Options for people with severe paralysis who have lost the ability to communicate orally are limited. We describe a method for communication in a patient with late-stage amyotrophic lateral sclerosis (ALS), involving a fully implanted brain-computer interface that consists of subdural electrodes placed over the motor cortex and a transmitter placed subcutaneously in the left side of the thorax. By attempting to move the hand on the side opposite the implanted electrodes, the patient accurately and independently controlled a computer typing program 28 weeks after electrode placement, at the equivalent of two letters per minute. The brain-computer interface offered autonomous communication that supplemented and at times supplanted the patient's eye-tracking device. (Funded by the Government of the Netherlands and the European Union; ClinicalTrials.gov number, NCT02224469 .).

GABA transmits phase information between the ventral and dorsal SCN oscillators. GABA can act excitatory in the dorsal SCN and inhibits neurons in the ventral SCN. We hypothesize that this difference results in asymmetrical interregional coupling within the SCN, with a stronger phase-shifting effect of the ventral on the dorsal SCN than vice versa. A model is proposed that focuses on this asymmetry and on the role of GABA in phase regulation.

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The circadian pacemaker of the suprachiasmatic nucleus (SCN) functions as a seasonal clock through its ability to encode day length [1-6]. To investigate the mechanism by which SCN neurons code for day length, we housed mice under long (LD 16:8) and short (LD 8:16) photoperiods. Electrophysiological recordings of multiunit activity (MUA) in the SCN of freely moving mice revealed broad activity profiles in long days and compressed activity profiles in short days. The patterns remained consistent after release of the mice in constant darkness. Recordings of MUA in acutely prepared hypothalamic slices showed similar differences between the SCN electrical activity patterns in vitro in long and short days. In vitro recordings of neuronal subpopulations revealed that the width of the MUA activity profiles was determined by the distribution of phases of contributing units within the SCN. The subpopulation patterns displayed a significantly broader distribution in long days than in short days. Long-term recordings of single-unit activity revealed short durations of elevated activity in both short and long days (3.48 and 3.85 hr, respectively). The data indicate that coding for day length involves plasticity within SCN neuronal networks in which the phase distribution of oscillating neurons carries information on the photoperiod's duration.

The timing of sleep and wakefulness in mammals is governed by a sleep homeostatic process and by the circadian clock of the suprachiasmatic nucleus (SCN), which has a molecular basis for rhythm generation. By combining SCN electrical activity recordings with electroencephalogram (EEG) recordings in the same animal (the Wistar rat), we discovered that changes in vigilance states are paralleled by strong changes in SCN electrophysiological activity. During rapid eye movement (REM) sleep, neuronal activity in the SCN was elevated, and during non-REM (NREM) sleep, it was lowered. We also carried out selective sleep deprivation experiments to confirm that changes in SCN electrical activity are caused by changes in vigilance state. Our results indicate that the 24-hour pattern in electrical activity that is controlled by the molecular machinery of the SCN is substantially modified by afferent information from the central nervous system.

Abstract:The neurophysiological underpinnings of functional magnetic resonance imaging (fMRI) are not well understood. To understand the relationship between the fMRI blood oxygen level dependent (BOLD) signal and neurophysiology across large areas of cortex, we compared task related BOLD change during simple finger movement to brain surface electric potentials measured on a similar spatial scale using electrocorticography (ECoG). We found that spectral power increases in high frequencies (65-95 Hz), which have been related to local neuronal activity, colocalized with spatially focal BOLD peaks on primary sensorimotor areas. Independent of high frequencies, decreases in low frequency rhythms (<30 Hz), thought to reflect an aspect of cortical-subcortical interaction, colocalized with weaker BOLD signal increase. A spatial regression analysis showed that there was a direct correlation between the amplitude of the task induced BOLD change on different areas of primary sensorimotor cortex and the amplitude of the high frequency change. Low frequency change explained an additional, different part of the spatial BOLD variance. Together, these spectral power changes explained a significant 36% of the spatial variance in the BOLD signal change (R 2 ¼ 0.36). These results suggest that BOLD signal change is largely induced by two separate neurophysiological mechanisms, one being spatially focal neuronal processing and the other spatially distributed low frequency rhythms. Hum Brain Mapp 33:1689-1699,

In mammals, the precise circadian timing of many biological processes depends on the generation of oscillations in neural activity of pacemaker cells in the suprachiasmatic nucleus (SCN). The ionic mechanisms that underlie these rhythms are largely unknown. Using the mouse brain slice preparation, we show that the magnitude of fast delayed rectifier (FDR) potassium currents has a diurnal rhythm that peaks during the day. Notably, this rhythm continues in constant darkness, providing the first demonstration of the circadian regulation of an intrinsic voltage-gated current in mammalian cells. Blocking this current prevented the daily rhythm in firing rate in SCN neurons. Kv3.1b and Kv3.2 potassium channels were widely distributed within the SCN, with higher expression during the day. We conclude that the FDR is necessary for the circadian modulation of electrical activity in SCN neurons and represents an important part of the ionic basis for the generation of rhythmic output.

Fragile X syndrome results from the absence of the fragile X mental retardation 1 (FMR1) gene product (FMRP). FMR1 has two paralogs in vertebrates: fragile X related gene 1 and 2 (FXR1 and FXR2). Here we show that Fmr1/Fxr2 double knockout (KO) and Fmr1 KO/Fxr2 heterozygous animals exhibit a loss of rhythmic activity in a light:dark (LD) cycle, and that Fmr1 or Fxr2 KO mice display a shorter free-running period of locomotor activity in total darkness (DD). Molecular analysis and in vitro electrophysiological studies suggest essentially normal function of cells in the suprachiasmatic nucleus (SCN) in Fmr1/Fxr2 double KO mice. However, the cyclical patterns of abundance of several core clock component messenger (m) RNAs are altered in the livers of double KO mice. Furthermore, FXR2P alone or FMRP and FXR2P together can increase PER1- or PER2-mediated BMAL1-Neuronal PAS2 (NPAS2) transcriptional activity in a dose-dependent manner. These data collectively demonstrate that FMR1 and FXR2 are required for the presence of rhythmic circadian behavior in mammals and suggest that this role may be relevant to sleep and other behavioral alterations observed in fragile X patients.