Tob Regulates the Timing of Sleep Onset at Night in Drosophila.

Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in Drosophila regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Drosophila Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in "evening neurons" (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these "evening" clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.

Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

Demographics, distribution and experiences of UK clinical academic trainees using GMC NTS Survey data.

Involvement in research plays an integral role in the delivery of high-quality patient care, benefitting doctors, patients and employers. It is important that access to clinical academic training opportunities are inclusive and equitable. To better understand the academic trainee population, distribution of academic posts and their reported experience of clinical training, we analysed 53 477 anonymous responses from General Medical Council databases and the 2019 National Training Survey. Academic trainees are more likely to be men, and the gender divide begins prior to graduation. There are very low numbers of international medical graduates and less than full-time academic trainees. A small number of UK universities produce a greater prevalence of doctors successfully appointed to academic posts; subsequent academic training also clusters around these institutions. At more senior levels, academic trainees are significantly more likely to be of white ethnicity, although among UK graduates, no ethnicity differences were seen. Foundation academic trainees report a poorer experience of some aspects of their clinical training placements, with high workloads reported by all academic trainees. Our work highlights important disparities in the demographics of the UK clinical academic trainee population and raises concerns that certain groups of doctors face barriers accessing and progressing in UK academic training pathways.

Demographics, distribution and experiences of UK clinical academic trainees using GMC NTS Survey data.

Involvement in research plays an integral role in the delivery of high-quality patient care, benefitting doctors, patients and employers. It is important that access to clinical academic training opportunities are inclusive and equitable. To better understand the academic trainee population, distribution of academic posts and their reported experience of clinical training, we analysed 53 477 anonymous responses from General Medical Council databases and the 2019 National Training Survey. Academic trainees are more likely to be men, and the gender divide begins prior to graduation. There are very low numbers of international medical graduates and less than full-time academic trainees. A small number of UK universities produce a greater prevalence of doctors successfully appointed to academic posts; subsequent academic training also clusters around these institutions. At more senior levels, academic trainees are significantly more likely to be of white ethnicity, although among UK graduates, no ethnicity differences were seen. Foundation academic trainees report a poorer experience of some aspects of their clinical training placements, with high workloads reported by all academic trainees. Our work highlights important disparities in the demographics of the UK clinical academic trainee population and raises concerns that certain groups of doctors face barriers accessing and progressing in UK academic training pathways.

Using game-like animations of geometric shapes to simulate social interactions: An evaluation of group score differences.

This study introduces a novel, game-like method for measuring social intelligence: the Social Shapes Test. Unlike other existing video or game-based tests, the Shapes Test uses animations of abstract shapes to represent social interactions. We explore demographic differences in Shapes Test scores compared to a written situational judgment test. Gender and race/ethnicity only had meaningful effects on written SJT scores while no effects were found for Shapes Test scores. This pattern of results remained after controlling for general mental ability and English language exposure. We also found metric invariance between demographic groups for both tests. Our results demonstrate the potential for using animated shape tasks as an alternative to written SJTs when designing future game-based assessments.

Interhemispheric interactions between the right angular gyrus and the left motor cortex: a transcranial magnetic stimulation study.

The interconnection of the angular gyrus of right posterior parietal cortex (PPC) and the left motor cortex (LM1) is essential for goal-directed hand movements. Previous work with transcranial magnetic stimulation (TMS) showed that right PPC stimulation increases LM1 excitability, but right PPC followed by left PPC-LM1 stimulation (LPPC-LM1) inhibits LM1 corticospinal output compared with LPPC-LM1 alone. It is not clear if right PPC-mediated inhibition of LPPC-LM1 is due to inhibition of left PPC or to combined effects of right and left PPC stimulation on LM1 excitability. We used paired-pulse TMS to study the extent to which combined right and left PPC stimulation, targeting the angular gyri, influences LM1 excitability. We tested 16 healthy subjects in five paired-pulsed TMS experiments using MRI-guided neuronavigation to target the angular gyri within PPC. We tested the effects of different right angular gyrus (RAG) and LM1 stimulation intensities on the influence of RAG on LM1 and on influence of left angular gyrus (LAG) on LM1 (LAG-LM1). We then tested the effects of RAG and LAG stimulation on LM1 short-interval intracortical facilitation (SICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI). The results revealed that RAG facilitated LM1, inhibited SICF, and inhibited LAG-LM1. Combined RAG-LAG stimulation did not affect SICI but increased LICI. These experiments suggest that RAG-mediated inhibition of LAG-LM1 is related to inhibition of early indirect (I)-wave activity and enhancement of GABAB receptor-mediated inhibition in LM1. The influence of RAG on LM1 likely involves ipsilateral connections from LAG to LM1 and heterotopic connections from RAG to LM1.NEW & NOTEWORTHY Goal-directed hand movements rely on the right and left angular gyri (RAG and LAG) and motor cortex (M1), yet how these brain areas functionally interact is unclear. Here, we show that RAG stimulation facilitated right hand motor output from the left M1 but inhibited indirect (I)-waves in M1. Combined RAG and LAG stimulation increased GABAB, but not GABAA, receptor-mediated inhibition in left M1. These findings highlight unique brain interactions between the RAG and left M1.

Prevalence and early-life determinants of mid-life multimorbidity: evidence from the 1970 British birth cohort.

BACKGROUND: We sought to: [1] estimate the prevalence of multimorbidity at age 46-48 in the 1970 British Cohort Study-a nationally representative sample in mid-life; and [2] examine the association between early-life characteristics and mid-life multimorbidity. METHOD: A prospective longitudinal birth cohort of a community-based sample from the 1970 British Cohort Study (BCS70). Participants included all surviving children born in mainland Britain in a single week in April 1970; the analytical sample included those with valid data at age 46-48 (n = 7951; 2016-2018). The main outcome was multimorbidity, which was operationalised as a binary indicator of two or more long-term health conditions where at least one of these conditions was of physical health. It also included symptom complexes (e.g., chronic pain), sensory impairments, and alcohol problems. RESULTS: Prevalence of mid-life multimorbidity was 33.8% at age 46-48. Those with fathers from unskilled social occupational class (vs professional) at birth had 43% higher risk of mid-life multimorbidity (risk ratio = 1.43, 95% confidence interval 1.15 to 1.77). After accounting for potential child and family confounding, an additional kilogram of birthweight was associated with 10% reduced risk of multimorbidity (risk ratio = 0.90, 95% confidence interval 0.84 to 0.96); a decrease of one body mass index point at age 10 was associated with 3% lower risk (risk ratio = 1.03, 95% confidence interval 1.01 to 1.05); one standard deviation higher cognitive ability score at age 10 corresponded to 4% lower risk (risk ratio = 0.96, 95% confidence interval 0.91 to 1.00); an increase of one internalising problem at age 16 was equated with 4% higher risk (risk ratio = 1.04, 95% confidence interval 1.00 to 1.08) and of one externalising problem at age 16 with 6% higher risk (risk ratio = 1.06, 1.03 to 1.09). CONCLUSION: Prevalence of multimorbidity was high in mid-life (33.8% at age 46-48) in Britain. Potentially modifiable early-life exposures, including early-life social circumstances, cognitive, physical and emotional development, were associated with elevated risk of mid-life multimorbidity.

Feasibility of Measuring Sedentary Time Using Data From a Thigh-Worn Accelerometer.

In large-scale cohort studies, sedentary behavior has been routinely measured using self-reports or devices that apply a count-based threshold. We employed a gold standard postural allocation technique using thigh inclination and acceleration to capture free-living sedentary behavior. Participants aged 46.8 (standard deviation (SD), 0.7) years (n = 5,346) from the 1970 British Cohort Study (United Kingdom) were fitted with a waterproofed thigh-mounted accelerometer device (activPAL3 micro; PAL Technologies Ltd., Glasgow, United Kingdom) worn continuously over 7 days; data were collected in 2016-2018. Usable data were retrieved from 83.0% of the devices fitted, with 79.6% of the sample recording at least 6 full days of wear (at least 10 waking hours). Total daily sitting time (average times were 9.5 (SD, 2.0) hours/day for men and 9.0 (SD, 2.0) hours/day for women) accounted for 59.4% and 57.3% of waking hours in men and women, respectively; 73.8% of sample participants recorded ≥8 hours/day of sitting. Sitting in prolonged bouts of 60 continuous minutes or more accounted for 25.3% and 24.4% of total daily sitting in men and women, respectively. In mutually adjusted models, male sex, underweight, obesity, education, poor self-rated health, television-viewing time, and having a sedentary occupation were associated with higher device-measured sitting times. Thigh-worn accelerometry was feasibly deployed and should be considered for larger-scale national surveys.

Attributing social meaning to animated shapes: A new experimental study of apparent behavior.

In 1944, Heider and Simmel reported that observers could perceive simple animated geometric shapes as characters with emotions, intentions, and other social attributes. This work has been cited over 3000 times and has had wide and ongoing influence on the study of social cognition and social intelligence. However, many researchers in this area have continued to use the original Heider and Simmel black-and-white video. We asked whether the original findings could be reproduced 75 years later by creating 32 new colored animated shape videos designed to depict various social plots and testing whether they can evoke similar spontaneous social attributions. Participants (N = 66) viewed our videos and were asked to write narratives which we coded for indicia of different types of social attributions. Consistent with Heider and Simmel, we found that participants spontaneously attributed social meaning to the videos. We observed that responses to our videos were also similar to responses to the original video reported by Klin (2000), despite being only 13-23 s and portraying a broader range of social plots. Participants varied in how many social attributions they made in response, and the videos varied in how much they elicited such responses. Our set of animated shape videos is freely available online for all researchers to use and forms the basis of a multiple-choice assessment of social intelligence (Brown et al., 2019).

EEG oscillations: how are they modulated during different phases of repetitive movements?

Voluntary movements are planned through the relative timing between submovements of movement sequences as part of the motor program. Different movement phases are characterized by specific amplitude modulation of cortical oscillations. The latter represent neurophysiological correlates of specific synchronization or desynchronization of different neuronal groups. In this Neuro Forum, we review recent evidence regarding the temporal relation between neurophysiological correlates of different phases of a repetitive motor task using electroencephalography and source localization using individualized MRI.

Differential effects of continuous theta burst stimulation over left premotor cortex and right prefrontal cortex on modulating upper limb somatosensory input.

Somatosensory evoked potentials (SEPs) represent somatosensory processing in non-primary motor areas (i.e. frontal N30 and N60) and somatosensory cortices (i.e. parietal P50). It is well-known that the premotor cortex (PMC) and prefrontal cortex (PFC) are involved in the preparation and planning of upper limb movements but it is currently unclear how they modulate somatosensory processing for upper limb motor control. In the current study, two experiments examined SEP modulations after continuous theta burst stimulation (cTBS) was used to transiently disrupt the left PMC (Experiment 1) and right PFC (Experiment 2). Both Experiment 1 (n=15) and Experiment 2 (n=16) used pre-post experimental designs. In both experiments participants performed a task requiring detection of varying amplitudes of attended vibrotactile (VibT) stimuli to the left index finger (D2) and execution of a pre-matched finger sequence with the right (contralateral) hand to specific VibT targets. During the task, SEPs were measured to median nerve (MN) stimulations time-locked during pre-stimulus (250 ms before VibT), early response selection (250 ms after VibT), late preparatory (750 ms after VibT) and execution (1250 ms VibT) phases. The key findings of Experiment 1 revealed significant decreases in N30 and N60 peak amplitudes after cTBS to PMC. In contrast, the results of Experiment 2, also found significant decreased N60 peak amplitudes as well as trends for increased N30 and P50 peak amplitudes. A direct comparison of Experiment 1 and Experiment 2 confirmed differential modulation of N30 peak amplitudes after PMC (gated) compared to PFC (enhanced) cTBS. Collectively, these results support that both the left PMC and right PFC have modulatory roles on early somatosensory input into non-primary motor areas, such as PMC and supplementary motor area (SMA), represented by frontal N30 and N60 SEPs. These results confirm that PMC and PFC are both part of a network that regulates somatosensory input for upper limb motor control.

Modulatory effects of movement sequence preparation and covert spatial attention on early somatosensory input to non-primary motor areas.

Early frontal somatosensory evoked potentials (SEPs) (i.e., N30) are known to be modulated by movement. Furthermore, individuals with prefrontal lesions have enhanced early frontal SEPs. However, it is currently unclear through what mechanism the prefrontal cortex may modulate early frontal SEPs. The current study investigated whether prefrontal modulatory effects on frontal SEPs may depend on the relevancy of somatosensory input for movement (i.e., interaction with motor areas). Two experiments were conducted to determine whether selective spatial attention alone (Experiment 1-Attend and Mentally Count) or when using attended somatosensory input in the preparation of finger sequences with the limb contralateral to somatosensory stimulation (Experiment 2-Attend for Movement Preparation) could modulate SEPs. In Experiment 1, SEPs elicited by median nerve (MN) stimulation at both wrists were measured in trials when individuals attended and mentally counted vibrotactile (VibT) input at either index finger. In Experiment 2, SEPs elicited by MN stimulation at the left wrist were measured in trials when individuals used attended VibT input at the left index finger to prepare finger sequences that were contralateral to MN stimulation. In both experiments, control conditions were performed where participants received passive VibT and MN stimulation. Results from Experiment 1 confirmed that selective spatial attention alone does not modulate frontal N30 peak amplitudes. However, Experiment 2 revealed that frontal N30 peak amplitudes were decreased (i.e., gated) when individuals used attended VibT input at the left index finger to prepare contralateral finger sequences. These results support a role of sensory gating of early frontal SEPs during finger sequence preparation of the limb contralateral to MN stimulation that may result from increased activity in prefrontal, motor preparatory areas, and basal ganglia.

Self-selection as an explanation for general mental ability test score differences between mobile and nonmobile devices in observational studies.

Past studies have reported divergent results regarding the effect of mobile devices on general mental ability (GMA) test scores. We investigate selection bias as an explanation for this inconsistency in GMA score differences between applicants using mobile or nonmobile devices reported in observational and lab studies. We initially found that mobile test-takers scored 0.58 SD lower than nonmobile test-takers in an operational sample of 76,948 applicants across over 400 occupations. However, we found that mobile device use was more prevalent among applicants with lower educational attainment and within jobs of lower complexity. These factors, among others, could potentially confound the observed GMA score differences between devices. The device effect shrank to d = 0.25 after controlling for selection bias in device choice using propensity score weighing. As an alternative, we also used poststratification to control for selection bias and this yielded an even weaker device effect (d = 0.10). Our results indicate that the large device effects obtained in prior operational studies are possibly inflated by selection bias. Therefore, it is important to control for these demographic and occupational differences between self-selected device groups when analyzing operational data for research purposes. Propensity score weighing and poststratification appear useful for reducing the impact of selection bias in real-world, observational data. We also strongly recommend the use of random assignment to prevent selection bias when evaluating device effects for new or adapted GMA or similar ability tests. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Social Shapes Test as a Self-Administered, Online Measure of Social Intelligence: Two Studies with Typically Developing Adults and Adults with Autism Spectrum Disorder.

The Social Shapes Test (SST) is a measure of social intelligence which does not use human faces or rely on extensive verbal ability. The SST has shown promising validity among adults without autism spectrum disorder (ASD), but it is uncertain whether it is suitable for adults with ASD. We find measurement invariance between adults with (n = 229) or without ASD (n = 1,049) on the 23-item SST. We also find that adults without ASD score higher on the SST than adults with ASD (d = 0.21). We also provide two, 14-item versions which demonstrated good parallel test-retest reliability and are positively related to scores on the Frith-Happé task. The SST is suitable for remote, online research studies.

Effect of aerobic exercise training on pulse wave velocity in adults with and without long-term conditions: a systematic review and meta-analysis.

RATIONALE: There is conflicting evidence whether aerobic exercise training (AET) reduces pulse wave velocity (PWV) in adults with and without long-term conditions (LTCs). OBJECTIVE: To explore whether PWV improves with AET in adults with and without LTC, to quantify the magnitude of any effect and understand the influence of the exercise prescription. DATA SOURCES: CENTRAL, MEDLINE and EMBASE were among the databases searched. ELIGIBILITY CRITERIA: We included studies with a PWV measurement before and after supervised AET of at least 3 weeks duration. Exclusion criteria included resistance exercise and alternative measures of arterial stiffness. DESIGN: Controlled trials were included in a random effects meta-analysis to explore the effect of AET on PWV. Uncontrolled studies were included in a secondary meta-analysis and meta-regression exploring the effect of patient and programme factors on change in PWV. The relevant risk of bias tool was used for each study design. RESULTS: 79 studies (n=3729) were included: 35 controlled studies (21 randomised control trials (RCT) (n=1240) and 12 non-RCT (n=463)) and 44 uncontrolled (n=2026). In the controlled meta- analysis, PWV was significantly reduced following AET (mean (SD) 11 (7) weeks) in adults with and without LTC (mean difference -0.63; 95% CI -0.82 to -0.44; p<0.0001). PWV was similarly reduced between adults with and without LTC (p<0.001). Age, but not specific programme factors, was inversely associated with a reduction in PWV -0.010 (-0.020 to -0.010) m/s, p<0.001. DISCUSSION: Short-term AET similarly reduces PWV in adults with and without LTC. Whether this effect is sustained and the clinical implications require further investigation.