Rhythmic tapping difficulties in adults who stutter: a deficit in Central Clock and/or Motor Implementation?

The study aims to better understand the origin of increased tapping variability and inaccuracy in people who stutter during paced and un-paced tapping. The overall question is to what extent these timing difficulties are related to a central clock deficit, a deficit in motor execution, or both.Finger tapping behavior of 16 adults who stutter (PWS) with different levels of musical training was compared with performance of 16 matching controls (PNS) in three finger tapping synchronization tasks ― a simple 1:1 isochronous pattern, a complex non-isochronous pattern, and a 4 tap:1 beat isochronous pattern ―, a continuation task (without external stimulation), and a reaction task involving aperiodic and unpredictable patterns. The results show that PWS exhibited larger negative asynchrony (expressed as phase angles), and increased synchronization variability (expressed as phase locking values) in paced tapping tasks, and that these differences from the PNS group were modulated by rhythmic complexity and musical training. The tapping asynchrony with a simple isochronous pattern correlated significantly with the average inter-tap duration, and with tap reaction times during the reaction task. The synchronization variability with a simple isochronous pattern correlated significantly with both the central clock and motor implementation variances as extracted during un-paced tapping, according to the Wing and Kristofferson’s model of timing.The results support the idea that increased tapping variability of PWS is associated with both a central clock and a motor execution deficit. The greater Negative Mean Asynchrony of PWS does not appear to be attributable to a deficit in time estimation but rather to a motor deficit. Several models and theories related to deficits in sensorimotor integration were considered to explain the interactions with beat strength, pattern complexity, and musical training.

A Low Energy Clock Network with a Huge Number of Local Synchronized Oscillators

<div>A clock system for a huge grid of small clock regions is presented. There is an oscillator in each clock region, which drives the local clock of a processing element (PE). The oscillators are kept synchronized by exploiting the phase of their neighbors. In an infinite mesh, the clock skew would be zero, but in a network of limited size there will be fringe effects. In a mesh with 25×25 oscillators, the maximum skew between neighboring regions is within 3.3 ps. By slightly adjusting the free running frequency of the oscillators, this skew can be reduced to 1.2 ps. The mesh may contain millions of clock regions.</div><div> Because there is no central clock, both power consumption and clock frequency can be improved compared to a conventional clock distribution network. A PE of 150×150 µm² running at 6.7 GHz with 93 master-slave flip-flops is used as an example. The PE-internal clock skew is less than 2.3 ps, and the energy consumption of the clock system 807 µW per PE. It corresponds to an effective gate and wire capacitance of 509 aF, or 7.3 gate capacitances.</div><div> Power noise is reduced by scheduling the local oscillators gradually along one of the grid’s axes. In this way, surge currents, which generally have their peaks at the clock edges, are distributed evenly over a full clock cycle.</div>

A Low Energy Clock Network with a Huge Number of Local Synchronized Oscillators

<div>A clock system for a huge grid of small clock regions is presented. There is an oscillator in each clock region, which drives the local clock of a processing element (PE). The oscillators are kept synchronized by exploiting the phase of their neighbors. In an infinite mesh, the clock skew would be zero, but in a network of limited size there will be fringe effects. In a mesh with 25×25 oscillators, the maximum skew between neighboring regions is within 3.3 ps. By slightly adjusting the free running frequency of the oscillators, this skew can be reduced to 1.2 ps. The mesh may contain millions of clock regions.</div><div> Because there is no central clock, both power consumption and clock frequency can be improved compared to a conventional clock distribution network. A PE of 150×150 µm² running at 6.7 GHz with 93 master-slave flip-flops is used as an example. The PE-internal clock skew is less than 2.3 ps, and the energy consumption of the clock system 807 µW per PE. It corresponds to an effective gate and wire capacitance of 509 aF, or 7.3 gate capacitances.</div><div> Power noise is reduced by scheduling the local oscillators gradually along one of the grid’s axes. In this way, surge currents, which generally have their peaks at the clock edges, are distributed evenly over a full clock cycle.</div>

Vasopressin resets the central circadian clock in a manner influenced by sex and vasoactive intestinal polypeptide signaling

Circadian rhythms in behavior and physiology are programmed by the suprachiasmatic nucleus (SCN) of the hypothalamus. A subset of SCN neurons produce the neuropeptide arginine vasopressin (AVP), but it remains unclear whether AVP signaling influences the SCN clock directly. Here we test that AVP signaling acting through V1A and V1B receptors influences molecular rhythms in SCN neurons. V1 receptor agonists were applied ex vivo to PERIOD2::LUCIFERASE SCN slices, allowing for real-time monitoring of changes in molecular clock function. V1A/B agonists reset the phase of the SCN molecular clock in a time-dependent manner, with larger magnitude responses by the female SCN. Further, we find evidence that both Gq and Gs signaling pathways interact with V1A/B-induced SCN resetting, and that this response requires vasoactive intestinal polypeptide (VIP) signaling. Collectively, this work indicates that AVP signaling resets SCN molecular rhythms in conjunction with VIP signaling and in a manner influenced by sex. This highlights the utility of studying clock function in both sexes and suggests that signal integration in central clock circuits regulates emergent properties important for the control of daily rhythms in behavior and physiology.

Low Temperature Effect on the Endocrine and Circadian Systems of Adult Danio rerio

The control of the biological rhythms begins with the activation of photo- and thermosensitive cells located in various organs of the fish such as brain, eye, and skin, but a central clock is still to be identified in teleosts. Thermal changes are stressors which increase cortisol and affect the rhythm of other hormones such as melatonin and growth hormone (GH), in both endo- and ectothermic organisms. Our aim was to investigate how temperature (23°C for 6 days) lower than the optimal (28°C) modulates expression of several gene pathways including growth hormone (gh1) and its receptors (ghra, ghrb), insulin-like growth factor1 (igf1a, igf1b) and its receptors (igf1ra, igf1rb), cortisol and its receptor (gr), the limiting enzyme of melatonin synthesis (arylalkylamine N-acetyltransferase, aanat) and melatonin receptors (mtnr1aa, mtnr1bb), as well as their relationship with clock genes in Danio rerio in early light and early dark phases of the day. Lower temperature reduced the expression of the hormone gene gh1, and of the related receptors ghra, ghrb, igf1ra, and igf1rb. Cortisol levels were higher at the lower temperature, with a decrease of its receptor (gr) transcripts in the liver. Interestingly, we found higher levels of aanat transcripts in the brain at 23°C. Overall, lower temperature downregulated the transcription of hormone related genes and clock genes. The results suggest a strong correlation of temperature challenge with the clock molecular mechanism and the endocrine systems analyzed, especially the growth hormone and melatonin axes, in D. rerio tissues.

Hugin+ neurons provide a link between sleep homeostat and circadian clock neurons

Sleep is controlled by homeostatic mechanisms, which drive sleep after wakefulness, and a circadian clock, which confers the 24-h rhythm of sleep. These processes interact with each other to control the timing of sleep in a daily cycle as well as following sleep deprivation. However, the mechanisms by which they interact are poorly understood. We show here that hugin+ neurons, previously identified as neurons that function downstream of the clock to regulate rhythms of locomotor activity, are also targets of the sleep homeostat. Sleep deprivation decreases activity of hugin+ neurons, likely to suppress circadian-driven activity during recovery sleep, and ablation of hugin+ neurons promotes sleep increases generated by activation of the homeostatic sleep locus, the dorsal fan-shaped body (dFB). Also, mutations in peptides produced by the hugin+ locus increase recovery sleep following deprivation. Transsynaptic mapping reveals that hugin+ neurons feed back onto central clock neurons, which also show decreased activity upon sleep loss, in a Hugin peptide–dependent fashion. We propose that hugin+ neurons integrate circadian and sleep signals to modulate circadian circuitry and regulate the timing of sleep.

Chronobiology and Metabolism: Is Ketogenic Diet Able to Influence Circadian Rhythm?

Circadian rhythms underpin most physiological processes, including energy metabolism. The core circadian clock consists of a transcription-translation negative feedback loop, and is synchronized to light-dark cycles by virtue of light input from the retina, to the central clock in the suprachiasmatic nucleus in the hypothalamus. All cells in the body have circadian oscillators which are entrained to the central clock by neural and humoral signals. In addition to light entrainment of the central clock in the brain, it now emerges that other stimuli can drive circadian clock function in peripheral tissues, the major one being food. This can then drive the liver clock to be misaligned with the central brain clock, a situation of internal misalignment with metabolic disease consequences. Such misalignment is prevalent, with shift workers making up 20% of the working population. The effects of diet composition on the clock are not completely clarified yet. High-fat diet and fasting influence circadian expression of clock genes, inducing phase-advance and phase-delay in animal models. Ketogenic diet (KD) is able to induce a metabolic switch from carbohydrate to fatty acid oxidation, miming a fasting state. In recent years, some animal studies have been conducted to investigate the ability of the KD to modify circadian gene expression, and demonstrated that the KD alters circadian rhythm and induces a rearrangement of metabolic gene expression. These findings may lead to new approaches to obesity and metabolic pathologies treatment.

Daily electrical activity in the master circadian clock of a diurnal mammal

Circadian rhythms in mammals are orchestrated by a central clock within the suprachiasmatic nuclei (SCN). Our understanding of the electrophysiological basis of SCN activity comes overwhelmingly from a small number of nocturnal rodent species, and the extent to which these are retained in day-active animals remains unclear. Here, we recorded the spontaneous and evoked electrical activity of single SCN neurons in the diurnal rodent Rhabdomys pumilio, and developed cutting-edge data assimilation and mathematical modeling approaches to uncover the underlying ionic mechanisms. As in nocturnal rodents, R. pumilio SCN neurons were more excited during daytime hours. By contrast, the evoked activity of R. pumilio neurons included a prominent suppressive response that is not present in the SCN of nocturnal rodents. Our modeling revealed and subsequent experiments confirmed transient subthreshold A-type potassium channels as the primary determinant of this response, and suggest a key role for this ionic mechanism in optimizing SCN function to accommodate R. pumilio’s diurnal niche.

Circadian Clock, Sleep, and Diet

Circadian rhythm is a fundamental process of sustaining metabolic homeostasis by predicting changes in the environment. This is driven by biological clocks, which operate within a 24-h period to orchestrate daily variation of metabolism and sleep. The central clock in the hypothalamus is the master keeper of the circadian rhythm and is primarily reset by light, while the feeding-fasting rhythm, that is, nutritional stimulus, entrains peripheral clocks in peripheral organs such as the intestine and liver. Nutritional stimuli are important modulators of peripheral circadian rhythms and may affect the central clock and sleep homeostasis through metabolic alterations. In this chapter, I will summarize the significance of circadian rhythm and sleep in metabolic regulation as well as discuss the impact that diet has on circadian rhythm and sleep.

A Biophysical Counting Mechanism for Keeping Time

The ability to estimate and produce appropriately timed responses is central to many behaviors including speaking, dancing, and playing a musical instrument. A classical framework for estimating or producing a time interval is the pacemaker-accumulator model in which pulses of a pacemaker are counted and compared to a stored representation. However, the neural mechanisms for how these pulses are counted remains an open question. The presence of noise and stochasticity further complicate the picture. We present a biophysical model of how to keep count of a pacemaker in the presence of various forms of stochasticity using a system of bistable Wilson-Cowan units asymmetrically connected in a one-dimensional array; all units receive the same input pulses from a central clock but only one unit is active at any point in time. With each pulse from the clock, the position of the activated unit changes thereby encoding the total number of pulses emitted by the clock. This neural architecture maps the counting problem into the spatial domain, which in turn translates count to a time estimate. We further extend the model to a hierarchical structure to be able to robustly achieve higher counts.