Abstract

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high- resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®), a noninvasive, allostatic neurotech- nology for relaxation and auto-calibration of neural oscilla- tions, on heart rate variability, brain asymmetry, and auto- nomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15–18) underwent a median of 14 (10–16) HIRREM sessions over 13 (8–17) days. Autonomic function was assessed from 10-min continu- ous heart rate and blood pressure recordings, pre- and post- HIRREM. One-minute epochs of temporal high-frequency (23–36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symp- toms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIR- REM (mean increase 51 %, range 10–143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65 %, range −6 to 180, p = 0.05). Baseline tempo- ral electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM ses- sion (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 μV (p = 0.02). There was a trend for improvements in self- reported symptoms related to the autonomic nervous sys- tem. Use of HIRREM was associated with reduced sympa- thetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high- frequency electrical activity, and a trend for reduced auto- nomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in auto- nomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management.

 Hz                 Hertz

HIRREM         High-resolution, relational, resonance-based, electroencephalic mirroring

LF                 Low frequency

µV                  Microvolts

HUT               Head upright tilt test

POTS              Postural orthostatic tachycardia syndrome SD     Standard deviation

SDNN             Standard deviation of the normal-to-normal interval

Introduction

 The pervasive role of the autonomic nervous system for regulating functionality across organ systems and behaviors is often underappreciated in both adult and pediatric medi- cine (Rees 2014). For example, unexplained gastrointesti- nal symptoms are common in children (Hyams et al. 1996), and autonomic testing for children with functional abdomi- nal pain can reveal differences in pathophysiology  that may be indicative of an underlying dysautonomia (Safder et al. 2009). One such dysautonomia is postural orthos- tatic tachycardia syndrome, or POTS, defined as excessive increase in heart rate (HR) upon upright posture (Freeman et al. 2011; Ojha et al. 2011). POTS may present with het- erogeneous symptoms including palpitations, shortness of breath, sleep disturbance, fatigue, nausea, abdominal pain, headache, lightheadedness, or syncope. Treatment may include agents intended to remediate dysregulation across cardiovascular, gastrointestinal, and neuropsychiatric sys- tems, including mineralocorticoids or saline for volume expansion, beta-blockers and other autonomic medications, and others (Raj et al. 2005; Garland et al. 2007). Yet the genesis of POTS symptomatology is likely multifactorial involving numerous descending structures of the central autonomic network including the brainstem, amygdala, insula, anterior cingulate cortex, hypothalamus, periaque- ductal gray, and others, and there is an important role for behavioral or other interventions that can impact this net- work systematically on a top-down basis (Benarroch 2012). Studies have shown that at the level of the cerebral hemi- spheres, regulation of the autonomic nervous system (ANS) is lateralized, with the right and left sides being associ- ated with sympathetic and parasympathetic management, respectively (Zamrini et al. 1990; Oppenheimer et al. 1992; Yoon et al. 1997; Hilz et al. 2001; Lee et al. 2014). Fur- thermore, there is evidence that it may be possible to detect asymmetrical contributions of  the  cerebral  hemispheres to management of the autonomic nervous system through the use of noninvasive scalp recordings. Changes in corti- cal potential measured from the left temporal scalp have been shown to correlate with measures of cardiac  function (Gray et al. 2007), and rightward dominance in temporal high-frequency brain electrical asymmetry calculated from scalp measures has been shown to correspond to higher rest- ing heart rate and lower baroreflex sensitivity in a hetero- geneous population (Tegeler et al. 2015b). Neurotechnology interventions have been shown to have a role for modulat- ing autonomic activity through engagement with patterns of lateralized activity in cortical regions associated with ANS management. Transcranial direct current stimulation at the left temporal lobe, for example, is an “open-loop” approach (one that provides stimulus without recording brain activ- ity) that has been applied at the left temporal region in order to augment parasympathetic functioning and potentially enhance performance in cyclists (Okano et al. 2015).

The potential contribution of hemispheric lateralization patterns to autonomic dysregulation in POTS has not previ- ously been explored. High-resolution, relational, resonance- based, electroencephalic mirroring (HIRREM®) is a novel, noninvasive closed-loop neurotechnology designed to facili- tate relaxation and auto-calibration of neural oscillations. HIRREM monitors brain electrical activity at high spectral resolutions using two-channel recordings (Gerdes et al. 2013). It applies software algorithms to generate unique and changing patterns of acoustic stimulation (tones of vari- able pitch and timing) that are based on real-time changes in dominant frequencies of brain electrical activity. In a ran- domized, controlled pilot trial for individuals with insom- nia, use of HIRREM was associated with improved sleep and reduced depressive symptoms (Tegeler et al. 2012),  and in an open-label study of patients with heterogeneous symptoms, use of HIRREM was associated with reduction in temporal lobe high-frequency electrical asymmetry and increased heart rate variability (Tegeler et al. 2013).

Presently, we report on the use of HIRREM in a series of adolescents with nausea and orthostatic symptoms who were diagnosed with POTS by an abnormal head upright tilt (HUT) test. Specifically, we examined pre- to post- HIRREM change in outcome measures of autonomic car- diovascular regulation including: heart rate variability as measured by standard deviation of the beat-to-beat interval (SDNN), baroreflex sensitivity (BRS), asymmetry in tem- poral lobe high-frequency (23–36 Hz) electrical activity, the sum of right and left temporal high-frequency electrical amplitudes, and autonomic symptom scores.

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