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

Athletes are at risk for sports-related mild traumatic brain injury (mTBI) or concussion. A majority of concussed athletes recover quickly and may be eligible for return to athletic participation after they are asymptomatic [1]. It is well established, however, that a subset develops a post-concussion syndrome or PPCS [2]. PPCS disturbances include physical (headache, dizziness, fatigue, balance problems, sleep disturbance), cognitive (memory and attention problems), and emotional (depression, anxiety, irritability) challenges that persist beyond 7 to 10 days after the concussion, affecting approximately 10 to 15 % of concussed athletes [3]. A 2013 review of PPCS management highlighted that while many studies have now been published on acute concussion, much remains unknown about optimal care for those with prolonged symptoms [4].

Supporting improved autonomic nervous system (ANS) regulation may be a strategic way to aid return to physical activity for athletes with PPCS. The ANS has pervasive influences on cardiovascular, pulmonary, gastrointestinal, immune, cognitive, emotional, and behavioral systems [5], and ANS dysregulation is a likely major pathway for the range of symptoms in mTBI [6]. Studies have reported that mTBI is associated with lower heart rate variability (HRV) [7, 8], indicating a loss of dynamic flexibility in the capacity of the ANS to optimize or fine-tune cardiovascular regulation. A subset of individuals with TBI subsequently manifests paroxysmal sympathetic hyperactivity [9, 10] which presents with symptoms of tachycardia, hypertension, tachypnea, and diaphoresis. Cerebral auto-regulation, the capacity of the cerebral vasculature to maintain intra-cranial blood pressure within a narrow range, is compromised in up to 30 % of patients with mTBI, and it is likely to depend critically on autonomic mechanisms [11–13].

The aim of the present study was to evaluate the potential role of high-resolution, relational, resonance-based electroencephalic mirroring (HIRREM®; Brain State Technologies, Scottsdale, AZ), a noninvasive, closed-loop, acoustic stimulation neurotechnology [14], as a means to support symptom reduction, improved autonomic function, and return to play among athletes with PPCS. HIRREM is designed to support auto-calibration of neural oscillations by recording brain electrical activity at high spectral resolutions, applying algorithms to analyze oscillatory patterns, translating selected electrical frequencies into sonic frequencies, and returning audible tones of variable pitch and timing back to the user, in real time. In contrast to conventional homeostatic therapeutics, HIRREM is aligned with the allostasis paradigm of physiological regulation [15, 16]. Allostasis views disease not as the product of fundamental abnormality of given biological mechanisms but rather as the relative persistence or rigidity of system set points that renders systems (and the organism as a whole) less capable of dynamic adaptation. Health is a capacity for successful engagement with changing conditions of the natural environment, and the brain is the seat for orchestration of various system functions in concert.

In that its intended use is to support individually unique and adaptively changing set points for brain electrical activity, HIRREM is an allostatic modality for health recovery. Auto-calibration of neural oscillations may manifest as reduction of maladaptive forms of asymmetry between the right and left hemispheres [14], in multiple lobes including regions likely to play a role for management of the sympathetic and parasympathetic divisions, respectively [17–19]. Asymmetry of brain electrical activity has been reported after sports concussion, and it has been proposed that dominant asymmetry in temporal lobe activity may be a consequence of traumatic stress [20, 21] associated with dysregulation in the ANS; moreover, noninvasive measurement of asymmetry in temporal lobe high-frequency electrical activity may discriminate between sympathetic and parasympathetic tendencies in autonomic cardiovascular regulation [22]. Auto-calibration of neural oscillations may also involve optimization of ratios of energy across the brain electrical frequency spectrum, which may be important in light of evidence suggesting that individuals with PPCS have relatively greater amplitudes in lower frequency ranges (1.5 to 5 Hz) [23].

We hypothesized that the use of HIRREM by athletes with PPCS would be associated with reduction in self-reported symptom scores, improved autonomic cardiovascular regulation, and improved reaction testing.

Table 1 summarizes the study participants with respect to their demographic profile, concussion history, number of HIRREM sessions, and subsequent return to athletic activity. Table 2 shows the mean change in self-report measures from baseline to post-HIRREM assessments. Total scores for all three self-report measures, and 14 of the 16 individual items of the RPQ, showed statistically significant improvements. Table 3 shows changes in measures of BRS and HRV. All measures of autonomic cardiovascular regulation increased, with several measures showing statistically significant change (Sequence Down, Sequence Up, Sequence All, and SDNN). Mean distance on the drop-stick reaction testing improved from 23.8 (SD 5.6) cm at baseline to 19.8 (SD 4.6) cm following HIRREM (p = 0.044; Wilcoxon p = 0.016). HIRREM was well tolerated, with no adverse events reported and no dropouts. For illustrative purposes, Fig. 1 represents averaged brain electrical activity at the left and right temporal lobes at baseline (a) and during the penultimate minute of the penultimate (21st) session (b), in a single study participant, showing movement toward greater left-right symmetry in amplitudes across the frequency spectrum and also reduction of amplitudes in higher frequency ranges.

Gender	Age	Number of concussions and primary athletic involvement	Months since the last concussion	Number of HIRREM sessions	Days from the final HIRREM session to post-HIRREM data collection	Post-HIRREM activity and participation status
Female	23	7; soccer	6	23	0	FE, EC
Male	20	2; baseball	9	36	16	FE, RA
Female	20	4; soccer	4	19	5	FE, RA
Male	22	2; basketball	9	16	2	FE, RA
Female	15	1; gymnastics	6	18	12	FE, RA
Female	15	1; soccer	5	26	6	FE, RA
Male	17	2; snowboarding	6	13	10	FE, RA
Male	18	3; football	11	17	27	FE, TM
Male	16	6; basketball	2	22	0	FE, RA
Female	16	3; cheerleading	0.75	16	61	FE, RA
Male	14	4; soccer	0.5	15	25	FE, RA
Female	19	1; lacrosse	6	15	15	FE, TM
Male	18	1; football	0.5	16	37	FE, EC
Male	19	2; cycling	2	14	0	FE, RA
Female	19	2; basketball	1	15	77	FE, EC

FE returned to full exercise, workouts, and recreational activity, RA returned to full participation in their athletic activity, TM transformed migraine with persisting mild daily headache, precluded return to competition, EC educational choice to not return to full participation in their athletic activity

Instrument (number of participants with data)	Baseline mean (SD)	Mean change after HIRREM (SD)	Paired t test p values	Wilcoxon p values
RPQ total (n = 12)	29.2 (14.9)	−19.7 (11.4)	<0.001	0.001
Headaches	3.0 (0.9)	−1.4 (1.3)	0.003	0.004
Dizziness	1.8 (1.4)	−1.1 (1.1)	0.005	0.014
Nausea/vomiting	1.3 (1.1)	−1.2 (1.0)	0.002	0.008
Noise sensitivity	1.7 (1.2)	−1.2 (0.7)	<0.001	0.002
Sleep disturbance	1.4 (1.2)	−0.8 (0.8)	0.005	0.016
Fatigue	2.3 (1.4)	−1.9 (1.1)	<0.001	0.002
Irritability/anger	1.7 (1.3)	−1.0 (1.2)	0.015	0.031
Depressed/tearful	1.4 (1.5)	−0.8 (1.5)	0.085	0.125
Frustrated/impatient	2.1 (1.4)	−1.3 (1.6)	0.016	0.022
Forgetful/poor memory	2.2 (1.6)	−1.7 (1.4)	0.002	0.008
Poor concentration	2.6 (1.4)	−1.9 (1.5)	0.001	0.008
Taking longer to think	2.4 (1.6)	−1.8 (1.3)	<0.001	0.001
Blurred vision	1.2 (1.3)	−0.8 (0.9)	0.011	0.031
Light sensitivity	1.9 (1.2)	−1.3 (0.8)	<0.001	0.002
Double vision	0.8 (1.2)	−0.5 (1.0)	0.111	0.188
Restlessness	1.4 (1.1)	−0.9 (0.9)	0.005	0.016
ISI (n = 15)	7.5 (4.1)	−4.1 (4.1)	0.002	0.003
CES-D (n = 10)	20.8 (14.2)	−12.0 (10.0)	0.004	0.004

Measure	Before HIRREM mean ± SE	After HIRREM mean ± SE	Paired t test p values	Wilcoxon p values
BRS Sequence Up (ms/mmHg)	23.5 ± 3.3	32.3 ± 5.2	0.019	0.041
BRS Sequence Down (ms/mmHg)	19.9 ± 2.4	34.0 ± 6.0	0.005	0.004
BRS Sequence All (ms/mmHg)	21.9 ± 2.6	43.1 ± 10.6	0.034	0.002
HF alpha (ms/mmHg)	25.3 ± 2.6	37.4 ± 5.6	0.027	0.073
SDNN (ms)	57.1 ± 4.0	71.2 ± 7.1	0.023	0.005
RMSSD (ms)	54.9 ± 6.0	61.6 ± 7.7	>0.2	>0.2
LF (ms2)	1397 ± 223	1840 ± 368	0.131	0.188
HF (ms2)	1715 ± 465	2155 ± 564	>0.2	>0.2

Following use of HIRREM, all 15 athletes returned to full exercise, workouts, and recreational activities, as well as return to learning and academic activities, and ten athletes returned to full participation in their respective sport. In accordance with current concussion management consensus practices [1], two college athletes were not allowed to return to full participation in their respective sport due to persisting, mild, chronic daily headaches. By history, both appeared to have had a pre-existing vascular headache condition and thus to possibly have experienced transformed migraine associated with the concussion. Three athletes resumed full exercise and workouts but chose to pursue educational opportunities rather than return to active participation in their team sport.

In this case series of young athletes with PPCS, the use of HIRREM was associated with significant reductions in concussion-related symptomatology including both physical and emotional symptoms, improvements in measures of autonomic cardiovascular regulation and reaction time, and for the majority, return to participation in competitive athletics. We are not aware of a precedent for demonstration of this full constellation of outcomes within a relatively short time frame after use of an intervention for individuals with PPCS. Nonetheless, the open-label nature of the study and the absence of a control group preclude definitive inference that the outcomes were a direct consequence of the HIRREM intervention.

A major question is whether, or to what degree, the outcomes may be attributed to placebo. The “placebo effect” may comprise contributions from the natural history of the disease, reporting biases, the influence of co-interventions, and the neurobiological placebo response [33]. The placebo response in turn includes changes mediated by doctor-patient interaction or subjective expectation. The time course for reduction of PPCS is variable, and a symptom trajectory for participants, had they not enrolled in the study, cannot be predicted retrospectively with confidence. There is little doubt that many with PPCS are living with the burden of a long clinical course, with symptoms lasting more than 2 years in some cases [34]. Most participants in the current study had stable patterns of symptoms, persisting for many months, in spite of the use of other therapeutic strategies, yet reported not only symptom reduction but also return to full participation in their athletic activity. Return to play is an objective behavior, and thus, subjective reporting bias (for example, “social desirability response bias”) would not appear to have been a major contributor to this outcome. Further, efficacious treatments for PPCS are largely wanting, and the 2012 Zurich guidelines specifically state that medications should not be used to mask symptoms that would otherwise prevent return to play. Thus, it would not seem likely that these results reflect primarily the natural history of the disease or that a co-intervention was the cause for these athletes’ return to play.

Although changes in the self-report questionnaires may be subject to reporting biases, the mean change in the RPQ (−19.7, SD 11.4) was notably larger than the change in the RPQ reported for both the active (−5.4) and sham (−7.0) intervention groups, from a recently published clinical trial for PPCS [35]. Components of the placebo response—especially doctor-patient relationships and subjective expectations—can facilitate robust and wide-ranging improvements in health. However, placebo responses in clinical studies are reportedly more prominent for continuous and subjective outcomes, compared to binary or objective outcomes [36]. Since return to competitive athletic activity can be considered a binary and objective outcome, with changes in HRV and reaction testing also being measured objectively, these findings do not appear to be consistent with typical characteristics of the placebo response. All told, it appears unlikely that the placebo phenomenon was the principal cause for return to play in these athletes.

There are other reports of promising results from interventions involving auto-regulatory strategies as a means to treat PPCS. For example, athletes with PPCS who participated in a graded aerobic exercise training program (five to six sessions per week until they were capable of exercise to voluntary exhaustion without symptoms) demonstrated significant reductions in symptoms and increased peak heart rate at maximal exercise [37]. Four to 16 weeks of subsystem aerobic exacerbation was recently reported to be superior to a full-body stretching program for reducing PPCS in adolescents [38]. A comprehensive program including graded aerobic exercise and visualization has been found to facilitate improvements for children with PPCS [39]. The basis for a concussion management strategy that places emphasis on evaluation of exercise tolerance and use of exercise as a treatment option [40] is further justified by the insight that aerobic exercise may have specific beneficial effects on cerebrovascular regulation for individuals with mild traumatic brain injury [41]. Physiologically, the allostatic approach of the HIRREM intervention overlaps with the rationale for exercise treatment for PPCS, in that both embrace the importance of recovering neural and cardiovascular regulatory competence.

In conclusion, this exploratory study found that the use of an allostatic, noninvasive, closed-loop, acoustic stimulation neurotechnology, HIRREM, by a series of young athletes with PPCS, was associated with significant reductions in clinical symptoms; improvements in autonomic cardiovascular regulation; return to exercise, recreational, and academic activities; and a high rate of return to play. The findings do not appear to be consistent with the natural history of the disease, doctor-patient interaction, subjective expectation, or other placebo components. A larger controlled study is warranted.