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RationalePatients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function.ObjectiveIn this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD.MethodsWe studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest.ResultsThere were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-β error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD.ConclusionsOur data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

Objectives: The present study constitutes the first randomized controlled trial to investigate the relation of lutein (L) and zeaxanthin (Z) to brain function using functional magnetic resonance imaging (fMRI). It was hypothesized that L and Z supplementation in older adults would enhance neural efficiency (i.e., reduce activation) and cognitive performance on a verbal learning task relative to placebo. Methods: A total of 44 community-dwelling older adults (mean age=72 years) were randomly assigned to receive either placebo or L+Z supplementation (12 mg/daily) for 1 year. Neurocognitive performance was assessed at baseline and post-intervention on an fMRI-adapted task involving learning and recalling word pairs. Imaging contrasts of blood-oxygen-level-dependent (BOLD) signal were created by subtracting active control trials from learning and recall trials. A flexible factorial model was employed to investigate the expected group (placebo vs. supplement) by time (baseline vs. post-intervention) interaction in pre-specified regions-of-interest. Results: L and Z appeared to buffer cognitive decline on the verbal learning task (Cohen’s d=.84). Significant interactions during learning were observed in left dorsolateral prefrontal cortex and anterior cingulate cortex (p < .05, family-wise-error corrected). However, these effects were in the direction of increased rather than decreased BOLD signal. Although the omnibus interaction was not significant during recall, within-group contrasts revealed significant increases in left prefrontal activation in the supplement group only. Conclusions: L and Z supplementation appears to benefit neurocognitive function by enhancing cerebral perfusion, even if consumed for a discrete period of time in late life. (JINS, 2018, 24, 77–90)

Diurnal rhythms have been observed in human behaviors as diverse as sleep, olfaction, and learning. Despite its potential impact, time of day is rarely considered when brain responses are studied by neuroimaging techniques. To address this issue, we explicitly examined the effects of circadian and homeostatic regulation on functional connectivity (FC) and regional cerebral blood flow (rCBF) in healthy human volunteers, using whole-brain resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). In common with many circadian studies, we collected salivary cortisol to represent the normal circadian activity and functioning of the hypothalamic–pituitary–adrenal (HPA) axis. Intriguingly, the changes in FC and rCBF we observed indicated fundamental decreases in the functional integration of the default mode network (DMN) moving from morning to afternoon. Within the anterior cingulate cortex (ACC), our results indicate that morning cortisol levels are negatively correlated with rCBF. We hypothesize that the homeostatic mechanisms of the HPA axis has a role in modulating the functional integrity of the DMN (specifically, the ACC), and for the purposes of using fMRI as a tool to measure changes in disease processes or in response to treatment, we demonstrate that time of the day is important when interpreting resting-state data.

Current treatments for smoking yield suboptimal outcomes, partly because of an inability to reduce cue-induced smoking. Mindfulness training (MT) has shown preliminary efficacy for smoking cessation, yet its neurobiological target remains unknown. Our prior work with nonsmokers indicates that MT reduces posterior cingulate cortex (PCC) activity. In individuals who smoke, the PCC, consistently a main hub of the “default mode network,” activates in response to smoking cues. In this randomized controlled trial, we tested the effects of app-delivered MT on PCC reactivity to smoking cues and whether individual differences in MT-mediated PCC changes predicted smoking outcomes. Smoking cue-induced PCC reactivity was measured using functional magnetic resonance imaging at baseline and 1 month after receiving smartphone app-based MT (n = 33) vs. an active control (National Cancer Institute’s QuitGuide, n = 34). Whether individual differences in treatment-related changes in PCC activity predicted smoking behavior was assessed. The MT group demonstrated a significant correlation between a reduction in PCC reactivity to smoking cues and a decline in cigarette consumption (r = 0.39, p = 0.02). No association was found in the control group (r = 0.08, p = 0.65). No effects of group alone were found in PCC or cigarette reduction. Post hoc analysis revealed this association is sex specific (women, r = 0.49, p = 0.03; men: r = −0.08, p = 0.79). This initial report indicates that MT specifically reduces smoking cue-induced PCC activity in a subject-specific manner, and the reduction in PCC activity predicts a concurrent decline in smoking. These findings link the hypothesized behavioral effects of MT for smoking to neural mechanisms particularly in women. This lays the groundwork for identifying individuals who may benefit from targeted digital therapeutic treatments such as smartphone-based MT, yielding improved clinical outcomes.

Cognitive control, which is critical for goal‐directed behavior, involves resolving conflicts between competing stimuli and is influenced by neurotransmitter interactions within cortico‐subcortical areas. This study investigated the relationship between baseline amino acid transmitter levels and interference control, focusing on the effects of experimentally enhancing catecholaminergic signaling. Using a double‐blind, placebo‐controlled crossover design with two dosage groups, n = 71 healthy human adults underwent proton magnetic resonance spectroscopy once to assess baseline GABA+ and Glx levels in the anterior cingulate cortex (ACC), striatum, and supplementary motor area (SMA). Participants then performed a subliminally primed flanker task inducing different scales of conflict twice while EEG was recorded: once after receiving a placebo (lactase) and once more under either low (0.25 mg/kg) or medium (0.50 mg/kg) doses of methylphenidate (MPH), which modulates the catecholaminergic and amino acid transmitter systems driving cognitive and interference control. Medium MPH doses were more effective than low doses at reducing subliminal interference effects, highlighting dose‐specific behavioral improvements. Higher striatal GABA+ levels led to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels were associated with better interference control at medium doses, suggesting a dose‐dependent shift from striatal to ACC dominance in conflict resolution. Neurophysiological (EEG data) analyses revealed increased theta‐band (TBA) and alpha‐band activity (ABA) overlapping in the mid‐superior‐frontal and inferior‐frontal clusters under conditions of heightened cognitive control demands. The findings highlight that whether and how amino acid transmitter levels in cognitive control‐relevant regions modulate interference conflicts depends on the degree of catecholaminergic signaling. We found medium methylphenidate doses (0.5 mg/kg) to be more effective than low doses (0.25 mg/kg) at reducing subliminal interference effects, with higher striatal GABA+ levels leading to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels led to better interference control at medium doses.

Real-time functional magnetic resonance imaging neurofeedback (rtfMRI NFB) is a promising method for targeted regulation of pathological brain processes in mental disorders. But most NFB approaches so far have used relatively restricted regional activation as a target, which might not address the complexity of the underlying network changes. Aiming towards advancing novel treatment tools for disorders like schizophrenia, we developed a large-scale network functional connectivity-based rtfMRI NFB approach targeting dorsolateral prefrontal cortex and anterior cingulate cortex connectivity with the striatum. In a double-blind randomized yoke-controlled single-session feasibility study with N ​= ​38 healthy controls, we identified strong associations between our connectivity estimates and physiological parameters reflecting the rate and regularity of breathing. These undesired artefacts are especially detrimental in rtfMRI NFB, where the same data serves as an online feedback signal and offline analysis target. To evaluate ways to control for the identified respiratory artefacts, we compared model-based physiological nuisance regression and global signal regression (GSR) and found that GSR was the most effective method in our data. Our results strongly emphasize the need to control for physiological artefacts in connectivity-based rtfMRI NFB approaches and suggest that GSR might be a useful method for online data correction for respiratory artefacts.

Nicotine dependence and major depressive disorder (MDD) are highly comorbid, yet causal links between these prevalent disorders are unclear. One possible mechanism is that nicotine ameliorates MDD-related neurobiological dysfunction in specific networks. For instance, cortico-striatal circuitry is enhanced by nicotine, and such paths are disrupted in individuals with MDD. Specifically, MDD has been associated with reduced connectivity between the nucleus accumbens (NAc) and rostral anterior cingulate cortex (rACC) but enhanced connectivity between the dorsal striatum (DS) and dorsolateral prefrontal cortex (DLPFC). Determining whether nicotine normalizes these circuits in non-smokers with MDD may elucidate mechanisms underlying links between disorders. This was tested by administering placebo and a 2-mg dose of nicotine to unmedicated non-smokers with and without MDD prior to collecting resting-state functional magnetic imaging data using a cross-over design. On placebo, individuals with MDD showed significantly reduced NAc–rACC and a trend for enhanced DS–DLPFC functional connectivity relative to healthy controls. In MDD, acute nicotine administration normalized both pathways to the level of healthy controls, while having no impact on healthy controls. Nicotine’s effects on NAc–rACC connectivity was influenced by anhedonia, consistent with the role of this network in reward and nicotine’s ability to enhance reward deficiencies in MDD. These results indicate that nicotine normalizes dysfunctional cortico-striatal communication in unmedicated non-smokers with MDD. Nicotine’s influence on these circuitries highlights a possible mechanism whereby individuals with MDD are more vulnerable to develop nicotine dependence. Findings suggest that nicotinic agents may have therapeutic effects on disrupted cortico-striatal connectivity.

The rostral anterior cingulate cortex (rACC) is consistently implicated in the neurobiology of depression. While the functional connectivity of the rACC has been previously associated with treatment response, there is a paucity of work investigating the specific directional interactions underpinning these associations. We compared the fMRI resting-state effective connectivity of 94 young people with major depressive disorder and 91 healthy controls. Following the fMRI scan, patients were randomized to receive cognitive behavioral therapy for 12 weeks, plus either fluoxetine or a placebo. Using spectral dynamic causal modelling, we examined the effective connectivity of the rACC with eight other regions implicated in depression: the left and right anterior insular cortex (AIC), amygdalae, and dorsolateral prefrontal cortex (dlPFC); and in the midline, the subgenual (sgACC) and dorsal anterior cingulate cortex (dACC). Parametric empirical Bayes was used to compare baseline differences between controls and patients and responders and non-responders to treatment. Depressed patients demonstrated greater inhibitory connectivity from the rACC to the dlPFC, AIC, dACC and left amygdala. Moreover, treatment responders illustrated greater inhibitory connectivity from the rACC to dACC, greater excitatory connectivity from the dACC to sgACC and reduced inhibitory connectivity from the sgACC to amygdalae at baseline. The inhibitory hyperconnectivity of the rACC in depressed patients aligns with hypotheses concerning the dominance of the default mode network over other intrinsic brain networks. Surprisingly, treatment responders did not demonstrate connectivity which was more similar to healthy controls, but rather distinct alterations that may have predicated their enhanced treatment response.

Default mode network (DMN) dysfunction (particularly within the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC)) has been implicated in major depressive disorder (MDD); however, its contribution to treatment outcome has not been clearly established. Here we tested the role of DMN functional connectivity as a general and differential biomarker for predicting treatment outcomes in a large, unmedicated adult sample with MDD. Seventy-five MDD outpatients completed fMRI scans before and 8 weeks after randomization to escitalopram, sertraline, or venlafaxine-XR. A whole-brain voxel-wise t-test identified profiles of pretreatment intrinsic functional connectivity that distinguished patients who were subsequently classified as remitters or non-remitters at follow-up. Connectivity was seeded in the PCC, an important node of the DMN. We further characterized differences between remitters, non-remitters, and 31 healthy controls and characterized changes pretreatment to posttreatment. Remitters were distinguished from non-remitters by relatively intact connectivity between the PCC and ACC/mPFC, not distinguishable from healthy controls, while non-remitters showed relative hypo-connectivity. In validation analyses, we demonstrate that PCC–ACC/mPFC connectivity predicts remission status with >80% cross-validated accuracy. In analyses testing whether intrinsic connectivity differentially relates to outcomes for a specific type of antidepressant, interaction models did not survive the corrected threshold. Our findings demonstrate that the overall capacity to remit on commonly used antidepressants may depend on intact organization of intrinsic functional connectivity between PCC and ACC/mPFC prior to treatment. The findings highlight the potential utility of functional scans for advancing a more precise approach to tailoring antidepressant treatment choices.

There is growing evidence for the use of acceptance-commitment therapy (ACT) for the treatment of obsessive-compulsive disorder (OCD). However, few fully implemented ACT have been conducted on the neural mechanisms underlying its effect on OCD. Thus, this study aimed to elucidate the neural correlates of ACT in patients with OCD using task-based and resting-state functional magnetic resonance imaging (fMRI). Patients with OCD were randomly assigned to the ACT ( = 21) or the wait-list control group ( = 21). An 8-week group-format ACT program was provided to the ACT group. All participants underwent an fMRI scan and psychological measurements before and after 8 weeks. Patients with OCD showed significantly increased activation in the bilateral insula and superior temporal gyri (STG), induced by the thought-action fusion task after ACT intervention. Further psycho-physiological interaction analyses with these regions as seeds revealed that the left insular-left inferior frontal gyrus (IFG) connectivity was strengthened in the ACT group after treatment. Increased resting-state functional connectivity was also found in the posterior cingulate cortex (PCC), precuneus, and lingual gyrus after ACT intervention Most of these regions showed significant correlations with ACT process measures while only the right insula was correlated with the obsessive-compulsive symptom measure. These findings suggest that the therapeutic effect of ACT on OCD may involve the salience and interoception processes (i.e. insula), multisensory integration (i.e. STG), language (i.e. IFG), and self-referential processes (i.e. PCC and precuneus). These areas or their interactions could be important for understanding how ACT works psychologically.