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Traumatic brain injury (TBI) and stroke are the most common causes of acquired brain injury (ABI), annually affecting 69 million and 15 million people, respectively. Following ABI, the relationship between brain network disruption and common cognitive issues including attention dysfunction is heterogenous. Using PRISMA guidelines, we systematically reviewed 43 studies published by February 2023 that reported correlations between attention and connectivity. Across all ages and stages of recovery, following TBI, greater attention was associated with greater structural efficiency within/between executive control network (ECN), salience network (SN), and default mode network (DMN) and greater functional connectivity (fc) within/between ECN and DMN, indicating DMN interference. Following stroke, greater attention was associated with greater structural connectivity (sc) within ECN; or greater fc within the dorsal attention network (DAN). In childhood ABI populations, decreases in structural network segregation were associated with greater attention. Longitudinal recovery from TBI was associated with normalization of DMN activity, and in stroke, normalization of DMN and DAN activity. Results improve clinical understanding of attention-related connectivity changes after ABI. Recommendations for future research include increased use of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) to measure connectivity at the point of care, standardized attention and connectivity outcome measures and analysis pipelines, detailed reporting of patient symptomatology, and casual analysis of attention-related connectivity using brain stimulation.

Animal models indicate that motor behaviour is shaped by monoamine neuromodulators released diffusely throughout the brain and spinal cord. As an alternative to conducting a single study to explore the effects of neuromodulators on the human motor system, we have identified and collated human experiments investigating motor effects of well-characterised drugs that act on serotonergic and noradrenergic networks. In doing so, we present strong neuropharmacology evidence that human motor pathways are affected by neuromodulators across both healthy and clinical populations, insight that cannot be determined from a single reductionist experiment. We have focused our review on the effects that monoaminergic drugs have on muscle responses to non-invasive stimulation of the motor cortex and peripheral nerves, and other closely related tests of motoneuron excitability, and discuss how these measurement techniques elucidate the effects of neuromodulators at motor cortical and spinal motoneuronal levels. Although there is some heterogeneity in study methods, we find drugs acting to enhance extracellular concentrations of serotonin tend to reduce the excitability of the human motor cortex, and enhanced extracellular concentrations of noradrenaline increases motor cortical excitability by enhancing intracortical facilitation and reducing inhibition. Both monoamines tend to enhance the excitability of spinal motoneurons. Overall, this review details the importance of neuromodulators for the output of human motor pathways and suggests that commonly prescribed monoaminergic drugs target the motor system in addition to their typical psychiatric/neurological indications., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT 2 receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT 2 antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 ± 4 years) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT 2 antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs), and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). 5-HT 2 antagonism reduced maximal torque (p < 0.001), and compared to placebo, reduced unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033) and conditioned MEP amplitude during contractions (p = 0.020). 5-HT 2 antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT 2 antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT 2 receptors to regulate motoneurone excitability but not intracortical circuits., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Serotonin (5-HT) modulates motoneuron excitability during muscle contractions, where the release of 5-HT in the central nervous system (CNS) is linked to the intensity of physical activity. Although there is evidence that enhanced availability of 5-HT can exacerbate fatigue, these effects on the development of fatigue during different contraction intensities are largely unknown. The purpose of this study was to investigate how enhanced 5-HT availability affects voluntary muscle activation and corticospinal excitability during fatigue-inducing contractions. Two experiments were performed. In the first experiment ( n = 11), 12 isometric elbow flexions at 20% maximal voluntary contractions (MVCs) were performed for 2 min each with 40-s rest periods. In the second experiment ( n = 14), 12 maximal isometric elbow flexions were held for 10 s each with 40-s rest periods. In both experiments, the selective serotonin reuptake inhibitor (20-mg paroxetine), or a placebo, was administered in a two-way crossover design. Muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex (both experiments 1 and 2 ), as well as motor point stimulation of the elbow flexors ( experiment 2 ) were assessed. Paroxetine reduced both motor cortical ( P = 0.018) and motor point voluntary activation ( P = 0.036) during the maximal contraction protocol. Paroxetine also reduced exercise-induced lengthening of the TMS silent period during the submaximal ( P = 0.037) and maximal ( P = 0.002) contraction protocols. Activation of inhibitory 5-HT 1A receptors on motoneurons likely exacerbated exercise-induced reductions in voluntary drive to the elbow flexors. However, 5-HT modulation of motor activity also appeared at the supraspinal level. NEW & NOTEWORTHY As serotonin release onto motoneurons may be scaled to the strength of muscle contraction, it may have different effects when neuromuscular fatigue is induced by contractions of different intensities. Enhanced levels of serotonin compromised voluntary activation of muscle when fatigue was induced by strong contractions but not weak contractions. This provides evidence that the serotonergic system has the greatest influence on fatigue that is generated with high neural drive to the target muscle.

The intrinsic electrical properties of motoneurons strongly affect motoneuron excitability to fast-acting excitatory ionotropic inputs. Serotonin (5-HT) is a neurochemical that alters the intrinsic properties of motoneurons, whereby animal models and in vitro experiments indicate that 5-HT increases motoneuron excitability by activating 5-HT 2 receptors on the somato-dendritic compartment. In the current study, we examined how antagonism of the 5-HT 2 receptor affects motoneuron excitability in humans. We hypothesised that motoneuron excitability would be reduced. The 5-HT 2 antagonist cyproheptadine was administered to 10 healthy participants in a double-blinded, placebo-controlled, crossover trial. Electrical cervicomedullary stimulation was used to deliver a synchronised excitatory volley to motoneurons to elicit cervicomedullary motor evoked potentials (CMEPs) in the surface electromyography (EMG) signal of the resting biceps brachii. Likewise, electrical peripheral nerve stimulation was used to generate antidromic spikes in motoneurons and cause recurrent discharges, which were recorded with surface EMG as F-waves in a resting hand muscle. Compared with placebo, we found that 5-HT 2 antagonism reduced the amplitude and persistence of F-waves but did not affect CMEP amplitude. 5-HT 2 antagonism also reduced maximal contraction strength. The reduced recurrent discharge of motoneurons with 5-HT 2 antagonism suggests that 5-HT 2 receptors modulate the electrical properties of the initial segment or soma to promote excitability. Conversely, as cyproheptadine did not affect motoneuron excitability to brief synaptic input, but affected maximal contractions requiring sustained input, it seems likely that the 5-HT 2 -mediated amplification of synaptic input at motoneuron dendrites is functionally significant only when excitatory input activates persistent inward currents., (© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Although there is evidence that 5-HT acts as an excitatory neuromodulator to enhance maximal force generation, it is largely unknown how 5-HT activity influences the ability to sustain a constant force during steady-state contractions. A total of 22 healthy individuals participated in the study, where elbow flexion force was assessed during brief isometric contractions at 10% maximal voluntary contraction (MVC), 60% MVC, MVC, and during a sustained MVC. The selective serotonin reuptake inhibitor, paroxetine, suppressed physiological tremor and increased force steadiness when performing the isometric contractions. In particular, a main effect of drug was detected for peak power of force within the 8-12 Hz range ( P = 0.004) and the coefficient of variation (CV) of force ( P < 0.001). A second experiment was performed where intermittent isometric elbow flexions (20% MVC sustained for 2 min) were repeatedly performed so that serotonergic effects on physiological tremor and force steadiness could be assessed during the development of fatigue. Main effects of drug were once again detected for peak power of force in the 8-12 Hz range ( P = 0.002) and CV of force ( P = 0.003), where paroxetine suppressed physiological tremor and increased force steadiness when the elbow flexors were fatigued. The findings of this study suggest that enhanced availability of 5-HT in humans has a profound influence of maintaining constant force during steady-state contractions. The action of 5-HT appears to suppress fluctuations in force regardless of the fatigue state of the muscle. NEW & NOTEWORTHY Converging lines of research indicate that enhanced serotonin availability increases maximal force generation. However, it is largely unknown how serotonin influences the ability to sustain a constant force. We performed two experiments to assess physiological tremor and force steadiness in unfatigued and fatigued muscle when serotonin availability was enhanced in the central nervous system. Enhanced availability of serotonin reduced physiological tremor amplitude and improved steadiness regardless of muscle fatigue.

Animal models indicate that serotonin (5-HT) release onto motoneurons facilitates motor output, particularly during strong motor activities. However, evidence for 5-HT effects during human movement are limited. This study examined how antagonism of the 5-HT 2 receptor, which is a 5-HT receptor that promotes motoneuron excitability, affects human movement. Ten healthy participants (24.2 ± 1.9 yr) ingested 8 mg of cyproheptadine (competitive 5-HT 2 antagonist) in a double-blinded, placebo-controlled, repeated-measures design. Transcranial magnetic stimulation (TMS) of the motor cortex was used to elicit motor evoked potentials (MEPs) from biceps brachii. First, stimulus-response curves (90%-160% active motor threshold) were obtained during very weak elbow flexions (10% of maximal). Second, to determine if 5-HT effects are scaled to the intensity of muscle contraction, TMS at a fixed intensity was applied during elbow flexions of 20%, 40%, 60%, 80%, and 100% of maximal. Cyproheptadine reduced the size of MEPs across the stimulus-response curves ( P = 0.045). Notably, MEP amplitude was 22.3% smaller for the cyproheptadine condition for the strongest TMS intensity. In addition, cyproheptadine reduced maximal torque ( P = 0.045), lengthened the biceps silent period during maximal elbow flexions ( P = 0.037), and reduced superimposed twitch amplitude during moderate-intensity elbow flexions ( P = 0.035). This study presents novel evidence that 5-HT 2 receptors influence corticospinal-motoneuronal output, which was particularly evident when a large number of descending inputs to motoneurons were active. Although it is likely that antagonism of 5-HT 2 receptors reduces motoneuron gain to ionotropic inputs, supraspinal mechanisms may have also contributed to the study findings. NEW & NOTEWORTHY Voluntary contractions and responses to magnetic stimulation of the motor cortex are dependent on serotonin activity in the central nervous system. 5-HT 2 antagonism decreased evoked potential size to high-intensity stimulation, and reduced torque and lengthened inhibitory silent periods during maximal contractions. We provide novel evidence that 5-HT 2 receptors are involved in muscle activation, where 5-HT effects are strongest when a large number of descending inputs activate motoneurons.

Key Points: During maximal effort contractions, intense serotonin release via the raphe-spinal pathway spills over from the somato-dendritic compartment to activate inhibitory 5-HT 1A receptors on the axon initial segment of motoneurons to reduce motoneuronal output. We investigated whether the same mechanism of central fatigue is present for low-intensity contractions, whereby weak serotonergic drive over an extended period may cause accumulation of serotonin and exacerbate central fatigue. Enhanced availability of serotonin did not directly influence motor pathways or motor performance during prolonged submaximal contraction. However, perceptions of muscle fatigue were greater, and the fatigue-induced lengthening of the silent period elicited via motor cortical stimulation was reduced with enhanced availability of serotonin. We propose that sustained low-intensity serotonergic neurotransmission influences supraspinal processes associated with fatigue, without directly influencing the output of the motor system during submaximal exercise., Abstract: Enhanced availability of serotonin (5-HT) exacerbates central fatigue that occurs during maximal effort contractions. However, it is unknown if 5-HT release contributes to central fatigue during prolonged submaximal contractions. Hence, we assessed the effect that enhanced availability of 5-HT has on sustained low-intensity fatiguing contractions. Fifteen individuals (22.3 ± 2.1 years) ingested the 5-HT reuptake inhibitor paroxetine in a human, double-blinded, placebo-controlled, repeated-measures design. Participants performed a low-intensity isometric elbow flexion for 30 min (15% of maximal voluntary contraction, MVC). Throughout the protocol, brief MVCs were performed and muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of the brachial plexus, and motor point stimulation of the biceps were obtained. Ratings of perceived fatigue were also acquired. Paroxetine did not influence torque or voluntary activation during brief MVCs performed throughout the low-intensity contraction. However, paroxetine increased the perception of fatigue throughout the contraction (P = 0.005), and shortened the biceps silent period elicited via TMS during sustained submaximal contraction (P = 0.003) and brief MVCs (P = 0.011). Overall, it appears that prolonged low-intensity contractions do not cause intense 5-HT release onto motoneurons, and therefore, 5-HT does not activate inhibitory extra-synaptic 5-HT 1A receptors of motoneurons to reduce their output. Although motor performance was unaffected by paroxetine, perceived fatigue was greater and intracortical inhibitory activity was reduced following the enhancement of endogenous concentrations of 5-HT during sustained submaximal contraction. Thus, 5-HT affects supraspinal processes during low-intensity contractions without directly altering motor pathways projecting to the muscle., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Neural circuits that comprise the indirect pathway in the basal ganglia have been implicated in tremor genesis, and possibly play a role in the voluntary activation of muscles. However, an absence of in vivo human studies that target striatal D 2 dopamine receptors of the indirect pathway have prevented causal links being made between the D 2 receptor and motor control. Healthy individuals ingested 3 mg of the competitive D 2 antagonist haloperidol in a double-blinded, placebo-controlled, two-way, cross-over study. Two experiments were performed to examine involuntary and voluntary movement. The first experiment (n = 10) assessed time- and frequency-domain measures of force tremor during isometric elbow flexions, and the second experiment (n = 8) examined voluntary activation of the elbow flexors during unfatigued and fatigued maximum contractions. Blockade of the D 2 receptor had no effect on tremor frequency, but increased the amplitude of force variability and 8-12 Hz power during moderate intensity isometric elbow flexions. These findings provide direct evidence that D 2 receptors relate to physiological tremor generation during muscle contractions, whereby the gain of tremor is increased after D 2 antagonism. The ability to voluntarily activate the elbow flexors was compromised under both non-fatigued and fatigued conditions. Consequently, the duration that maximum contractions could be sustained was reduced with D 2 antagonism. These results provide further support that the D 2 receptor has a critical role in skeletal muscle activation, where central fatigue is exacerbated by enhancing activity of the indirect basal ganglia pathway during maximum muscle contractions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Subluminous Type Ia supernovae, such as the Type Iax-class prototype SN 2002cx, are described by a variety of models such as the failed detonation and partial deflagration of an accreting carbon-oxygen white dwarf star or the explosion of an accreting, hybrid carbon-oxygen-neon core. These models predict that bound remnants survive such events with, according to some simulations, a high kick velocity. We report the discovery of a high proper motion, low-mass white dwarf (LP 40-365) that travels at a velocity greater than the Galactic escape velocity and whose peculiar atmosphere is dominated by intermediate-mass elements. Strong evidence indicates that this partially burnt remnant was ejected following a subluminous Type Ia supernova event. This supports the viability of single-degenerate supernova progenitors., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The optical counterpart of the new extreme ultraviolet source EUVE J1016-053 (=RE 1016-053) is known to show intermittent sharp Balmer and HE I emission and traces of an M dwarf associated with a white dwarf optical spectrum. We present extensive optical spectroscopy showing the emission lines vary in velocity and intensity on a period of 0d.78929 +/- 0d.00003. The phase of the emission-line strengths lags that of the velocities by 0.237 +/- 0.013 cycle, consistent with the quarter-cycle offset expected if emission arises from the side of the secondary facing the hot white dwarf. EUVE J1016-053 is another example of an extreme ultraviolet illumination-effect binary, which only recently emerged from a common-envelope phase of binary evolution. Based on spectroscopic measurements and new BVR photometry, we find that the M dwarf secondary's contribution to the combined light is smaller than previously reported, probably because of the difficulty of avoiding contamination from a third star 3".2 distant. The velocity of the weak H II absorption is in antiphase to the emission, suggesting that it originates in the white dwarf photosphere. The mass function implied by the emission-line motion is f(M) = 0.28 +/- 0.08 M solar. Assuming the He II absorption does follow the white dwarf, the mass ratio MWD/MdM is 1.8 +/- 0.5, and the gravitational redshift is 45 +/- 14 km s-1. The modulation of the emission lines suggests the inclination i > 40 degrees, but plausible masses demand this inclination be well above the value.