Placebo-Controlled Trial of Familiar Auditory Sensory Training for Acute Severe Traumatic Brain Injury: A Preliminary Report

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research-article2015

NNRXXX10.1177/1545968314554626Neurorehabilitation and Neural RepairPape et al

Communications Case Reports

Placebo-Controlled Trial of Familiar Auditory Sensory Training for Acute Severe Traumatic Brain Injury: A Preliminary Report

Neurorehabilitation and Neural Repair 1­–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1545968314554626 nnr.sagepub.com

Theresa Louise-Bender Pape, DrPH, MA1,2, Joshua M. Rosenow, MD2,3, Monica Steiner, MD1,4, Todd Parrish, PhD2, Ann Guernon, MS1,5, Brett Harton, MS1, Vijaya Patil, MD1,4, Dulal K. Bhaumik, PhD1,6, Shane McNamee, MD7, Matthew Walker, MD8, Kathleen Froehlich9, Catherine Burress9, Cheryl Odle, MBA1, Xue Wang, PhD2, Amy A. Herrold, PhD1, Weihan Zhao, PhD6, Domenic Reda, PhD1, Trudy Mallinson, PhD10, Mark Conneely, MD11, and Alexander J. Nemeth, MD2 Abstract Background. Sensory stimulation is often provided to persons incurring severe traumatic brain injury (TBI), but therapeutic effects are unclear. Objective. This preliminary study investigated neurobehavioral and neurophysiological effects related to sensory stimulation on global neurobehavioral functioning, arousal, and awareness. Methods. A double-blind randomized placebocontrolled trial where 15 participants in states of disordered consciousness (DOC), an average of 70 days after TBI, were provided either the Familiar Auditory Sensory Training (FAST) or Placebo of silence. Global neurobehavioral functioning was measured with the Disorders of Consciousness Scale (DOCS). Arousal and awareness were measured with the Coma-NearComa (CNC) scale. Neurophysiological effect was measured using functional magnetic resonance imaging (fMRI). Results. FAST (n = 8) and Placebo (n = 7) groups each showed neurobehavioral improvement. Mean DOCS change (FAST = 13.5, SD = 8.2; Placebo = 18.9, SD = 15.6) was not different, but FAST patients had significantly (P = .049; 95% confidence interval [CI] = −1.51, −.005) more CNC gains (FAST = 1.01, SD = 0.60; Placebo = 0.25, SD = 0.70). Mixed-effects models confirm CNC findings (P = .002). Treatment effect, based on CNC, is large (d = 1.88, 95% CI = 0.77, 3.00). Number needed to treat is 2. FAST patients had more fMRI activation in language regions and whole brain (P values .05) different from the average healthy group’s FAC.

Results Of the 50 patients screened, 21 were enrolled (Figure 1). Five were withdrawn prior to randomization and 16 were randomized to groups with 15 completing the study. Final fMRI samples included 4 FAST, 5 Placebo, and 7 healthy control participants. Six TBI participants were eliminated from imaging analyses due to excessive motion, signal dropout, or head size that prohibited scanning.

Group Comparability The groups for the total study sample (n = 15) did not significantly differ according to average days required to provide the 168 doses (FAST mean = 44, SD = 4 days; Placebo mean = 46, SD = 10 days; P = .57), demographics (Table 1), prognostic factors including baseline clinical conditions and nonstudy interventions. Relative to the FAST group, the Placebo group did, however, have significantly more contusions,47,48 was enrolled into the study earlier after injury,47 had a better injury severity score, and fewer subdural hematomas. The FAST group also received more anticonvulsants and antihypertensive medications27,49 (for additional findings, see Supplement Section IIa). The final fMRI groups (FAST n = 4; Placebo n = 5) do not significantly differ by demographics, baseline clinical states, causes of injury, time between injury and study enrollment or randomization, injury severity scores, number of lesions, or by nonstudy interventions. FAST and Placebo groups also indicate no differences at baseline according to neural activation in response to the 8 auditory stimuli and 8 combinations of the stimuli within the whole brain and 15 ROIs (All P values >.353) suggesting that nonstudy treatments do not influence fMRI signal (also see Tables S2 and S3 in Supplement Section IIb).

Clinical Findings The FAST and Placebo groups had an equal number of patients in VS and MCS at baseline (Table 1, P = 0.46). At endpoint, fewer patients in the total sample remained in VS (13%, 2/15) and MCS (53%, 8/15), with 5 patients emerging from MCS (33%). The FAST and Placebo groups each had 1 patient emerge from VS (FAST: 1 of 2; Placebo: 1 of

3), but the FAST group had 4 patients emerge from MCS with only 1 Placebo patient emerging from MCS.

CNC Interrater Reliability The mean total CNC scores (n = 40 pairs) for each group do not differ according to raters (FAST CNC means: Rater A mean = 16.4, SD = 9.7, Rater B mean = 15.4, SD = 8.6, P = .49, r = .85) (Placebo CNC means: Rater A mean = 19.2, SD = 5.2, Rater B mean = 19.4, SD = 9.7, P = .91, r = .61) (see Supplement Sections IIc and IId for additional data quality analyses).

Neurobehavioral Results Average change in DOCS measures do not differ between groups (FAST mean = 13.5, SD = 8.2; Placebo mean = 18.9, SD = 15.6; P = .465; 95% confidence interval [CI] = −11.1, 21.9), but the FAST group had significantly greater average change in CNC measures (FAST mean = 1.0, SD = 0.6; Placebo mean = 0.25, SD = 0.7; P = .049; 95% CI = −1.51, −.005). Findings from the mixed-effect longitudinal analyses (Table 2 and Figure 2) indicate (a) a significant difference with CNC slopes (P = .0022; FAST: Intercept = 53.1, Slope = −0.07; Placebo: Intercept = 53.4, Slope = −0.08), with the FAST group recovering more quickly than the Placebo group (mean slope difference −0.63 points per week), and (b) the largest effect occurring within the first week (ie, second CNC measure in Figure 2) of the intervention with small consistent gains thereafter (see Supplement Section IIe for additional neurobehavioral results). The hypothesized treatment effect based on DOCS measures was 0.91.37 We did not detect this hypothesized effect. At endpoint, the 2 groups differed on average by 3.25 DOCS units. Although we recruited only 50% of the planned sample size, which reduced power to 0.51, the observed effect size (d = 0.24; CI = −.52, .99) based on DOCS measures is much smaller than the hypothesized treatment effect (d = .91) indicating that we did not miss a significant treatment effect due to low power (also see Supplement Section IIf). Based on CNC measures, the groups differed at Endpoint, by an average of 4.1 CNC units. The effect size (d = 1.88, 95% CI = 0.77, 3.00), based on CNC measures, is considered large and indicates that 96% of the FAST group will have CNC measures above the mean of the Placebo group; only 37% of the 2 groups will have overlapping measures. Conservatively, the lower CI limit for the effect size based on CNC measures (0.77) is also considered a large effect size. In the absence of an established minimally clinically important difference for the CNC, interpretation of this effect size is challenging.50 To compute NNT, we assumed that a change of 2 CNC units is important because our CNC Pooled SD is 6, and previous

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Table 1.  Demographic and Prognostic Factors and Nonstudy Treatments Received.

Demographic factors Age at injury Male gender Race/ethnic group  White  Black  Hispanic  Asian Education achieved at injury   High school graduate or GED   Some college, no degree   Bachelor degree   Graduate or professional degree Causes of injuries  Automobile   Motorcycle and snowmobile   Assaults and falls   Pedestrian struck by moving vehicle Prognostic factors and injury severity Days between injury and study enrollment Days between enrollment and randomization Injury severity score at injury Highest abbreviated injury severity score at injury Glasgow Coma Scale score at injury CNC baseline measure DOCS baseline measure Baseline clinical states   Vegetative state   Minimally conscious state # of Lesions—All lobes # of Areas with contusions # of Areas with subdural hematomas # of Mass lesions # of Areas with subarachnoid hemorrhages # of Areas with diffuse axonal injury Nonstudy treatments received during provision of study protocols CNS modulator Benzodiazepine Muscle relaxant Anticonvulsant Antidepressant/SSRI Nonnarcotic analgesic Narcotic analgesic Anticoagulant Gastrointestinal Antihypertensive Antibiotic Nutritional supplement Alpha-blocker for continence Hours of prescribed rehabilitation services # of Informal stimulation interactions # of Informal talking interactions # of Informal music interactions # of Other informal auditory interactions # of Informal touching interactions # of Informal visual interactions # of Informal olfactory interactions # of Informal interactions with other stimuli

All (N = 15)

FAST (n = 8)

Placebo (n = 7)

P Values

  35.1, SD = 11.0 12 (80%)

  35.6, SD = 11.0 6 (75%)

  34.4, SD = 12.0 6 (86%)

.84 .61

7 (47%) 3 (20%) 3 (20%) 2 (13%)

3 (37.5%) 2 (25%) 2 (25%) 1 (12.5%)

4 (57.1%) 1 (14.3%) 1 (14.3%) 1 (14.3%)

.45 .61 .61 .92

5 (33%) 4 (27%) 4 (27%) 2 (13%)

4 (50%) 1 (12.5%) 2 (25%) 1 (12.5%)

1 (14.3%) 3 (42.9%) 2 (28.6%) 1 (14.3%)

.14 .19 .88 .92

6 (40%) 4 (27%) 3 (20%) 2 (13%)

3 (50%) 2 (50%) 2 (67%) 1 (50%)

3 (50%) 2 (50%) 1 (33%) 1 (50%)

  .97    

  69.8, SD = 42.8 14.5, SD = 7.9   31.3, SD = 13.1   4.7, SD = 0.6   4.0, SD = 1.2 53.5, SD = 3.0 50.4, SD = 6.3

  78.8, SD = 47.3 14.0, SD = 7.6   34.1, SD = 14.4   4.5, SD = 0.8   3.7, SD = 0.6 54.5, SD = 2.6 49.8, SD = 6.1

5 (33%) 10 (67%)   8.7, SD = 2.8   6.6, SD = 3.6   1.8, SD = 2.7   1.7, SD = 2.6   2.3, SD = 3.3   6.9, SD = 3.62

2 (25%) 6 (75%)   7.5, SD = 2.2   4.3, SD = 2.7   3.2, SD = 3.3   2.7, SD = 3.1   2.2, SD = 2.4   5.5, SD = 2.9

9 (81.8%) 7 (63.6%) 3 (27.3%) 4 (36.4%) 4 (36.4%) 9 (81.8%) 1 (9.1%) 8 (72.7%) 8 (72.7%) 6 (54.5%) 4 (36.4%) 3 (27.3%) 4 (36.4%) 51.0, SD = 53 260.0, SD = 177.0 74.0, SD = 48.2 33.0, SD = 23.0 19.0, SD = 20.6 65.0, SD = 43.1 23.0, SD = 22.2 26.0, SD = 26.8 21.0, SD = 29.5

4 (50%) 3 (37.5%) 2 (25%) 4 (50%) 2 (25%) 5 (62.5%) 0 4 (50%) 4 (50%) 5 (62.5%) 3 (37.5%) 2 (25%) 2 (25%)   74.2, SD = 62.0   308.0, SD = 217.0   85.0, SD = 59.9   34.0, SD = 26.4   27.0, SD = 23.8   77.0, SD = 52.7   25.0, SD = 27.7   34.0, SD = 33.4   26.0, SD = 38.0

  59.6, SD = 38.0   15, SD = 8.0   27.5, SD = 11.2   5.0, SD = 0.0   4.3, SD = 1.5   52.4, SD = 3.2 47.65, SD = 7.5

       

3 (43%) 4 (57%) 9.7, SD = 3.0 8.6, SD = 3.3 0.6, SD = 1.1 0.9, SD = 1.9 2.4 ± 4.2 8.1 ± 3.9

5 (71.4%) 4 (57.1%) 1 (14.3%) 0 2 (28.6%) 4 (57.1%) 1 (14.3%) 4 (57.1%) 4 (57.1%) 1 (14.3%) 1 (14.3%) 1 (14.3%) 2 (28.6%)   21.0, SD = 12.0   196.0, SD = 81.0   59.0, SD = 23.0   30.0, SD = 19.7   9.0, SD = 9.0   48.0, SD = 19.8   21.0, SD = 14.0   16.0, SD = 9.2   13.0, SD = 11.4

.41 .82 .37 .10 .52 .18 .65 .46 .16 .03* .72 .22 .90 .20 .15 .30 .62 .02* .82 .89 .25 .62 .62 .04* .30 .62 .82 .14 .26 .28 .77 .10 .19 .75 .18 .43

Abbreviations: FAST, Familiar Auditory Sensory Training; CNC, Coma-Near-Coma scale; DOCS, Disorders of Consciousness Scale; CNS, central nervous system; SD = Standard Deviation; SSRI = serotonin reuptake inhibitors. *Significant difference between groups with P ≤ .05.

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Pape et al Table 2.  CNC Means by Groups and Time. CNC Means, Standard Deviations (95% Confidence Intervals [CI])  

1 Baseline

2

3

4

5

6

7

8 Endpoint

FAST

54.5, 2.6 (52.3, 56.7) 52.4, 3.2 (49.5, 55.3)

49.4, 5.2 (45.1, 53.8) 53.2, 1.7 (51.6, 54.8)

50.6, 3.9 (47.3, 53.9) 54.6, 4.4 (50.6, 58.7)

49.6, 4.0 (46.3, 53.0) 52.7, 1.3 (51.5, 53.9)

49.8, 3.7 (46.7, 52.9) 51.7, 3.7 (48.3, 55.2)

48.8, 4.6 (44.9, 52.6) 54.9, 4.8 (50.5, 59.4)

49.1, 3.8 (45.9, 52.3) 53.6, 2.6 (51.2, 56.0)

47.0, 4.7 (43.1, 51.0) 51.1, 2.5 (48.8, 53.5)

Placebo

Abbreviations: CNC = Coma-Near-Coma scale; FAST, Familiar Auditory Sensory Training. Placebo CI = mean ± (SD/sqrt(7)) * (2.447); FAST CI = mean ± (SD/(sqrt(8)) * (2.36).

Figure 2.  Mean Coma-Near-Coma Scale (CNC) Rasch measures 2 times per week during the provision of study intervention according to study groups.

CNC Rasch transformed measures are equal interval measures ranging from 0 to 100 with lower scores indicating more arousal and awareness. CNC measures improved significantly faster in the FAST group than in the placebo group during the first 4 weeks of the treatment interval. Vertical bar denotes the standard error.

work suggests that .3 SD is important.50 Two of the 7 placebo patients (0.29) achieved a change of more than 2 CNC units, while 7 of the 8 FAST patients (0.88) made a CNC change of more than 2 units. The NNT then is 1.7 (rounded to 2),39 which indicates that you would need to treat 2 persons with the FAST for 4 weeks, rather than placebo, in order to find 1 additional patient who would improve more than 2 CNC units.

Functional MRI Results Between Groups Findings from examinations of neural activation between groups indicate that the FAST group had significant mean activation changes (Figure 3) in response to the following: 1. Right Heschl’s region for all auditory stimuli combined (P = .039; t = −2.885df; CI = −72.4, −2.99)

(µFAST base = 0, SD = 0; µFAST end = 19.3, SD = 27.8; µPlacebo base = 23.8, SD = 28.3; µPlacebo end = 29.8, SD = 36.7) 2. Right Heschl’s region for a nonfamiliar voice reading a short story (P = .033; t = −3.124df; CI = −50.7, −3.5) (µFAST base = 2.5, SD = 3.5; µFAST end = 13.3, SD = 16.7; µPlacebo base = 17.0, SD = 18.9; µPlacebo end = 22.8, SD = 28.8) 3. Right Wernicke’s for a nonfamiliar voice reading the short story after accounting for the familiar voice reading the same short story (P = .034; t = 5.2922df; CI = 0.87, 8.5) (µFAST base = 0.0, SD = 0.0; µFAST end = 4.7, SD = 1.5; µPlacebo base = 0.0, SD = 0.0; µPlacebo end = 0.0, SD = 0.0) 4. Whole brain in response to familiar voice calling subject’s name aloud (P = .040; t = 2.517df; CI = 61.7, 2071.7) (µFAST base = 644.8, SD = 44.4; µFAST end

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Figure 3.  Responsivity to fMRI auditory testing paradigm.

Tasks With Significangly Changed Responsivity: FV SON = Familiar voice calling patient’s name aloud; NFV Lang = Nonfamiliar voice reading fMRI specific short story aloud; FV Lang = Familiar voice reading same short story aloud. Slice maps on right side of figure are provided for slice orientation. Wericke’s and Heschl’s in the lower right hand corner are provided for spatial orientation.

= 1338.3, SD = 698.3; µPlacebo base = 579.8, SD = 640.9; µPlacebo end = 206.6, SD = 172.3) 5. Left Heschl’s region for bell ringing (P = .028; t = −3.0695df; CI = −117.6, −10.4) (µFAST base = 46.0, SD = 31.1; µFAST end = 0.0, SD = 0.0; µPlacebo base = 13.0, SD = 16.8; µPlacebo end = 23.3, SD = 26.9) 6. Left prefrontal region for bell ringing (P = .048; t = −2.3967df; CI = −15.4, −0.1) (µFAST base = 5.3, SD = 6.4; µFAST end = 0.5, SD = 1.0; µPlacebo base = 0.2, SD = 0.5; µPlacebo end = 3.2, SD = 4.4)

Functional MRI Results Within TBI Subjects Relative to Healthy Controls The within-subject analyses indicate that the majority of TBI patients in both groups (75% to 100%) had FACs that significantly differed from the average healthy group’s FACs. The Placebo group (6% to 16%) had twice the number of FACs that significantly differed from healthy controls compared to the FAST group (0% to 7%) and about twice the number of ROIs (17% to 44%) that significantly differed from healthy control ROI FACs (for elaboration of findings see Supplement Section IIg).

Discussion For persons with DOC after TBI, the FAST protocol is significantly related to more CNC gains. The observed effect size for CNC measures indicates that you would need to treat 2 persons with the FAST for 4 weeks, rather than placebo, in order to find 1 additional patient who would improve more than 2 CNC units. This finding is supported by CNC mixed effects analyses, descriptive clinical findings, and changes in neural activation in response to specified auditory stimuli. Findings from nonrandomized and noncontrolled studies suggest that sensory stimulation might enhance arousal to and awareness of vocal,51 acoustic,11 and familiar stimuli and furthermore that arousal and awareness might be enhanced when stimulation is provided in short and frequent increments.52 Our findings, derived from a placebo controlled RCT, demonstrate that sensory stimulation using familiar vocal and linguistic stimuli provided in 10-minute increments 4 times per day is related to improved arousal and awareness. We found that the observed treatment effect, based on CNC measures, is significantly different between groups, and when based on the DOCS-25 measures it is not. Absence of significant differences in DOCS measures (both over time and between groups) may reflect that DOCS measures

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Pape et al are based on best elicited responses whereas CNC scores reflect consistency of responses. Consistency translates to more arousal and awareness manifested as more ability to follow auditory commands, visually track, localize to sounds, vocalize, and respond to pain and touch. We tested the hypothesis that study participants demonstrating neurobehavioral gains will also demonstrate neural activation changes that resemble the neural activation of healthy persons. Our finding that the majority of FAST patients had fewer FACs differing significantly from healthy persons suggests that the FAST protocol supports adaptive neurobehavioral recovery. Evidence is emerging to indicate that this patient population, when provided with common treatments such as neuropharmacologic therapies,53 do make previously undetected neurobehavioral gains. The translation of these statistically significant gains to clinical impact is challenging, in part, because the minimally clinically important differences for the neurobehavioral tests are not yet available.28 It is also challenging because the mechanisms underlying these neurobehavioral gains have yet to be determined. The observed FAST effect, as measured by the CNC (d = 1.88), and the evidence of adaptive neural activation, together suggest that gains in arousal and awareness may be important for supporting adaptive recovery. While this study suggests that the FAST protocol may be important to support adaptive recovery, we do not know what the patients in VS and MCS are doing with the sensory input. This raises the question of whether or not it is possible to have increased neural activation in logical brain regions given specified stimuli and not engage key neural networks? That is, do treatments related to improved arousal and awareness such as the FAST enable recovery of awareness by “exercising” key networks (eg, language, attention, default mode) or by engaging these networks via exercising of residual neural integrity within key networks? The finding that the majority of FAST patients had fewer FACs significantly differing from healthy persons suggests that the FAST protocol supports adaptive neurobehavioral recovery and that the neurosciences literature regarding the responsiveness of the healthy brain can be leveraged to advance our understanding of the functional neural activation findings related to the FAST protocol. The reported fMRI findings regarding neural activation in response to auditory stimuli salient to this study, interpreted within the context of the neurosciences literature provides insights into the mechanisms of plasticity that could be contributing to the improved arousal and awareness. These inferences are made in the next paragraphs to identify avenues for future research. The FAST group had significantly increased whole brain activation in response to a familiar voice calling a patient’s name aloud, which is consistent with existing evidence that calling a healthy person’s name aloud captures that person’s attention and primes their brain to attend to incoming

stimuli.13-16 Together, this evidence suggests that the FAST protocol supported recovery by priming the brain to receive information that subsequently enhanced covert awareness of incoming information. The FAST group had significantly increased activation within Heschl’s and Wernicke’s regions in response to a nonfamiliar voice reading the SCATBI story aloud. Since the only difference between the FAST and Placebo groups is that the FAST group was provided with familiar stories told by familiar voices, this finding is consistent with evidence (from healthy persons and persons in states of DOC) that familiar voices enhance likelihood of eliciting brain responses to novel auditory information included in the fMRI auditory paradigm.13-16,43,44 This suggests that improved arousal and awareness could be due to repetitive exposure to familiar voices or familiar stories. These findings also correspond with the plasticity principles of saliency and specificity specifying that the nature of the neural changes (increased activation within language regions) is dictated by the nature of the training experience,54 which is repetitive exposure to familiar voices and familiar stories. The theoretical basis for the FAST is based, in part, on applying the principles of saliency and specificity.8 The FAST group had reduced activation in response to a nonvocal sound (bell) within Prefrontal and Heschl’s regions. This reduced response is likely due to habituation to a nonfamiliar sound that lacks saliency to the patient. Our findings regarding changes in neural activation together with evidence from the literature suggests that repetitive exposure to familiar voices and familiar stories contributed to improved arousal and awareness, in part, because of a priming effect and because of the saliency and specificity of the FAST. The effect of brain priming on subsequent processing of stimuli needs more direct examination with this patient population. Future research could, for example, measure the patient’s activation in response to their name being called aloud immediately followed by nonvocal versus vocal stimuli. Future research is also needed to directly inform us about the injured brain’s response to less salient and less specific stimuli. Research comparing neural activation in response to familiar stories versus nonfamiliar stories read aloud by familiar versus nonfamiliar voices would, for example, inform us about how salient and how specific sensory stimuli needs to be to yield a therapeutic effect. Studies examining responses to linguistic versus nonlinguistic acoustic stimuli would also inform us about the acoustic parameter(s) driving the brain’s responses. Additional avenues for future research also include examinations of different doses, maintenance of effects, and effects when the FAST is coupled with other treatments and interventions. Given restrictive eligibility criteria, enrollment was lower than planned and a study limitation is achieved sample size. Future research on a

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larger sample is needed and should also represent subacute and chronic recovery stages to determine FAST effects by time postinjury.

UL1RR025741). The Nick Kot Charity for traumatic brain injury (www.nkc4tbi.com).

Supplementary material

Conclusions We conclude that persons remaining in states of DOC for 29 to 170 days after TBI and receiving FAST for 4 weeks have more clinically meaningful CNC gains compared to a group not receiving any structured sensory stimulation. Our results suggest that improved arousal and awareness may be due to the FAST protocol priming the brain to be more responsive to salient stimuli. Clinicians should consider providing the FAST protocol to support patient engagement in neurorehabilitation. Findings indicate that clinicians should consider FAST as a neurorehabilitation intervention though additional research is needed to confirm findings. Acknowledgments The authors thank Ms Bessie Weiss, the nurses, and staff within Northwestern University’s clinical research unit who demonstrated a dedication to excellence that makes clinical trial research possible. We also recognize Dr Elliott Roth, Northwestern University Feinberg School of Medicine, who supported our research efforts.

Authors’ Note Study Statisticians: Dulal Bhaumik, Weihan Zhao, and Domenic Reda. Study Psychometrician: Trudy Mallinson. Clinical Trial Registry: NCT00557076; The Efficacy of Familiar Voice Stimulation During Coma Recovery; http://www. clinicaltrials.gov/ct2/show/NCT00557076?term=NCT00557076 &rank=1. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the US Department of Veterans Affairs or the US government.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development Merit Grant # B4591R and career development transition award #B4949N. Northwestern University’s Clinical and Translation Sciences Institute, which is supported by the National Center for Research Resources, National Institutes of Health (Grant

For this article is available on the Neurorehabilitation & Neural Repair Web site at http://nnr.sagepub.com/content/by/ supplemental-data.

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