Dorsal ACC Research Articles

GABA (gamma-aminobutyric acid) levels in dorsal anterior cingulate cortex are negatively associated with food motivation in a pediatric sample

Food motivation varies between individuals, affecting body weight and risk for eating disorders. Prior neuroimaging studies in youth and adults have revealed functional and structural alterations in the anterior cingulate cortex [ACC] in those with obesity and disordered eating but have not investigated their neurochemical underpinnings. In a sample of 37 children aged 4 to 13 years old, we used Magnetic Resonance Spectroscopy [MRS] to assess levels of γ-aminobutyric acid [GABA] – the major inhibitory neurotransmitter in the human brain – quantified relative to creatine in a 27-ml voxel including the dorsal ACC. We used the CEBQ to assess trait food motivation. In analyses adjusting for age, lower GABA+/Cr levels in the dorsal ACC were associated with higher trait enjoyment of food. Higher enjoyment of food scores were in turn associated with higher energy intake during an ad libitum test meal and during a postprandial task assessing intake in the absence of hunger, and higher body weight. Our results indicate a role for GABA function in the dorsal ACC in determining individual variation in food motivation in children.

Generalized Encoding of the Relative Subjective Value of Cognitive Effort in the Dorsal ACC.

Making choices about whether and when to engage cognitive effort are a common feature of everyday experience, with important consequences for academic, career, and health outcomes. Yet, despite their hypothesized importance, very little is understood about the underlying mechanisms that support this form of human cost-benefit decision-making. To investigate these mechanisms, we used the Cognitive Effort Discounting Paradigm (Cog-ED) during fMRI scanning to precisely quantify the neural encoding of varying cognitive effort demands relative to reward outcomes, within two distinct cognitive domains (working memory, speech comprehension). The findings provide strong evidence that the dorsal anterior cingulate cortex (dACC) plays a central and selective role in this decision-making process. Trial-by-trial modulations in dACC activation tracked the relative subjective value of the low-effort, low-reward option, with the strongest activity occurring when this was of greater value than the high-effort, high-reward option. In contrast, dACC activity was not modulated by decision difficulty, though such effects were found in other frontoparietal regions. Critically, dACC activity was also strongly correlated across the two decision-making task domains and further predicted subsequent choice behavior in both. Together, the results suggest that dACC activity modulation reflects a domain-general valuation comparison mechanism, which acts to bias participants away from decisions to engage in cognitive effort, when the perceived subjective costs of such engagement outweigh the reward-related benefits. These findings complement work in other cost domains and species by pointing to a clear role of the dACC in representing subjective value differences between choice options during cost-benefit decision-making.

Treatment effect of trauma-focused treatment and/or integrated trauma-focused and personality disorder treatment on brain activation during an emotional face task

IntroductionPost-traumatic stress disorder (PTSD) and personality disorders are highly comorbid. There is some evidence that trauma-focused treatment normalises activation in brain areas involved in the fear circuit and regions involved in emotion regulation in people with PTSD. Although we assume that working mechanism of personality disorder treatments relies on improving emotion regulation and associated brain regions, there is as of yet little evidence of neurobiological effects of personality treatment on people with PTSD and comorbid PD.ObjectivesTo 1) study the effect of trauma-focused and/or trauma-focused and personality disorder treatment n brain activation in participants with PTSD and comorbid personality disorders and 2) relate change in brain activation to symptom improvement.MethodsParticipants with PTSD and comorbid borderline and/or cluster c personality disorders from the PROSPER-trials (Prediction and Outcome Study for PTSD and personality disorders) were randomized to either trauma-focused treatment (TFT) or TFT with personality disorder treatment (TFT+PT). Brain activation was measured with an emotional face task during functional magnetic resonance imaging scanning before and after treatment. Regions of interest for the analyses were the amygdala, dorsal ACC, insula, ventromedial prefrontal cortex (PFC), ventrolateral PFC and dorsolateral PFC. Bayesian multilevel analyses were conducted to analyze change in brain activation. Clinical measures were clinician-administered PTSD severity, self-rated emotion regulation problems, depression severity and dissociation severity.ResultsWe included 42 participants with a pre- and posttreatment scan (24 with TFT, 18 TFT+PT). Analyses on the pre-post data are currently being run and will be presented in April.ConclusionsThis is one of the first studies to conduct functional MRI analyses on treatment in participants with both PTSD and personality disorders.Disclosure of InterestNone Declared

Altered task-related decoupling of the rostral anterior cingulate cortex in depression

Dysfunctional activity of the rostral anterior cingulate cortex (rACC) – an extensively connected hub region of the default mode network – has been broadly linked to cognitive and affective impairments in depression. However, the nature of aberrant task-related rACC suppression in depression is incompletely understood. In this study, we sought to characterize functional connectivity of rACC activity suppression (‘deactivation’) – an essential feature of rACC function – during external task engagement in depression. Specifically, we aimed to explore neural patterns of functional decoupling and coupling with the rACC during its task-driven suppression. We enrolled 81 15- to 25-year-old young people with moderate-to-severe major depressive disorder (MDD) before they commenced a 12-week clinical trial that assessed the effectiveness of cognitive behavioral therapy plus either fluoxetine or placebo. Ninety-four matched healthy controls were also recruited. Participants completed a functional magnetic resonance imaging face matching task known to elicit rACC suppression. To identify brain regions associated with the rACC during its task-driven suppression, we employed a seed-based functional connectivity analysis. We found MDD participants, compared to controls, showed significantly reduced ‘decoupling’ of the rACC with extended task-specific regions during task performance. Specifically, less decoupling was observed in the occipital and fusiform gyrus, dorsal ACC, medial prefrontal cortex, cuneus, amygdala, thalamus, and hippocampus. Notably, impaired decoupling was apparent in participants who did not remit to treatment, but not treatment remitters. Further, we found MDD participants showed significant increased coupling with the anterior insula cortex during task engagement. Our findings indicate that aberrant task-related rACC suppression is associated with disruptions in adaptive neural communication and dynamic switching between internal and external cognitive modes that may underpin maladaptive cognitions and biased emotional processing in depression.

Aberrant Neurofunctional Responses During Emotional and Attentional Processing Differentiate ADHD Youth With and Without a Family History of Bipolar I Disorder

Objective: To compare neurofunctional responses in emotional and attentional networks of psychostimulant-free ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: ADHD youth with (high-risk, HR, n = 48) and without (low-risk, LR, n = 50) a first-degree relative with BD and healthy controls (n = 46) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional distracters. Region-of-interest analyses were performed for bilateral amygdala (AMY), ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and anterior (ACC) and posterior cingulate cortex (PCC). Results: Compared with HC, HR, but not LR, exhibited predominantly left-lateralized AMY, VLPFC, DLPFC, PCC, and rostral ACC hyperactivation to emotional distractors, whereas LR exhibited right VLPFC and bilateral dorsal ACC hypoactivation to attentional targets. Regional responses correlated with emotional and attention symptoms. Conclusion: Aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.

Script-driven imagery of socially salient autobiographical memories in major depressive disorder

Cues of social rejection and affiliation represent proximal risk and protective factors in the onset and maintenance of depression. Such cues are thought to activate an evolutionarily primed neuro-cognitive alarm system, alerting the agent to the benefits of inclusion or the risk of social exclusion within social hierarchies focused on ensuring continued access to resources. In tandem, autobiographical memory is thought to be over-general and negatively biased in Major Depressive Disorder (MDD) which can contribute to maintenance and relapse. How memories of social rejection and affiliation are experienced and processed in MDD remains unexplored. Eighteen participants with recurrent and chronic MDD and 18 never-depressed controls listened to and vividly revisited autobiographical social experiences in an ecologically valid script-driven imagery paradigm using naturalistic memory narratives in an fMRI paradigm. Memories of Social Inclusion and Social Rejection broadly activated a common network of regions including the bilateral insula, thalamus and pre/postcentral gyrus across both groups. However, having a diagnosis of MDD was associated with an increased activation of the right middle frontal gyrus irrespective of memory type. Changes in positive affect were associated with activity in the dorsal ACC in the MDD group and in the insular cortex of the Control group. Our findings add to the evidence for complex representations for both positive and negative social signals in MDD and suggest neural sensitivity in MDD towards any socially salient information as opposed to selective sensitivity towards negative social experiences.

Sex Determines Anterior Cingulate Cortex Cortical Thickness in the Course of Depression

BackgroundMajor depressive disorder (MDD) is a severe psychiatric disorder affecting women more than men. Changes in anterior cingulate cortex cortical thickness (ACC CT) may be crucial to understanding sex influences in MDD onset and recurrency. MethodsTaken from the large open-source REST-meta-MDD database, we contrasted 499 patients with MDD (381 first-episode MDD, 118 recurrent MDD) and 524 healthy control participants using linear mixed-effects models and normative modeling and investigated whether sex differences affected ACC CT and its subregions differently during the course of depressive illness. ResultsOverall, females showed thinner ACC CT compared with males. Female patients with a first depressive episode showed significantly thinner ACC CT compared with male patients with first-episode MDD (Cohen’s d = −0.65), including in the perigenual ACC and the subgenual ACC, but not in the dorsal ACC. Moreover, male patients with first-episode depression showed thicker ACC CT (including subgenual ACC and pregenual ACC) compared to the male patients with recurrent MDD (Cohen’s d = 1.24), but they also showed significantly thicker cortices in the same subregions in comparison to never-depressed males (Cohen’s d = 0.85). No lateralization differences were observed in ACC CT or its subdivisions. ConclusionsSex determined ACC CT changes over the course of depressive illness. Because the ACC subdivisions in question are associated with dysregulation of emotions, our observations substantiate the need for early and prolonged sex-specific clinical interventions.

Voxel-wise Mapping of Functional Magnetic Resonance Imaging in Impression Formation

Social interactions often involve encountering inconsistent information about social others. We conducted a functional magnetic resonance imaging (fMRI) study to comprehensively investigate voxel-wise temporal dynamics showing how impressions are anchored and/or adjusted in response to inconsistent social information. The participants performed a social impression task inside an fMRI scanner in which they were shown a male face, together with a series of four adjectives that described the depicted person''s personality traits, successively presented beneath the image of the face. Participants were asked to rate their impressions of the person at the end of each trial on a scale of 1 to 8 (where 1 is most negative and 8 is most positive). We established two hypothetical models that represented two temporal patterns of voxel activity: Model 1 featured decreasing patterns of activity towards the end of each trial, anchoring impressions to initially presented information, and Model 2 showed increasing patterns of activity toward the end of each trial, where impressions were being adjusted using new and inconsistent information. Our data-driven model fitting analyses showed that the temporal activity patterns of voxels within the ventral anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex, amygdala, and fusiform gyrus fit Model 1 (i.e., they were more involved in anchoring first impressions) better than they did Model 2 (i.e., showing impression adjustment). Conversely, voxel-wise neural activity within dorsal ACC and lateral OFC fit Model 2 better than it did Model 1, as it was more likely to be involved in processing new, inconsistent information and adjusting impressions in response. Our novel approach to model fitting analysis replicated previous impression-related neuroscientific findings, furthering the understanding of neural and temporal dynamics of impression processing, particularly with reference to functionally segmenting each region of interest based on relative involvement in impression anchoring as opposed to adjustment.

Partly recovery and compensation in anterior cingulate cortex after SSRI treatment—evidence from multi-voxel pattern analysis over resting state fMRI in depression

BackgroundAnterior cingulate cortex (ACC) plays an essential role in the pathophysiology of major depressive disorder (MDD) and its treatment. However, it's still unclear whether the effects of disease and antidepressant treatment on ACC perform diversely in neural mechanisms. MethodsFifty-nine MDD patients completed resting-state fMRI scanning twice at baseline and after 12-week selective serotonin reuptake inhibitor (SSRI) treatment, respectively in acute state and remission state. Fifty-nine demographically matched healthy controls were enrolled. Using fractional amplitude of low-frequency fluctuation (fALFF) in ACC as features, we performed multi-voxel pattern analysis over pretreatment MDD patients vs health control (HC), and over pretreatment MDD patients vs posttreatment MDD patients. ResultsDiscriminative regions in ACC for MDD impairment and changes after antidepressants were obtained. The intersection set and difference set were calculated to form ACC subregions of recovered, unrecovered and compensative, respectively. The recovered ACC subregion mainly distributed in rostral ACC (80 %) and the other two subregions had nearly equal distribution over dorsal ACC and rostral ACC. Furthermore, only the compensative subregion had significant changed functional connectivity with cingulo-opercular control network (CON) after antidepressant treatment. LimitationsThe number of subjects was relatively small. The results need to be validated with larger sample sizes and multisite data. ConclusionsThis finding suggested that the local function of ACC was partly recovered on regulating emotion after antidepressant by detecting the common subregional targets of depression impairment and antidepressive effect. Besides, changed fALFF in the compensative ACC subregion and its connectivity with CON may partly compensate for the cognition deficits.

Pupil dilation during negative prediction errors is related to brain choline concentration and depressive symptoms in adolescents

Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.

Neural Circuitry Mechanisms of Response to Ketamine in PTSD: Preliminary Findings

Patients with chronic PTSD (N=21), who participated in a larger RCT of repeated ketamine (NMDA receptor antagonist) infusions, compared to psychoactive placebo control midazolam, completed fMRI scans before and after repeated infusions to investigate neural circuitry changes associated with PTSD improvement. Participants were randomized to receive six intravenous infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg), three times/week for two consecutive weeks. MRI scans included two emotion-processing tasks and a task-free scan. The CAPS-5 was administered before and after repeated infusions. Leave-one-out cross-validated elastic-net regression analyses were employed to evaluate potential associations between PTSD improvement and changes in a-priori imaging measures. ROIs in pre-registered analyses included dorsal and rostral ACC, vmPFC, anterior hippocampus, anterior insula, and amygdala. PTSD symptom improvement was associated with increased vmPFC-amygdala connectivity during emotional face-viewing (change score retained in the model with minimum predictive error in left-out participants; standardized β=2.90); this association was more pronounced with ketamine than midazolam (interaction β=0.86) and persisted after adjusting for depressive symptoms (β=0.69). PTSD symptom improvement was associated with decreased dACC activation during emotional conflict regulation (Face-Stroop) and increased resting state vmPFC-anterior insula connectivity, only in participants treated with ketamine (βs=-2.82, 0.60). Exploratory dynamic causal modeling analysis revealed that PTSD improvement was associated with increased top-down inhibition of amygdala by vmPFC only following ketamine, but not midazolam infusions. Preliminary results from this study suggest that a course of repeated ketamine infusions might reduce PTSD symptom severity by normalizing hypofrontal control over amygdala in response to social signals of threat.

Anterior Cingulate Cortex Signals the Need to Control Intrusive Thoughts during Motivated Forgetting.

How do people limit awareness of unwanted memories? When such memories intrude, a control process engages the right DLPFC (rDLPFC) to inhibit hippocampal activity and stop retrieval. It remains unknown how the need for control is detected, and whether control operates proactively to prevent unwelcome memories from being retrieved, or responds reactively, to counteract intrusions. We hypothesized that dorsal ACC (dACC) detects the emergence of an unwanted trace in awareness and transmits the need for inhibitory control to rDLPFC. During a memory suppression task, we measured in humans (both sexes) trial-by-trial variations in the theta power and N2 amplitude of dACC, two EEG markers that are thought to reflect the need for control. With simultaneous EEG-fMRI recordings, we tracked interactions among dACC, rDLPFC, and hippocampus during suppression. We found a clear role of dACC in detecting the need for memory control and upregulating prefrontal inhibition. Importantly, we identified distinct early (300–450 ms) and late (500–700 ms) dACC contributions, suggesting both proactive control before recollection and reactive control in response to intrusions. Stronger early activity was associated with reduced hippocampal activity and diminished BOLD signal in dACC and rDLPFC, suggesting that preempting retrieval reduced overall control demands. In the later window, dACC activity was larger, and effective connectivity analyses revealed robust communication from dACC to rDLPFC and from rDLPFC to hippocampus, which are tied to successful forgetting. Together, our findings support a model in which dACC detects the emergence of unwanted content, triggering top-down inhibitory control, and in which rDLPFC countermands intruding thoughts that penetrate awareness.SIGNIFICANCE STATEMENT Preventing unwanted memories from coming to mind is an adaptive ability of humans. This ability relies on inhibitory control processes in the prefrontal cortex to modulate hippocampal retrieval processes. How and when reminders to unwelcome memories come to trigger prefrontal control mechanisms remains unknown. Here we acquired neuroimaging data with both high spatial and temporal resolution as participants suppressed specific memories. We found that the anterior cingulate cortex detects the need for memory control, responding both proactively to early warning signals about unwelcome content and reactively to intrusive thoughts themselves. When unwanted traces emerge in awareness, anterior cingulate communicates with prefrontal cortex and triggers top-down inhibitory control over the hippocampus through specific neural oscillatory networks.

Dissociation of basolateral and central amygdala effective connectivity predicts the stability of emotion-related impulsivity in adolescents and emerging adults with borderline personality symptoms: a resting-state fMRI study.

Borderline personality disorder (BPD) is associated with altered activity in the prefrontal cortex (PFC) and amygdala, yet no studies have examined fronto-limbic circuitry in borderline adolescents and emerging adults. Here, we examined the contribution of fronto-limbic effective connectivity (EC) to the longitudinal stability of emotion-related impulsivity, a key feature of BPD, in symptomatic adolescents and young adults. We compared resting-state EC in 82 adolescents and emerging adults with and without clinically significant borderline symptoms (n BPD = 40, ages 13-30). Group-specific directed networks were estimated amongst fronto-limbic nodes including PFC, ventral striatum (VS), central amygdala (CeN), and basolateral amygdala (BLA). We examined the association of directed centrality metrics with initial levels and rates of change in emotion-related impulsivity symptoms over a one-year follow-up using latent growth curve models (LGCMs). In controls, ventromedial prefrontal cortex (vmPFC) and dorsal ACC had a directed influence on CeN and VS, respectively. In the BPD group, bilateral BLA had a directed influence on CeN, whereas in the healthy group CeN influenced BLA. LGCMs indicated that emotion-related impulsivity was stable across a one-year follow-up in the BPD group. Further, higher EC of R CeN to other regions in controls was associated with stronger within-person decreases in emotion-related impulsivity. Functional inputs from BLA and vmPFC appear to play competing roles in influencing CeN activity. In borderline adolescents and young adults, BLA may predominate over CeN activity, while in controls the ability of CeN to influence BLA activity predicted more rapid reductions in emotion-related impulsivity.

Distinct Brain Mechanisms for Conflict Adaptation within and across Conflict Types.

Cognitive conflict, like other cognitive processes, shows the characteristic of adaptation, that is, conflict effects are attenuated when immediately following a conflicting event, a phenomenon known as the conflict adaptation effect (CAE). One important aspect of CAE is its sensitivity to the intertrial coherence of conflict type, that is, behavioral CAE occurs only if consecutive trials are of the same conflict type. Although reliably observed behaviorally, the neural mechanisms underlying such a phenomenon remains elusive. With a paradigm combining the classic Simon task and Stroop task, this fMRI study examined neural correlates of conflict adaptation both within and across conflict types. The results revealed that when the conflict type repeated (but not when it alternated), the CAE-like neural activations were observed in dorsal ACC, inferior frontal gyrus (IFG), superior parietal lobe, and so forth (i.e., regions within typical task-positive networks). In contrast, when the conflict type alternated (but not when it repeated), we found CAE-like neural deactivations in the left superior frontal gyri (i.e., a region within the typical task-negative network). Network analyses suggested that the regions of ACC, IFG, superior parietal lobe, and superior frontal gyrus can be clustered into two antagonistic networks, and the ACC-IFG connection was associated with the within-type CAE. This evidence suggests that our adaptation to cognitive conflicts within a conflict type and across different types may rely on these two distinct neural mechanisms.

Not all smokers are alike: the hidden cost of sustained attention during nicotine abstinence

Nicotine Withdrawal Syndrome (NWS)-associated cognitive deficits are notably heterogeneous, suggesting underlying endophenotypic variance. However, parsing this variance in smokers has remained challenging. In this study, we identified smoker subgroups based on response accuracy during a Parametric Flanker Task (PFT) and then characterized distinct neuroimaging endophenotypes using a nicotine state manipulation. Smokers completed the PFT in two fMRI sessions (nicotine sated, abstinent). Based on response accuracy in the stressful, high cognitive demand PFT condition, smokers split into high (HTP, n = 21) and low task performer (LTP, n = 24) subgroups. Behaviorally, HTPs showed greater response accuracy (88.68% ± 5.19 SD) vs. LTPs (51.04% ± 4.72 SD), independent of nicotine state, and greater vulnerability to abstinence-induced errors of omission (EOm, p = 0.01). Neurobiologically, HTPs showed greater BOLD responses in attentional control brain regions, including bilateral insula, dorsal ACC, and frontoparietal Cx for the [correct responses (–) errors of commission] PFT contrast in both states. A whole-brain functional connectivity (FC) analysis with these subgroup-derived regions as seeds identified two circuits: Precentral Cx↔Insula and Insula↔Occipital Cx, with abstinence-induced FC strength increases seen only in HTPs. Finally, abstinence-induced FC and behavior (EOm) differences were positively correlated for HTPs in a Precentral Cx↔Orbitofrontal cortical circuit. In sum, only the HTP subgroup demonstrated sustained attention deficits following 48-hr nicotine abstinence, a stressor in dependent smokers. Unpacking underlying smoker heterogeneity with this ‘dual (task and abstinence) stressor’ approach revealed discrete smoker subgroups with differential attentional deficits to withdrawal that could be novel pharmacological/behavioral targets for therapeutic interventions to improve cessation outcomes.

The effect of N-acetylcysteine and working memory training on glutamate concentrations in the dACC and rACC in regular cocaine users – A randomized proof of concept study

IntroductionCurrent treatments for cocaine use disorder (CUD) are not very effective and better treatments are needed. This study investigates the effectiveness of a combined intervention that targets the assumed underlying glutamate pathology in cocaine users. To this end, the combined effects of N-acetylcysteine (NAC) and working memory (WM) training on glutamate concentrations in the dorsal and rostral ACC were investigated in a randomized, double-blind placebo-controlled design. MethodsIn this study, 38 regular cocaine-using men were randomized to either 25-days with 2400 mg/day NAC and WM-training or 25 days with placebo with WM-training. Cocaine use, impulsivity, and glutamate concentrations in the dACC and rACC using proton Magnetic Resonance Spectroscopy were assessed at baseline and after treatment. ResultsTwenty-four participants completed the study, of which 9 received NAC and 15 received placebo. There were no baseline correlations of glutamate concentrations in the dACC or rACC with cocaine use measures or impulsivity. Additionally, there were no effects of NAC, WM-training, or the combination thereof on (changes in) glutamate concentrations in the dACC or rACC. DiscussionThis randomized proof of concept study could not confirm our hypotheses. Possible explanations are insufficient power and the possible absence of deviant baseline glutamate concentrations in the included participants. Future studies should consider larger samples and a non-using control group to confirm baseline deviations in glutamate in cocaine users.

Neurochemistry of response inhibition and interference in gambling disorder: a preliminary study of γ-aminobutyric acid (GABA+) and glutamate-glutamine (Glx).

Neurobehavioral research on the role of impulsivity in gambling disorder (GD) has produced heterogeneous findings. Impulsivity is multifaceted with different experimental tasks measuring different subprocesses, such as response inhibition and distractor interference. Little is known about the neurochemistry of inhibition and interference in GD. We investigated inhibition with the stop signal task (SST) and interference with the Eriksen Flanker task, and related performance to metabolite levels in individuals with and without GD. We employed magnetic resonance spectroscopy (MRS) to record glutamate-glutamine (Glx/Cr) and inhibitory, γ-aminobutyric acid (GABA+/Cr) levels in the dorsal ACC (dACC), right dorsolateral prefrontal cortex (dlPFC), and an occipital control voxel. We found slower processing of complex stimuli in the Flanker task in GD (P<.001, η2p=0.78), and no group differences in SST performance. Levels of dACC Glx/Cr and frequency of incongruent errors were correlated positively in GD only (r=0.92, P=.001). Larger positive correlations were found for those with GD between dACC GABA+/Cr and SST Go error response times (z=2.83, P=.004), as well as between dACC Glx/Cr and frequency of Go errors (z=2.23, P=.03), indicating general Glx-related error processing deficits. Both groups expressed equivalent positive correlations between posterror slowing and Glx/Cr in the right dlPFC (GD: r=0.74, P=.02; non-GD: r=.71, P=.01). Inhibition and interference impairments are reflected in dACC baseline metabolite levels and error processing deficits in GD.

Dorsal Anterior Cingulate Cortex Encodes the Integrated Incentive Motivational Value of Cognitive Task Performance

Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well understood how these signals are "bundled" in the brain to modulate cognitive control. The dorsal ACC (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, although this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation analyses suggest that dACC encoded the incentives in terms of their integrated subjective motivational value, and that this value signal was most proximally associated with task performance. Finally, we confirmed that these incentive integration effects were selectively present in dACC. Together, the results support an account in which dACC integrates motivational signals to compute the expected value of goal-directed cognitive control.SIGNIFICANCE STATEMENT How are primary and secondary incentives integrated in the brain to influence goal-directed behavior? Using an innovative experimental fMRI paradigm that combines motivational incentives that have historically been studied independently between species (e.g., monetary rewards for humans, food rewards for animals), we examine the relationship between incentive motivational value and cognitive control allocation. We find evidence that the integrated incentive motivational value of combined incentives is encoded in human dorsal ACC. Further, self-reported motivational shifts mediated the effects of incentive-modulated dorsal ACC activity on task performance, revealing convergence in how self-reported and experimentally induced motivation are encoded in the human brain. Our findings may inform future translational studies examining affective/motivational and cognitive impairments in psychopathology (e.g., anxiety, depression, addiction).

Schizophrenia and bipolar disorder are associated with opposite brain reward anticipation-associated response.

Blunted and exaggerated neuronal response to rewards are hypothesized to be core features of schizophrenia spectrum disorders (SZ) and bipolar disorder (BD), respectively. Nonetheless, direct tests of this hypothesis, in which response between SZ and BD is compared in the same study, are lacking. Here we examined the functional correlates of reward processing during the Incentivized Control Engagement Task (ICE-T) using 3T fMRI. Reward-associated activation was examined in 49 healthy controls (HCs), 52 recent-onset individuals with SZ, and 22 recent-onset individuals with Type I BD using anterior cingulate (ACC), anterior insula, and ventral striatal regions of interest. Significant group X reward condition (neutral vs. reward) interactions were observed during reward anticipation in the dorsal ACC (F(2,120) = 4.21, P = 0.017) and right insula (F(2,120) = 4.77, P = 0.010). The ACC interaction was driven by relatively higher activation in the BD group vs. HCs (P = 0.007) and vs. individuals with SZ (P = 0.010). The insula interaction was driven by reduced activation in the SZ group relative to HCs (P = 0.018) and vs. people with BD (P = 0.008). A composite of reward anticipation-associated response across all associated ROIs also differed significantly by diagnosis (F(1,120) = 5.59, P = 0.02), BD > HC > SZ. No effects of group or group X reward interactions were observed during reward feedback. These results suggest that people with SZ and BD have opposite patterns of activation associated with reward anticipation but not reward receipt. Implications of these findings in regard to Research Domain Criteria-based classification of illness and the neurobiology of reward in psychosis are discussed.

Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) Imaging in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is characterised by structural and functional deficits in the cortico-striato-thalamic-cortical (CSTC) circuitry and abnormal neurochemical changes are thought to modulate these deficits. The hypothesis that an imbalanced concentration of the brain neurotransmitters, in particular glutamate (Glu) and gamma-amino-butyric acid (GABA), could impair the normal functioning of the CSTC, thus leading to OCD symptoms, has been tested in humans using magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). This chapter summarises these neurochemical findings and represents an attempt to condense such scattered literature. We also discuss potential challenges in the field that may explain the inconsistent findings and suggest ways to overcome them. There is some convergent research from MRS pointing towards abnormalities in the brain concentration of neurometabolite markers of neuronal integrity, such as N-acetylaspartate (NAA) and choline (Cho). Lower NAA levels have been found in dorsal and rostral ACC of OCD patients (as compared to healthy volunteers), which increase after CBT and SSRI treatment, and higher Cho concentration has been reported in the thalamus of the OCD brain. However, findings for other neurometabolites are very inconsistent. Studies have reported abnormalities in the concentrations of creatine (Cr), GABA, glutamate (Glu), glutamine (Gln), Ins (myo-inositol), and serotonin (5-HT), but most of the results were not replicated. The question remains whether the NAA and Cho findings are genuinely the only neurochemical abnormalities in OCD or whether the lack of consistent findings for the other neurometabolites is caused by the lower magnetic field (1-3 Tesla (T)) used by the studies conducted so far, their small sample sizes or a lack of proper control for medication effects. To answer these questions and to further inform the biological underpinning of the symptoms and the cognitive problems at the basis of OCD we need better controlled studies using clear medicated vs unmedicated groups, larger sample sizes, stronger magnetic fields (e.g. at 7T), and more consistency in the definition of the regions of interest.