ-aminobutyric acid activity.14 The effects of tDCS have been
Key Words: Neurorehabilitation, Noninvasive Brain Stimulation, observed for up to an hour after a single stimulation session
Clinical Implementation, tDCS, TMS, Neurological Disorders and may persist for days or even months after multiple days
(Am J Phys Med Rehabil 2023;102:S79–S84) of stimulation.15
Transcranial magnetic stimulation is a noninvasive brain
stimulation method that induces changes in neuronal firing
via electromagnetic induction.16 Typically, a brief and strong
eurological disorders are a leading cause of adult disability
N 1
worldwide. Neurorehabilitation procedures involving
physical, occupational, speech and language therapy, and medi-
current is delivered through a stimulation coil over the scalp,
which induces a perpendicular time-varying magnetic field
that penetrates the scalp without attenuation. This magnetic
cal management are the standard of care for motor, speech, swal- field will induce a weak and short-lived current at the site of
lowing, and cognitive deficits after stroke, Parkinson disease, stimulation. The geometry of the coil used for TMS affects
the focality and depth of the stimulation.17 Electromyography
can be used to record the resulting compound action potentials,
From the Department of Physical Medicine and Rehabilitation, Johns Hopkins Uni-
versity School of Medicine, Baltimore, Maryland (RS, KMC-A, AP, J. Sinkowitz,
known as motor-evoked potentials.
J. Stilling, MAA, GC, PAC); and Division of Neuromodulation and Physical Single pulses of TMS have short-term effects, while repetitive
Medicine Devices, Office of Product Evaluation and Quality, Food and Drug pulses of TMS of the same intensity have been shown to have
Administration, Silver Spring, Maryland (GC).
All correspondence should be addressed to: Rajani Sebastian, PhD, CCC-SLP, more lasting effects.16 For that reason, repetitive TMS (rTMS)
Department of Physical Medicine and Rehabilitation, Johns Hopkins University is typically used in therapeutic studies in which modulation of
School of Medicine, 600 N Wolfe St, Phipps 183, Baltimore, MD 21287. excitability beyond the stimulation period are sought. Depend-
R.S. and K.M.C.-A. are the cofirst authors.
Financial disclosure statements have been obtained, and no conflicts of interest have ing on the frequency, duration, and intensity of the stimulation,
been reported by the authors or by any individuals in control of the content of rTMS can lead to depolarization or hyperpolarization of neu-
this article.
Supplemental digital content is available for this article. Direct URL citations appear
rons and thus changes in the excitability of the stimulated cor-
in the printed text and are provided in the HTML and PDF versions of this article tex over different time courses.16 Low frequency rTMS (≤1 Hz)
on the journal’s Web site (www.ajpmr.com). leads to reduced cortical excitability,18 whereas high-frequency
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0894-9115 rTMS (3–5 Hz) increases cortical excitability.19 The aftereffects
DOI: 10.1097/PHM.0000000000002135 of rTMS are likely mediated by N-methyl-D-aspartate receptor,

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 Sebastian et al. Volume 102, Number 2 (Suppl), February 2023

calcium channel effects, GABAergic neurons, and nonsynaptic OVERVIEW OF THE JOHNS HOPKINS
mechanisms, including alterations in brain-derived neurotrophic NIBS PROGRAM
factor levels.20 The JH-NIBS program is medically managed by a phys-
To date, NIBS has been tested across a diverse range of iatrist and combines high-intensity, impairment-based behav-
populations in the field of physical medicine and rehabilitation ioral therapy conducted by a licensed physical therapist (PT),
(see the studies2–7,21 for reviews). Noninvasive brain stimula-
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occupational therapist (OT), and/or speech-language patholo-

tion techniques are generally considered safe, with low level gist (SLP), with tDCS or rTMS in the outpatient rehabilita-
of risk of adverse effects and few contraindications.22–24 Com- tion setting. Importantly, although the JH-NIBS Program
pared with tDCS, TMS is more expensive, less portable, gener- operates within the confines of a traditional clinical setting,
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ates muscle contractions, and sound stimuli during application we maintain the same level of uniformity and compliance that
that may increase discomfort and carries a very rare risk of in- would be observed with these interventions administered in a
ducing seizures. In addition, tDCS is more easily paired with research scenario.
simultaneous therapy, making it more amenable to widespread The NIBS clinical program involves careful coordination
clinical use. Because the development of safety guidelines, among a number of clinical and administrative staff. There
TMS-induced seizures are extremely rare events, especially are five categories of personnel including NIBS physicians, re-
when considering the number of subjects who have undergone habilitation therapists, technicians, researchers, and a program
TMS procedures worldwide without complications.22 coordinator. Please see Table 1 for a more detailed description
Although a growing body of evidence suggests that the of the roles and responsibilities of each of the NIBS personnel.
use of NIBS can aid in the recovery of stroke and other neu- This is in line with a recent recommendation from an Interna-
rological conditions,22,23 it remains to be clarified whether tional Federation of Clinical Neurophysiology committee.25
the possible therapeutic effects of NIBS are clinically mean- Each of these NIBS personnel plays an important role in the
ingful and how to optimally perform NIBS in a clinical set- patient’s journey through the JH-NIBS Program. Figure 2 de-
ting. Currently, there is no clear patient profile or biomarker picts this “journey” from first contact to discharge. Analysis
describing the type of patient who would most benefit from of patient data as well as outcome measures of the JH-NIBS
stimulation nor the optimal target and time window for treat- Program has been approved by the Johns Hopkins University
ment implementation after injury. Although there have been School of Medicine Institutional Review Board.
numerous studies testing its safety and efficacy, large clinical
trials that clearly delineate a single approach have been lack-
Training of the NIBS Technician and Therapists
ing. Furthermore, given the heterogeneity of neurological
conditions and impairments, it is unlikely that a single or even Before the launch of the clinical program, the NIBS techni-
a few studies will be able to delineate a standard approach to cian and all therapists are trained in tDCS/rTMS principles/
the implementation of NIBS in the clinical setting in the near treatment techniques, monitoring of each patient’s progress/
future. Despite these limitations, a series of principles have adverse effects, and guidelines for discontinuation of a session
been described that seem to underlie the effectiveness of and/or study participation including emergencies. In addition,
NIBS techniques (Fig. 1). These are (1) pairing NIBS with be- the NIBS technician receives more detailed training in adminis-
havioral training, (2) targeting brain regions involved in the tering tDCS and rTMS to patients including the specific aspects
behavior, and (3) repeating the interventions at relatively high of safety such as contraindications, NIBS parameter settings, de-
frequency (e.g., daily). The goal of the Johns Hopkins vices, the 10–20 EEG system, and a basic emergency response.
Non-invasive Brain Stimulation Rehabilitation Program (JH-
NIBS program) is to improve patients’ clinical outcomes by Initial Clinical Evaluations
pairing the appropriate NIBS technique with high-intensity re- Before enrollment in the JH-NIBS program, all patients un-
habilitation training exercises. dergo an initial evaluation by a physiatrist trained in NIBS tech-
This program has been treating patients since 2017. The niques for rehabilitation. The initial evaluation includes a de-
present article describes the components of the program, as tailed review of medical history and of available imaging records
well as its clinical implementation in neurorehabilitation. (magnetic resonance imaging and/or computed tomography

FIGURE 1. Set of principles that research suggests underlie the effectiveness of NIBS techniques for rehabilitation.

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 Volume 102, Number 2 (Suppl), February 2023 Clinical Implementation of NIBS

TABLE 1. Description of the roles and responsibilities of each of the NIBS personnel

Title Description and Role

NIBS physician An expert in noninvasive brain stimulation and rehabilitation who is board certified in physical medicine and rehabilitation.
Performs initial patient eligibility screening and conducts assessments before, midway, and after the NIBS program.
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NIBS rehabilitation Physical therapist, OT, and/or SLP with expertise in treating patients with neurological injury and disease.
therapist(s) Provides high-intensity, high-frequency, individualized rehabilitation interventions in accordance with research-based
clinical practice; administers clinical outcome measures before and at the end of NIBS.
NIBS technician A specialist in administering brain stimulation, both TMS and tDCS.
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Applies brain stimulation and monitors for adverse events during each treatment session; fields patient and family
questions about NIBS modalities; compiles outcome measure summary sheet for patients and NIBS physicians at the
conclusion of NIBS.
NIBS program Administrator
coordinator Manages patient, physician, and therapist scheduling, answers programmatic questions, collects payment.
NIBS research team A group of 4–6 researchers in the field of NIBS and rehabilitation. Note these individuals may have other roles in the program
(e.g., NIBS physician).
Manage the NIBS IRB for data clinical outcomes collection, enter outcome measures in to secure database (e.g., Qualtrics),
perform data analysis, and data presentation.

scans) to determine candidacy for enrollment in the clinical pro- a partially damaged region or (2) compensatory: enhance the
gram as well as modality of stimulation (tDCS vs rTMS). Please function of nondamaged areas that are part of the impaired net-
see inclusion/exclusion criteria in Table 2. Physicians perform a work with the goal of facilitating compensation by a nondamaged
comprehensive evaluation including management of common brain region. Refer to Figure 3 for details and patient examples.
poststroke problems, such as mood, attention, sleep, spasticity,
pain, bowel, and bladder management. We use the Patient Intervention
Health Questionnaire-926 to screen for depression and General
Anxiety Disorder-727 to screen for anxiety. Patients are opti- Treatment Sessions
mized medically before beginning evaluation and treatment by Depending on the patient’s presentation and needs, they
therapists to remove barriers for full training participation. After participate in one, two, or all three therapy disciplines (PT,
the physiatrist evaluation, the rehabilitation therapists administer OT, SLP) during the JH-NIBS Program. However, tDCS is
a series of clinical assessments that are used to determine prog- only administered in conjunction with up to two therapy disci-
ress after the program is completed. plines per day, and rTMS is administered before therapy ses-
sions or in isolation once daily (e.g., to treat symptoms such
as pain or focal dystonia). Patients prioritize impairments they
Establishing Individual Stimulation Parameters wished to improve. Thus, the decision about which therapies
After the completion of the evaluations, the NIBS physician are done in conjunction with tDCS is made by the patient
and rehabilitation therapists meet to determine the treatment and NIBS physician. Patients engage in the NIBS Rehabilita-
plan for all qualifying patients. This consists of determining tion Program for 3 consecutive weeks, receiving 5 sessions a
the appropriate individualized therapy plan and the stimula- week, for each of the prescribed therapy disciplines. Treatment
tion target based on the training plan. Determining the place- parameters for neurorehabilitation using NIBS have not yet
ment of the electrodes or coil (e.g., the montage and the neu- been standardized and vary from 5 to 15 sessions across a
ral targets) is based on previous work4,5,28 and the expertise timeframe of days to multiple weeks. The rationale for using
of the neurorehabilitation team. For example, in stroke multiple session of tDCS in our NIBS program is based on
neurorehabilitation, we determine the stimulation target follow- the premise that the short-lasting effects from a single session
ing the two approaches: (1) restorative: enhance the activation of of tDCS will accumulate with repeated sessions.29 Previous

FIGURE 2. Depiction of the pathway through the Johns Hopkins NIBS Rehabilitation Program. Initial contact is between the NIBS coordinator and the
patient or caregiver. Throughout the course of the program, the patient will interact with multiple members of the NIBS team including the physician,
therapists, and brain stimulation technician. These individuals work together with the patient to individualize the program and the goals based on the
patient’s impairments and therapy goals.

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 Sebastian et al. Volume 102, Number 2 (Suppl), February 2023

surements system is used to guide electrode placement for

TABLE 2. Inclusion and exclusion criteria
tDCS. Stimulation montage is determined based on lesion site
Inclusion Criteria Exclusion Criteria and therapy type/goal for each patient. For example, for phys-
ical therapy, one target region of the brain is the primary motor
Impaired mobility, Aneurysm clips cortex (M1) for motor recovery after stroke. The anode is
speech, language,
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placed on the lesioned M1, and the cathode (reference elec-

cognition or swallowing
trode) is placed over the contralateral orbit (Fig. 3). Many pa-
Ability to engage in Cardiac pacemakers
therapy 5 a wk tients experience expected, mild adverse effects typically de-
Cochlear implants
for 3 wks scribed as mild itching, irritation, or burning sensations under-
Intracardiac lines
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neath the electrodes that disappear after several minutes.

Pregnancy
Considering the extensive exclusion criteria, screening procedure,
Other intracranial or
intraoccular metal and constant monitoring of the patients, we have not observed
or foreign objects any unexpected serious adverse events. Please note that most
Caution patients (approximately 95%) enrolled in the JH-NIBS Pro-
Craniotomy, cranioplasty, gram receive the noninvasive brain stimulation modality tDCS.
history of seizures,
implanted medical pump,
other implantable devices Repetitive Transcranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation is delivered
using a Magstim Super Rapid2 (Magstim Co Ltd, Whitland,
work suggests that more sessions seem to provide additional United Kingdom) stimulator connected to a figure-of-eight
benefit with no additional adverse effects.30 cooled air-film coil. The TMS neuronavigation software
(Brainsight2; Rogue, Montreal, Quebec, Canada) is used to
identify the desired target. Stereotaxic localization of the
Transcranial Direct Current Stimulation TMS stimulation site is determined through a coregistration
Transcranial direct current stimulation is delivered using method between the TMS coil position and the patient’s head
the neuroConn DC-stimulator at a constant current of 2 mA projected on the patient’s brain magnetic resonance imaging
(with a 10-sec fade-in/fade-out) using two 5  5-cm surface using Montreal Neurologic Institute coordinates. The
sponge electrodes soaked in saline solution secured by Coban air-cooled 70-mm rTMS coil is placed tangentially at 45 de-
self-adherent wrap. A NIBS technician places the electrodes grees over the target. To determine stimulation intensity and
before the start of therapy. The stimulation duration is 25 mins. resting motor threshold values, electromyography electrodes
Stimulation starts at the same time as the behavioral therapy. are attached to the first dorsal interossei muscle, contralateral
Therapy continues for another 35 mins after the completion to the side of stimulation. Stimulation location, intensity, dura-
of 25 mins of tDCS. The 10/20 electroencephalogram mea- tion, and number of sessions is determined based on anatomic

FIGURE 3. Diagram depicting factors considered by the NIBS physicians when determining the stimulation location for a given patient. Green arrow
and box highlight a patient example of a restorative approach; orange arrow and box highlight a patient example of a compensatory approach. CT,
computed tomography; CVA, cerebral vascular accident; MCA, middle cerebral artery; MRI, magnetic resonance imaging; PD, Parkinson disease; TBI,
traumatic brain injury; TMS, transcranial magnetic stimulation; UE, upper extremity. Note that motor-evoked potential may not be available for all
patients.

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 Volume 102, Number 2 (Suppl), February 2023 Clinical Implementation of NIBS

location of postulated symptom generation. For example, in fo- Posttreatment Clinical Evaluation
cal and multifocal dystonia treatment we follow the protocol After the completion of the 3-wk tDCS paired with rehabilita-
published by Borich et al.,31 consisting of 15 sessions of a tion therapy or rTMS, patients undergo posttreatment evaluation.
low frequency (1 Hz), moderate intensity (90% resting motor This evaluation consists of the repeat administration of the
threshold), repetitive TMS pulse (900 pulses over 15 mins) di- same therapy outcome measures used at baseline. This is crit-
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rected over first dorsal interosseous representation of M1/pri- ical for understanding an individual’s responsiveness to the
mary motor cortex, contralateral to the side of dystonia. Pa- JH-NIBS Clinical Program. Patients then meet with the NIBS
tients experience mild headache or scalp discomfort following physiatrist to discuss program outcomes and recommendations
the session, without any serious or unexpected adverse events for future care including the appropriateness for future NIBS
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reported to date. boosters. After this, the NIBS team met to review and discuss
patient-specific progress, update, and change goals/program as
necessary.
Therapy
Therapists involved in the program assess the clinical Outcome Measures
outcome metrics and select the appropriate evidenced based All patients receive a battery of clinical assessments be-
therapy training tasks focused to reduce impairment. In this fore and after the treatment to track changes in clinical metrics
manner, each patient receives a customized course of high- of impairment and participation. This includes objective and
intensity, task-specific, impairment focused, evidence-based self-reported measures of function that are administered at
therapy. For example, patients with poststroke aphasia receive the beginning and end of the NIBS program. The various out-
multimodal language therapy targeting deficits at the level of come measures for each discipline are listed in Supplementary
impairment and progressing accordingly. Expressive lan- Table 1 (Supplemental Digital Content 1, http://links.lww.com/
guage techniques include picture/object naming, sentence PHM/B876).
completions, and divergent and convergent naming with and
without orthographic demand. Receptive language tasks in-
clude auditory/written word comprehension, yes/no ques- SUMMARY
tions, environmental and body commands, as well as reading The therapeutic benefit of NIBS, its optimal delivery,
comprehension at various levels. Patients with gait impair- identification of patients who would most benefit from stimu-
ment receive task-specific, high-intensity gait training, which lation, and other variables associated with the clinical use of
may include over ground walking, assistive device training, tDCS and rTMS remains incompletely understood. However,
treadmill walking, walking in an overhead harness system, there are certain principles that are thought to be fundamental
and treadmill walking with pneumatic unweighting for body for the efficacy of NIBS to drive behavioral changes. Specifi-
weight support. Patients with impaired balance receive train- cally, pairing NIBS with behavioral training, targeting brain re-
ing that include static and dynamic sitting and standing bal- gions involved in the behavior, and repetition of the interven-
ance in variable conditions (adjusted base of support, contri- tions at relatively high frequency (e.g., daily) are critical to
bution of vision, perturbations, surfaces with different de- drive the effectiveness of NIBS. Following these principles, to-
grees of stability/compliance, with dual-task demands) and gether with the intent of reducing neurological impairment by
progress as rapidly as appropriate to help the patient achieve providing high-intensity training, which are the core ingredi-
safety and stability with functional task. Patients with paresis ents, we have put together to develop the Johns Hopkins NIBS
or decreased strength receive targeted strength training both program. We hope that the description of this clinical program
in isolation (e.g., ankle dorsiflexion with yellow TheraBand) will help inform individualized, effective, and efficient tDCS/
and in the context of a functional task (e.g., repeated sit-to- rTMS treatment recommendations for neurorehabilitation spe-
stands biasing weight-bearing toward the paretic leg). Patients cialists working with stroke patients and other neurological dis-
with upper extremity deficits receive impairment focused orders, in addition to helping our patients directly.
training in strength (e.g., shoulder shrugs), coordination
(e.g., reaching and grasping for objects and placing them on ACKNOWLEDGMENTS
shelves), and/or finger individuation (e.g., pinching pegs or The authors thank William Stokes, Rehabilitation Thera-
marbles and placing them in holes). pists, and patients involved in the JH-NIBS clinical program.

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