Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Personal insult disrupts regulatory brain networks in violent offenders.

The failure to adequately regulate negative emotions represents a prominent characteristic of violent offenders. In this functional magnetic resonance imaging study, we used technical, nonsocial frustration to elicit anger in violent offenders (n = 19) and then increased the provocation by adding personal insults (social provocation). The aim was to investigate neural connectivity patterns involved in anger processing, to detect the effect of increasing provocation by personal insult, and to compare anger-related connectivity patterns between offenders and noncriminal controls (n = 12). During technical frustration, the offenders showed increased neural connectivity between the amygdala and prefrontal cortex compared to the controls. Conversely, personal insults, and thus increased levels of provocation, resulted in a significant reduction of neural connectivity between regions involved in cognitive control in the offenders but not controls. We conclude that, when (nonsocially) frustrated, offenders were able to employ regulatory brain networks by displaying stronger connectivity between regulatory prefrontal and limbic regions than noncriminal controls. In addition, offenders seemed particularly sensitive to personal insults, which led to increased implicit aggression (by means of motoric responses) and reduced connectivity in networks involved in cognitive control (including dorsomedial prefrontal cortex, precuneus, middle/superior temporal regions).

Gene coexpression patterns predict opiate-induced brain-state transitions.

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.

A meta-analysis on shared and distinct neural correlates of the decision-making underlying altruistic and retaliatory punishment.

Individuals who violate social norms will most likely face social punishment sanctions. Those sanctions are based on different motivation aspects, depending on the context. Altruistic punishment occurs if punishment aims to re-establish the social norms even at cost for the punisher. Retaliatory punishment is driven by anger or spite and aims to harm the other. While neuroimaging research highlighted the neural networks supporting decision-making in both types of punishment in isolation, it remains unclear whether they rely on the same or distinct neural systems. We ran an activation likelihood estimation meta-analysis on functional magnetic resonance imaging data on 24 altruistic and 19 retaliatory punishment studies to investigate the neural correlates of decision-making underlying social punishment and whether altruistic and retaliatory punishments share similar brain networks. Social punishment reliably activated the bilateral insula, inferior frontal gyrus, midcingulate cortex (MCC), and superior and medial frontal gyri. This network largely overlapped with activation clusters found for altruistic punishment. However, retaliatory punishment revealed only one cluster in a posterior part of the MCC, which was not recruited in altruistic punishment. Our results support previous models on social punishment and highlight differential involvement of the MCC in altruistic and retaliatory punishments, reflecting the underlying different motivations.

Resting-state functional connectivity and structural differences between smokers and healthy non-smokers.

Previous studies have shown an association between cigarette use and altered resting-state functional connectivity (rsFC) in many large-scale networks, sometimes complemented by measures of cortical atrophy. In this study, we aimed to further explore the neural differences between smokers and healthy non-smokers through the integration of functional and structural analyses. Imaging data of fifty-two smokers and forty-five non-smokers were analyzed through an independent component analysis for group differences in rsFC. Smokers showed lower rsFC within the dorsal attention network (DAN) in the left superior and middle frontal gyrus and left superior division of the lateral occipital cortex compared to non-smokers; moreover, cigarette use was found to be associated with reduced grey matter volume in the left superior and middle frontal gyrus and right orbitofrontal cortex, partly overlapping with functional findings. Within smokers, daily cigarette consumption was positively associated with increased rsFC within the cerebellar network and the default mode network and decreased rsFC within the visual network and the salience network, while carbon monoxide level showed a positive association with increased rsFC within the sensorimotor network. Our results suggest that smoking negatively impacts rsFC within the DAN and that changes within this network might serve as a circuit-based biomarker for structural deficits.

Meta-analysis of variance in tDCS effects on response inhibition.

Deficiencies in response inhibition are associated with numerous mental health conditions, warranting innovative treatments. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, modulates cortical excitability and has shown promise in improving response inhibition. However, tDCS effects on response inhibition often yield contradictory findings. Previous research emphasized the importance of inter-individual factors that are mostly ignored in conventional meta-analyses of mean effects. We aimed to fill this gap and promote the complementary use of the coefficient of variation ratio and standardized mean effects. The systematic literature search included single-session and sham-controlled tDCS studies utilizing stop-signal task or Go-NoGo tasks, analyzing 88 effect sizes from 53 studies. Considering the impact of inter-individual factors, we hypothesized that variances increase in the active versus sham tDCS. However, the results showed that variances between both groups did not differ. Additionally, analyzing standardized mean effects supported previous research showing an improvement in the stop-signal task but not in the Go-NoGo task following active tDCS. These findings suggest that inter-individual differences do not increase variances in response inhibition, implying that the heterogeneity cannot be attributed to higher variance in response inhibition during and after active tDCS. Furthermore, methodological considerations are crucial for tDCS efficacy.

The influence of the COMT Val158Met polymorphism on prefrontal TDCS effects on aggression.

Increasing dorsolateral prefrontal cortex (DLPFC) activity by anodal transcranial direct current stimulation (tDCS) enhances cognitive control and might reduce aggression. The Val158Met polymorphism within the catechol-O-methyltransferase gene (rs4680) plays a pivotal role in prefrontal dopamine signaling, displaying associations with aggressive behavior, and potentially influencing the effects of tDCS. In a double-blind, sham-controlled study, we investigated the influence of rs4680 on tDCS effects on aggression. While undergoing functional magnetic resonance imaging, 89 healthy male participants performed the Taylor aggression paradigm before and immediately after tDCS. Actively stimulated participants (n = 45) received anodal tDCS (1.5 mA) for 20 min targeting the right DLPFC. Carriers of the val-allele (val+; n = 46; active tDCS n = 23) were compared to met-allele homozygotes (val-; n = 43; active tDCS n = 22). Analysis revealed decreased aggressive behavior in the val- group following active tDCS (p < 0.001). The val+ group showed increased aggression during the second session (p < 0.001) with an even higher increase following active as compared to sham tDCS (p < 0.001). No effects of stimulation or rs4680 on brain activation were found. Our study provides evidence for opposite tDCS effects on aggressive behavior in val-carriers and val-noncarriers. By shedding light on genetic factors predicting tDCS responsivity, the study will help to pave the way toward individualized-and thus more effective-tDCS treatment options.

HD-tDCS induced changes in resting-state functional connectivity: Insights from EF modeling.

BACKGROUND: High-definition transcranial direct current stimulation (HD-tDCS) holds promise for therapeutic use in psychiatric disorders. One obstacle for the implementation into clinical practice is response variability. One way to tackle this obstacle is the use of Individualized head models. OBJECTIVE: This study investigated the variability of HD-tDCS induced electric fields (EFs) and its impact on resting-state functional connectivity (rsFC) during different time windows. METHODS: In this randomized, double-blind, and sham controlled study, seventy healthy males underwent 20 min of 1.5 mA HD-tDCS on the right inferior frontal gyrus (rIFG) while undergoing resting-state functional magnetic resonance imaging (rs-fMRI). Individual head models and EF simulations were created from anatomical images. The effects of HD-tDCS on rsFC were assessed using a seed-to-voxel analysis. A subgroup analysis explored the relationship between EF magnitude and rsFC during different stimulation time windows. RESULTS: Results highlighted significant variability in HD-tDCS-induced EFs. Compared to the sham group, the active group showed increased rsFC between the rIFG and the left prefrontal cortex, during and after stimulation. During active stimulation, EF magnitude correlated positively with rsFC between the rIFG and the left hippocampus initially, and negatively during the subsequent period. CONCLUSION: This study indicated an HD-tDCS induced increase of rsFC between left and right prefrontal areas. Furthermore, an interaction between the magnitude and the duration of HD-tDCS on rsFC was observed. Due to the high EF variability that was apparent, these findings highlight the need for individualized HD-tDCS protocols and the creation of head models to optimize effects and reduce response heterogeneity.

High-definition transcranial direct current stimulation (HD-tDCS) for the enhancement of working memory - A systematic review and meta-analysis of healthy adults.

BACKGROUND: High-definition transcranial direct current stimulation (HD-tDCS) administers weak electric current through multiple electrodes, enabling focal brain stimulation. An increasing number of studies investigate the effects of anodal HD-tDCS on the enhancement of working memory (WM). The effectiveness of the technique is, however, still unclear. OBJECTIVE/HYPOTHESIS: This systematic review analyzed the current literature on anodal HD-tDCS for WM enhancement, investigating its effectiveness and the influence of different moderators to allow for comparison with conventional tDCS. METHODS: Following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, a comprehensive literature review was conducted using PubMed, Web of Science, and Scopus. Sixteen single- or double-blind, sham-controlled studies were included in the review. Eleven studies were included in the meta-analysis, focusing solely on stimulation of the left prefrontal cortex (PFC). RESULTS: No significant effect of anodal HD-tDCS on the left PFC for WM accuracy (g = 0.23, p = 0.08), and reaction time (g = 0.03, p = 0.75 after trim-and-fill) was found. Further analysis revealed heterogeneity in the accuracy results. Here, moderator analysis indicated a significant difference between studies that repeatedly used HD-tDCS enhanced WM training and studies with one-time use of HD-tDCS (p < 0.001), the latter having a smaller effect size. Another moderator was the research design, with differences between within-subjects-, and between-subjects designs (p < 0.05). Within-subject studies showed lower effect sizes and substantially lower heterogeneity. Qualitative analysis reinforced this finding and indicated that the motivation of the participant to engage in the task also moderates the effectiveness of HD-tDCS. CONCLUSION: This review highlights the importance of inter-individual differences and the setup for the effectiveness of anodal, HD-tDCS augmented WM training. Limited evidence for increased sensitivity of HD-tDCS to these factors as compared to conventional tDCS is provided.

Consequences of prefrontal tDCS on inhibitory control and reactive aggression.

Increased aggression and impulsivity represent a key component of several psychiatric disorders, including substance use disorder, which is often associated with deficient prefrontal brain activation. Thus, innovative tools to increase cognitive control are highly warranted. The current study investigates the potential of transcranial direct current stimulation (tDCS), a tool to modulate cortical activation and to increase cognitive control in individuals with a high potential for impulsive and aggressive behavior. In a double-blind, sham-controlled study, we applied anodal tDCS over the right dorsolateral prefrontal cortex in an all-male sample of alcohol-dependent patients (AD), tobacco users (TU) and healthy controls (HC), who completed the Taylor Aggression Paradigm and Stop Signal Reaction Time Task twice. While there were no observable effects of tDCS in controls, the results revealed altered aggressive behavior in AD following active stimulation. Specifically, these individuals did not show the standard increase in aggression over time seen in the other groups. Furthermore, improved response inhibition was found in AD and TU following active but not sham stimulation. Our study demonstrates that prefrontal tDCS improves our laboratory measure of impulse control in at-risk groups, illustrating the importance of sample characteristics such as nicotine intake and personality traits for understanding the effects of brain stimulation.

Morphology of the criminal brain: gray matter reductions are linked to antisocial behavior in offenders.

Aggression and psychopathy are multifaceted conditions determined interpersonal and antisocial factors. Only a few studies analyze the link between these separate factors and specific brain morphology distinctively. A voxel-based morphometry (VBM) analysis was performed on 27 violent offenders and 27 controls aiming to associate sub-features of aggressive and psychopathic behavior with specific gray matter volumes. Trait aggression was assessed using two self-report tests (Aggression Questionnaire, AQ, and Reactive-Proactive-Aggression Questionnaire, RPQ) and psychopathy with the Psychopathy Checklist-Revised (PCL-R). Total and sub-scale scores of these tests were correlated to the brain morphometry of the offenders group in separate analyses. It was found that psychopathic behavior was negatively correlated with prefrontal gray matter volume and that this result was primarily driven by the antisocial behavior sub-scale of the PCL-R. Furthermore, less gray matter in right superior frontal and left inferior parietal regions with increasing antisocial behavior could be observed. One cluster comprising the right middle and superior temporal gyrus was negatively correlated with both, reactive aggression and antisocial behavior. These results outline (1) the importance of distinctively analyzing sub-features that contribute to aggressive and psychopathic behavior, given that the negative correlation of psychopathy global scores with prefrontal volume was driven by one single facet of the PCL-R scale (antisocial behavior). Moreover, these results indicate (2) fronto-temporo-parietal network deficits in antisocial, criminal offenders, with a particular strong effect in the temporal lobe.

Altered psychophysiological correlates of risk-taking in borderline personality disorder.

Elevated levels of risk-taking behavior as well as affective instability are both cardinal features of Borderline Personality Disorder (BPD). To our knowledge, there are no studies which directly investigate underlying affective processes of risk-taking behavior in BPD, despite the centrality of affect in BPD symptomatology, and indications of affective dysregulation contributing to increased risk-taking behavior in BPD. Here, we examined risk-taking behavior in BPD and its underlying affective processes, using skin conductance responses (SCRs) as a proxy. Twenty-three individuals with BPD and 24 healthy controls performed a modified version of the Balloon Analogue Risk Task, where decisions take place over a time scale of several seconds, enabling us to investigate a continuous integral of SCRs in anticipation of decisions. We used trial-by-trial mixed model analyses to account for within- and between-participant effects, as well as large variability that are often observed in SCRs. In contrast to healthy controls, who showed elevated SCRs in response to high risk, individuals with BPD did not show differential physiological sensitivity towards different risk levels. In addition, increased SCRs--under low risk--were related to more cautious risk-taking behavior in HCs. However, increased SCRs under low risk in BPD were related to greater risk-taking behavior. Alterations in the processing of affective signals, such as SCRs in the context of risk, may impair adaptation to environmental demands and may lead to increased risk-taking behavior in BPD.

On the Complexity of Aggressive Behavior: Contextual and Individual Factors in the Taylor Aggression Paradigm.

As many paths lead to aggression, understanding which situations and which person-specific traits facilitate or impede aggressive behavior is crucial. Provocation is among one of the most frequently reported predictors of aggressive behavior. However, it remains unclear whether the reaction to provocation is universal across different forms of aggression and whether individuals differ in their reactivity to such signals. Using the Taylor Aggression Paradigm (TAP), we investigated the influence of individual and contextual factors on physical and non-physical aggression in healthy men and women. The impact of trait aggression, sex, provocation, and the success of a competition against a fictitious opponent on aggressive behavior was examined in three different versions of the TAP. While equal provocation and punishment modalities were used in the first two versions, monetary deductions in the first and heat stimulus in the second study, the third experiment used non-physical provocation to trigger physical punishment. Trial-by-trial analyses revealed that provocation, independent of its specific nature, is a strong predictor for aggressive behavior, especially in highly aggressive participants. Although women initially showed less aggression than men, sex differences were diminished under prolonged, increasing provocation when provocation and punishment modality were identical. Only when modalities diverged, women, compared with men, were more hesitant to punish their opponent. These results, thus, extend evidence that women show lower levels of aggression under low provocation. However, high levels of provocation have similar effects on males' and females' reactive aggressive behavior across different forms of aggression. When competing for money, losing against the fictitious opponent was functioning as an additional provocative signal stimulating aggressive responses. Differences in aggressive responding have to be interpreted in the context of the specific type of provocation and aggression that is investigated since these modalities are shown to interact with individual characteristics.

The influence of the OPRM1 (A118G) polymorphism on behavioral and neural correlates of aggression in healthy males.

Current models of aggression suggest that in addition to personality traits and environmental factors, biological vulnerability associated with genetics substantially impacts aggressive behavior. In a functional imaging study, we investigated the influence of the single nucleotide polymorphism of the mu 1 subtype opioid receptor gene (OPRM1), implicated in sociability, on correlates of trait and state aggression to delineate the function of these influences in aggression. A key aim was further to differentiate different aspects of aggressive reactions - namely, the reaction to provocation and the decision to punish an opponent. 59 healthy males performed a modified Taylor Aggression Paradigm during functional magnetic resonance imaging. The implementation of the paradigm allowed for individual assessments of the decision to behave aggressively, the experience of provocation and the ramification of punishment for the participant or the opponent. The influence of variation in the OPRM1 gene was measured by the functional A118G polymorphism. G allele carriers showed lower levels of general aggression and self-reported physical aggression. Additionally, these participants exhibited increased activation in dorsolateral prefrontal, orbitofrontal, anterior cingulate and insular cortices when choosing higher punishments for the opponent. The OPRM1 polymorphism did not influence aggression in reaction to social provocation. Thus, we suggest that this genetic variant affects one's trait aggressiveness rather than actual behavioral reactivity to provocation. Investigating brain regions that are specifically linked to provocation yielded activation in cortico-limbic circuits which might mediate the evaluation of provocation and the experience of anger and thus shed light on neural processes underlying the risk for aggressive behavior. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Increased short-interval intracortical inhibition in un-medicated patients with schizophrenia.

BACKGROUND: Schizophrenia is associated with changes in inhibitory and facilitatory brain networks which can be assessed by motor cortex excitability. OBJECTIVE: Here, we investigate differences between large cross-sectional samples of un-medicated and medicated patients with schizophrenia and healthy controls in single- and double-pulse transcranial magnetic stimulation parameters. METHODS: We measured right abductor digiti minimi muscle activity in 71 un-medicated, 43 medicated patients and 131 healthy controls. To exclude sample bias analyses were repeated with groups comparable for age and gender (un-medicated: n = 43; medicated: n = 38; controls: n = 49). RESULTS: Un-medicated patients showed increased short-interval intracortical inhibition (SICI) in contrast to medicated patients and healthy controls. No group differences were found for resting and active motor threshold, cortical silent period and intracortical facilitation. CONCLUSION: Increases in SICI are in contrast to literature and highlight the necessity for large-scaled multi-centric studies with high methodological standards.