Neural Clock Research Articles

Diverse Time Encoding Strategies Within the Medial Premotor Areas of the Primate.

The measurement of time in the subsecond scale is critical for many sophisticated behaviors, yet its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the neural activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing. During single interval categorization, we found that preSMA encodes a subjective category limit by reaching a peak of activity at a time that divides the set of test intervals into short and long. We also observed neural signals associated with the category selected by the subjects and the reward outcomes of the perceptual decision. On the other hand, we have studied the behavioral and neurophysiological basis of rhythmic timing. First, we have shown in different tapping tasks that macaques are able to produce predictively and accurately intervals that are cued by auditory or visual metronomes or when intervals are produced internally without sensory guidance. In addition, we found that the rhythmic timing mechanism in MPC is governed by different layers of neural clocks. Next, the instantaneous activity of single cells shows ramping activity that encodes the elapsed or remaining time for a tapping movement. In addition, we found MPC neurons that build neural sequences, forming dynamic patterns of activation that flexibly cover all the produced interval depending on the tapping tempo. This rhythmic neural clock resets on every interval providing an internal representation of pulse. Furthermore, the MPC cells show mixed selectivity, encoding not only elapsed time, but also the tempo of the tapping and the serial order element in the rhythmic sequence. Hence, MPC can map different task parameters, including the passage of time, using different cell populations. Finally, the projection of the time varying activity of MPC hundreds of cells into a low dimensional state space showed circular neural trajectories whose geometry represented the internal pulse and the tapping tempo. Overall, these findings support the notion that MPC is part of the core timing mechanism for both single interval and rhythmic timing, using neural clocks with different encoding principles, probably to flexibly encode and mix the timing representation with other task parameters.

Brain Dopamine-Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects.

Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.

Detecting Time Concept Competence in Children with Autism Spectrum and Attention Disorders.

The importance of time concept in human existence is “ancient history” celebrated in the biblical book Ecclesiastes. Indeed, our time-sensitive mechanisms are literally carved into our biology and neurology on a molecular level, gifting us with neural clocks. However, time in human consciousness is not the time indicated by physical clocks: time is a subjective reality in our psychological makeup due to the nature of the temporal neural mechanisms and unique properties of physical time. Nonetheless, subjective time requires anchoring to physical time which permeates our language, endeavors, and entire existence, a process hinging on time-related skills such as estimates and measures of passage and duration of time. Moreover, accurate time reading, a critical adaptive life-skill, is imperative for effective function in all societal activities. Because it embodies the complexity of the time construct, it is central to instruction of time concept in primary education. It is often measured in children by clock drawings, a cognitive integrative skill with errors pointing to neuroanatomical differences impacting the integrity of executive function. Time competence in children with atypical neurobiological development and high prevalence, as in autism spectrum disorders (ASD), and attention disorders (ADHD), is often compromised, calling for investigation of its function. This thematic review article aims to: 1) discuss the complexity of time concept and its underlying bio-neurological mechanisms, 2) elucidate difficulties children with ASD and those with ADHD exhibit in temporal development, and 3) demonstrate the use of a set of clinical tools in uncovering temporal competence and ecological executive function in two children with ASD, and a child with ADHD, using a clock drawing task and error analyses; children’s time knowledge questionnaire; a behavior rating parent questionnaire examining ecological executive function, and parent open-ended questions related to their children’s time difficulties. A discussion, directions, and a take-home message round out the article.

Neural Repetition Suppression Modulates Time Perception: Evidence From Electrophysiology and Pupillometry.

Human time perception is malleable and subject to many biases. For example, it has repeatedly been shown that stimuli that are physically intense or that are unexpected seem to last longer. Two competing hypotheses have been proposed to account for such biases: One states that these temporal illusions are the result of increased levels of arousal that speeds up neural clock dynamics, whereas the alternative "magnitude coding" account states that the magnitude of sensory responses causally modulates perceived durations. Common experimental paradigms used to study temporal biases cannot dissociate between these accounts, as arousal and sensory magnitude covary and modulate each other. Here, we present two temporal discrimination experiments where two flashing stimuli demarcated the start and end of a to-be-timed interval. These stimuli could be either in the same or a different location, which led to different sensory responses because of neural repetition suppression. Crucially, changes and repetitions were fully predictable, which allowed us to explore effects of sensory response magnitude without changes in arousal or surprise. Intervals with changing markers were perceived as lasting longer than those with repeating markers. We measured EEG (Experiment 1) and pupil size (Experiment 2) and found that temporal perception was related to changes in ERPs (P2) and pupil constriction, both of which have been related to responses in the sensory cortex. Conversely, correlates of surprise and arousal (P3 amplitude and pupil dilation) were unaffected by stimulus repetitions and changes. These results demonstrate, for the first time, that sensory magnitude affects time perception even under constant levels of arousal.

Marking Time: Colorful New Insights into Master Clock Circuits

A neural clock controls what we do each day, and understanding its circuitry is important for health. In this issue of Neuron, Shan etal. visualize molecular rhythms in subtypes of master clock neurons to test principles of cell identity and network wiring.

The effect of space on subjective time is mediated by apparent velocity.

In contrast to the intuitive and traditional assumption of a centralized and universal neural clock, many recent studies have provided evidence against this idea. Here, we investigated whether subjective duration is estimated by a mechanism that tracks the trajectory of a moving object. Such a mechanism would integrate over the velocity and the spatial distance the object traveled to derive its duration. We exposed observers to a moving object that covered either a small or large spatial distance. We found that subjective duration decreased after this exposure when intervals were tested that were defined by stimuli covering a large, but not by stimuli covering a small, spatial distance. We compared the effects of our velocity exposure to previously used adaptation to a drifting grating and found a dependence of spatial distance only for velocity exposure. The finding that temporal estimations decrease after exposure to fast-moving stimuli selectively at large distances suggests that subjective duration is derived from measurements of velocity and space.

Feeding Time Entrains the Olfactory Bulb Circadian Clock in Anosmic PER2::LUC Mice

Circadian rhythms in many brain regions and peripheral organs can be entrained by daily feeding schedules. The set of feeding-related signals that entrain peripheral clocks are tissue specific and include nutrients, metabolic hormones and temperature. Signals that entrain neural circadian clocks to mealtime have yet to be established for any brain region. The olfactory bulb (OB) contains a robust circadian clock that can cycle independently of the suprachiasmatic nucleus (SCN) master pacemaker. We used PER2::LUC mice to evaluate the suitability of the OB for analysis of inputs that mediate entrainment of neural clocks by feeding schedules. Explants of SCN and OB from mice fed ad-libitum exhibited robust circadian rhythms of bioluminescence for three or more days in vitro, with rhythm peaks occurring late in the day and night, respectively. Mice restricted to a 4 h meal/day in the light period exhibited food anticipatory activity and a 6.3 h advance of the OB PER2::LUC rhythm. The cumulative phase shift of the OB rhythm increased gradually in OB explants harvested after 2–7 days of restricted feeding. In mice anosmic after nasal irrigation with zinc sulfate and fed ad-libitum for one week, OB phases were desynchronized. Group synchrony in anosmic mice was restored by restricted feeding. The OB circadian clock is food-entrainable, entrains gradually to a mid-day meal, and requires neither olfaction nor circadian signaling from olfactory sensory neurons. The OB can be used as a model system for analysis of input pathways by which circadian clocks in the brain entrain to daily mealtimes.

Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue.

Metabolic homeostasis requires coordination between circadian clocks in different tissues. Also, systemic signals appear to be required for some transcriptional rhythms in the mammalian liver and the Drosophila fat body. Here we show that free-running oscillations of the fat body clock require clock function in the PDF-positive cells of the fly brain. Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF). NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver. These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms.

A massively asynchronous, parallel brain.

Whether the visual brain uses a parallel or a serial, hierarchical, strategy to process visual signals, the end result appears to be that different attributes of the visual scene are perceived asynchronously—with colour leading form (orientation) by 40 ms and direction of motion by about 80 ms. Whatever the neural root of this asynchrony, it creates a problem that has not been properly addressed, namely how visual attributes that are perceived asynchronously over brief time windows after stimulus onset are bound together in the longer term to give us a unified experience of the visual world, in which all attributes are apparently seen in perfect registration. In this review, I suggest that there is no central neural clock in the (visual) brain that synchronizes the activity of different processing systems. More likely, activity in each of the parallel processing-perceptual systems of the visual brain is reset independently, making of the brain a massively asynchronous organ, just like the new generation of more efficient computers promise to be. Given the asynchronous operations of the brain, it is likely that the results of activities in the different processing-perceptual systems are not bound by physiological interactions between cells in the specialized visual areas, but post-perceptually, outside the visual brain.

Light Stimulates the Mouse Adrenal through a Retinohypothalamic Pathway Independent of an Effect on the Clock in the Suprachiasmatic Nucleus

The brain's master circadian pacemaker resides within the hypothalamic suprachiasmatic nucleus (SCN). SCN clock neurons are entrained to the day/night cycle via the retinohypothalamic tract and the SCN provides temporal information to the central nervous system and to peripheral organs that function as secondary oscillators. The SCN clock-cell network is thought to be the hypothalamic link between the retina and descending autonomic circuits to peripheral organs such as the adrenal gland, thereby entraining those organs to the day/night cycle. However, there are at least three different routes or mechanisms by which retinal signals transmitted to the hypothalamus may be conveyed to peripheral organs: 1) via retinal input to SCN clock neurons; 2) via retinal input to non-clock neurons in the SCN; or 3) via retinal input to hypothalamic regions neighboring the SCN. It is very well documented that light-induced responses of the SCN clock (i.e., clock gene expression, neural activity, and behavioral phase shifts) occur primarily during the subjective night. Thus to determine the role of the SCN clock in transmitting photic signals to descending autonomic circuits, we compared the phase dependency of light-evoked responses in the SCN and a peripheral oscillator, the adrenal gland. We observed light-evoked clock gene expression in the mouse adrenal throughout the subjective day and subjective night. Light also induced adrenal corticosterone secretion during both the subjective day and subjective night. The irradiance threshold for light-evoked adrenal responses was greater during the subjective day compared to the subjective night. These results suggest that retinohypothalamic signals may be relayed to the adrenal clock during the subjective day by a retinal pathway or cellular mechanism that is independent of an effect of light on the SCN neural clock network and thus may be important for the temporal integration of physiology and metabolism.

EPA-0692 – Mice lacking the circadian modulators sharp1 and sharp2 display altered sleep and mixed state endophenotypes of psychiatric disorders

Introduction Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. Methods In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays, global gene expression profiling and bioinformatic modeling. Gene expression in human brains samples was performed with qRT-PCR. Results EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1 , which are also significantly downregulated in the frontal cortex of schizophrenic patients. Conclusions Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2

Neurophysiology of timing in the hundreds of milliseconds: multiple layers of neuronal clocks in the medial premotor areas.

The precise quantification of time in the subsecond scale is critical for many complex behaviors including music and dance appreciation/execution, speech comprehension/articulation, and the performance of many sports. Nevertheless, its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the cell activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing during a synchronization-continuation tapping task (SCT). In this task the rhythmic behavior of monkeys was synchronized to a metronome of isochronous stimuli in the hundreds of milliseconds range (synchronization phase), followed by a period where animals internally temporalized their movements (continuation phase). Overall, we found that the time-keeping mechanism in MPC is governed by different layers of neural clocks. Close to the temporal control of movements are two separate populations of ramping cells that code for elapsed or remaining time for a tapping movement during the SCT. Thus, the sensorimotor loops engaged during the task may depend on the cyclic interplay between two neuronal chronometers that quantify in their instantaneous discharge rate the time passed and the remaining time for an action. In addition, we found MPC neurons that are tuned to the duration of produced intervals during the rhythmic task, showing an orderly variation in the average discharge rate as a function of duration. All the tested durations in the subsecond scale were represented in the preferred intervals of the cell population. Most of the interval-tuned cells were also tuned to the ordinal structure of the six intervals produced sequentially in the SCT. Hence, this next level of temporal processing may work as the notes of a musical score, providing information to the timing network about what duration and ordinal element of the sequence are being executed. Finally, we describe how the timing circuit can use a dynamic neural representation of the passage of time and the context in which the intervals are executed by integrating the time-varying activity of populations of cells. These neural population clocks can be defined as distinct trajectories in the multidimensional cell response-space. We provide a hypothesis of how these different levels of neural clocks can interact to constitute a coherent timing machine that controls the rhythmic behavior during the SCT.

Translational Profiling of Clock Cells Reveals Circadianly Synchronized Protein Synthesis

Author SummaryThe circadian clock controls daily rhythms in physiology and behavior via mechanisms that regulate gene expression. While numerous studies have examined the clock regulation of gene transcription and documented rhythms in mRNA abundance, less is known about how circadian changes in protein synthesis contribute to the orchestration of physiological and behavioral programs. Here we have monitored mRNA ribosomal association (as a proxy for translation) to globally examine the circadian timing of protein synthesis specifically within clock cells of Drosophila. The results reveal, for the first time in any organism, the complete circadian program of protein synthesis (the “circadian translatome”) within these cells. A novel finding is that most mRNAs within clock cells are translated at one of two predominant circadian phases—midday or mid-night—times of low energy expenditure. Our work also finds that many clock cell processes, including metabolism, redox state, signaling, neurotransmission, and even protein synthesis itself, are coordinately regulated such that mRNAs required for similar cellular functions are translated in synchrony at the same time of day.

Emerging roles for post-transcriptional regulation in circadian clocks

Circadian clocks temporally organize behavior and physiology across the 24-h day. Great progress has been made in understanding the molecular basis of timekeeping, with a focus on transcriptional feedback networks that are post-translationally modulated. Yet emerging evidence indicates an important role for post-transcriptional regulation, from splicing, polyadenylation and mRNA stability to translation and non-coding functions exemplified by microRNAs. This level of regulation affects virtually all aspects of circadian systems, from the core timing mechanism and input pathways that synchronize clocks to the environment and output pathways that control overt rhythmicity. We hypothesize that post-transcriptional control confers on circadian clocks enhanced robustness as well as the ability to adapt to different environments. As much of what is known derives from nonneural cells or tissues, future work will be required to investigate the role of post-transcriptional regulation in neural clocks.

Neural Bases for Individual Differences in the Subjective Experience of Short Durations (Less than 2 Seconds)

The current research was designed to establish whether individual differences in timing performance predict neural activation in the areas that subserve the perception of short durations ranging between 400 and 1600 milliseconds. Seventeen participants completed both a temporal bisection task and a control task, in a mixed fMRI design. In keeping with previous research, there was increased activation in a network of regions typically active during time perception including the right supplementary motor area (SMA) and right pre-SMA and basal ganglia (including the putamen and right pallidum). Furthermore, correlations between neural activity in the right inferior frontal gyrus and SMA and timing performance corroborate the results of a recent meta-analysis and are further evidence that the SMA forms part of a neural clock that is responsible for the accumulation of temporal information. Specifically, subjective lengthening of the perceived duration were associated with increased activation in both the right SMA (and right pre-SMA) and right inferior frontal gyrus.

Divergent roles of clock genes in retinal and suprachiasmatic nucleus circadian oscillators.

The retina is both a sensory organ and a self-sustained circadian clock. Gene targeting studies have revealed that mammalian circadian clocks generate molecular circadian rhythms through coupled transcription/translation feedback loops which involve 6 core clock genes, namely Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1 and that the roles of individual clock genes in rhythms generation are tissue-specific. However, the mechanisms of molecular circadian rhythms in the mammalian retina are incompletely understood and the extent to which retinal neural clocks share mechanisms with the suprachiasmatic nucleus (SCN), the central neural clock, is unclear. In the present study, we examined the rhythmic amplitude and period of real-time bioluminescence rhythms in explants of retina from Per1-, Per2-, Per3-, Cry1-, Cry2-, and Clock-deficient mice that carried transgenic PERIOD2::LUCIFERASE (PER2::LUC) or Period1::luciferase (Per1::luc) circadian reporters. Per1-, Cry1- and Clock-deficient retinal and SCN explants showed weakened or disrupted rhythms, with stronger effects in retina compared to SCN. Per2, Per3, and Cry2 were individually dispensable for sustained rhythms in both tissues. Retinal and SCN explants from double knockouts of Cry1 and Cry2 were arrhythmic. Gene effects on period were divergent with reduction in the number of Per1 alleles shortening circadian period in retina, but lengthening it in SCN, and knockout of Per3 substantially shortening retinal clock period, but leaving SCN unaffected. Thus, the retinal neural clock has a unique pattern of clock gene dependence at the tissue level that it is similar in pattern, but more severe in degree, than the SCN neural clock, with divergent clock gene regulation of rhythmic period.

Physiological responses of the circadian clock to acute light exposure at night

Circadian rhythms in physiological, endocrine and metabolic functioning are controlled by a neural clock located in the suprachiasmatic nucleus (SCN). This structure is endogenously rhythmic and the phase of this rhythm can be reset by light information from the eye. A key feature of the SCN is that while it is a small structure containing on the order of about 20,000 cells, it is amazingly heterogeneous. It is likely that anatomical heterogeneity reflects an underlying functional heterogeneity. In this review, we examine the physiological responses of cells in the SCN to light stimuli that reset the phase of the circadian clock, highlighting where possible the spatial pattern of such responses. Increases in intracellular calcium are an important signal in response to light, and this increase triggers many biochemical cascades that mediate responses to light. Furthermore, only some cells in the SCN are actually endogenously rhythmic, and these cells likely do not receive strong direct input from the retina. Therefore, this review also considers how light information is conveyed from the retinorecipient cells to the endogenously rhythmic cells that track circadian phase. A number of neuropeptides, including vasoactive intestinal polypeptide, gastrin-releasing peptide and substance P, may be particularly important in relaying such signals, but other neurochemicals such as GABA and nitric oxide may participate as well. A thorough understanding of the intracellular and intercellular responses to light, as well as the spatial arrangements of such responses may help identify important pharmacological targets for therapeutic interventions to treat sleep and circadian disorders.

Accumulation of Neural Activity in the Posterior Insula Encodes the Passage of Time

AbstractThe experience of time, i.e. the estimation of duration, is fundamental for perception and behavior and, therefore, essential for the survival of the individual organism. Over the last decades, neuroimaging, neurophysiological and clinical neuropsychological studies have pointed to many different brain areas involved in the processing of time. However, the core neural substrates and the processes accounting for the encoding of duration, which could form a timekeeping mechanism (essentially, a neural clock), are still unknown. Here we present evidence of neurophysiological activity in circumscribed areas of the human brain that is involved in the encoding of duration. Time-activity curves of neural activation derived from event-related functional magnetic resonance imaging (fMRI) during a time estimation task show that bilateral posterior insula as well as superior temporal and inferior parietal cortices build up activation when individuals are presented with 9 or 18 seconds tone intervals. Since the build up of neuronal activation peaks at the end of the interval, it appears that this accumulator-type activity encodes duration. Because of the close connection between posterior insula and ascending internal body signals, the accumulation of physiological changes in body states might constitute our experience of time. These results could be the starting point for a neural model of human time perception in the multiple-seconds range in which specific brain regions accumulate brain activity for the representation of duration.

Mapping the 40-Hz auditory steady-state response using current density reconstructions

We mapped the 40-Hz aSSR from nine normal subjects using PET-independent low-resolution electroencephalographic tomography (LORETA) as well as PET-weighted LORETA and minimum norm (MinNorm) current density reconstructions. In grand mean data, PET-independent LORETA identified seven sites with peaks in current density in right temporal lobe, right brainstem/cerebellum, right parietal lobe, left cerebellum/temporal lobe, and right frontal lobe. PET-weighted LORETA found six of the same sites as the PET-independent LORETA: the right brainstem source was eliminated and two right-frontal sources were added. Both LORETA analyses revealed considerable phase dispersion across identified sources. In both LORETA analyses, the relative time course of activation measured from an arbitrary starting phase progressed from right temporal lobe to right mid-frontal lobe to right parietal–frontal to right inferior parietal and finally to left cerebellum and left temporal lobe. MinNorm analysis incorporating PET information identified sources in the same locations as specified in the PET data. These sources were synchronized, with their amplitudes peaking almost simultaneously. Both PET-independent and PET-weighted LORETA results suggest that the aSSR is: (1) the result of a reverberating network with two or more groups of sources that recurrently excite each other or (2) the result of sequential auditory processing through various levels of a hierarchical network. In contrast, the PET-weighted MinNorm results suggest that the 40-Hz response represents simultaneous activation over widely spaced areas of the brain, perhaps due to synchronization of γ-band activity to a common neural clock.

Circadian Biology: Fibroblast Clocks Keep Ticking

Real-time cellular imaging of gene expression has revealed that fibroblasts contain a robust, self-sustained and cell-autonomous circadian oscillator, with a range of properties that both overlap and contrast with those of the neural clock of the suprachiasmatic nuclei.