Concussions from blast and non-blast mechanisms can lead to prolonged post concussive
symptoms (PPCS) with debilitating consequences for return to service, functional
independence, and quality of life. Unfortunately, algorithmic rehabilitation modalities
are of limited generalizability and have small effect sizes, potentially because of
limited target engagement, while medications are modestly efficacious but carry
significant risks (e.g., addiction).
Cognitive symptoms after mTBI are common and debilitating: Contrary to conventional
wisdom, mTBI are often not "mild" in regard to disability, with up to 22% of patients
reporting functional impairment at one year following injury. In particular, executive
functions (such as working memory, set shifting, and response inhibition) appear to be
more sensitive to TBI damage and have a greater impact on overall functioning. Despite
advances in our understanding of PPCS, no single treatment yet targets putative TBI
mechanisms. Medications such as methylphenidate, while modestly helpful, carry adverse
consequences such as disinhibition and cardiovascular effects, and little evidence
currently exists to recommend any other class of medication. Cognitive rehabilitation is
only mildly helpful: Since the 2009 meeting of the Defense Centers for Excellence of
Psychological Health and Traumatic Brain Injury, little consensus has been reached
regarding the utility or optimum means of delivery for therapist-based rehabilitation of
cognitive deficits. Importantly, several limitations in the evidence base have impeded
progress toward a standardized approach to post-TBI cognitive symptoms, including: 1)
varied rehabilitation interventions used (i.e., therapist-based, computer-based); 2)
varied outcome measures studied; and 3) lack of generalization of benefits to global
functioning. The most recent trials of cognitive rehabilitation interventions in military
populations have attempted to compare these different rehabilitation approaches. While
these studies demonstrate that cognitive rehabilitation interventions can improve
subjective symptoms and quality of life after mTBI, it is not clear how this benefit is
achieved, nor if it is actually targeting a mTBI related mechanism.
Neuromodulation can accelerate cognitive recovery: Multiple studies have described use of
tDCS in TBI for cognitive performance, nearly all targeting the left DLPFC node of the
CCN, with variable improvements noted from a variety of different stimulation protocols.
Of note, a recent meta-analysis of tDCS for working memory in neuropsychiatric
populations showed that anodal tDCS produces significant improvement in online (during
stimulation) working memory accuracy (standardized mean difference = 0.77).
rTMS also shows promise for treating mTBI: rTMS is a powerful neuromodulation technique
that induces robust neuroplasticity, effectively treats disease, and is better
characterized in terms of its mechanism of action. Recently, several small naturalistic
and controlled studies have been reported, indicating that both excitatory and inhibitory
rTMS are safe in the mTBI population and can improve post concussive headaches, chronic
pain, tinnitus, and depression. A recent negative trial of non-specific rTMS for
cognition in severe TBI highlights the important need for more precise methods of patient
selection, treatment selection, and target engagement.
Study procedures involve a baseline testing visit, 16 treatment visits, and a
post-treatment testing visit. Participants will also be contacted at 3 months and 6
months post treatment for follow-up.
Baseline Testing Visit: Study assessments for collecting demographic information, history
and TBI data, symptom severity information, and neuropsychological testing will be
completed at the baseline testing visit. Testing will be performed by trained study
personnel under direct supervision of the study Co-Investigators.
Baseline Visit, MRI scanning: Subjects will undergo a 60-minute MRI using a 3T Siemens
Prisma scanner at both the Albuquerque (MRN) and Minneapolis (CMRR) sites.
High-resolution T1- and T2-weighted images (1 x 1 x 1 mm resolution), DTI, pCASL, resting
state fMRI, and task-related fMRI will be collected. All anatomical data will be reviewed
by a board-certified neuroradiologist blinded to group identification. All positive
findings will be coded for presence, location, severity and pathology of each
abnormality, consistent with the imaging CDEs. Participants will undergo structural and
functional MRI scanning at rest and during a multisensory working memory task. The MMWM
is a continuous performance test in which subjects respond to simultaneous sequences of
visual (squares on a grid) and auditory (spoken numbers) stimuli by pressing a button if
stimuli in either or both sensory modalities match a previous stimulus (1-back or
2-back).
Neuromodulation + Training Sessions (16 total; 1 hr each): In Albuquerque, following
completion of the Baseline Visit, participants will receive either active HD-tDCS, active
rTMS, or sham stimulation to the left DLPFC for a total of 30 minutes, 4 days/week, for 4
consecutive weeks. During neuromodulation sessions, subjects will describe physical
sensations such as tingling or itching using a 10-point anchored Likert scale.
Administration of HD-tDCS will be stopped immediately if subjects report 8 or above for
discomfort, or if subjects wish to stop at any time. Subjects will have their mood,
energy, pain, and arousal levels assessed using visual analog 10-point scales. These
checks will occur every ten minutes during the stimulation session.
HD-tDCS: The Star-Stim 8 high-definition transcranial electrical stimulator will be used
to administer HD-tDCS. Targeting of the left DLPFC will be done by utilizing a standard
EEG cap fitted snugly to the subject's head. Several 10-20 EEG system positions will be
measured and confirmed to ensure that the cap is correctly oriented on the head. Round, 1
cm2 HD-tDCS electrodes will be utilized to deliver anodal current and receive cathodal
current. Two anodal electrodes will be placed on the scalp over the functionally
determined DLPFC, delivering approximately 1 mA of current each, in order to reduce
overall sensation. Six return electrodes will be placed in various positions around the
anodes. Precise electrode placement for each subject will be determined according to
current modeling software that will use each individual's MRI T1 images to construct a
3-dimensional finite element model aiming to maximize current density within the DLPFC
while minimizing current density outside of it. Current for the treatment condition will
be applied at 2.0 mA for 30 minutes for a total delivered charge of 60 mA-min. Current
will be ramped up over 1 minute at initiation and ramped down over 1 minute with
termination. Impedances are monitored in real-time for each channel to ensure that they
do not exceed recommended limits (e.g., 200 kilo-ohms).
rTMS: Participants will receive 16 sessions of TMS to the functional area in the DLPFC
identified with fMRI while performing a working memory task. A Magventure MagPro
Transcranial Magnetic Stimulator (Albuquerque, NM) and a Magstim Rapid 2 Transcranial
Magnetic Stimulator (Minneapolis, MN) will be used to administer active and sham rTMS to
the left dorsolateral prefrontal cortex in 54 Veterans and Warfighters (36 active, 18
sham) with mTBI and cognitive postconcussive symptoms. At the first session, dose
titration will be performed. After sitting comfortably in the chair the subject's head is
held with a moldable pillow, and they are given earplugs to protect against coil
discharge noise. Surface electromyography leads will be applied to clean skin over the
right hand over the first dorsal interosseous (FDI) muscle. The motor cortex hotspot for
the muscle will be identified with single-pulse TMS delivered to the contralateral
hemisphere. Resting motor threshold will be determined to be the lowest stimulation
intensity necessary to elicit a motor-evoked potential meeting TMS Clinical Society
conventional criteria of 50 uV peak-to-peak on 5 out of 10 trials. The subject's fMRI
data is loaded into the neuronavigation tracking computer to locate the functional
hotspot within the DLPFC. An infrared camera connected to the targeting computer will
track the three-dimensional positions of the subject's head and the TMS coil in real
time, via affixed tracking markers. The TMS coil is then positioned over the left
forehead using the co-registered MRI data and identified head landmarks. In each session,
up to 1800 pulses will be delivered according to conventional parameters for excitatory
TMS (e.g, 60 trains of 10 triplet pulses, frequency 5 Hz, train duration 2 seconds,
intertrain interval 8 seconds). Magnetic field strength will be 120% of resting motor
threshold. Ramp up of magnetic field strength may be utilized in the first session for
tolerability. Side effects will be monitored and coil angle adjusted to improve
tolerability if necessary without compromising placement.
Sham: The sham group (n=36 total) will be split: half (n=18) will receive sham HD-tDCS,
and half (n=18) will receive sham rTMS. Participants receiving sham HD-tDCS will receive
a current ramp up to the intensity of the real intervention in 30 seconds, then the
current will ramp down to < 0.1 mA, an amount that has been shown not to have any
physiologic effect. With 1 minute left in the stimulation session, the current will ramp
up to full strength in 30 seconds, then ramp down in 30 seconds. This paradigm is used as
a control condition, rather than the absence of stimulation, to equate aspects of the
procedure (preparation and application of electrodes), and to give the participant a
degree of physical sensation that is somewhat similar to that of the real stimulation
group while remaining well below the level sufficient to affect brain function and
behavior. To accomplish a double blind, the HD-tDCS machine is programmed to randomize
sham versus active stimulation and keeps track of the stimulation protocol for later
querying. Sham rTMS is delivered with a sham coil, which delivers no physiologically
active magnetic fields to the brain. It creates a similar sound as the active rTMS coil,
and features electrodes that contact the skin and deliver a mild electrical current which
resembles the sensations caused by typical rTMS pulses. Double blind is maintained
through use of randomized program codes assigned to each subject, and which dictate the
choice of coil for the participant.
Cognitive Training Tasks: For all groups, participants will be administered the APT-3
training battery for 30 minutes at each session, during treatment and sham. Each
session's material will be determined by the study staff in advance according to a
predetermined syllabus, and the participant will proceed through the material as
efficiently as they can. If rTMS is given, the training will take place after rTMS is
completed. If HD-tDCS is given, the training will take place concurrently while the
stimulation is occurring.
Post-treatment Visit: After the 16 neuromodulation + training sessions are completed, the
testing and assessments from the Baseline Visit is repeated for the Post-treatment Visit,
including neuropsychological testing, symptom assessment, and MRI. Demographic
information will not be repeated.
Long term follow-up (30 min each): At 3 months and 6 months after receiving
neuromodulation and cognitive training, subjects will be contacted via telephone and
administered symptom burden and quality of life assessment tools.