Childhood trauma exposure and reward processing in healthy adults: A functional neuroimaging study.

The association between childhood trauma exposure and risk of developing psychopathology may in part be mediated by the effects of chronic stress on dopaminergic neurotransmission. However, little is known about the differential effects of distinct trauma types on reward processing, particularly in adults without concurrent medical or psychiatric disorders. We examined the association of childhood trauma exposure, including the differential effects of abuse and neglect, with reward processing in healthy adults (n = 114). Functional magnetic resonance imaging during a monetary incentive delay task was used to assess neural activity in the ventral striatum and orbitofrontal cortex in relation to reward anticipation and reward outcome, respectively. Exposure to childhood trauma, including abuse and neglect, was assessed using the Childhood Trauma Questionnaire-Short Form. We found a significant effect for abuse on ventral striatal activation during reward anticipation, adjusting for age, sex, scanner site, educational level, and household monthly income. There were no effects for abuse or neglect, independently or combined, on orbitofrontal cortex activation during reward outcome. Our findings suggest differential effects of childhood abuse on ventral striatum activation during reward anticipation in healthy adults.

Experimental control of conflict in a predictive visual probe task: Highly reliable bias scores related to anxiety.

Concerns have been raised about the low reliability of measurements of spatial attentional bias via RT differences in dot-probe tasks. The anticipatory form of the bias, directed towards predicted future stimuli, appears to have relatively good reliability, reaching around 0.70. However, studies thus far have not attempted to experimentally control task-related influence on bias, which could further improve reliability. Evoking top-down versus bottom-up conflict may furthermore reveal associations with individual differences related to mental health. In the current study, a sample of 143 participants performed a predictive Visual Probe Task (predVPT) with angry and neutral face stimuli online. In this task, an automatic bias is induced via visually neutral cues that predict the location of an upcoming angry face. A task-relevant bias was induced via blockwise shifts in the likely location of target stimuli. The bias score resulting from these factors was calculated as RTs to target stimuli at locations of predicted but not actually presented angry versus neutral faces. Correlations were tested with anxiety, depression, self-esteem and aggression scales. An overall bias towards threat was found with a split-half reliability of 0.90, and 0.89 after outlier removal. Avoidance of threat in blocks with a task-relevant bias away from threat was correlated with anxiety, with correction for multiple testing. The same relationship was nominally significant for depression and low self-esteem. In conclusion, we showed high reliability of spatial attentional bias that was related to anxiety.

Anticipated Attack Slows Responses in a Cued Virtual Attack Emotional Sternberg Task.

Threatening stimuli have varying effects, including reaction time (RT) increase in working memory tasks. This could reflect disruption of working memory or, alternatively, a reversible state of freezing. In the current series of experiments, reversible slowing due to anticipated threat was studied using the cued Virtual Attack Emotional Sternberg Task (cVAEST). In this task visually neutral cues indicate whether a future virtual attack could or could not occur during the maintenance period of a Sternberg task. Three studies (N = 47, 40, and 40, respectively) were performed by healthy adult participants online. The primary hypothesis was that the cVAEST would evoke anticipatory slowing. Further, the studies aimed to explore details of this novel task, in particular the interval between the cue and probe stimuli and the memory set size. In all studies it was found that threat anticipation slowed RTs on the working memory task. Further, Study 1 (memory set size 3) showed a decrease in RT when the attack occurred over all Cue Stimulus Intervals (CSIs). In Study 2 a minimal memory set of one item was used, under which circumstances RTs following attacks were only faster shortly after cue presentation (CSI 200 and 500 ms), when RTs were high for both threat and safe cues. Study 3 replicated results of Study 2 with more fine-grained time intervals. The results confirm that anticipation of attack stimuli can reversibly slow responses on an independent working memory task. The cVAEST may provide a useful method to study such threat-induced response slowing.

Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients.

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group.

The YOUth cohort study: MRI protocol and test-retest reliability in adults.

The YOUth cohort study is a unique longitudinal study on brain development in the general population. As part of the YOUth study, 2000 children will be included at 8, 9 or 10 years of age and planned to return every three years during adolescence. Magnetic resonance imaging (MRI) brain scans are collected, including structural T1-weighted imaging, diffusion-weighted imaging (DWI), resting-state functional MRI and task-based functional MRI. Here, we provide a comprehensive report of the MR acquisition in YOUth Child & Adolescent including the test-retest reliability of brain measures derived from each type of scan. To measure test-retest reliability, 17 adults were scanned twice with a week between sessions using the full YOUth MRI protocol. Intraclass correlation coefficients were calculated to quantify reliability. Global brain measures derived from structural T1-weighted and DWI scans were reliable. Resting-state functional connectivity was moderately reliable, as well as functional brain measures for both the inhibition task (stop versus go) and the emotion task (face versus house). Our results complement previous studies by presenting reliability results of regional brain measures collected with different MRI modalities. YOUth facilitates data sharing and aims for reliable and high-quality data. Here we show that using the state-of-the art YOUth MRI protocol brain measures can be estimated reliably.

The YOUth study: Rationale, design, and study procedures.

Behavioral development in children shows large inter-individual variation, and is driven by the interplay between biological, psychological, and environmental processes. However, there is still little insight into how these processes interact. The YOUth cohort specifically focuses on two core characteristics of behavioral development: social competence and self-regulation. Social competence refers to the ability to engage in meaningful interactions with others, whereas self-regulation is the ability to control one's emotions, behavior, and impulses, to balance between reactivity and control of the reaction, and to adjust to the prevailing environment. YOUth is an accelerated population-based longitudinal cohort study with repeated measurements, centering on two groups: YOUth Baby & Child and YOUth Child & Adolescent. YOUth Baby & Child aims to include 3,000 pregnant women, their partners and children, wheras YOUth Child & Adolescent aims to include 2,000 children aged between 8 and 10 years old and their parents. All participants will be followed for at least 6 years, and potentially longer. In this paper we describe in detail the design of this study, the population included, the determinants, intermediate neurocognitive measures and outcomes included in the study. Furthermore, we describe in detail the procedures of inclusion, informed consent, and study participation.

Association Between a Variable Number Tandem Repeat Polymorphism Within the DAT1 Gene and the Mesolimbic Pathway in Parkinson's Disease.

The loss of ventral striatal dopaminergic neurons in Parkinson's disease (PD) predicts an impact on the reward system. The ventrostriatal system is involved in motivational processing and its dysfunction may be related to non-motor symptoms such as depression and apathy. We previously documented that patients with PD had blunted Blood Oxygen Level Dependent functional magnetic resonance imaging (BOLD fMRI) reward task related activity during both reward anticipation (i.e., in the ventral striatum) and reward outcome (i.e., in the orbitofrontal cortex). Evidence for the modulation of brain function by dopaminergic genes in PD is limited. Genes implicated in dopamine transmission, such as the dopamine transporter gene (DAT1) may influence the clinical heterogeneity seen in PD, including reward processing. This study therefore sought to determine whether genetic differences in the DAT gene are associated with brain activity associated with response to reward in PD patients and controls. A sample of PD cases on treatment (n = 15) and non-PD controls (n = 30) from an ethnic group unique to South Africa were genotyped. We found a three-way interaction between GENOTYPE × BOLD fMRI REWARD × DIAGNOSIS [F (1, 40) = 4.666, p = 0.037, partial η2 = 0.104]. PD patients with the DAT1 homozygous 10/10 repeat genotype showed a relative decrease in orbitofrontal cortex reward outcome related activity compared to the patient group who did not have this repeat. PD patients with other genotypes showed an expected increase in orbitofrontal cortex reward outcome related activity compared to controls. Given the small sample size of the PD group with the 10/10 repeat, these results should be considered preliminary. Nevertheless, these preliminary findings highlight the potential modulation of dopamine transporter polymorphisms on orbitofrontal reward system activity in PD and highlight the need for further studies.

Towards an integrated account of the development of self-regulation from a neurocognitive perspective: A framework for current and future longitudinal multi-modal investigations.

Self-regulation is the ability to monitor and modulate emotions, behaviour, and cognition in order to adapt to changing circumstances. Developing adequate self-regulation is associated with better social coping and higher educational achievement later in life; poor self-regulation has been linked to a variety of detrimental developmental outcomes. Here, we focus on the development of neurocognitive processes essential for self-regulation. We outline a conceptual framework emphasizing that this is inherently an integrated, dynamic process involving interactions between brain maturation, child characteristics (genetic makeup, temperament, and pre- and perinatal factors) and environmental factors (family characteristics, parents and siblings, peers, and broader societal influences including media development). We introduce the Consortium of Individual Development (CID), which combines a series of integrated large-scale, multi-modal, longitudinal studies to take essential steps towards the ultimate goal of understanding and supporting this process.

Spatial anticipatory attentional bias for threat: Reliable individual differences with RT-based online measurement.

Cues that predict the future location of emotional stimuli may evoke an anticipatory form of automatic attentional bias. The reliability of this bias towards threat is uncertain: experimental design may need to be optimized or individual differences may simply be relatively noisy in the general population. The current study therefore aimed to determine the split-half reliability of the bias, in a design with fewer factors and more trials than in previous work. A sample of 63 participants was used for analysis, who performed the cued Visual Probe Task online, which aims to measure an anticipatory attentional bias. The overall bias towards threat was tested and split-half reliability was calculated over even and odd blocks. Results showed a significant bias towards threat and a reliability of around 0.7. The results support systematic individual differences in anticipatory attentional bias and demonstrate that RT-based bias scores, with online data collection, can be reliable.

Predictive cues and spatial attentional bias for alcohol: Manipulations of cue-outcome mapping.

Previous studies suggest that cues predicting the outcome of attentional shifts provide a measure of anticipatory alcohol-related attentional bias that is correlated with risky drinking and has high reliability. However, this is complicated by potential contributions of visual features of cues to reliability, unrelated to their predictive value. Further, little is known of the sensitivity of the bias to variations in cue-outcome mapping manipulations, limiting our theoretical and methodological knowledge: Does the bias robustly follow varying cue-outcome mappings, or are there automatic cue-related associative processes involved? The current studies aimed to address these issues. Participants performed variations of the cued Visual Probe Task (cVPT) in which cues were non-predictive; in which there were multiple cue pairs, used simultaneously and serially; and in which the cue-outcome mapping was reversed. The major findings were, first, that previously found reliability cannot be attributed to aspects of the cues not related to outcome-prediction; second, that reliability of the bias does not survive deviations from a simple, consistent cue-outcome mapping; third, that all predictive versions of the task showed a bias towards alcohol; fourth, that the bias did not simply follow awareness of the cue-outcome mapping; and finally, that only in the case of simultaneous multiple cue pairs, an association with risky drinking was replicated. The results provide support for the reliability of the anticipatory attentional bias for alcohol, suggest that relatively persistent associative processes underlie the bias in the alcohol context, and provide a foundation for future work using the cVPT.

Reward-Related Striatal Responses Following Stress in Healthy Individuals and Patients With Bipolar Disorder.

BACKGROUND: Stress has a major impact on the onset and recurrence of mood episodes in bipolar disorder (BD), but the underlying mechanisms remain unknown. Previous studies have shown distinct time-dependent effects of stress on reward processing in healthy individuals. Impaired reward processing is a core characteristic of BD, and altered reward processing during recovery from stress could influence the development and course of bipolar disorder. METHODS: We investigated brain responses during reward processing 50 minutes after stress using functional magnetic resonance imaging in 40 healthy control subjects and 40 patients with euthymic BD assigned to either an acute stress test (Trier Social Stress Test) or a no-stress condition. RESULTS: Acute stress increased cortisol levels in both healthy control subjects and patients with BD. Ventral striatal responses to reward outcome were increased in healthy control subjects during stress recovery but not in patients with BD. For anticipation, no differences were found between the groups following stress. CONCLUSIONS: For the first time, we show altered reward processing in patients with BD during the recovery phase of stress. These data suggest reduced neural flexibility of hedonic signaling in response to environmental challenges. This may increase the susceptibility to stressful life events in the future and play a role in the development of further psychopathology in the longer term.

Threat-induced impulsivity in Go/Nogo tasks: Relationships to task-relevance of emotional stimuli and virtual proximity.

Threatening stimuli are thought to induce impulsive responses, but Emotional Go/Nogo task results are not in line with this. We extend previous research by testing effects of task-relevance of emotional stimuli and virtual proximity. Four studies were performed to test this in healthy college students. When emotional stimuli were task-relevant, threat both increased commission errors and decreased RT, but this was not found when emotional stimuli were task-irrelevant. This was found in both between-subject and within-subject designs. These effects were found using a task version with equal go and nogo rates, but not with 90-10% go-nogo rates. Proximity was found to increase threat-induced speeding, with task-relevant stimuli only, although effects on accuracy were less clear. Threat stimuli can thus induce impulsive responding, but effects depend on features of the task design. The results may be of use in understanding theoretically unexpected results involving threat and impulsivity and designing future studies.

Efavirenz is associated with altered fronto-striatal function in HIV+ adolescents.

Neurotoxicity associated with the antiretroviral efavirenz (EFV) has been documented in HIV-infected adults, but there are no data on the impact of EFV on brain function in adolescents. We investigated potential alterations in fronto-striatal function associated with EFV use in adolescents. A total of 86 adolescents underwent a Stop Signal Anticipation Task (SSAT) during functional MRI (fMRI), 39 HIV+ adolescents receiving EFV, 27 HIV+ adolescents on antiretroviral therapy without EFV (matched on age, gender, education, CD4 cell count and HIV viral load) and 20 HIV- matched controls (matched on age and gender). The task required participants to give timed GO responses with occasional STOP signals at fixed probabilities. Reactive inhibition was modelled as a correct STOP response and proactive inhibition was modelled after response slowing as the STOP probability increases. A priori mask-based regions associated with reactive and proactive inhibition were entered into two respective multivariate ANOVAs. The EFV treatment group showed significantly blunted proactive inhibitory behavioural responses compared to HIV+ adolescents not receiving EFV. There was no difference in reactive inhibition between treatment groups. We also demonstrated a significant effect of EFV treatment on BOLD signal in proactive inhibition regions. There was no difference in regions involved in reactive inhibition. We found no differences between adolescents not receiving EFV and HIV- controls, showing that functional and behavioural differences were unique to the EFV group. Here, we demonstrate for the first time a potential adverse impact of EFV on higher cortical function in young HIV+ adolescents.

A consensus guide to capturing the ability to inhibit actions and impulsive behaviors in the stop-signal task.

Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.

Objective and Subjective Improvement of Cognition After Discontinuing Efavirenz in Asymptomatic Patients: A Randomized Controlled Trial.

BACKGROUND: Efavirenz is well known for its clinical cognitive side effects. Even asymptomatic patients who switch for other reasons than neurocognitive complaints have reported a subjective improvement in cognitive functioning after discontinuing efavirenz. The aim of this study was to assess the effect on cognition of switching Atripla (TDF/FTC/EFV) to Eviplera (TDF/FTC/RPV), hypothesizing an improvement when discontinuing efavirenz. SETTING: A randomized controlled design with a highly comparable comparator drug was used to minimize bias and to differentiate drug versus learning effects. An extensive sensitive neuropsychological assessment (NPA) was used to detect subtle changes. METHODS: Virologically suppressed, cognitively asymptomatic male HIV-infected patients on Atripla were included and randomized (2:1) to switch to Eviplera (switch group) or continue on Atripla (control group) for 12 weeks. At baseline and week 12, patients underwent an extensive NPA. RESULTS: Fourteen control and 34 switch subjects completed the study. There were no differences at baseline. Group analysis demonstrated a significantly better improvement for the switch group on the domains attention (P = 0.041) and speed of information processing (P = 0.014). Normative comparison analyses showed that 5 of the 34 patients who switched (15%) improved on NPA score as compared to the control group. Interestingly, subjective improvement after discontinuing efavirenz made 74% of the switch group chose for a regime without efavirenz after study completion. CONCLUSIONS: Switching from Atripla to Eviplera resulted in objective cognitive improvement on the group level in cognitively asymptomatic patients. Discrepancies in objective and subjective cognitive complaints make it challenging to identify patients who would benefit from discontinuing efavirenz.

Using subjective expectations to model the neural underpinnings of proactive inhibition.

Proactive inhibition - the anticipation of having to stop a response - relies on objective information contained in cue-related contingencies in the environment, as well as on the subjective interpretation derived from these cues. To date, most studies of brain areas underlying proactive inhibition have exclusively considered the objective predictive value of environmental cues, by varying the probability of stop-signals. However, by only taking into account the effect of different cues on brain activation, the subjective component of how cues affect behavior is ignored. We used a modified stop-signal response task that includes a measurement for subjective expectation, to investigate the effect of this subjective interpretation. After presenting a cue indicating the probability that a stop-signal will occur, subjects were asked whether they expected a stop-signal to occur. Furthermore, response time was used to retrospectively model brain activation related to stop-expectation. We found more activation during the cue period for 50% stop-signal probability, when contrasting with 0%, in the mid and inferior frontal gyrus, inferior parietal lobe and putamen. When contrasting expected vs. unexpected trials, we found modest effects in the mid frontal gyrus, parietal, and occipital areas. With our third contrast, we modeled brain activation during the cue with trial-by-trial variances in response times. This yielded activation in the putamen, inferior parietal lobe, and mid frontal gyrus. Our study is the first to use the behavioral effects of proactive inhibition to identify the underlying brain regions, by employing an unbiased task-design that temporally separates cue and response.

Freeze or Forget? Virtual Attack Effects in an Emotional Sternberg Task.

Emotionally salient stimuli have the ability to disrupt cognitive processing. This kind of disruption involves effects on working memory and may be related to mental health problems. To explore the nature of such emotional interference on working memory, a Virtual Attack Emotional Sternberg Task (VAEST) was used. Neutral faces were presented as distractors and warning signals, which were sometimes followed by a virtual attack, created by having the neutral face turn angry while the image was enlarged. The attack was hypothesized to have one of two effects: to disrupt cognitive processing and thereby increase interference effects, or to terminate a state of freezing and thereby reduce interference effects. The task was successfully completed online by a sample of 59 students. Results clearly show that the virtual attack caused a reduction of interference relative to no-attack trials. The apparent cognitive disruption caused by emotional distractors may thus reflect freezing, which can be reversed by a freeze-terminating stimulus.

Reward processing dysfunction in ventral striatum and orbitofrontal cortex in Parkinson's disease.

BACKGROUND: Parkinson's disease is a growing concern as the longevity of the world's population steadily increases. Both ageing and Parkinson's disease have an impact on dopamine neurotransmission. It is therefore important to investigate their relative impact on the fronto-striatal reward system. There has been little investigation of reward processing in terms of anticipation and reward outcome in Parkinson's disease. Abnormal responses during reward processing have previously been demonstrated in whole-brain analysis of Parkinson's patients with mild lateralized disease, but the exact impact in regions specific to reward processing is still unknown. OBJECTIVE: Here we aim to investigate the impact of Parkinson's disease on the orbitofrontal ventral striatal reward system in patients with moderate to severe clinical symptoms. METHODS: We utilized a monetary incentive delay (MID) task in 17 Parkinson's patients who were compared to two control groups stratified by age. The MID paradigm reliably activates the ventral striatum during reward anticipation and the orbitofrontal cortex during reward outcome processing. RESULTS: Relative to the two control groups, Parkinson's disease patients had abnormal task related activity during both reward anticipation in the ventral striatum and reward outcome in the orbitofrontal cortex. There were no effects of ageing. CONCLUSION: These findings demonstrate abnormalities in anticipatory as well as reward outcome processing while treated primarily with levodopa. The orbitofrontal dysfunction during reward outcome processing may have specificity in Parkinson's disease, as it has been shown to be relatively unaffected by normal ageing.

Symptom attribution and frontal cortical thickness in first-episode schizophrenia.

AIM: Misattribution of symptoms is a common feature of schizophrenia, and likely involves impairment of metacognitive function that may be mediated by the frontal cortex. We aimed to compare frontal cortical thickness in first-episode schizophrenia (FES) patients with matched controls, and investigate its relationship with the symptom attribution dimension of insight in FES patients. METHODS: We examined frontal cortical thickness in 92 minimally treated FES patients at baseline presentation and 93 healthy controls aged 16-45 years. We examined for correlations between symptom attribution as determined by the Birchwood Insight Scale (BIS) symptom relabeling subscale score and cortical thickness of frontal regions of interest (ROIs). We then examined for an association between symptom attribution and cortical thickness using multiple regression analysis. RESULTS: FES patients exhibited significantly reduced cortical thicknesses for a number of frontal regions, namely the left medial orbitofrontal, left superior frontal, left frontal pole, right rostral middle frontal, right lateral orbitofrontal and right superior frontal regions. Reduced cortical thickness in FES patients was associated with symptom misattribution for the left and right rostral middle frontal, left caudal anterior cingulate, right superior frontal, and left and right pars triangularis regions. Reduced left rostral middle frontal thickness and left anterior cingulate thickness remained significant on regression analysis. CONCLUSION: Our findings suggest that frontal neuroanatomical deficits that are present early in the disease process may be critical to the pathogenesis of symptom attribution in schizophrenia.

Striatal activity during reactive inhibition is related to the expectation of stop-signals.

Successful response inhibition relies on the suppression of motor cortex activity. The striatum has previously been linked to motor cortex suppression during the act of inhibition (reactive), but activation was also seen during anticipation of stop signals (proactive). More specifically, striatal activation increased with a higher stop probability. Using functional magnetic resonance imaging with specific regions of interest, we investigate for the first time whether activation in the striatum during reactive inhibition is related to previously formed expectations. We used a modified stop-signal response task in which subjects were asked trial by trial, after being presented a stop-signal probability cue, whether they actually expected a stop to occur. This enabled us to investigate the subjective expectation of a stop signal during each trial. We found that striatal activity during reactive inhibition was higher when subjects expected stop signals. These results help explain conflicting findings of previous studies on the association between striatal activation and inhibition, since we demonstrate a crucial role of the subjects' expectation of a stop signal and thus their ability to prepare for a stop in advance. In conclusion, the current results show for the first time that striatal contributions to reactive response inhibition are, in part, related to subjective anticipation.