Enhanced availability of serotonin limits muscle activation during high-intensity, but not low-intensity, fatiguing contractions.

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-HT1A 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.

Enhanced serotonin availability amplifies fatigue perception and modulates the TMS-induced silent period during sustained low-intensity elbow flexions.

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-HT1A 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-HT1A 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.

Antagonism of the D2 dopamine receptor enhances tremor but reduces voluntary muscle activation in humans.

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 D2 dopamine receptors of the indirect pathway have prevented causal links being made between the D2 receptor and motor control. Healthy individuals ingested 3 mg of the competitive D2 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 D2 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 D2 receptors relate to physiological tremor generation during muscle contractions, whereby the gain of tremor is increased after D2 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 D2 antagonism. These results provide further support that the D2 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.

Polysubstance-induced relapse of schizoaffective disorder refractory to high-dose antipsychotic medications: a case report.

BACKGROUND: The high prevalence of comorbid illicit drug use in persons with chronic psychotic illness represents a strong determinant of psychotic relapse and rehospitalization. Epidemiological studies indicate changing patterns of illicit drug use in Australia, which are concerning because of increased use of crystal methamphetamine, also known as "ice." An important complication of habitual use of crystal methamphetamine is the development of a dose-dependent acute psychotic reaction. We report a case of an acute psychotic relapse in response to polydrug use most notable for multiple recent binges of crystal methamphetamine. Unlike previously described case reports, our patient's acute psychosis was refractory to ultra-high doses of multiple antipsychotic medications. This presented safety challenges due to the risk of serious side effects with high-dose antipsychotic medications. CASE PRESENTATION: A 30-year-old white man with a past history of schizoaffective disorder was brought to our emergency department by the police in a state of extreme agitation, combativeness, and paranoia after use of cannabis and crystal methamphetamine. Despite existing compliance with zuclopenthixol decanoate depot medication, he required multiple emergency injections of zuclopenthixol acetate, and regular high-dose droperidol, chlorpromazine, and lorazepam. However, he remained severely agitated and psychotic with continuous threats of harm to others. A test of antipsychotic drug metabolism by cytochrome P450 enzymes did not reveal a pharmacogenetic cause for the poor therapeutic efficacy of antipsychotic medications. His psychosis did not appear to be modified by psychoactive medications but was instead self-limited to the presence of endogenous methamphetamine within his system. He fully recovered 96 to 120 hours post-presentation and was discharged home with out-patient clinic follow-up. CONCLUSIONS: The current case highlights the challenging nature of a severe psychotic relapse precipitated by illicit substances that is resistant to medical management. High doses of multiple antipsychotic medications may be required to manage dangerous behaviors associated with these acute psychotic relapses. These patients require close monitoring for adverse effects with adjustment of dosing to ensure the optimal balance of risk versus benefit while the patient is acutely psychotic. The results are of relevance for the management of psychiatric emergencies in emergency departments and acute mental health settings.

From tremor to movement: differences in variability and coupling during bilateral finger actions.

This study examined changes in movement variability, coupling, and muscle activity across three different bilateral finger movements (e.g., postural, isometric, and isotonic). It was predicted that movements characterized by increased interlimb coupling would be associated with increased levels of muscle activity and reduced movement variability. The results demonstrated task-specific differences in interlimb relations with coupling being lowest during postural tasks and highest under isotonic conditions. However, a similar pattern was not observed for muscle activity and movement variability. Of the three tasks, postural tremor movements were more variable and had lower levels of muscle activity. Alternatively, increased muscle activity and more regular movement dynamics were seen under isometric conditions. Overall, it would appear that differences in bilateral coupling across tasks are not reflective of a single driving mechanism but rather reflect differential contribution from intrinsic neuromuscular and mechanical sources.

Differences in rapid initiation and termination of voluntary postural sway associated with ageing and falls-risk.

The authors examined differences between young adults (n = 25) and healthy older adults (n = 48) in reaction time and the relations between center of pressure (COP) and center of mass (COM) motions during rapid initiation and termination of voluntary postural sway. Older adults were divided into low and high falls-risk groups based on Physiological Profile Assessment scores of sensorimotor function. Low falls-risk older adults had slower reaction times during anteroposterior sway initiation and decreased COP-COM separation during anteroposterior and medialateral sway initiation and anteroposterior continuous voluntary sway compared with young adults. High falls-risk older adults had slower initiation and termination reaction times in all response directions and decreased COP-COM separation during sway initiation and continuous voluntary sway in the anteroposterior and medialateral directions compared with young adults. Compared with low falls-risk older adults, high falls-risk older adults had slower initiation and termination reaction times in all response directions and decreased COP-COM separation during medialateral continuous voluntary sway. Reaction time and COP-COM measures significantly predicted group status in discriminant models with sensitivities and specificities of 72-100%. Overall, these findings highlight important associations of age-related declines in sensorimotor function related to an increased risk of falling with slower postural reaction time and reduced postural stability.

What are the relations between voluntary postural sway measures and falls-history status in community-dwelling older adults?

OBJECTIVES: To determine whether a series of voluntary postural sway tasks could differentiate and accurately identify the falls-history status of older adults, and to examine the relations between voluntary sway measures and falls risk. DESIGN: Case-control study. SETTING: University biomechanics laboratory. PARTICIPANTS: Healthy community-dwelling older adults (N=51) aged 65 to 94 years who were divided into nonfaller (n=36), single faller (n=10), and multiple faller (n=5) groups based on a 12-month history of falls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants underwent a falls-risk assessment using the Physiological Profile Assessment (PPA) and then performed 6 voluntary postural sway tasks. The tasks included maximum static leans, maximum voluntary sway, continuous voluntary sway, rapid initiation of voluntary sway, rapid termination of voluntary sway, and rapid orthogonal switches of voluntary sway between the anterior-posterior and medial-lateral directions. Center of pressure amplitudes and reaction time measures were examined using analysis of covariance, Pearson's correlation, and discriminant function analyses. RESULTS: Multiple fallers had increased age; increased falls risk; slower initiation, termination, and orthogonal switch reaction times; and reduced center of pressure amplitude during sway initiation and continuous voluntary sway compared with nonfallers. Few differences were observed between the nonfallers and single fallers. Voluntary sway measures were significantly correlated with each other and with PPA score. Two postural reaction time measures and age identified 80% of multiple fallers and 98% of nonmultiple fallers. Similarly, PPA score and age identified 80% of multiple fallers and 100% of nonmultiple fallers. CONCLUSIONS: The slower and less effective balance responses of multiple fallers compared with nonfallers and the comparable sensitivity and specificity of PPA score and reactive voluntary sway measures indicate that postural reaction time is a strong determinant of falls risk.

Voluntary sway and rapid orthogonal transitions of voluntary sway in young adults, and low and high fall-risk older adults.

BACKGROUND: Falls amongst older people have been linked to reduced postural stability and slowed movement responses. The objective of this study was to examine differences in postural stability and the speed of response between young adults, low fall-risk older adults, and high fall-risk older adults during voluntary postural sway movements. METHODS: Twenty-five young adults (25+/-4 years), and 32 low fall-risk (74+/-5 years), and 16 high fall-risk (79+/-7 years) older adults performed voluntary sway and rapid orthogonal transitions of voluntary sway between the anterior-posterior and medial-lateral directions. Measures included reaction and movement time and the amplitudes of the centre of pressure, centre of mass, and the separation distance between the centre of pressure and centre of mass. FINDINGS: Both fall-risk groups compared to the young had slower reaction and movement time, greater centre of pressure and/or centre of mass amplitude in the orthogonal (non-target) direction during voluntary sway, and reduced anterior-posterior and medial-lateral separation between the centre of pressure and centre of mass during voluntary sway and orthogonal transitions. High compared to low fall-risk individuals had slower reaction and movement time, increased non-target centre of mass amplitude during voluntary sway, and reduced medial-lateral centre of pressure and centre of mass separation during voluntary sway and orthogonal transitions. INTERPRETATION: Age-related deterioration of postural control resulted in slower reactive responses and reduced control of the direction of body movement during voluntary sway and orthogonal transitions. Slower postural reaction and movement time and reduced medial-lateral control of the centre of mass during voluntary sway movements are associated with increased fall-risk in community-living older people.

Age-related differences in postural reaction time and coordination during voluntary sway movements.

The elderly are known to exhibit declines in postural control during standing and walking, however little is known about how the elderly react under time-critical and challenging postural situations. The purpose of this study was to examine age-related differences in reaction time (RT) and the pattern of temporal coordination between center of pressure (COP), trunk and head motion during voluntary postural sway movements. Healthy young (n=10; mean=24 years; SD=5 years) and elderly men (n=8; mean=75 years; SD=2 years) stood on a force plate with tri-axial accelerometers attached to the head and lower trunk. Participants were required to generate sway in the anterior-posterior (AP) or medial-lateral (ML) direction in response to an auditory cue during two different testing conditions called Static reaction and Dynamic reaction. Static reactions involved the initiation of voluntary sway in either the AP or ML direction from quiet stance. Dynamic reactions involved an orthogonal switch of voluntary sway between the AP and ML directions. Compared to the young, elderly individuals exhibited slower RT during both Static and Dynamic reaction, and smaller differences in RT and phasing between COP, trunk, and head motion. The results of this study suggest that the elderly adopted more rigid coordination strategies compared to the young when executing a rapid change in direction of whole body motion. The rigid movement strategy of the elderly was presumably generated in an effort to compensate for increased challenge to the maintenance of stability.