A Preliminary Study of the Effectiveness of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology in the Treatment of Athletes with Persisting Post-concussion Symptoms

The present case series is drawn from an ongoing, open-label, single-site feasibility study of HIRREM for individuals age 11 or older with diverse neurological, cardiovascular, and psychophysiological conditions (ClinicalTrials.gov Identifier: NCT02709369). The study was performed in accordance with the ethical standards of the Declaration of Helsinki and was approved by the Institutional Review Board of Wake Forest University Health Sciences. Study participation includes a baseline enrollment visit consisting of informed consent, completion of self-report inventories, short-term recording of blood pressure and heart rate, and a HIRREM assessment. Subsequently, subjects undergo a series of HIRREM sessions, followed by up to two post-HIRREM data collection visits (see below for details). The ongoing need for the use of benzodiazepine, anti-psychotic, anti-epileptic, or opioid analgesic medications is an exclusion criterion to participation. Through referrals and informal networks at a university medical center, 16 athletes with PPCS who had been involved in athletics at the club, high school, and collegiate levels were alerted to the study and screened for eligibility. One was excluded because of academic scheduling conflicts, and 15 provided informed consent (or assent, for minors) to enroll. Seven participants were females, and their mean age was 18.1 years (SD 2.6). They reported 2.7 (SD 1.8) prior concussions, symptom duration of 4.6 (SD 3.4) months since the last concussion, and at least 10 days elapsed since the last concussion. All reported prior treatment with rest, medications, vestibular therapy, or other modalities.

Each participant had a baseline HIRREM assessment (45 min) to obtain information regarding patterns of brain electrical rhythms, especially with respect to asymmetry and proportionation of energy along the frequency spectrum [14]. A series of two-channel, 3-min recordings were acquired from at least six locations on the scalp (F3/F4, C3/C4, T3/T4, P3/P4, FZ/OZ, O1/O2), with the participant at rest and while carrying out a task. Recording at each location consisted of 1 min with the eyes closed, 1 min eyes partially open, and 1 min eyes open while performing a specific mental task (e.g., recalling numbers, reading a passage). Data from the assessment were used to identify specific protocols for the initial HIRREM session.

The HIRREM sessions were scheduled to maximize frequency and efficiency, with participants generally completing two sessions in a half day, separated by a 20- to 30-min break. Each session lasted approximately 90–120 min and consisted of five to nine individualized HIRREM protocols. A protocol is a combination of sensor montage and specific software design. During protocols, brain electrical activity is recorded noninvasively and subject to high-resolution spectral analysis. A proprietary mathematical algorithm selects a dominant brain frequency for translation into an acoustic stimulus, which is delivered back to the user through earphones (Creative EP-630 or Sony Stereo Headphones MDR-EX58V) with as little as an 8-ms delay. For each session, a set of protocols is chosen by the technologist to permit “acoustic mirroring” for multiple cortical locations and frequency bands during the session. Protocols lasted from 6 to 40 min and were done with eyes either closed or open depending on the function of the cortical region or the client’s subjective status (eyes closed to facilitate relaxation; eyes open in frontal regions for executive management), all with the participant sitting or reclining comfortably in a chair.

The HIRREM process is individualized for each recipient, such that the specific protocols chosen, the session length, and the total number of sessions are variable. Technologists timed sessions and chose protocols to facilitate an overall trend toward greater hemispheric symmetry and more optimal proportionation in frequency ranges, between and within cortical regions, based upon data from the initial assessment and the ensuing sessions [14]. Participants received a mean of 18.7 (SD 6.0) HIRREM sessions, over a mean of 29.6 (SD 23.2) days, with 11.3 (SD 4.6) days of actually coming to the study site to receive the intervention. Ten participants had at least one break in sessions (defined as a period with at least 5 days between sessions), and four participants had at least two breaks.

Self-reported symptoms were recorded on the day of the HIRREM assessment and also during a post-HIRREM data collection visit that took place a mean of 19.5 (SD 23.1) days following the last HIRREM session, with sensitivity to academic scheduling constraints. The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) is a 16-item survey that assesses the severity of the most common post-concussion symptoms on a scale of 0 to 4, with a total score range from 0 to 64 (least to greatest symptom severity). Items are compared to levels before the head injury and are reported as a 24-h recall [24]. The Insomnia Severity Index (ISI) is a 7-item survey that assesses the severity, nature, and impact of insomnia symptoms on quality of life over the previous 2 weeks [25]. It is scored on a five-point Likert scale from 0 (no problem) to 4 (very severe problem) on a composite score range from 0 to 28. Composite scores can be stratified into the following clinical severities of insomnia: absence (0–7), subthreshold (8–14), moderate (15–21), and severe (22–28). Its internal consistency was found to be 0.74, and a correlation with sleep diaries was also established [26]. The Center for Epidemiologic Studies Depression Scale (CES-D) is a 20-item survey that screens for risk of depression on the basis of affective depressive symptomatology [27]. Each question identifies a depressive symptom and is scored on a four-point Likert scale from 0 (“rarely”; <1 day/week) to 3 (“most or all of the time”; 5–7 days/week). Four questions have positive valence with reverse scoring. The cumulative score ranges from 0 to 60 with a score of 16 commonly used as a clinically relevant cutoff. Its internal consistency varies by demographics, with alpha coefficients between 0.60 and 0.90 and 3-month test-retest validity above 0.60 [28, 29]. Because of changes in procedures for the larger parent cohort study over the duration of the present case series, not all participants provided data for the RPQ and the CES-D.

Blood pressure (BP) and heart rate (HR) were acquired from 10-min recordings of noninvasive finger arterial pressure measurements and electrocardiography, with participants breathing at their spontaneous rate while lying quietly, supine. These recordings were obtained at the pre-HIRREM enrollment visit, just prior to the assessment of the pattern of brain electrical frequencies and amplitudes, and again during the post-HIRREM data collection visit. Systolic BP and beat-to-beat, RR intervals (RRI) files generated via the data acquisition system (BIOPAC acquisition system and Acknowledge 4.2 software, Santa Barbara, CA), at 1000 Hz, were analyzed using Nevrokard BRS software (Nevrokard BRS, Medistar, Ljubljana, Slovenia). Analysis was conducted on the first complete 5-min epoch that was considered to be acceptable for analysis. For calculation of standard deviation of beat-to-beat interval (SDNN), the RRI were visually inspected, and the data considered as artifact were manually removed. Evaluation included measures of spontaneous baroreflex sensitivity (BRS), in the frequency domain as high-frequency (HF) alpha index and in the time domain as Sequence BRS Up, Down, and All [30, 31]. Heart rate variability (HRV) was derived in the time domain as SDNN and root mean square of the difference of successive intervals (RMSSD) and in the spectral domain as absolute low- and high-frequency power.

For seven participants, reaction testing was performed during the baseline assessment and post-HIRREM data collection visits using a drop-stick apparatus that has been validated as a way to quantify the impact of athletic concussion on psychomotor performance [32]. Following two practice trials, participants performed eight trials for measurement, and a mean distance value was calculated.

For mean comparisons, two-tailed paired t tests were performed to evaluate pre- to post-HIRREM changes. In consideration of the sample size, the nonparametric Wilcoxon signed-rank test was used to corroborate the t test findings.

Participants were asked about their physical activity level including participation in competitive athletics at two time points: their post-HIRREM data collection visit and in the course of additional follow-up data collection (phone call, email, or office visit) that took place 1 to 3 months after the post-HIRREM data collection visit.