The neuron mixer and its impact on human brain dynamics.

A signal mixer facilitates rich computation, which has been the building block of modern telecommunication. This frequency mixing produces new signals at the sum and difference frequencies of input signals, enabling powerful operations such as heterodyning and multiplexing. Here, we report that a neuron is a signal mixer. We found through ex vivo and in vivo whole-cell measurements that neurons mix exogenous (controlled) and endogenous (spontaneous) subthreshold membrane potential oscillations, producing new oscillation frequencies, and that neural mixing originates in voltage-gated ion channels. Furthermore, we demonstrate that mixing is evident in human brain activity and is associated with cognitive functions. We found that the human electroencephalogram displays distinct clusters of local and inter-region mixing and that conversion of the salient posterior alpha-beta oscillations into gamma-band oscillations regulates visual attention. Signal mixing may enable individual neurons to sculpt the spectrum of neural circuit oscillations and utilize them for computational operations.

Characteristics of motor evoked potentials in patients with peripheral vascular disease.

With an aging population, it is common to encounter people diagnosed with peripheral vascular disease (PVD). Some will undergo surgeries during which the spinal cord may be compromised and intraoperative neuromonitoring with motor evoked potentials (MEPs) is employed to help mitigate paralysis. No data exist on characteristics of MEPs in older, PVD patients, which would be valuable for patients undergoing spinal cord at-risk surgery or participating in neurophysiological research. Transcranial magnetic stimulation, which can be delivered to the awake patient, was used to stimulate the motor cortex of 20 patients (mean (±SD)) age 63.2yrs (±11.5) with confirmed PVD, every 10 minutes for one hour with MEPs recorded from selected upper and lower limb muscles. Data were compared to that from 20 healthy volunteers recruited for a protocol development study (28yrs (±7.6)). MEPs did not differ between patient's symptomatic and asymptomatic legs. MEP amplitudes were not different for a given muscle between patients and healthy participants. Except for vastus lateralis, disease severity did not correlate with MEP amplitude. There were no differences over time in the coefficient of variation of MEP amplitude at each time point for any muscle in patients or in healthy participants. Although latencies of MEPs were not different between patients and healthy participants for a given muscle, they were longer in older participants. The results obtained suggest PVD alone does not impact MEPs; there were no differences between more symptomatic and less symptomatic legs. Further, in general, disease severity did not corelate with MEP characteristics. With an aging population, more patients with PVD and cardiovascular risk factors will be participating in neurophysiological studies or undergoing surgery where spinal cord integrity is monitored. Our data show that MEPs from these patients can be easily evoked and interpreted.

Pulse-width modulated temporal interference (PWM-TI) brain stimulation.

BACKGROUND: Electrical stimulation involving temporal interference of two different kHz frequency sinusoidal electric fields (temporal interference (TI)) enables non-invasive deep brain stimulation, by creating an electric field that is amplitude modulated at the slow difference frequency (within the neural range), at the target brain region. OBJECTIVE: Here, we investigate temporal interference neural stimulation using square, rather than sinusoidal, electric fields that create an electric field that is pulse-width, but not amplitude, modulated at the difference frequency (pulse-width modulated temporal interference, (PWM-TI)). METHODS/RESULTS: We show, using ex-vivo single-cell recordings and in-vivo calcium imaging, that PWM-TI effectively stimulates neural activity at the difference frequency at a similar efficiency to traditional TI. We then demonstrate, using computational modelling, that the PWM stimulation waveform induces amplitude-modulated membrane potential depolarization due to the membrane's intrinsic low-pass filtering property. CONCLUSIONS: PWM-TI can effectively drive neural activity at the difference frequency. The PWM-TI mechanism involves converting an envelope amplitude-fixed PWM field to an amplitude-modulated membrane potential via the low-pass filtering of the passive neural membrane. Unveiling the biophysics underpinning the neural response to complex electric fields may facilitate the development of new brain stimulation strategies with improved precision and efficiency.

Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers.

Introduction: Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs). Materials and methods: In the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus. Results: This non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS. Significance: These results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy.