JOURNAL OF NEUROTRAUMA XX:1–7 (Month XX, 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/neu.2014.3449

Noninvasive Brain Stimulation for Persistent Postconcussion Symptoms in Mild Traumatic Brain Injury Lisa Koski,1 Theodore Kolivakis,2 Camilla Yu,3 Jen-Kai Chen,4 Scott Delaney,5 and Alain Ptito 6

Abstract

Mild traumatic brain injury (mTBI) is typically followed by various postconcussive symptoms (PCS), including headache, depression, and cognitive deficits. In 15–25% of cases, PCS persists beyond the usual 3-month recovery period, interfering with activities of daily living and responding poorly to pharmacotherapy. We tested the safety, tolerability, and efficacy of repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) for alleviating PCS. Fifteen eligible patients with mTBI and PCS > 3 months postinjury consented to 20 sessions of rTMS (20 · 5-sec trains; 10 Hz at 110% threshold), with clinical and functional magnetic resonance imaging (fMRI) assessments before and after intervention and clinical assessment at 3-month follow-up. Primary outcomes were tolerability, safety, and efficacy, as measured with the PCS Scale. Secondary outcomes included the Cognitive Symptoms Questionnaire, neuropsychological test performance, and working memory task-associated activity as assessed with fMRI. Twelve patients completed all sessions. Three withdrew because of worsening symptoms or for an unrelated event. Stimulation intensity was increased gradually across sessions, and all subjects tolerated the protocol by the sixth session. Commonly reported side effects among completers were increased headache (n = 3) and greater sleep disturbance (n = 3). Participants also reported positive outcomes such as less sleep disturbance (n = 3), and better mental focus (n = 3). On average, PCS scores declined by 14.6 points ( p = 0.009) and fMRI task-related activation peaks in the DLPFC increased after rTMS. rTMS is safe, tolerated by most patients with mTBI, and associated with both a reduction in severity of PCS and an increase in taskrelated activations in DLPFC. Assessment of this intervention in a randomized, control trial is warranted. Key words: brain trauma; concussion; fMRI; head injury; rTMS

neurological conditions,13,14 might be a useful treatment strategy for alleviating PCS. Clinical improvement was reported after noninvasive brain stimulation in severe and chronically altered states of consciousness.15 However, the literature contains only three single case studies16–18 and no prospective open-label or randomized, clinical trials of rTMS in patients with mTBI. Recent reviews call for investigation into rTMS as an intervention for TBI, highlighting its potential to influence not only mood, but also cognitive symptoms, specifically deficits in working memory (WM).19,20 This pilot study aimed to explore the safety, tolerability, and efficacy of high-frequency rTMS over the left DLPFC for treatment of PCS after mTBI. The hypothesis that effects of rTMS are

Introduction

M

ost recovery from mild traumatic brain injury (mTBI) occurs within 3 months after the insult1; however, between 15–25% of mTBI cases have persistent postconcussive symptoms (PCS). These include somatic complaints such as headaches and fatigue, as well as anxiety, irritability, and cognitive deficits that interfere with their activities of daily living.2–5 Also, a marked increase in the prevalence of depression can be seen a few years after traumatic brain injury.6–10 Thus, we hypothesized that repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC), an effective treatment for depressive symptoms in major depressive disorder11,12 and various

1 Department of Psychology, McGill University Health Center (MUHC), Department of Neurology/Neurosurgery and Department of Psychology, McGill University, and Mental Illness and Addiction Axis, Research Institute of the MUHC, McGill University, Montreal, Quebec, Canada. 2 Department of Neurology/Neurosurgery and Department of Psychiatry, McGill University, Montreal, Quebec, Canada. 3 Department of Physiology, McGill University, Montreal, Quebec, Canada. 4 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. 5 Department of Emergency Medicine, McGill University Health Center and McGill Sport Medicine Clinic, McGill University, Montreal, Quebec, Canada. 6 Department of Psychology, McGill University Health Center and Department of Neurology/Neurosurgery, McGill University, Montreal, Quebec, Canada.

1

2 mediated through enhanced functioning of the DLPFC was also examined in a subset of participants who underwent functional magnetic resonance imaging (fMRI) studies of the substrates of WM ability, before and after the rTMS intervention. Methods Sample Fifteen eligible adult patients from a TBI clinic meeting criteria for mTBI with persistent PCS (PCS Symptom Scale score > 21)24 6 months or more postinjury were identified by physicians of the McGill University Health Center (Montreal, Quebec, Canada). The study psychiatrist (T.K.) screened all referred patients to confirm that they met criteria for eligibility. Patients were excluded if they had comorbid neurological or psychiatric history, or if they had contraindications to rTMS. Patients with a past diagnosis of depression or with current depressive symptoms were not excluded from the present study given that a premorbid history of affective or anxiety disorder is predictive of persistent symptoms after mTBI.21 Participants provided informed consent for this study, which was approved by the institutional research ethics board. Intervention Four weeks of rTMS on five consecutive weekdays (20 sessions) were administered using a figure-8 coil attached to a MagPro stimulator (MagVenture A/S, Farum, Denmark). Intensity was calibrated based on the resting motor threshold, that is, the minimum intensity of stimulation evoking a visible muscle twitch on at least five of ten consecutive TMS pulses over the primary motor cortex. The left DLPFC was targeted by proceeding 5 cm anterior to the motor cortex in a parasagittal plane. Stimulation was delivered in 20 five-second trains of 10-Hz stimulation at 110% of threshold, with an intertrain interval of 25 sec, consistent with the induction of cortical facilitation and with recent rTMS protocols for depression.22 Outcome measures Patient characteristics and baseline scores were summarized in terms of distributions, means, standard deviations, and ranges. Participants were assessed within 2 weeks preceding the first rTMS session, within 2 weeks following the final rTMS session, and 3 months after the last rTMS session. Side effects reported by patients during the 4-week intervention were documented to assess safety. Spontaneously reported positive effects were also recorded. Tolerability was defined as the intensity of stimulation tolerated at each session relative to the target intensity prescribed by protocol. The primary outcome measure was the PCS Symptom Scale.23 It consists of 22 symptoms assessed by the subject on a scale from zero to six, six being a severe problem.24 PCS status is classified based on the total score summed across all items: 0–21/126 = no symptom; 22–41 = mild; 42–84 = moderate; and 105–126 = severe. Studies in healthy nonconcussed athletes have established that scores greater than 20 are considered abnormal,24 and this tool is currently used to assess PCS in professional sports. In addition to the total score, we also examined individual items to identify whether certain symptoms are more amenable to change after rTMS. The immediate effect of rTMS was analyzed with a paired two-tailed t-test evaluating changes in the total PCS score between baseline and postintervention assessments. Secondary analyses were performed on the individual items of the PCS Symptom Scale to identify which symptoms were amenable to change after rTMS, with correction for multiple comparisons based on the false discovery rate (FDR) method.25 In the subset of patients for whom 3-month follow-up data were available, duration of effect was assessed by comparing PCS total scores at baseline versus follow-up.

KOSKI ET AL. Cognitive symptoms were measured using a Rasch-analyzed self-report 13-item scale assessing the amount of time in the past month a specific cognitive failure, such as lost train of thought, has been a problem (rarely, sometimes, often, or almost always). Response options for each item are weighted to yield a continuous interval measure of symptom severity. Participants also completed a battery of tests that are sensitive to the types of cognitive impairment associated with mTBI, that is, attention and processing speed (Ruff’s 2 & 7, Symbol Digit Modalities Test, computerized simple, and choice visual reaction time), executive functioning (Trail Making Test, Victoria Stroop Test), and memory (Rey Auditory-Verbal Learning Test),26,27 using alternate forms where possible to minimize practice effects. Effects of rTMS on these outcomes were examined in exploratory analyses. Neurophysiological effects were examined by comparing the extent to which patients recruited the left DLPFC during performance of a WM test before versus after the final rTMS intervention. Verbal and nonverbal WM tasks used in fMRI were the same ones we have used previously to demonstrate reduced activity in the DLPFC during WM performance, compared to baseline performance, among concussed athletes.28 Working memory tasks. Subjects first memorized a set of five visual stimuli to be used in all trials and completed 48 practice trials before scanning. In each trial, random sets of four of these stimuli were projected onto a head-coil–mounted mirror. A fifth stimulus was presented after a 1-sec delay and the subject indicated with a mouse button press whether it did or did not appear among the preceding set of four. Control tasks. Subjects first learned to associate each stimulus with a left or right button press. In each trial, one stimulus was presented four times, and the subject had to respond with a left or right button press to the fifth stimulus presented. fMRI scanning was carried out using a 3T Siemens Magnetom Trio A Tim System (Siemens AG, Munich, Germany) with a 32channel head coil. Each fMRI session started with the acquisition of high-resolution T1-weighted three-dimensional (3D) anatomical images using 3D magnetization-prepared rapid gradient echo sequence (repetition time [TR] = 23 ms; echo time [TE] = 2.98 ms; slice thickness = 1 mm; image matrix = 256 · 256; flip angle [FA] = 30 degrees; field of view [FOV] = 256 mm, interleaved excitation). Blood-oxygenation-level–dependent (BOLD) fMRI data were acquired using T2*-weighted gradient echo echo-planar images (TR = 3000 ms; TE = 50 ms; FA = 90 degrees; in-plane resolution = 2.34 · 2.34 mm; FOV = 300 mm; 128 · 128 image matrix). Each whole-brain functional scan included 120 acquisitions (37 contiguous slices, 4-mm thickness, - 35 degrees relative to an anterior and posterior commissure line, interleaved excitation order). Each scan lasted 6 min, with activation and baseline conditions alternating every eight trials (60 sec). fMRI time series were corrected for movement artefacts and smoothed with a 6-mm full-width at half-maximum Gaussian filter. Whole-brain voxel-wise statistical analysis was performed with fMRIstat.29 BOLD data were first converted to percentage of the whole volume. Significant percent BOLD changes between experimental (i.e., WM task) and baseline (i.e., control task) conditions were determined at each voxel, based on a linear model with correlated errors (Y = Xb + e) using methods described in detail elsewhere.30 Data from each individual run were then normalized to the MNI305 template using an in-house algorithm31 and combined together using a fixed-effects analysis for the following comparisons: 1) verbal WM minus verbal control condition and 2) nonverbal WM minus nonverbal control condition. Group averaging across participants was achieved with a mixed effects linear model and the resulting T-statistic images were thresholded using the minimum given by a Bonferroni’s correction and random field theory to correct for multiple comparisons, taking into account the nonisotropic spatial

TMS TO TREAT POSTCONCUSSION SYMPTOMS correlation of the errors.32 Threshold for significance was established at t = 4.0 for the activation peaks, or t = 3.10 for activation clusters greater than 222 mm3, based on the number of resolution elements in the acquisition volume (2880 resels). To test for differences in brain activity between pre- and postrTMS treatment, subtraction analysis was carried out on group average data using a fixed-effects model. In post-pre subtraction, positive t-statistics show brain regions that have greater increase in activity during WM against control task for post-rTMS scan relative to pre-rTMS scan, and vice versa for the pre-post. The WM-related percent BOLD signal change relative to the control task was also extracted at voxels of interest obtained from this analysis, which were identified as 6-mm radius gray matter volume centred at the voxels with the highest t-value from the group subtraction analysis. Results Participants Table 1 shows the participant and clinical characteristics of the sample. Age ranged from 20 to 60 years, 60% were male, and mean years of formal education was 14.1. Sixty percent reported a history of three or more concussions, including the index event, and the PCS score at the time of referral ranged from 20 to 55 (mean, 37.5). The time since the most recent concussion ranged widely from 6 months to 28 years. Two thirds were enrolled within 3 years of their concussion, and the rest were 8 or more years after their concussion. Nine of 15 patients (60%) exhibited elevated depressive symptoms based on Hamilton Depression Rating Scale (HAM-D) scores, with 20% falling in the range considered to represent severe depressive symptomatology. Four patients were being treated with antidepressant medication. On neuropsychological testing, the group, on average, scored close to the mean for published age- and/or education-matched normative data; however, individual subject data extended into the impaired range on most of the tests administered (details available from the authors on request). Feasibility, retention, side effects Of the 15 participants enrolled in the study, 12 completed all 20 rTMS sessions and the pre- and postintervention assessments. Three left the study after a few rTMS sessions because of worsening symptoms (n = 2) or after 16 sessions for an unrelated event (n = 1). The noncompleters were older in age than the completers ( p = 0.003). The stimulation intensity dictated by protocol was Table 1. Demographic and Clinical Characteristics of the mTBI Sample (n = 15) Years of age (mean – SD, range) Years of education (mean – SD, range) Sex (no. male/female) No. of concussions (1/2/3 + ) Years since most recent concussion (range) HAM-D (none/mild/moderate/severe) PCS score at referral (mean – SD, range) Medicationsa (antidepressant/analgesic)

34.3 – 10.8, 20–60 14.1 – 4.2, 9–20 9/6 4/1/9 0.5–28 6/4/2/3 37.5 – 10.9, 20–55 5/6

Baseline cognitive test performance values are given as z-scores, unless otherwise indicated. a Antidepressant medications included tricyclics (n = 2), selective serotonin reuptake inhibitors/serotonin and noradrenaline reuptake inhibitors (n = 3), or none (n = 10). Analgesics included celecoxib (n = 2), acetaminophen (n = 3), Florinal (n = 1), methocarbamol (n = 1), a cocktail of five opioid and other analgesics (n = 1), or none (n = 9). SD, standard deviation; HAM-D, Hamilton Depression Rating Scale; PCS, postconcussive symptoms.

3 experienced as intolerable at the first session for 9 of 12 completers; however, the intensity was increased gradually across sessions and all were tolerating the protocol by the beginning of the second week of treatment (sixth session). Side effects reported by the 12 completers were headache (n = 3), a single episode of vertigo (n = 1), anxiety about the procedures (n = 1), and increased sleep/disturbance (n = 3). Positive reported side effects included less sleep disturbance (n = 3), better focus (n = 3), less mental ‘‘fog’’ (n = 2), greater energy (n = 1), and less irritability (n = 1). Effects of repetitive transcranial magnetic stimulation on postconcussion symptoms Table 2 shows pre- versus postintervention comparisons for each outcome measure. Severity of PCS declined by an average of 14.6 points after completion of the rTMS intervention, when compared with the preintervention assessment (standard deviation [SD], 16.1; effect size, 0.91; p = 0.009). Older participants showed greater reductions in PCS symptoms than younger participants (r = 0.6; p < 0.05, uncorrected). Figure 2 shows the individual change in PCS total score for the 12 completers as well as the 3-month follow-up scores in the 8 participants for whom these data were available. A reduction in PCS symptom severity is observed in the week or two following completion of the 20 rTMS sessions. A change on the PCS Scale of 5 points or more has been used previously to interpret change over time among concussed athletes studied in the month following injury.24 By this criterion, 9 of 12 completers improved, whereas 1 participant worsened. The mean change scores for all symptoms were in the direction of lower severity postintervention. Paired comparisons of individual PCS symptoms (Fig. 2) showed a decline in ratings of headache, fatigue, trouble falling asleep, numbness or tingling, and trouble remembering, although only the comparison for headache approached significance after correction for multiple comparisons ( p adjusted for FDR, 0.052). No significant changes were noted on the Cognitive Symptoms Questionnaire or in the majority of neuropsychological test scores. A trend was observed toward more rapid completion of colornaming tasks (Stroop Test time), better inhibition and response control (decreased Stroop interference), and more efficient access to semantic representations (category fluency). Effect of repetitive transcranial magnetic stimulation on dorsolateral prefrontal cortex working memory activation Similar activations were observed for the verbal and nonverbal tasks, but with a more bilateral activation pattern in the latter. Before rTMS, areas showing significant task-related BOLD increases, relative to the control condition, included rostral insula, dorsal anterior cingulate cortex (ACC), supplementary motor area, premotor cortex, left thalamus, superior parietal lobule, and occipital cortex. DLPFC (Brodmann area 9/46), a key contributor to WM, was activated below the level for statistical significance for the verbal task and reached significance in the right DLPFC only for the nonverbal task. After rTMS, the activation pattern was more robust, particularly in the prefrontal cortex, where subthreshold peaks became significant. Whole-brain subtraction analysis directly comparing pre- versus post-rTMS scans confirmed significant post-treatment BOLD signal increase in the DLPFC for both verbal and nonverbal WM (Fig. 1). Before treatment with rTMS, significant WM-related decreases in BOLD activity were observed in the medial orbitofrontal cortex, posterior cingulate cortex, retrosplenial cortex, parahippocampus,

4

KOSKI ET AL. Table 2. Mean and SD of Outcomes Across Assessment Time Points

Outcome PCS total score Cognitive symptoms Digit Span total Longest Digit Span forward Symbol Digit Modalities Ruff’s 2 & 7 Automatic Speed Automatic Accuracy Controlled Speed Controlled Accuracy Trail Making Test A Trail Making Test B

Preintervention Change post-pre 45.8 – 17.2 390.1 – 295.9 11.0 – 2.7 7.2 – 1.2 55.9 – 9.9 169.3 – 48.7 96.8 – 2.7 146.6 – 30.2 93.3 – 5.1 23.3 – 5.1 51.8 – 11.9

{

- 14.6 – 16.1 - 155.7 – 320.1 - 0.1 – 2.8 - 0.4 – 1.1 1.1 – 9.9 10.0 – 24.7 1.3 – 3.1 11.3 – 24.0 3.0 – 6.3 - 1.1 – 4.1 - 0.6 – 13.9

Outcome Stroop Card A Stroop Card B Stroop Card C–time Stroop Interference Score Phonemic fluency–no. F words Category fluency–no. animals Rey AVLT – Total Learning Rey AVLT–Delayed Recall Simple RT–mean (ms) Choice No-go RT–mean (ms) Working Memory no. correct

Preintervention Change post-pre 12.5 – 4.5 16.1 – 6.2 24.0 – 9.6 1.9 – 0.4 13.4 – 4.8 22.4 – 5.7 56.7 – 5.3 11.3 – 2.6 637 – 126 748 – 165 19.5 – 9.0

- 0.1 – 1.5 - 1.8 – 1.8{ - 4.4 – 4.4{ 0.3 – 0.3{ 0.9 – 3.5 3.3 – 4.6{ - 1.3 – 9.2 - 0.1 – 3.3 - 35 – 75 - 54 – 98* - 2.4 – –5.1

*p £ 0.10; {p £ 0.05; {p £ 0.01.

inferior parietal lobule, and superior temporal gyrus, with more bilateral patterns for the nonverbal task. After rTMS, greater deactivation was observed in the medial frontal gyrus (Brodmann area 10), bilateral hippocampus and parahippocampus, inferior parietal lobule, and rostral ACC. Direct comparisons of the WM scans showed significantly greater deactivation in the rostral ACC in post-TMS scan, compared with the pretreatment scan (Fig. 1). Neither WM task yielded significant BOLD signal increases in the reverse analysis (pre > post). (table of activation peaks available from the authors on request). Discussion To our knowledge, this is the first article to report on the effects of a 4-week (20-session) rTMS intervention as a treat-

ment for postacute mTBI symptoms. An rTMS protocol known to be effective for treating major depressive disorder was associated with a decrease in ratings of PCS. Analyses of individual symptom change showed a statistically reliable decrease in ratings of headaches, with decreases at the uncorrected level for symptoms of fatigue, trouble falling asleep, difficulty remembering, and numbness or tingling. The majority (80%) of participants tolerated the procedures well, provided allowance was made for a gradual increase to the target stimulation intensity over the first week of the intervention. Side effects were minimal, and no seizures or other serious side effects were observed in this group of patients with mTBI. Three-month follow-up data in a subset of the sample suggested that the effects of rTMS in mTBI may be of limited duration, such that booster sessions would be required to maintain the improvements observed

FIG. 1. Left panel: post-rTMS > pre-rTMS subtraction analysis indicated significantly stronger task-related activation after rTMS intervention in bilateral DLPFC for the verbal WM task and in the right DLPFC for the nonverbal WM task. Right panel: post-rTMS > pre-rTMS subtraction analysis indicated significantly stronger task-related deactivation after rTMS intervention in the rostral anterior cingulate region for both verbal and visual WM tasks. Note: The locations of these significant peaks are shown in coronal slices and the percent BOLD signal change relative to baseline is shown for the verbal (above) and nonverbal (below) tasks in the pre- and the post-rTMS scanning sessions. WM, working memory; rTMS, repetitive transcranial magnetic stimulation; BOLD, blood-oxygenation-level–dependent; DLPFC, dorsolateral prefrontal cortex; rACC, rostral anterior cingulate cortex. Color image is available online at www.liebertpub.com/neu

TMS TO TREAT POSTCONCUSSION SYMPTOMS

5

FIG. 2. Left panel: individual PCS total scores before, immediately after; right panel: 3 months after intervention, and PCS score mean difference ( – SD) in individual symptom ratings post- and pre-rTMS (n = 12). rTMS, repetitive transcranial magnetic stimulation; PCS, postconcussive symptoms. immediately after intervention, much like for treatment of depression. The absence of a control group is a limitation of this study because a decline in symptom ratings could result from the expectation that a novel treatment approach targeting the brain as the source of PCS would prove beneficial. Nevertheless, strong support for rTMS intervention as an efficient treatment for postacute mTBI symptoms emerged from our analysis of BOLD signal changes in DLPFC activity observed with fMRI before and after intervention. In previous work involving comparisons with a matched healthy control group, patients with mTBI showed a characteristic pattern of deficient activation of the DLPFC during performance of the WM task that correlated with the severity of symptoms.28 In the present study, greater activations in DLPFC and greater reductions in activity of the ACC during WM task performance were observed after rTMS. These observations are consistent with the hypothesis that changes in patterns of neural activity consequent to rTMS may underlie its effects on PCS reporting. Further study is needed to understand how an rTMS protocol targeting the left DLPFC produces increases in task-related activity of this region in both cerebral hemispheres, and how this might result in a decrease in persistent symptoms of mTBI. The analysis of change in individual symptoms yielded unexpected findings. High-frequency stimulation of the left DLPFC aims to treat depression by reversing the suppression of activity in this area that is often observed in depressed individuals. Contrary to our expectations, the most reliable improvement was a reduction in headache, whereas changes in mood-related symptoms were inconsistent across subjects. Transient headache is the most commonly reported side effect of rTMS,33 and 3 patients did report headache on at least one occasion during their treatment. Nevertheless, the longer-term impact was to reduce the self-reported

severity of headaches over the span of 3 days preceding assessment. Indeed, randomized, clinical trials now support the analgesic effects of rTMS in the treatment of a variety of painful conditions, including migraine headaches,34 neuropathic pain,35 and fibromyalgia.36 For treatment of pain disorders, the primary motor cortex is the best-studied target of rTMS; however, targeting the prefrontal cortex may also have analgesic effects,37,38 and in one study, individuals with comorbid migraine disorder who were undergoing rTMS for treatment of pharmacologically resistant depression showed an unexpected reduction in headaches.39 A recent study comparing individuals with persistent symptoms after mTBI versus symptomatic individuals with no history of head injury reported that only headaches and patient-reported cognitive failures reliably discriminated between those with and without head injury.40 In this context, our observation of a reduction in both headache and subjectively reported memory lapses subsequent to rTMS suggests a relatively targeted effect of this intervention on the specific symptoms that are more closely associated with the persistent effects of a mild brain injury. Before proceeding to a randomized, clinical trial, further work to empirically establish clinically important change for the PCS Scale is essential. Nevertheless, this preliminary evidence for a benign side-effects profile, effects on PCS symptoms, and a mechanism of action through modulation of DLPFC activity represent significant first steps in evaluating the potential benefits of rTMS as a treatment option for this difficult-to-treat population. Acknowledgments The authors acknowledge the following individuals: Serge Gallant (assistance with copyediting, preparation of figures and

6 tables, and clerical assistance); Elena Lebedeva (data collection and supervision of personnel); and Marcel Mazaltarim and Philippe Mazaltarim (coordination and delivery of rTMS protocol and assistance with data collection). Author Disclosure Statement Dr. Koski reports grants from the Canadian Institutes of Health Research (CIHR) and nonfinancial support from the MS Society of Canada during the conduct of the study. Dr. Kolivakis reports personal fees and sat on the advisory board of AstraZeneca, personal fees and sat on the advisory board of Lundbeck, personal fees and sat on the advisory board of Sunovion, personal fees and sat on the advisory board of Eli Lilly, personal fees and sat on the advisory board of Janssen-Ortho, personal fees and sat on the advisory board of GlaxoSmithKline, and personal fees and sat on the advisory board of Bristol-Myers Squibb, outside the submitted work. Dr. Ptito reports grants from the CIHR. References 1. Carroll, L.J., Cassidy, J.D., Holm, L., Kraus, J., and Coronado, V.G. (2004). Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J. Rehabil. Med. 43 Suppl., 113–125. 2. Bottari, C., Dutil, E., Dassa, C., and Rainville, C. (2008). Independence in instrumental activities of daily living and its relationship to executive function in persons with traumatic brain injury. Brain Inj. 22 (Supplement 1), 1–127. 3. Bottari, C., Dutil, E., Dassa, C., and Rainville, C. (2008). Relationship of TBI severity and socio-demographic characteristics to independence in everyday activities. Brain Inj. 22 (Supplement 1), 1–127. 4. Bottari, C., Dassa, C., Rainville, C., and Dutil, E. (2009). The criterion-related validity of the IADL Profile with measures of executive functions, indices of trauma severity and sociodemographic characteristics. Brain Inj. 23, 322–335. 5. Bottari, C., Dassa, C., Rainville, C., and Dutil, E. (2009). The factorial validity and internal consistency of the Instrumental Activities of Daily Living Profile in individuals with a traumatic brain injury. Neuropsychol. Rehabil. 19, 177–207. 6. Rose, E.J., Simonotto, E., and Ebmeier, K.P. (2006). Limbic overactivity in depression during preserved performance on the n-back task. Neuroimage 29, 203–215. 7. Deb, S., Lyons, I., and Koutzoukis, C. (1998). Neuropsychiatric sequelae one year after a minor head injury. J. Neurol. Neurosurg. Psychiatry 65, 899–902. 8. Jorge, R.E., Robinson, R.G., Arndt, S.V., Starkstein, S.E., Forrester, A.W., and Geisler, F. (1993). Depression following traumatic brain injury: a 1 year longitudinal study. J. Affect. Disord. 27, 233–243. 9. Seel, R.T., Kreutzer, J.S., Rosenthal, M., Hammond, F.M., Corrigan, J.D., and Black, K. (2003). Depression after traumatic brain injury: a National Institute on Disability and Rehabilitation Research Model Systems multicenter investigation. Arch. Phys. Med. Rehabil. 84, 177–184. 10. Kreutzer, J.S., Seel, R.T., and Gourley, E. (2001). The prevalence and symptom rates of depression after traumatic brain injury: a comprehensive examination. Brain Inj. 15, 563–576. 11. Daskalakis, Z.J., Levinson, A.J., and Fitzgerald, P.B. (2008). Repetitive transcranial magnetic stimulation for major depressive disorder: a review. Can. J. Psychiatry 53, 555–566. 12. Lam, R.W., Chan, P., Wilkins-Ho, M., and Yatham, L.N. (2008). Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can. J. Psychiatry 53, 621–631. 13. Epstein, C.M., Evatt, M.L., Funk, A., Girard-Siqueira, L., Lupei, N., Slaughter, L., Athar, S., Green, J., McDonald, W., and DeLong, M.R. (2007). An open study of repetitive transcranial magnetic stimulation in treatment-resistant depression with Parkinson’s disease. Clin. Neurophysiol. 118, 2189–2194. 14. Jorge, R.E., Robinson, R.G., Tateno, A., Narushima, K., Acion, L., Moser, D., Arndt, S., and Chemerinski, E. (2004). Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study. Biol. Psychiatry 55, 398–405.

KOSKI ET AL. 15. Angelakis, E., Liouta, E., Andreadis, N., Korfias, S., Ktonas, P., Stranjalis, G., and Sakas, D.E. (2013). Transcranial direct current stimulation effects in disorders of consciousness. Arch. Phys. Med. Rehabil. 95, 283–289. 16. Fitzgerald, P.B., Hoy, K.E., Maller, J.J., Herring, S., Segrave, R., McQueen, S., Peachey, A., Hollander, Y., Anderson, J.F., and Daskalakis, Z.J. (2011). Transcranial magnetic stimulation for depression after a traumatic brain injury: a case study. J. ECT 27, 38–40. 17. Cosentino, G., Giglia, G., Palermo, A., Panetta, M., Lo Baido, R., Brighina, F., and Fierro, B. (2010). A case of post-traumatic complex auditory hallucinosis treated with rTMS. Neurocase 16, 267–272. 18. Kreuzer, P.M., Landgrebe, M., Frank, E., and Langguth, B. (2013). Repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus after traumatic brain injury: a case study. J. Head Trauma Rehabil. 28, 386–389. 19. Villamar, M.F., Santos Portilla, A., Fregni, F., and Zafonte, R. (2012). Noninvasive brain stimulation to modulate neuroplasticity in traumatic brain injury. Neuromodulation 15, 326–338. 20. Demirtas-Tatlidede, A., Vahabzadeh-Hagh, A.M., Bernabeu, M., Tormos, J.M., and Pascual-Leone, A. (2012). Noninvasive brain stimulation in traumatic brain injury. J. Head Trauma Rehabil. 27, 274–292. 21. Ponsford, J., Cameron, P., Fitzgerald, M., Grant, M., Mikocka-Walus, A., and Scho¨nberger, M. (2012). Predictors of postconcussive symptoms 3 months after mild traumatic brain injury. Neuropsychology 26, 304–313. 22. Schutter, D.J. (2009). Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol. Med. 39, 65–75. 23. Maroon, J.C., Lovell, M.R., Norwig, J., Podell, K., Powell, J.W., and Hartl, R. (2000). Cerebral concussion in athletes: evaluation and neuropsychological testing. Neurosurgery 47, 659–669; discussion, 669–672. 24. Lovell, M.R., Iverson, G.L., Collins, M.W., Podell, K., Johnston, K.M., Pardini, D., Pardini, J., Norwig, J., and Maroon, J.C. (2006). Measurement of symptoms following sports-related concussion: reliability and normative data for the post-concussion scale. Appl. Neuropsychol. 13, 166–174. 25. Benjamini, Y., and Hochberg, Y. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. Roy. Stat. Soc. B (Method.) 57, 289–300. 26. Macciocchi, S.N., Barth, J.T., Alves, W., Rimel, R.W., and Jane, J.A. (1996). Neuropsychological functioning and recovery after mild head injury in collegiate athletes. Neurosurgery 39, 510–514. 27. Grindel, S.H., Lovell, M.R., and Collins, M.W. (2001). The assessment of sport-related concussion: the evidence behind neuropsychological testing and management. Clin. J. Sport. Med. 11, 134–143. 28. Chen, J.K., Johnston, K.M., Collie, A., McCrory, P., and Ptito, A. (2007). A validation of the post concussion symptom scale in the assessment of complex concussion using cognitive testing and functional MRI. J. Neurol. Neurosurg. Psychiatry 78, 1231–1238. 29. Worsley, K.J., Liao, C., Aston, J., Petre, V., Duncan, G., Morales, F., and Evans, A. (2002). A general statistical analysis for fMRI data. Neuroimage 15, 1–15. 30. Friston, K., Fletcher, P., Josephs, O., Holmes, A., Rugg, M., and Turner, R. (1998). Event-related fMRI: characterizing differential responses. Neuroimage 7, 30–40. 31. Collins, D.L., Neelin, P., Peters, T.M., and Evans, A.C. (1994). Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J. Comput. Assist. Tomogr. 18, 192–205. 32. Worsley, K.J. (2005). Spatial smoothing of autocorrelations to control the degrees of freedom in fMRI analysis. Neuroimage 26, 635–641. 33. Loo, C.K., McFarquhar, T.F., and Mitchell, P.B. (2008). A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Int. J. Neuropsychopharmacol. 11, 131–147. 34. Misra, U.K., Kalita, J., and Bhoi, S.K. (2013). High-rate repetitive transcranial magnetic stimulation in migraine prophylaxis: a randomized, placebo-controlled study. J Neurol. 260, 2793–2801. 35. Leung, A., Donohue, M., Xu, R., Lee, R., Lefaucheur, J.-P., Khedr, E.M., Saitoh, Y., Andre´-Obadia, N., Rollnik, J., Wallace, M., and Chen, R. (2009). rTMS for suppressing neuropathic pain: a metaanalysis. J. Pain 10, 1205–1216. 36. Passard, A., Attal, N., Benadhira, R., Brasseur, L., Saba, G., Sichere, P., Perrot, S., Januel, D., and Bouhassira, D. (2007). Effects of unilateral

TMS TO TREAT POSTCONCUSSION SYMPTOMS repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 130, 2661–2670. 37. Nahmias, F., Debes, C., de Andrade, D.C., Mhalla, A., and Bouhassira, D. (2009). Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers. Pain 147, 224–232. 38. Borckardt, J.J., Smith, A.R., Reeves, S.T., Madan, A., Shelley, N., Branham, R., Nahas, Z., and George, M.S. (2009). A pilot study investigating the effects of fast left prefrontal rTMS on chronic neuropathic pain. Pain Med. 10, 840–849. 39. O’Reardon, J.P., Fontecha, J.F., Cristancho, M.A., and Newman, S. (2007). Unexpected reduction in migraine and psychogenic headaches following rTMS treatment for major depression: a report of two cases. CNS Spectr. 12, 921–925.

7 40. Dean, P.J., O’Neill, D., and Sterr, A. (2012). Post-concussion syndrome: prevalence after mild traumatic brain injury in comparison with a sample without head injury. Brain Inj. 26, 14–26.

Address correspondence to: Lisa Koski, PhD The Allan Memorial Institute P2.142, 1025 Pine Avenue West Montreal, Quebec, H3A 1A1 Canada E-mail: [email protected]

Noninvasive brain stimulation for persistent postconcussion symptoms in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is typically followed by various postconcussive symptoms (PCS), including headache, depression, and cognitive defic...
344KB Sizes 0 Downloads 4 Views