Summary Spontaneous activity in the sensory periphery drives infant brain activity and is thought to contribute to the formation of retinotopic and somatotopic maps [1–3]. In infant rats during active (or REM) sleep, brainstem-generated spontaneous activity triggers hundreds of thousands of skeletal muscle twitches each day [4]; sensory feedback arising from the resulting limb movements is a primary activator of forebrain activity, including spindle bursts in somatosensory cortex [1]. The rodent whisker system, with its precise isomorphic mapping of individual whiskers to discrete brain areas, has been a key contributor to our understanding of somatotopic maps and developmental plasticity [5–7]. However, in contrast with other sensory systems—and even though whisker movements are controlled by dedicated skeletal muscles [8, 9]—spontaneous whisker activity has not been entertained as a contributing factor to the development of this system [10]. Here we report in 3- to 6-day-old rats that whiskers twitch rapidly and asynchronously during active sleep. In addition, neurons in whisker thalamus exhibit bursts of activity that are tightly associated with twitches, but occur infrequently during waking. Finally, we observed barrel-specific cortical activity during periods of twitching. This is the first report of self-generated, sleep-related twitches in the developing whisker system, a sensorimotor system that is unique for the precision with which it can be experimentally manipulated. Therefore, the discovery of whisker twitching will allow us to attain a fuller understanding of the contributions of peripheral sensory activity to somatosensory integration and plasticity in the developing nervous system [11–13].

The cerebellum is critical for sensorimotor integration and undergoes extensive postnatal development. During the first postnatal week in rats, climbing fibers polyinnervate Purkinje cells and, before granule cell migration, mossy fibers make transient, direct connections with Purkinje cells. Activity-dependent processes are assumed to play a critical role in the development and refinement of these and other aspects of cerebellar circuitry. However, the sources and patterning of activity have not been described. We hypothesize that sensory feedback (i.e., reafference) from myoclonic twitches in sleeping newborn rats is a prominent driver of activity for the developing cerebellum. Here, in 6-day-old rats, we show that Purkinje cells exhibit substantial state-dependent changes in complex and simple spike activity—primarily during active sleep. In addition, this activity increases significantly during bouts of twitching. Moreover, the surprising observation of twitch-dependent increases in simple spike activity at this age suggests a functional engagement of mossy fibers before the parallel fiber system has developed. Based on these and other results, we propose that twitching comprises a unique class of self-produced movement that drives critical aspects of activity-dependent development in the cerebellum and other sensorimotor systems.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for medication-refractory major depression, yet the mechanisms of action for this intervention are poorly understood. Here we investigate cerebral cortex thickness as a possible biomarker of rTMS treatment response. Methods: Longitudinal change in cortical thickness is evaluated relative to clinical outcomes across 48 participants in 2 cohorts undergoing left dorsolateral prefrontal cortex rTMS as a treatment for depression. Results: Our results reveal changes in thickness in a region of the left rostral anterior cingulate cortex that correlate with clinical response, with this region becoming thicker in patients who respond favorably to rTMS and thinner in patients with a less favorable response. Moreover, the baseline cortical thickness in this region correlates with rTMS treatment response – those patients with thinner cortex before treatment tended to have the most clinical improvement. Conclusions: This study is the first analysis of longitudinal cortical thickness change with rTMS as a treatment for depression with similar results across two cohorts. These results support further investigation into the use of structural MRI as a possible biomarker of rTMS treatment response.

Background: No consensus exists in the clinical transcranial magnetic stimulation (TMS) field as to the best method for targeting the left dorsolateral prefrontal cortex (DLPFC) for depression treatment. Two common targeting methods are the Beam F3 method and the 5.5 cm rule. Objective: Evaluate the anatomical reliability of technician-identified DLPFC targets and obtain consensus average brain and scalp MNI152 coordinates. Methods: Three trained TMS technicians performed repeated targeting using both the Beam F3 method and 5.5 cm rule in ten healthy subjects (n ¼ 162). Average target locations were plotted on 7T structural MRIs to compare inter-and intra-rater reliability, respectively. Results: (1) Beam F3 inter-and intra-rater reliability was superior to 5.5 cm targeting (p ¼ 0.0005 and 0.0035). (2) The average Beam F3 location was 2.6±1.0 cm anterolateral to the 5.5 cm method. Conclusions: Beam F3 targeting demonstrates greater precision and reliability than the 5.5 cm method and identifies a different anatomical target.

Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduced Alzheimers disease (AD) pathology such as amyloid and tau levels, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a randomized, placebo-controlled trial (n = 15) in volunteers with probable mild AD after 4 months of one-hour daily 40Hz sensory stimulation (NCT 04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep activity and cognitive function. 40Hz light and sound GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our novel 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD. After 3 months of daily stimulation, the 40Hz GENUS group showed reduced ventricular dilation and stabilization of the hippocampal size compared to the control group. Functional connectivity was found to improve in the default mode network as well as with the medial visual network after 3 months of stimulation. Furthermore, actigraphy recordings show that circadian rhythmicity also improved with 40Hz stimulation. 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, structure 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 novel disease modifying therapeutic for Alzheimers dementia.

Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer’s disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.

Background Our lab previously showed that 40 Hz sensory stimulation can modulate neural oscillations, ameliorate Alzheimer’s disease (AD) pathology, and improve cognition in AD mouse models (Iaccarino, Singer et al., Nature, 2016; Martorell, Paulson et al., Cell, 2019; Adaikkan et al., Neuron, 2019). To determine the safety and feasibility of 40 Hz sensory stimulation as a potential therapeutic for AD, human subjects, including AD patients, were exposed to various stimulation modalities and their electrophysiological responses were studied. Method We developed a device that delivers light and sound at desired frequencies for human use. Cognitively healthy (24 males, 22 females; age range 20‐75) and AD subjects (7 males, 10 females; age range 55‐88) were stimulated with our device while their scalp electroencephalogram (EEG) was recorded. Epilepsy patients with intracranial electrodes (1 male, 1 female; age 19) were also exposed to our device for sensory stimulation while recording the intracranial EEG (iEEG). The EEG signals were screened for interictal/ictal spikes and analyzed to evaluate spectral characteristics. Result The EEG signals from cognitively healthy and AD subjects as well as epilepsy patients did not show any interictal/ictal spikes during or after the stimulation. In all subject groups, our sensory stimulation increased the spectral power and coherence at 40 Hz, with the concurrent visual and auditory stimulation leading to more widespread and coordinated 40 Hz oscillations than visual or auditory stimulation alone. iEEG signals showed that our sensory stimulation can entrain deeper brain regions. An hour‐long continuous 40 Hz stimulation using concurrent visual and auditory stimuli in healthy older subjects showed 40 Hz power and coherence both increasing over time. Following the hour‐long stimulation, gamma power and coherence were elevated compared to the pre‐stimulation levels. Conclusion Our non‐invasive sensory stimulation at gamma frequency safely induces highly coordinated 40 Hz oscillations in cognitively healthy and AD subjects. This serves as a preliminary study for a placebo‐controlled, randomized control trial to test the effect of our sensory stimulation on AD. The application of non‐invasive techniques to modulate gamma oscillations in the human brain is a novel and potentially very powerful disease modifying therapeutic for the treatment of dementia.

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