Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges.

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

Lateral inhibition in V1 controls neural & perceptual contrast sensitivity.

Lateral inhibition is a central principle for sensory system function. It is thought to operate by the activation of inhibitory neurons that restrict the spatial spread of sensory excitation. Much work on the role of inhibition in sensory systems has focused on visual cortex; however, the neurons, computations, and mechanisms underlying cortical lateral inhibition remain debated, and its importance for visual perception remains unknown. Here, we tested how lateral inhibition from PV or SST neurons in mouse primary visual cortex (V1) modulates neural and perceptual sensitivity to stimulus contrast. Lateral inhibition from PV neurons reduced neural and perceptual sensitivity to visual contrast in a uniform subtractive manner, whereas lateral inhibition from SST neurons more effectively changed the slope (or gain) of neural and perceptual contrast sensitivity. A neural circuit model identified spatially extensive lateral projections from SST neurons as the key factor, and we confirmed this with direct subthreshold measurements of a larger spatial footprint for SST versus PV lateral inhibition. Together, these results define cell-type specific computational roles for lateral inhibition in V1, and establish their unique consequences on sensitivity to contrast, a fundamental aspect of the visual world.

Multisensory Flicker Modulates Widespread Brain Networks and Reduces Interictal Epileptiform Discharges in Humans.

Modulating brain oscillations has strong therapeutic potential. However, commonly used non-invasive interventions such as transcranial magnetic or direct current stimulation have limited effects on deeper cortical structures like the medial temporal lobe. Repetitive audio-visual stimulation, or sensory flicker, modulates such structures in mice but little is known about its effects in humans. Using high spatiotemporal resolution, we mapped and quantified the neurophysiological effects of sensory flicker in human subjects undergoing presurgical intracranial seizure monitoring. We found that flicker modulates both local field potential and single neurons in higher cognitive regions, including the medial temporal lobe and prefrontal cortex, and that local field potential modulation is likely mediated via resonance of involved circuits. We then assessed how flicker affects pathological neural activity, specifically interictal epileptiform discharges, a biomarker of epilepsy also implicated in Alzheimer's and other diseases. In our patient population with focal seizure onsets, sensory flicker decreased the rate interictal epileptiform discharges. Our findings support the use of sensory flicker to modulate deeper cortical structures and mitigate pathological activity in humans.

Deep brain stimulation of hypothalamus for narcolepsy-cataplexy in mice.

BACKGROUND: Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions. OBJECTIVE: We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration. METHODS: Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos. RESULTS: Brief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain. CONCLUSION: Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.