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Non-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

Natural environments elicit both phase-locked and non-phase-locked neural responses to the stimulus in the brain. The interpretation of the BOLD signal to date has been based on an association of the non-phase-locked power of high-frequency local field potentials (LFPs), or the related spiking activity in single neurons or groups of neurons. Previous studies have not examined the prediction of the BOLD signal by phase-locked responses. We examined the relationship between the BOLD response and LFPs in the same nine human subjects from multiple corresponding points in the auditory cortex, using amplitude modulated pure tone stimuli of a duration to allow an analysis of phase locking of the sustained time period without contamination from the onset response. The results demonstrate that both phase locking at the modulation frequency and its harmonics, and the oscillatory power in gamma/high-gamma bands are required to predict the BOLD response. Biophysical models of BOLD signal generation in auditory cortex therefore require revision and the incorporation of both phase locking to rhythmic sensory stimuli and power changes in the ensemble neural activity.

Background: Windowed Fourier decompositions (WFD) are widely used in measuring stationary and non-stationary spectral phenomena and in describing pairwise relationships among multiple signals. Although a variety of WFDs see frequent application in electrophysiological research, including the short-time Fourier transform, continuous wavelets, band-pass filtering and multitaper-based approaches, each carries certain drawbacks related to computational efficiency and spectral leakage. This work surveys the advantages of a WFD not previously applied in electrophysiological settings. New Methods: A computationally efficient form of complex demodulation, the demodulated band transform (DBT), is described. Results: DBT is shown to provide an efficient approach to spectral estimation with minimal susceptibility to spectral leakage. In addition, it lends itself well to adaptive filtering of non-stationary narrowband noise. Comparison with existing methods: A detailed comparison with alternative WFDs is offered, with an emphasis on the relationship between DBT and Thomson's multitaper. DBT is shown to perform favorably in combining computational efficiency with minimal introduction of spectral leakage. Conclusion: DBT is ideally suited to efficient estimation of both stationary and non-stationary spectral and cross-spectral statistics with minimal susceptibility to spectral leakage. These qualities are broadly desirable in many settings., Comment: This version fixes a number of minor errors and typos

It has been proposed that tinnitus is generated by aberrant neural activity that develops among neurons in tonotopic of regions of primary auditory cortex (A1) affected by hearing loss, which is also the frequency region where tinnitus percepts localize ( Eggermont and Roberts, 2004 , Roberts et al., 2010 , Roberts et al., 2013 ). These models suggest (1) that differences between tinnitus and control groups of similar age and audiometric function should depend on whether A1 is probed in tinnitus frequency region (TFR) or below it, and (2) that brain responses evoked from A1 should track changes in the tinnitus percept when residual inhibition (RI) is induced by forward masking. We tested these predictions by measuring (128-channel EEG) the sound-evoked 40-Hz auditory steady-state response (ASSR) known to localize tonotopically to neural sources in A1. For comparison the N1 transient response localizing to distributed neural sources in nonprimary cortex (A2) was also studied. When tested under baseline conditions where tinnitus subjects would have heard their tinnitus, ASSR responses were larger in a tinnitus group than in controls when evoked by 500 Hz probes while the reverse was true for tinnitus and control groups tested with 5 kHz probes, confirming frequency-dependent group differences in this measure. On subsequent trials where RI was induced by masking (narrow band noise centered at 5 kHz), ASSR amplitude increased in the tinnitus group probed at 5 kHz but not in the tinnitus group probed at 500 Hz. When collapsed into a single sample tinnitus subjects reporting comparatively greater RI depth and duration showed comparatively larger ASSR increases after masking regardless of probe frequency. Effects of masking on ASSR amplitude in the control groups were completely reversed from those in the tinnitus groups, with no change seen to 5 kHz probes but ASSR increases to 500 Hz probes even though the masking sound contained no energy at 500 Hz (an “off-frequency” masking effect). In contrast to these findings for the ASSR, N1 amplitude was larger in tinnitus than control groups at both probe frequencies under baseline conditions, decreased after masking in all conditions, and did not relate to RI. These results suggest that aberrant neural activity occurring in the TFR of A1 underlies tinnitus and its modulation during RI. They indicate further that while neural changes occur in A2 in tinnitus, these changes do not reflect the tinnitus percept. Models for tinnitus and forward masking are described that integrate these findings within a common framework.

Several components of evoked auditory potentials and magnetic fields have been reported to be enhanced by musical training and by laboratory discrimination training. The P2 component, believed to originate in secondary auditory cortex (A2), is highly plastic, and enhanced both in trained musicians and by a variety of acoustic discrimination tasks. The 40-Hz auditory steady-state response (SSR) is believed to be generated in primary auditory cortex (A1). This response has been reported to be larger for trained musicians; however, in previous research SSR amplitude was not enhanced by laboratory training at pitch discrimination in non-musician adults. To explore whether competitive interactions among frequency representations in A1 may constrain remodeling, we designed a training procedure that provided subjects with experience of a single carrier frequency for 10 training sessions, alternating training and passive control blocks. P2 amplitude increased across sessions (p

We investigated whether attention modulates the 40-Hz auditory steady-state response (SSR) which localizes to cortical sources in the region of primary auditory cortex (A1). Subjects in Group E performed a tone discrimination task requiring sustained attention. This task was preceded and followed by a passive stage in which identical stimuli were presented while subjects viewed a silent video. Control groups received three successive passive stages only (with or without the video). SSR amplitude increased from the passive baseline in Group E and with respect to both control groups when the discrimination task was performed, and reverted to baseline afterwards. The SSR source waveform was enhanced in the right hemisphere, implying modulation of A1 by attention in this hemisphere. SSR phase and 3d source parameters did not shift when the discrimination task was introduced, implying similar SSR A1 generators in the passive and task conditions. Enhancement of N1, P2, and N2 during the discrimination task pointed to concurrent modulation of secondary auditory cortex by attention.