[Movement as a Neuromodulator: How Physical Activity Influences the Physiology of Adolescent Depression]. / Bewegung als Neuromodulator: Wie körperliche Aktivität die Physiologie der adoleszenten Depression reguliert.

Movement as a Neuromodulator: How Physical Activity Influences the Physiology of Adolescent Depression Abstract: In the context of adolescent depression, physical activity is becoming increasingly recognized for its positive effects on neuropathology. Current scientific findings indicate that physical training affects the biological effects of depression during adolescence. Yet the pathophysiology of adolescent depression is not yet fully understood. Besides psychosocial and genetic influences, various neurobiological factors are being discussed. One explanation model describes a dysfunction of the hypothalamus-pituitary-adrenal axis (HPA axis) with a sustained elevation in cortisol concentration. Recent studies highlight neuroimmunological processes and a reduced concentration of growth factors as causative factors. These changes appear to lead to a dysregulation of the excitation and inhibition balance of the cerebral cortex as well as to cerebral morphological alterations. Regular physical training can potentially counteract the dysregulation of the HPA axis and normalize cortisol levels. The release of proinflammatory cytokines is inhibited, and the expression of growth factors involved in adult neurogenesis is stimulated. One should ensure the synergistic interaction of biological and psychosocial factors when designing the exercise schedule (endurance or strength training, group or individual sports, frequency, duration, and intensity). Addressing these open questions is essential when integrating physical activity into the guidelines for treating depressive disorders in children and adolescents.

Functional connectivity during smooth pursuit eye movements.

Smooth pursuit eye movements (SPEM) hold the image of a slowly moving stimulus on the fovea. The neural system underlying SPEM primarily includes visual, parietal, and frontal areas. In the present study, we investigated how these areas are functionally coupled and how these couplings are influenced by target motion frequency. To this end, healthy participants (n = 57) were instructed to follow a sinusoidal target stimulus moving horizontally at two different frequencies (0.2 Hz, 0.4 Hz). Eye movements and blood oxygen level-dependent (BOLD) activity were recorded simultaneously. Functional connectivity of the key areas of the SPEM network was investigated with a psychophysiological interaction (PPI) approach. How activity in five eye movement-related seed regions (lateral geniculate nucleus, V1, V5, posterior parietal cortex, frontal eye fields) relates to activity in other parts of the brain during SPEM was analyzed. The behavioral results showed clear deterioration of SPEM performance at higher target frequency. BOLD activity during SPEM versus fixation occurred in a geniculo-occipito-parieto-frontal network, replicating previous findings. PPI analysis yielded widespread, partially overlapping networks. In particular, frontal eye fields and posterior parietal cortex showed task-dependent connectivity to large parts of the entire cortex, whereas other seed regions demonstrated more regionally focused connectivity. Higher target frequency was associated with stronger activations in visual areas but had no effect on functional connectivity. In summary, the results confirm and extend previous knowledge regarding the neural mechanisms underlying SPEM and provide a valuable basis for further investigations such as in patients with SPEM impairments and known alterations in brain connectivity.NEW & NOTEWORTHY This study provides a comprehensive investigation of blood oxygen level-dependent (BOLD) functional connectivity during smooth pursuit eye movements. Results from a large sample of healthy participants suggest that key oculomotor regions interact closely with each other but also with regions not primarily associated with eye movements. Understanding functional connectivity during smooth pursuit is important, given its potential role as an endophenotype of psychoses.

Neural correlates of proactive and reactive inhibition of saccadic eye movements.

Although research on goal-directed, proactive inhibitory control (IC) and stimulus-driven, reactive IC is growing, no previous study has compared proactive IC in conditions of uncertainty with regard to upcoming inhibition to conditions of certain upcoming IC. Therefore, we investigated effects of certainty and uncertainty on behavior and blood oxygen level dependent (BOLD) signal in proactive and reactive IC. In two studies, healthy adults performed saccadic go/no-go and prosaccade/antisaccade tasks. The certainty manipulation had a highly significant behavioral effect in both studies, with inhibitory control being more successful under certain than uncertain conditions on both tasks (p ≤ 0.001). Saccadic go responses were significantly less efficient under conditions of uncertainty than certain responding (p < 0.001). Event-related functional magnetic resonance imaging (fMRI) (one study) revealed a dissociation of certainty- and uncertainty-related proactive inhibitory neural correlates in the go/no-go task, with lateral and medial prefrontal and occipital cortex showing stronger deactivations during uncertainty than during certain upcoming inhibition, and lateral parietal cortex being activated more strongly during certain upcoming inhibition than uncertainty or certain upcoming responding. In the antisaccade task, proactive BOLD effects arose due to stronger deactivations in uncertain response conditions of both tasks and before certain prosaccades than antisaccades. Reactive inhibition-related BOLD increases occurred in inferior parietal cortex and supramarginal gyrus (SMG) in the go/no-go task only. Proactive IC may imply focusing attention on the external environment for encoding salient or alerting events as well as inhibitory mechanisms that reduce potentially distracting neural processes. SMG and inferior parietal cortex may play an important role in both proactive and reactive IC of saccades.

Effects of nicotine on smooth pursuit eye movements in healthy non-smokers.

RATIONALE: The non-selective nicotinic acetylcholine receptor (nAChR) agonist nicotine has been argued to improve attention via enhanced filtering of irrelevant stimuli. Here, we tested this hypothesis in the context of smooth pursuit eye movements (SPEMs), an oculomotor function previously shown to improve with nicotine in some but not all studies. OBJECTIVES: In order to test whether nicotine improves performance particularly when the inhibition of distracting stimuli is required, SPEM was elicited in conditions with or without peripheral distractors. Additionally, different target frequencies were employed in order to parametrically vary general processing demands on the SPEM system. METHODS: Healthy adult non-smokers (N = 18 females, N = 13 males) completed a horizontal sinusoidal SPEM task at different target frequencies (0.2 Hz, 0.4 Hz, 0.6 Hz) in the presence or absence of peripheral distractors in a double-blind, placebo-controlled, cross-over design using a 2 mg nicotine gum. RESULTS: Nicotine increased peak pursuit gain relative to placebo (p < .001), but an interaction with distractor condition (p = .001) indicated that this effect was most pronounced in the presence of distractors. Catch-up saccade frequency was reduced by nicotine (p = .01), particularly at higher target frequencies (two-way interaction, p = .04). However, a three-way interaction (p = .006) indicated that the reduction with nicotine was strongest at the highest target frequency (0.6 Hz) only without distractors, whereas in the presence of distractors, it was strongest at 0.4-Hz target frequency. There were no effects of nicotine on subjective state measures. CONCLUSIONS: Together, these findings support a role of both distractor inhibition and general processing load in the effects of nicotine on smooth pursuit.

Effects of nicotine and atomoxetine on brain function during response inhibition.

The nicotinic acetylcholine receptor (nAChR) agonist nicotine and the noradrenaline transporter inhibitor atomoxetine are widely studied substances due to their propensity to alleviate cognitive deficits in psychiatric and neurological patients and their beneficial effects on some aspects of cognitive functions in healthy individuals. However, despite growing evidence of acetylcholine-noradrenaline interactions, there are only very few direct comparisons of the two substances. Here, we investigated the effects of nicotine and atomoxetine on response inhibition in the stop-signal task and we characterised the neural correlates of these effects using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T. Nicotine (7 mg dermal patch) and atomoxetine (60 mg per os) were applied to N = 26 young, healthy adults in a double-blind, placebo-controlled, cross-over, within-subjects design. BOLD images were collected during a stop-signal task that controlled for infrequency of stop trials. There were no drug effects on behavioural performance or subjective state measures. However, there was a pronounced upregulation of activation in bilateral prefrontal and left parietal cortex following nicotine during successful compared to unsuccessful stop trials. The effect of nicotine on BOLD during failed stop trials was correlated across individuals with a measure of trait impulsivity. Atomoxetine, however, had no discernible effects on BOLD. We conclude that nicotine effects on brain function during inhibitory control are most pronounced in individuals with higher levels of impulsivity. This finding is compatible with previous evidence of nicotine effects on stop-signal task performance in highly impulsive individuals and implicates the nAChR in the neural basis of impulsivity.

Combining trait and state model systems of psychosis: The effect of sleep deprivation on cognitive functions in schizotypal individuals.

Model systems of psychosis play an important role in pathophysiology and drug development research. Schizotypal individuals display similar cognitive impairments as schizophrenia patients in several domains. Therefore, schizotypy may be interpreted as a trait model system of psychosis. In addition, experimentally controlled sleep deprivation is a putative state psychosis model that evokes subclinical psychosis-like states. We aimed to further validate these model systems by examining them in relation to central cognitive biomarkers of schizophrenia. Most of all, we were interested in investigating, for the first time, effects of their combination on cognitive function. Healthy subjects with high (N = 17) or low (N = 19) levels of schizotypy performed a cognitive task battery after one night of normal sleep and after 24 h of sleep deprivation. Sleep deprivation impaired performance in the go/nogo and n-back tasks relative to the normal sleep control condition. No differences between groups or interactions of group with sleep condition were found. The role of sleep deprivation as a model of psychosis is thus supported to some extent by impairments in inhibitory control. However, classical measures of cognition may be less able to detect deficits in schizotypy, in line with evidence of more basic information processing dysfunctions in schizotypy.

Fronto-parietal coding of goal-directed actions performed by artificial agents.

With advances in technology, artificial agents such as humanoid robots will soon become a part of our daily lives. For safe and intuitive collaboration, it is important to understand the goals behind their motor actions. In humans, this process is mediated by changes in activity in fronto-parietal brain areas. The extent to which these areas are activated when observing artificial agents indicates the naturalness and easiness of interaction. Previous studies indicated that fronto-parietal activity does not depend on whether the agent is human or artificial. However, it is unknown whether this activity is modulated by observing grasping (self-related action) and pointing actions (other-related action) performed by an artificial agent depending on the action goal. Therefore, we designed an experiment in which subjects observed human and artificial agents perform pointing and grasping actions aimed at two different object categories suggesting different goals. We found a signal increase in the bilateral inferior parietal lobule and the premotor cortex when tool versus food items were pointed to or grasped by both agents, probably reflecting the association of hand actions with the functional use of tools. Our results show that goal attribution engages the fronto-parietal network not only for observing a human but also a robotic agent for both self-related and social actions. The debriefing after the experiment has shown that actions of human-like artificial agents can be perceived as being goal-directed. Therefore, humans will be able to interact with service robots intuitively in various domains such as education, healthcare, public service, and entertainment.

Combining two model systems of psychosis: The effects of schizotypy and sleep deprivation on oculomotor control and psychotomimetic states.

Model systems of psychosis, such as schizotypy or sleep deprivation, are valuable in informing our understanding of the etiology of the disorder and aiding the development of new treatments. Schizophrenia patients, high schizotypes, and sleep-deprived subjects are known to share deficits in oculomotor biomarkers. Here, we aimed to further validate the schizotypy and sleep deprivation models and investigated, for the first time, their interactive effects on smooth pursuit eye movements (SPEM), prosaccades, antisaccades, predictive saccades, and measures of psychotomimetic states, anxiety, depression, and stress. To do so, n = 19 controls and n = 17 high positive schizotypes were examined after both a normal sleep night and 24 h of sleep deprivation. Schizotypes displayed higher SPEM global position error, catch-up saccade amplitude, and increased psychotomimetic states. Sleep deprivation impaired SPEM, prosaccade, antisaccade, and predictive saccade performance and increased levels of psychotomimetic experiences. Additionally, sleep deprivation reduced SPEM gain in schizotypes but not controls. We conclude that oculomotor impairments are observed in relation to schizotypy and following sleep deprivation, supporting their utility as biomarkers in model systems of psychosis. The combination of these models with oculomotor biomarkers may be particularly fruitful in assisting the development of new antipsychotic or pro-cognitive drugs.

Effects of nicotine on response inhibition and interference control.

Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

Facing competition: Neural mechanisms underlying parallel programming of antisaccades and prosaccades.

The antisaccade task is a prominent tool to investigate the response inhibition component of cognitive control. Recent theoretical accounts explain performance in terms of parallel programming of exogenous and endogenous saccades, linked to the horse race metaphor. Previous studies have tested the hypothesis of competing saccade signals at the behavioral level by selectively slowing the programming of endogenous or exogenous processes e.g. by manipulating the probability of antisaccades in an experimental block. To gain a better understanding of inhibitory control processes in parallel saccade programming, we analyzed task-related eye movements and blood oxygenation level dependent (BOLD) responses obtained using functional magnetic resonance imaging (fMRI) at 3T from 16 healthy participants in a mixed antisaccade and prosaccade task. The frequency of antisaccade trials was manipulated across blocks of high (75%) and low (25%) antisaccade frequency. In blocks with high antisaccade frequency, antisaccade latencies were shorter and error rates lower whilst prosaccade latencies were longer and error rates were higher. At the level of BOLD, activations in the task-related saccade network (left inferior parietal lobe, right inferior parietal sulcus, left precentral gyrus reaching into left middle frontal gyrus and inferior frontal junction) and deactivations in components of the default mode network (bilateral temporal cortex, ventromedial prefrontal cortex) compensated increased cognitive control demands. These findings illustrate context dependent mechanisms underlying the coordination of competing decision signals in volitional gaze control.

Neural effects of methylphenidate and nicotine during smooth pursuit eye movements.

INTRODUCTION: Nicotine and methylphenidate are putative cognitive enhancers in healthy and patient populations. Although they stimulate different neurotransmitter systems, they have been shown to enhance performance on overlapping measures of attention. So far, there has been no direct comparison of the effects of these two stimulants on behavioural performance or brain function in healthy humans. Here, we directly compare the two compounds using a well-established oculomotor biomarker in order to explore common and distinct behavioural and neural effects. METHODS: Eighty-two healthy male non-smokers performed a smooth pursuit eye movement task while lying in an fMRI scanner. In a between-subjects, double-blind design, subjects either received placebo (placebo patch and capsule), nicotine (7mg nicotine patch and placebo capsule), or methylphenidate (placebo patch and 40mg methylphenidate capsule). RESULTS: There were no significant drug effects on behavioural measures. At the neural level, methylphenidate elicited higher activation in left frontal eye field compared to nicotine, with an intermediate response under placebo. DISCUSSION: The reduced activation of task-related regions under nicotine could be associated with more efficient neural processing, while increased hemodynamic response under methylphenidate is interpretable as enhanced processing of task-relevant networks. Together, these findings suggest dissociable neural effects of these putative cognitive enhancers.

Association of COMT and SLC6A3 polymorphisms with impulsivity, response inhibition and brain function.

Evidence of the genetic correlates of inhibitory control is scant. Two previously studied dopamine-related polymorphisms, COMT rs4680 and the SLC6A3 3' UTR 40-base-pair VNTR (rs28363170), have been associated with response inhibition, however with inconsistent findings. Here, we investigated the influence of these two polymorphisms in a large healthy adult sample (N = 515) on a response inhibition battery including the antisaccade, stop-signal, go/no-go and Stroop tasks as well as a psychometric measure of impulsivity (Barratt Impulsiveness Scale) (Experiment 1). Additionally, a subsample (N = 144) was studied while performing the go/no-go, stop-signal and antisaccade tasks in 3T fMRI (Experiment 2). In Experiment 1, we did not find any significant associations of COMT or SLC6A3 with inhibitory performance or impulsivity. In Experiment 2, no association of COMT with BOLD was found. However, there were consistent main effects of SLC6A3 genotype in all inhibitory contrasts: Homozygosity of the 10R allele was associated with greater fronto-striatal BOLD response than genotypes with at least one 9R allele. These findings are consistent with meta-analyses showing that the 10R allele is associated with reduced striatal dopamine transporter expression, which in animal studies has been found to lead to increased extracellular dopamine levels. Our study thus supports the involvement of striatal dopamine in the neural mechanisms of cognitive control, in particular response inhibition.

Methylphenidate effects on brain activity as a function of SLC6A3 genotype and striatal dopamine transporter availability.

We pharmacologically challenged catecholamine reuptake, using methylphenidate, to investigate its effects on brain activity during a motor response inhibition task as a function of the 3'-UTR variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) gene (SLC6A3) and the availability of DATs in the striatum. We measured the cerebral hemodynamic response of 50 healthy males during a Go/No-Go task, a measure of cognitive control, under the influence of 40 mg methylphenidate and placebo using 3T functional magnetic resonance imaging. Subjects were grouped into 9-repeat (9R) carriers and 10/10 homozygotes on the basis of the SLC6A3 VNTR. During successful no-go trials compared with oddball trials, methylphenidate induced an increase of blood oxygen level-dependent (BOLD) signal for carriers of the SLC6A3 9R allele but a decrease in 10/10 homozygotes in a thalamocortical network. The same pattern was observed in caudate and inferior frontal gyrus when successful no-go trials were compared with successful go trials. We additionally investigated in a subset of 35 participants whether baseline striatal DAT availability, ascertained with (123)I-FP-CIT single photon emission computed tomography, predicted the amount of methylphenidate-induced change in hemodynamic response or behavior. Striatal DAT availability was nominally greater in 9R carriers compared with 10/10 homozygotes (d=0.40), in line with meta-analyses, but did not predict BOLD or behavioral changes following MPH administration. We conclude that the effects of acute MPH administration on brain activation are dependent on DAT genotype, with 9R carriers showing enhanced BOLD following administration of a prodopaminergic compound.

Neural mechanisms of smooth pursuit eye movements in schizotypy.

Patients with schizophrenia as well as individuals with high levels of schizotypy are known to have deficits in smooth pursuit eye movements (SPEM). Here, we investigated, for the first time, the neural mechanisms underlying SPEM performance in high schizotypy. Thirty-one healthy participants [N = 19 low schizotypes, N = 12 high schizotypes (HS)] underwent functional magnetic resonance imaging at 3T with concurrent oculographic recording while performing a SPEM task with sinusoidal stimuli at two velocities (0.2 and 0.4 Hz). Behaviorally, a significant interaction between schizotypy group and velocity was found for frequency of saccades during SPEM, indicating impairments in HS in the slow but not the fast condition. On the neural level, HS demonstrated lower brain activation in different regions of the occipital lobe known to be associated with early sensory and attentional processing and motion perception (V3A, middle occipital gyrus, and fusiform gyrus). This group difference in neural activation was independent of target velocity. Together, these findings replicate the observation of altered pursuit performance in highly schizotypal individuals and, for the first time, identify brain activation patterns accompanying these performance changes. These posterior activation differences are compatible with evidence of motion processing deficits from the schizophrenia literature and, therefore, suggest overlap between schizotypy and schizophrenia both on cognitive-perceptual and neurophysiological levels. However, deficits in frontal motor areas observed during pursuit in schizophrenia were not seen here, suggesting the operation of additional genetic and/or illness-related influences in the clinical disorder.

Functional magnetic resonance imaging of sensorimotor transformations in saccades and antisaccades.

Saccades to peripheral targets require a direct visuomotor transformation. In contrast, antisaccades, saccades in opposite direction of a peripheral target, require more complex transformation processes due to the inversion of the spatial vector. Here, the differential neural mechanisms underlying sensorimotor control in saccades and antisaccades were investigated using functional magnetic resonance imaging (fMRI) at 3T field strength in 22 human volunteers. We combined a task factor (prosaccades: look towards target; antisaccades: look away from target) with a parametric factor of transformation demand (single vs. multiple peripheral targets) in a two-factorial block design. Behaviorally, a greater number of peripheral targets resulted in decreased spatial accuracy and increased reaction times in antisaccades. No effects were seen on the percentage of antisaccade direction errors or on any prosaccade measures. Neurally, a greater number of targets led to increased BOLD signal in the posterior parietal cortex (PPC) bilaterally. This effect was partially qualified by an interaction that extended into somatosensory cortex, indicating greater increases during antisaccades than prosaccades. The results implicate the PPC as a sensorimotor interface that is especially important in nonstandard mapping for antisaccades and point to a supportive role of somatosensory areas in antisaccade sensorimotor control, possibly by means of proprioceptive processes.

Dyadic movement synchronization while performing incongruent trajectories requires mutual adaptation.

Unintentional movement synchronization is often emerging between interacting humans. In the present study, we investigate the extent to which the incongruence of movement trajectories has an influence on unintentional dyadic movement synchronization. During a target-directed tapping task, a participant repetitively moved between two targets in front of another participant who performed the same task in parallel but independently. When the movement path of one participant was changed by placing an obstacle between the targets, the degree of their unintentional movement synchronization was measured. Movement synchronization was observed despite of their substantially different movement trajectories. A deeper investigation of the participant's unintentional behavior shows, that although the actor who cleared the obstacle puts unintentional effort in establishing synchrony by increasing movement velocity-the other actor also unintentionally adjusted his/her behavior by increasing dwell times. Results are discussed in the light of joint action, movement interference and obstacle avoidance behavior.