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.

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.

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.

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.

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.

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.

The effect of aging on fronto-striatal reactive and proactive inhibitory control.

Inhibitory control, like most cognitive processes, is subject to an age-related decline. The effect of age on neurofunctional inhibition processing remains uncertain, with age-related increases as well as decreases in activation being reported. This is possibly because reactive (i.e., outright stopping) and proactive inhibition (i.e., anticipation of stopping) have not been evaluated separately. Here, we investigate the effects of aging on reactive as well as proactive inhibition, using functional MRI in 73 healthy subjects aged 30-70years. We found reactive inhibition to slow down with advancing age, which was paralleled by increased activation in the motor cortex. Behaviorally, older adults did not exercise increased proactive inhibition strategies compared to younger adults. However, the pattern of activation in the right inferior frontal gyrus (rIFG) showed a clear age-effect on proactive inhibition: rather than flexibly engaging the rIFG in response to varying stop-signal probabilities, older subjects showed an overall hyperactivation. Whole-brain analyses revealed similar hyperactivations in various other frontal and parietal brain regions. These results are in line with the neural compensation hypothesis of aging: processing becomes less flexible and efficient with advancing age, which is compensated for by overall enhanced activation. Moreover, by disentangling reactive and proactive inhibition, we can show for the first time that the age-related increase in activation during inhibition that is reported generally by prior studies may be the result of compensation for reduced neural flexibility related to proactive control strategies.

Prefrontal cortical thinning in HIV infection is associated with impaired striatal functioning.

While cortical thinning has been associated with HIV infection, it is unclear whether this reflects a direct effect of the virus, whether it is related to disruption of subcortical function or whether it is better explained by epiphenomena, such as drug abuse or comorbid medical conditions. The present study investigated the relationship between cortical thickness and subcortical function in HIV+ patients. Specifically, we examined the relationship between prefrontal cortical thickness and striatal function. Twenty-three largely treatment naïve, non-substance abusing HIV+ participants and 19 healthy controls matched for age, gender, and educational status were included. Cortical morphometry was performed using FreeSurfer software analysis. Striatal function was measured during an fMRI stop-signal anticipation task known to engage the striatum. Any cortical regions showing significant thinning were entered as dependent variables into a single linear regression model which included subcortical function, age, CD4 count, and a measure of global cognitive performance as independent predictors. The only cortical region that was significantly reduced after correction for multiple comparisons was the right superior frontal gyrus. Striatal activity was found to independently predict superior frontal gyral cortical thickness. While cortical thinning in HIV infection is likely multifactorial, viral induced subcortical dysfunction appears to play a role.

The role of stop-signal probability and expectation in proactive inhibition.

The subjective belief of what will happen plays an important role across many cognitive domains, including response inhibition. However, tasks that study inhibition do not distinguish between the processing of objective contextual cues indicating stop-signal probability and the subjective expectation that a stop-signal will or will not occur. Here we investigated the effects of stop-signal probability and the expectation of a stop-signal on proactive inhibition. Twenty participants performed a modified stop-signal anticipation task while being scanned with functional magnetic resonance imaging. At the beginning of each trial, the stop-signal probability was indicated by a cue (0% or > 0%), and participants had to indicate whether they expected a stop-signal to occur (yes/no/don't know). Participants slowed down responding on trials with a > 0% stop-signal probability, but this proactive response slowing was even greater when they expected a stop-signal to occur. Analyses were performed in brain regions previously associated with proactive inhibition. Activation in the striatum, supplementary motor area and left dorsal premotor cortex during the cue period was increased when participants expected a stop-signal to occur. In contrast, activation in the right inferior frontal gyrus and right inferior parietal cortex activity during the stimulus-response period was related to the processing of contextual cues signalling objective stop-signal probability, regardless of expectation. These data show that proactive inhibition depends on both the processing of objective contextual task information and the subjective expectation of stop-signals.

Impact of aging on frontostriatal reward processing.

Healthy aging is associated with a progressive decline across a range of cognitive functions. An important factor underlying this decline may be the age-related impairment in stimulus-reward processing. Several studies have investigated age-related effects, but compared young versus old subjects. This is the first study to investigate the effect of aging on brain activation during reward processing within a continuous segment of the adult life span. We scanned 49 healthy adults aged 40-70 years, using functional MRI. We adopted a simple reward task, which allowed separate evaluation of neural responses to reward anticipation and receipt. The effect of reward on performance accuracy and speed was not related to age, indicating that all subjects could perform the task correctly. We identified a whole-brain significant age-related decline of ventral striatum activation during reward anticipation as compared to neutral anticipation. Importantly, the specificity of this finding was underscored by the observation that there was no general decline in activation during anticipation. Activation in the ventral striatum increased with age during reward receipt as compared to receiving neutral outcome. Finally, activation in the ventromedial prefrontal cortex during outcome was not affected by age. Our data demonstrate that the typical shift in striatal activation from reward receipt to reward anticipation in young adults disappears with healthy aging. These changes are consistent the well-ocumented age-related decline of striatal dopamine availability, and may provide a stepping stone for further research of age-related neurodegenerative diseases.

HIV Infection Is Associated with Impaired Striatal Function during Inhibition with Normal Cortical Functioning on Functional MRI.

The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with frontostriatal dysfunction. While frontostriatal systems play a key role in behavioral inhibition, there are to our knowledge no fMRI studies investigating the potential impact of HIV on systems involved during the inhibition of voluntary movement. A total of 17 combined antiretroviral therapy (cART) naïve HIV+ participants as well as 18 age, gender, ethnic, education matched healthy controls performed a modified version of the stop-signal paradigm. This paradigm assessed behavior as well as functional brain activity associated with motor execution, reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing before stopping). HIV+ participants showed significantly slower responses during motor execution compared to healthy controls, whereas they had normal proactive response slowing. Putamen hypoactivation was evident in the HIV+ participants based on successful stopping, indicating subcortical dysfunction during reactive inhibition. HIV+ participants showed normal cortical functioning during proactive inhibition. Our data provide evidence that HIV infection is associated with subcortical dysfunction during reactive inhibition, accompanied by relatively normal higher cortical functioning during proactive inhibition. This suggests that HIV infection may primarily involve basic striatal-mediated control processes in cART naïve participants.

Common and unique neural networks for proactive and reactive response inhibition revealed by independent component analysis of functional MRI data.

Response inhibition involves proactive and reactive modes. Proactive inhibition is goal-directed, triggered by warning cues, and serves to restrain actions. Reactive inhibition is stimulus-driven, triggered by salient stop-signals, and used to stop actions completely. Functional MRI studies have identified brain regions that activate during proactive and reactive inhibition. It remains unclear how these brain regions operate in functional networks, and whether proactive and reactive inhibition depend on common networks, unique networks, or a combination. To address this we analyzed a large fMRI dataset (N=65) of a stop-signal task designed to measure proactive and reactive inhibition, using independent component analysis (ICA). We found 1) three frontal networks that were associated with both proactive and reactive inhibition, 2) one network in the superior parietal lobe, which also included dorsal premotor cortex and left putamen, that was specifically associated with proactive inhibition, and 3) two right-lateralized frontal and fronto-parietal networks, including the right inferior frontal gyrus and temporoparietal junction as well as a bilateral fronto-temporal network that were uniquely associated with reactive inhibition. Overlap between networks was observed in dorsolateral prefrontal and parietal cortices. Taken together, we offer a new perspective on the neural underpinnings of inhibitory control, by showing that proactive inhibition and reactive inhibition are supported by a group of common and unique networks that appear to integrate and interact in frontoparietal areas.

Functional differences in emotion processing during adolescence and early adulthood.

Adolescence is a transitional period between childhood and adulthood and is characterized by emotional instability. Underlying this behavior may be an imbalance between the limbic subcortical areas and the prefrontal cortex. Here, we investigated differences in these regions during adolescence and young adulthood. Fifty subjects aged 10 to 24 viewed and rated neutral, negative, and positive pictures (IAPS: International Affective Picture System), while being scanned with functional MRI. Only those trials in which there was a match between the subject's response and the IAPS rating were included in the analyses. Task performance (matching accuracy, reaction times) did not differ across age. Activity in the amygdala and hippocampus decreased with age when processing emotional salient stimuli versus neutral stimuli. In contrast, activation in the ventrolateral prefrontal cortex increased with age. Importantly, we show for the first time that these age-related changes are paralleled by an increase in functional coupling of the amygdala and hippocampus with the orbitofrontal cortex and ventrolateral prefrontal cortex. These findings are in line with the general notion that brain development from childhood to adulthood is characterized by a gradual increase in frontal control over subcortical regions. Understanding these developmental changes is important as these may underlie typical adolescent behavior.

Distinct neural responses to conscious versus unconscious monetary reward cues.

Human reward pursuit is often assumed to involve conscious processing of reward information. However, recent research revealed that reward cues enhance cognitive performance even when perceived without awareness. Building on this discovery, the present functional MRI study tested two hypotheses using a rewarded mental-rotation task. First, we examined whether subliminal rewards engage the ventral striatum (VS), an area implicated in reward anticipation. Second, we examined differences in neural responses to supraliminal versus subliminal rewards. Results indicated that supraliminal, but not subliminal, high-value reward cues engaged brain areas involved in reward processing (VS) and task performance (supplementary motor area, motor cortex, and superior temporal gyrus). This pattern of findings is striking given that subliminal rewards improved performance to the same extent as supraliminal rewards. So, the neural substrates of conscious versus unconscious reward pursuit are vastly different-but despite their differences, conscious and unconscious reward pursuit may still produce the same behavioral outcomes.

Frontostriatal activity and connectivity increase during proactive inhibition across adolescence and early adulthood.

During adolescence, functional and structural changes in the brain facilitate the transition from childhood to adulthood. Because the cortex and the striatum mature at different rates, temporary imbalances in the frontostriatal network occur. Here, we investigate the development of the subcortical and cortical components of the frontostriatal network from early adolescence to early adulthood in 60 subjects in a cross-sectional design, using functional MRI and a stop-signal task measuring two forms of inhibitory control: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping). During development, reactive inhibition improved: older subjects were faster in reactive inhibition. In the brain, this was paralleled by an increase in motor cortex suppression. The level of proactive inhibition increased, with older subjects slowing down responding more than younger subjects when anticipating a stop-signal. Activation increased in the right striatum, right ventral and dorsal inferior frontal gyrus, and supplementary motor area. Moreover, functional connectivity during proactive inhibition increased between striatum and frontal regions with age. In conclusion, we demonstrate that developmental improvements in proactive inhibition are paralleled by increases in activation and functional connectivity of the frontostriatal network. These data serve as a stepping stone to investigate abnormal development of the frontostriatal network in disorders such as schizophrenia and attention-deficit hyperactivity disorder.

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition.

BACKGROUND: Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. METHODS: Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). RESULTS: We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. LIMITATIONS: Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. CONCLUSION: Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit.

Transcranial magnetic stimulation and functional MRI reveal cortical and subcortical interactions during stop-signal response inhibition.

Stopping an action requires suppression of the primary motor cortex (M1). Inhibitory control over M1 relies on a network including the right inferior frontal cortex (rIFC) and the supplementary motor complex (SMC), but how these regions interact to exert inhibitory control over M1 is unknown. Specifically, the hierarchical position of the rIFC and SMC with respect to each other, the routes by which these regions control M1, and the causal involvement of these regions in proactive and reactive inhibition remain unclear. We used off-line repetitive TMS to perturb neural activity in the rIFC and SMC followed by fMRI to examine effects on activation in the networks involved in proactive and reactive inhibition, as assessed with a modified stop-signal task. We found repetitive TMS effects on reactive inhibition only. rIFC and SMC stimulation shortened the stop-signal RT (SSRT) and a shorter SSRT was associated with increased M1 deactivation. Furthermore, rIFC and SMC stimulation increased right striatal activation, implicating frontostriatal pathways in reactive inhibition. Finally, rIFC stimulation altered SMC activation, but SMC stimulation did not alter rIFC activation, indicating that rIFC lies upstream from SMC. These findings extend our knowledge about the functional organization of inhibitory control, an important component of executive functioning, showing that rIFC exerts reactive control over M1 via SMC and right striatum.

Expectations and violations: delineating the neural network of proactive inhibitory control.

The ability to stop a prepared response (reactive inhibition) appears to depend on the degree to which stopping is expected (proactive inhibition). Functional MRI studies have shown that activation during proactive and reactive inhibition overlaps, suggesting that the whole neural network for reactive inhibition becomes already activated in anticipation of stopping. However, these studies measured proactive inhibition as the effect of stop-signal probability on activation during go trials. Therefore, activation could reflect expectation of a stop-signal (evoked by the stop-signal probability cue), but also violation of this expectation because stop-signals do not occur on go trials. We addressed this problem, using a stop-signal task in which the stop-signal probability cue and the go-signal were separated in time. Hence, we could separate activation during the cue, reflecting expectation of the stop-signal, from activation during the go-signal, reflecting expectation of the stop-signal or violation of that expectation. During the cue, the striatum, the supplementary motor complex (SMC), and the midbrain activated. During the go-signal, the right inferior parietal cortex (IPC) and the right inferior frontal cortex (IFC) activated. These findings suggest that the neural network previously associated with proactive inhibition can be subdivided into two components. One component, including the striatum, the SMC, and the midbrain, activated during the cue, implicating this network in proactive inhibition. Another component, consisting of the right IPC and the right IFC, activated during the go-signal. Rather than being involved in proactive inhibition, this network appears to be involved in processes associated with violation of expectations.

Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation.

The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep-brain-stimulation treatment for obsessive-compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate "top-down" (cortex → nucleus accumbens)- from "bottom-up" (nucleus accumbens → cortex)-directed synchronization (functional connectivity). "Top-down"-directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward-related processing and may be relevant to understanding the mechanisms of deep-brain stimulation and its beneficial effects on psychiatric conditions.

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.