2003). This phenomenon has been referred to as stochastic resonance or stochastic facilitation, and it has been demonstrated for visual, auditory, and tactile sensory #NLG8189 randurls[1|1|,|CHEM1|]# modalities (McDonnell and Ward 2011). An implication

of stochastic facilitation is that the system noise level may be a critical parameter for neural information processing (McIntosh et al. 2010; McDonnell and Ward 2011). If noise levels systematically change through HIRREM, it could be hypothesized Inhibitors,research,lifescience,medical that HIRREM impacts endogenous noise levels and thereby impacts overall efficiency of information processing. Possible contribution of placebo effects or other nonspecific factors Delivery of HIRREM entails up to 10 or more visits (90 min each) with HIRREM technologists, Inhibitors,research,lifescience,medical instruction to relax while listening to musical tones, and being recumbent in a comfortable chair situated in a quiet environment. This combination of social interaction and relaxation induction might be predicted to produce improvements in self-reported well-being irrespective of the specific pitch or timing of musical tones produced through the HIRREM software algorithms. To establish definitively that clinical Inhibitors,research,lifescience,medical improvements associated with HIRREM are attributable to the specificity of software algorithms and not placebo effects or other nonspecific factors, placebo-controlled

trials are indicated. As a preliminary illustration of the contrast between nonspecific relaxation induction and

HIRREM, Figure 6 shows high-frequency (23–36 Hz) amplitudes in bilateral temporal lobes during exposure to three different types of sounds for a 37-year-old man with insomnia (Insomnia Severity Inhibitors,research,lifescience,medical Index Score 18, Inhibitors,research,lifescience,medical indicating moderate clinical insomnia) who presented to a community-based setting for HIRREM provision. Prior to beginning the standard HIRREM assessment and proceeding with the HIRREM intervention, the subject agreed to listen to three consecutive sets (12 min each) of “relaxing sounds“ while undergoing continuous EEG recording (using HIRREM technology as described in High-resolution spectral analysis of electroencephalic data and dynamic, iterative engagement of dominant frequencies). The first two sound sets were commercially available sound generators for white noise (http://www.simplynoise.com) and random musical all tones (Winchime 3.0; http://www.sagebrush.com). The third sound set was a HIRREM protocol for the temporal lobes. In the interval before the second and third sound sets, the subject rested (1 min) and participated in a digit-recall task (1 min). Figures 6A and B demonstrate a consistent left hemispheric dominance while the subject listened to white noise and random musical tones, and no change in the amplitudes over the course of the sound sets.