Exerkines and long-term synaptic potentiation: Mechanisms of exercise-induced neuroplasticity.

Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.

An 8-week compassion and mindfulness-based exposure therapy program improves posttraumatic stress symptoms.

The persistence of posttraumatic stress symptoms (PTSS) can be debilitating. However, many people experiencing such symptoms may not qualify for or may not seek treatment. Potentially contributing to ongoing residual symptoms of PTSS is emotion dysregulation. Meanwhile, the research area of mindfulness and compassion has grown to imply emotion regulation as one of its underlying mechanisms; yet, its influence on emotion regulation in PTSS cohort is unknown. Here, we explored the potential effectiveness of an 8-week Compassion-oriented and Mindfulness-based Exposure Therapy (CoMET) for individuals with PTSS using a waitlist control design. A total of 28 individuals (27 females, age range = 18-39 years) participated in the study (17 CoMET; 11 waitlist control). Following CoMET, participants reported significant decreases in PTSS severity (from clinical to non-clinical levels), emotion dysregulation and experiential avoidance, as well as significant increases in mindfulness, self-compassion and quality of life. Electroencephalogram-based brain network connectivity analysis revealed an increase in alpha-band connectivity following CoMET in a network that includes the amygdala, suggesting that CoMET successfully induced changes in functional connectivity between brain regions that play a crucial role in emotion regulation. In sum, the current study demonstrated promising intervention outcomes of CoMET in effectively alleviating the symptoms of PTSS via enhanced emotion regulation.

Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex.

PURPOSE: Acute intermittent hypoxia (AIH) is a safe and non-invasive treatment approach that uses brief, repetitive periods of breathing reduced oxygen air alternated with normoxia. While AIH is known to affect spinal circuit excitability, the effects of AIH on cortical excitability remain largely unknown. We investigated the effects of AIH on cortical excitability within the primary motor cortex. METHODS: Eleven healthy, right-handed participants completed two testing sessions: (1) AIH (comprising 3 min in hypoxia [fraction of inspired oxygen ~ 10%] and 2 min in normoxia repeated over five cycles) and (2) normoxia (NOR) (equivalent duration to AIH). Single- and paired-pulse transcranial magnetic stimulations were delivered to the primary motor cortex, before and 0, 25, and 50 min after AIH and normoxia. RESULTS: The mean nadir in arterial oxygen saturation was lower (p < 0.001) during the cycles of AIH (82.5 ± 4.9%) than NOR (97.8 ± 0.6%). There was no significant difference in corticospinal excitability, intracortical facilitation, or intracortical inhibition between AIH and normoxia conditions at any time point (all p > 0.05). There was no association between arterial oxygen saturation and changes in corticospinal excitability after AIH (r = 0.05, p = 0.87). CONCLUSION: Overall, AIH did not modify either corticospinal excitability or excitability of intracortical facilitatory and inhibitory circuits within the primary motor cortex. Future research should explore whether a more severe or individualised AIH dose would induce consistent, measurable changes in corticospinal excitability.

Modulating functional connectivity with non-invasive brain stimulation for the investigation and alleviation of age-associated declines in response inhibition: A narrative review.

Response inhibition, the ability to withhold a dominant and prepotent response following a change in circumstance or sensory stimuli, declines with advancing age. While non-invasive brain stimulation (NiBS) has shown promise in alleviating some cognitive and motor functions in healthy older individuals, NiBS research focusing on response inhibition has mostly been conducted on younger adults. These extant studies have primarily focused on modulating the activity of distinct neural regions known to be critical for response inhibition, including the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (pre-SMA). However, given that changes in structural and functional connectivity have been associated with healthy aging, this review proposes that NiBS protocols aimed at modulating the functional connectivity between the rIFG and pre-SMA may be the most efficacious approach to investigate-and perhaps even alleviate-age-related deficits in inhibitory control.

Age-Related Changes in Frontal Network Structural and Functional Connectivity in Relation to Bimanual Movement Control.

Changes in both brain structure and neurophysiological function regulating homotopic as well as heterotopic interhemispheric interactions (IHIs) are assumed to be responsible for the bimanual performance deficits in older adults. However, how the structural and functional networks regulating bimanual performance decline in older adults, as well as the interplay between brain structure and function remain largely unclear. Using a dual-site transcranial magnetic stimulation paradigm, we examined the age-related changes in the interhemispheric effects from the dorsolateral prefrontal cortex and dorsal premotor cortex onto the contralateral primary motor cortex (M1) during the preparation of a complex bimanual coordination task in human. Structural properties of these interactions were assessed with diffusion-based fiber tractography. Compared with young adults, older adults showed performance declines in the more difficult bimanual conditions, less optimal brain white matter (WM) microstructure, and a decreased ability to regulate the interaction between dorsolateral prefrontal cortex and M1. Importantly, we found that WM microstructure, neurophysiological function, and bimanual performance were interrelated in older adults, whereas only the task-related changes in IHI predicted bimanual performance in young adults. These results reflect unique interactions between structure and function in the aging brain, such that declines in WM microstructural organization likely lead to dysfunctional regulation of IHI, ultimately accounting for bimanual performance deficits. SIGNIFICANCE STATEMENT: The structural and functional changes in the aging brain are associated with a decline in movement control, compromising functional independence. We used MRI and noninvasive brain stimulation techniques to investigate white matter microstructural organization and neurophysiological function in the aging brain, in relation to bimanual movement control. We found that less optimal brain microstructural organization and task-related modulations in neurophysiological function resulted in poor bimanual performance in older adults. By interrelating brain structure, neurophysiological function, and behavior, the current study provides a comprehensive picture of biological alterations in the aging brain that underlie declines in bimanual performance.

Noninvasive brain stimulation can elucidate and interact with the mechanisms underlying motor learning and retention: implications for rehabilitation.

Seminal work in animals indicates that learning a motor task results in long-term potentiation (LTP) in primary motor cortex (M1) and a subsequent occlusion of LTP induction (Rioult-Pedotti et al. J Neurophysiol 98: 3688-3695, 2007). Using various forms of noninvasive brain stimulation in conjunction with a motor learning paradigm, Cantarero et al. (J Neurosci 33: 12862-12869, 2013) recently provided novel evidence to support the hypothesis that retention of motor skill is contingent upon this postlearning occlusion.

Cognitive and neuroscientific perspectives of healthy ageing.

With dementia incidence projected to escalate significantly within the next 25 years, the United Nations declared 2021-2030 the Decade of Healthy Ageing, emphasising cognition as a crucial element. As a leading discipline in cognition and ageing research, psychology is well-equipped to offer insights for translational research, clinical practice, and policy-making. In this comprehensive review, we discuss the current state of knowledge on age-related changes in cognition and psychological health. We discuss cognitive changes during ageing, including (a) heterogeneity in the rate, trajectory, and characteristics of decline experienced by older adults, (b) the role of cognitive reserve in age-related cognitive decline, and (c) the potential for cognitive training to slow this decline. We also examine ageing and cognition through multiple theoretical perspectives. We highlight critical unresolved issues, such as the disparate implications of subjective versus objective measures of cognitive decline and the insufficient evaluation of cognitive training programs. We suggest future research directions, and emphasise interdisciplinary collaboration to create a more comprehensive understanding of the factors that modulate cognitive ageing.

Functional role of left PMd and left M1 during preparation and execution of left hand movements in older adults.

A disruptive transcranial magnetic stimulation (TMS) approach was used to determine whether the increased frontal activation and reduced hemispheric laterality brain activation patterns observed in older adults during motor tasks play a functional role. Young and older adults abducted their left index finger as soon as possible after a visual imperative signal presented 500 ms after a warning signal. TMS was applied to the dorsal premotor (PMd) or primary motor (M1) cortex in the left or right hemisphere at seven times during response preparation and execution. Both groups exhibited faster reaction times in their left hand after stimulation of the left PMd (i.e., ipsilateral to the responding hand) relative to trials with no TMS, indicating a functional role of the left PMd in the regulation of impulse control. This result also suggests that the function of the left PMd appears to be unaffected by the healthy aging process. Right M1 TMS resulted in a response time delay in both groups. Only for older adults did left M1 stimulation delay responses, suggesting the involvement of ipsilateral motor pathways in the preparation of motor actions in older adults.

Slow and steady is not as easy as it sounds: interlimb coordination at slow speed is associated with elevated attentional demand especially in older adults.

The present study investigated age-related changes in the attentional demands associated with interlimb coordination involving upper and lower limbs performed at three different movement frequencies. Younger and older adults performed rhythmical, 180° out-of-phase flexion-extension movements of the knee and elbow with either ipsilateral (right arm, right leg) or contralateral (right arm, left leg) limbs at 20, 60, and 100 % of each individual's maximum movement frequency. A concurrent vocal reaction time task (dual task) was used to assess attentional load. There were two major findings: (1) The attentional cost associated with undertaking the required coordination patterns was greatest at the slowest movement frequency, and this additional attentional load was most pronounced for older adults; (2) the manipulation of movement frequency had a distinct effect on the coordination performance: moving at the fastest frequency degraded the accuracy and stability of coordination, while moving at the slowest movement frequency led to increased temporal variability, particularly in older adults. Coordination performance at slowest movement frequency required the greatest cognitive demand in older adults relative to other movement frequencies, suggesting that going 'slow and steady' is not necessarily less attentionally demanding for older adults.

Comparison of online and offline applications of dual-site transcranial alternating current stimulation (tACS) over the pre-supplementary motor area (preSMA) and right inferior frontal gyrus (rIFG) for improving response inhibition.

The efficacy of transcranial alternating current stimulation (tACS) is thought to be brain state-dependent, such that tACS during task performance would be hypothesised to offer greater potential for improving performance compared to tACS at rest. However, to date, no empirical study has tested this postulation. The current study compared the effects of dual-site beta tACS applied during a stop signal task (online) to the effects of the same tACS protocol applied prior to the task (offline) and a sham control stimulation in 53 young, healthy adults (32 female; 18-35 yrs). The right inferior frontal gyrus (rIFG) and centre (midline) of the pre-supplementary motor area (preSMA), which are thought to play critical roles in action cancellation, were simultaneously stimulated, sending phase-synchronised stimulation for 15 min with the aim of increasing functional connectivity. The offline group showed significant within-group improvement in response inhibition without showing overt task-related changes in functional connectivity measured with EEG connectivity analysis, suggesting offline tACS is efficacious in inducing behavioural changes potentially via a post-stimulation early plasticity mechanism. In contrast, neither the online nor sham group showed significant improvements in response inhibition. However, EEG connectivity analysis revealed significantly increased task-related functional connectivity following online stimulation and a medium effect size observed in correlation analyses suggested that an increase in functional connectivity in the beta band at rest was potentially associated with an improvement in response inhibition. Overall, the results indicate that both online and offline dual-site beta tACS can be beneficial in improving inhibitory control via distinct underlying mechanisms.

Age-related differences in corticomotor excitability and inhibitory processes during a visuomotor RT task.

This study tested the postulation that change in the ability to modulate corticospinal excitability and inhibitory processes underlie age-related differences in response preparation and generation during tasks requiring either rapid execution of a motor action or actively withholding that same action. Younger (n = 13, mean age = 26.0 years) and older adults (n = 13, mean age = 65.5 years) performed an RT task in which a warning signal (WS) was followed by an imperative signal (IS) to which participants were required to respond with a rapid flexion of the right thumb (go condition) or withhold their response (no-go condition). We explored the neural correlates of response preparation, generation, and inhibition using single- and paired-pulse TMS, which was administered at various times between WS and IS (response preparation phase) and between IS and onset of response-related muscle activity in the right thumb (response generation phase). Both groups exhibited increases in motor-evoked potential amplitudes (relative to WS onset) during response generation; however, this increase began earlier and was more pronounced for the younger adults in the go condition. Moreover, younger adults showed a general decrease in short-interval intracortical inhibition during response preparation in both the go and no-go conditions, which was not observed in older adults. Importantly, correlation analysis suggested that for older adults the task-related increases of corticospinal excitability and intracortical inhibition were associated with faster RT. We propose that the declined ability to functionally modulate corticospinal activity with advancing age may underlie response slowing in older adults.

Influence of tDCS over right inferior frontal gyrus and pre-supplementary motor area on perceptual decision-making and response inhibition: A healthy ageing perspective.

A wide body of literature suggests that transcranial direct current stimulation (tDCS) administered over the prefrontal cortex can improve executive function - including decision-making and inhibitory control - in healthy young adults. However, the effects of tDCS in older adults are largely unknown. Here, using a double-blind, sham-controlled approach, changes in a combined perceptual decision-making and inhibitory control task were assessed before and after the application of tDCS (1 mA, 20 minute) targeting the right inferior frontal gyrus (rIFG) or pre-supplementary motor area (preSMA) in 42 young (18-34 years) and 41 older (60-80 years) healthy adults. Compared to sham stimulation, anodal tDCS over the preSMA improved decision-making speed for both age groups. Furthermore, the inhibitory control performance of older and younger adults was improved by preSMA and rIFG stimulation, respectively. This study provides evidence that tDCS can improve both perceptual decision-making and inhibitory control in healthy older adults, with the causal role of the preSMA and rIFG regions in cognitive control appearing to vary as a function of healthy ageing.

Anodal Transcranial Direct Current Stimulation Reduces Secondary Hyperalgesia Induced by low Frequency Electrical Stimulation in Healthy Volunteers.

The aim of the study was to determine whether transcranial direct current stimulation (tDCS) reduced pain and signs of central sensitization induced by low frequency electrical stimulation in healthy volunteers. Thirty-nine participants received tDCS stimulation under 4 different conditions: anodal tDCS of the primary motor cortex (M1), anodal tDCS of the dorsolateral prefrontal cortex (DLPFC), anodal tDCS over M1 and DLPFC concurrently, and sham tDCS. Participants were blind to the tDCS condition. The order of the conditions was randomized among participants. Pain ratings to pinpricks, the current level that evoked moderate pain, and pain induced by low frequency electrical stimulation were assessed in the forearm by an experimenter who was blind to the tDCS conditions. Anodal tDCS at M1 increased the current level that evoked moderate pain compared to sham and other conditions. Anodal tDCS of DLPFC completely abolished secondary hyperalgesia. Unexpectedly, however, concurrent anodal tDCS over M1 and DLPFC did not reduce pain or hyperalgesia more than M1 alone or DLPFC alone. Overall, these findings suggest that anodal tDCS over M1 suppresses pain, and that anodal tDCS over DLPFC modulates secondary hyperalgesia (a sign of central sensitization) in healthy participants. PERSPECTIVE: Anodal transcranial current stimulation (atDCS) at the left motor cortex and the dorsolateral prefrontal cortex increased the electrically-evoked pain threshold and reduced secondary hyperalgesia in healthy participants. Replication of this study in chronic pain populations may open more avenues for chronic pain treatment.

Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol for a multicentre randomised controlled clinical trial.

INTRODUCTION: There are no well-established biomedical treatments for the core symptoms of autism spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve clinical and cognitive outcomes in ASD. We describe here the protocol for a funded multicentre randomised controlled clinical trial to investigate whether a course of rTMS to the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain activation in ASD, can improve social communication in adolescents and young adults with ASD. METHODS AND ANALYSIS: This study will evaluate the safety and efficacy of a 4-week course of intermittent theta burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (n=150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, and neurophysiological assessments before and at multiple time points up to 6 months after iTBS. Safety will be assessed via a structured questionnaire and adverse event reporting. The study will be conducted from November 2020 to October 2024. ETHICS AND DISSEMINATION: The study was approved by the Human Research Ethics Committee of Monash Health (Melbourne, Australia) under Australia's National Mutual Acceptance scheme. The trial will be conducted according to Good Clinical Practice, and findings will be written up for scholarly publication. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620000890932).

Induced Suppression of the Left Dorsolateral Prefrontal Cortex Favorably Changes Interhemispheric Communication During Bimanual Coordination in Older Adults-A Neuronavigated rTMS Study.

Recent transcranial magnetic stimulation (TMS) research indicated that the ability of the dorsolateral prefrontal cortex (DLPFC) to disinhibit the contralateral primary motor cortex (M1) during motor preparation is an important predictor for bimanual motor performance in both young and older healthy adults. However, this DLPFC-M1 disinhibition is reduced in older adults. Here, we transiently suppressed left DLPFC using repetitive TMS (rTMS) during a cyclical bimanual task and investigated the effect of left DLPFC suppression: (1) on the projection from left DLPFC to the contralateral M1; and (2) on motor performance in 21 young (mean age ± SD = 21.57 ± 1.83) and 20 older (mean age ± SD = 69.05 ± 4.48) healthy adults. As predicted, without rTMS, older adults showed compromised DLPFC-M1 disinhibition as compared to younger adults and less preparatory DLPFC-M1 disinhibition was related to less accurate performance, irrespective of age. Notably, rTMS-induced DLPFC suppression restored DLPFC-M1 disinhibition in older adults and improved performance accuracy right after the local suppression in both age groups. However, the rTMS-induced gain in disinhibition was not correlated with the gain in performance. In sum, this novel rTMS approach advanced our mechanistic understanding of how left DLPFC regulates right M1 and allowed us to establish the causal role of left DLPFC in bimanual coordination.

Emotion and motor preparation: A transcranial magnetic stimulation study of corticospinal motor tract excitability.

In the present study, we examined whether preparing motor responses under different emotional conditions alters motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation delivered to the motor cortex. Analyses revealed three findings: (1) Reaction times were expedited during exposure to unpleasant images, as compared with pleasant and neutral images; (2) force amplitude was greater during exposure to unpleasant images, as compared with pleasant and neutral images; and (3) MEPs were larger while participants viewed unpleasant images, as compared with neutral images. Hence, coupling the preparation of motor responses with the viewing of emotional images led to arousal-driven changes in corticospinal motor tract excitability, whereas movement speed and force production varied as a function of emotional valence. These findings demonstrate that the effects of emotion on the motor system manifest at varying sensitivity levels across behavioral and neurophysiological measures. Moreover, they validate the action readiness component of emotional experience by demonstrating that emotional states influence the execution of future movements but, alone, do not lead to overt movement.

Suicide in the Northern Territory, 2001-2006.

OBJECTIVE: The aim of the present study was to characterize suicide in the Northern Territory (NT) for the 6 year period 1 January 2001-31 December 2006. METHOD: Suicide death rates by area (Australia, NT), sex, and Indigenous status for the period of 2001-2006 were obtained from the National Coroners Information System through the Victorian Institute of Forensic Medicine. Population figures were obtained from the Australian Bureau of Statistics. RESULTS: For this period the suicide rate of NT (21.6 per 100 000) was double the national rate ( 11 ), and the rate for NT Indigenous people (36.7) was significantly higher (p < 0.001) than that of NT non-Indigenous people (14.7). There was a decline in the suicide rate for Australia of -8.6%; for NT, -6.3%; for NT non-Indigenous, -3.3%; and for NT Indigenous, -9.0%. The sex difference was significant (p < 0.001) for both Australia and the NT with male subjects having a higher suicide rate than female subjects. With respect to age group, some evidence suggested an earlier peak for NT Indigenous compared to NT non-Indigenous people. Hanging was more common in NT than in the rest of the country and accounted for 87% of Indigenous suicide. CONCLUSION: Suicide is more common in NT than in Australia generally, and more common in NT Indigenous than NT non-Indigenous people. There is evidence of a decline in suicide rates across the board.

A Brief Review of the EEG Literature on Mindfulness and Fear Extinction and its Potential Implications for Posttraumatic Stress Symptoms (PTSS).

Neuroimaging studies in the area of mindfulness research have provided preliminary support for the idea of fear extinction as a plausible underlying mechanism through which mindfulness exerts its positive benefits. Whilst brain regions identified in the fear extinction network are typically found at a subcortical level, studies have also demonstrated the feasibility of cortical measures of the brain, such as electroencephalogram (EEG), in implying subcortical activations of the fear extinction network. Such EEG studies have also found evidence of a relationship between brain reactivity to unpleasant stimuli (i.e., fear extinction) and severity of posttraumatic stress symptoms (PTSS). Therefore, the present paper seeks to briefly review the parallel findings between the neurophysiological literature of mindfulness and fear extinction (particularly that yielded by EEG measures), and discusses the implications of this for fear-based psychopathologies, such as trauma, and finally presents suggestions for future studies. This paper also discusses the clinical value in integrating EEG in psychological treatment for trauma, as it holds the unique potential to detect neuromarkers, which may enable earlier diagnoses, and can also provide neurofeedback over the course of treatment.

Data-driven selection of conference speakers based on scientific impact to achieve gender parity.

A lack of diversity limits progression of science. Thus, there is an urgent demand in science and the wider community for approaches that increase diversity, including gender diversity. We developed a novel, data-driven approach to conference speaker selection that identifies potential speakers based on scientific impact metrics that are frequently used by researchers, hiring committees, and funding bodies, to convincingly demonstrate parity in the quality of peer-reviewed science between men and women. The approach enables high quality conference programs without gender disparity, as well as generating a positive spiral for increased diversity more broadly in STEM.