Fronto‐cingulate effective connectivity in obsessive compulsive disorder: A study with fMRI and dynamic causal modeling

FRONTIERS COMMENTARY article Front. Psychiatry, 04 May 2016 Volume 7 - 2016 | https://doi.org/10.3389/fpsyt.2016.00078

Despite emotion regulation being altered in patients with obsessive-compulsive disorder (OCD), no studies have investigated its relation to multimodal amygdala connectivity. We compared corticolimbic functional and structural connectivity between OCD patients and healthy controls (HCs), and correlated this with the dispositional use of emotion regulation strategies and with OCD severity. OCD patients (n=73) and HCs (n=42) were assessed for suppression and reappraisal strategies using the Emotion Regulation Questionnaire (ERQ) and for OCD severity using the Yale-Brown Obsessive-Compulsive Scale. Resting-state functional magnetic resonance imaging (rs-fMRI) connectivity maps were generated using subject-specific left amygdala (LA) and right amygdala (RA) masks. We identified between-group differences in amygdala whole-brain connectivity, and evaluated the moderating effect of ERQ strategies. Significant regions and amygdala seeds were used as targets in probabilistic tractography analysis. Patients scored higher in suppression and lower in reappraisal. We observed higher rs-fMRI RA-right postcentral gyrus (PCG) connectivity in HC, and in patients this was correlated with symptom severity. Reappraisal scores were associated with higher negative LA-left insula connectivity in HC, and suppression scores were negatively associated with LA-precuneus and angular gyri connectivity in OCD. Structurally, patients showed higher mean diffusivity in tracts connecting the amygdala with the other targets. RA-PCG connectivity is diminished in patients, while disrupted emotion regulation is related to altered amygdala connectivity with the insula and posterior brain regions. Our results are the first showing, from a multimodal perspective, the association between amygdala connectivity and specific emotional processing domains, emphasizing the importance of amygdala connectivity in OCD pathophysiology.

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Obsessive–compulsive disorder (OCD) is characterized by anxiety-provoking, obsessive thoughts. Patients usually react to these thoughts with repetitive behaviours that reduce anxiety and are perceived as rewarding. Hence, reward plays a major role in the psychopathology of OCD. Previous studies showed altered activation in frontostriatal networks, among others, in association with the processing of reward in patients with OCD. Potential alterations in connectivity within these networks have, however, barely been explored. We investigated a sample of patients with OCD and healthy controls using functional MRI and a reward learning task presented in an event-related design. Dynamic causal modelling (DCM) was used to estimate effective connectivity. Our sample included 37 patients with OCD and 39 healthy controls. Analyses of task-related changes in connectivity showed a significantly altered effective connectivity between the ventromedial prefrontal cortex (vmPFC) and the orbitofrontal cortex (OFC), among others, both in terms of endogenous connectivity as well as modulatory effects under positive feedback. Clinical measures of compulsion correlated with the effect of feedback input on visual sensory areas. The reported alterations should be interpreted within the context of the task and the a priori–defined network considered in the analysis. This disrupted connectivity in parts of the default mode network and the frontostriatal network may indicate increased rumination and self-related processing impairing the responsiveness toward external rewards. This, in turn, may underlie the general urge for reinforcement accompanying compulsive behaviours.

Background: A large amount of resting-state functional magnetic resonance imaging (rs-fMRI) studies have revealed abnormalities of regional homogeneity (ReHo, an index of localized intraregional connectivity) in the obsessive-compulsive disorder (OCD) in the past few decades, However, the findings of these ReHo studies have remained inconsistent. Hence, we performed a meta-analysis to investigate the concurrence across ReHo studies for clarifying the most consistent localized connectivity underpinning this disorder.Methods: A systematic review of online databases was conducted for whole-brain rs-fMRI studies comparing ReHo between OCD patients and healthy control subjects (HCS). Anisotropic effect size version of the seed-based d mapping, a voxel-wise meta-analytic approach, was adopted to explore regions of abnormal ReHo alterations in OCD patients relative to HCS. Additionally, meta-regression analyses were conducted to explore the potential effects of clinical features on the reported ReHo abnormalities.Results: Ten datasets comprising 359 OCD patients and 361 HCS were included. Compared with HCS, patients with OCD showed higher ReHo in the bilateral inferior frontal gyri and orbitofrontal cortex (OFC). Meanwhile, lower ReHo was identified in the supplementary motor area (SMA) and bilateral cerebellum in OCD patients. Meta-regression analysis demonstrated that the ReHo in the OFC was negatively correlated with illness duration in OCD patients.Conclusions: Our meta-analysis gave a quantitative overview of ReHo findings in OCD and demonstrated that the most consistent localized connectivity abnormalities in individuals with OCD are in the prefrontal cortex. Meanwhile, our findings provided evidence that the hypo-activation of SMA and cerebellum might be associated with the pathophysiology of OCD.

The aim of this study is to determine whether the levels of zonulin and occludin, tight junctions (TJ) proteins in the intestinal epithelium, will differ between obsessive compulsive disorder (OCD) patients and healthy controls. We also intended to investigate whether these would vary in OCD patients with and without major depressive disorder (MDD) comorbidity and in comparison with healthy controls. Sixty patients diagnosed with OCD and 30 healthy controls were included in the study. The cases were administered the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Hamilton Depression Rating Scale (HDRS). The patients were divided into two subgroups based on their HDRS scores and presence of MDD comorbidity. Zonulin and occludin levels were measured using the ELISA method. The research was carried out between April 2021 and October 2021. Zonulin and occludin levels were significantly higher in the OCD patient group than in the control group (p<0.001). The levels of both were also significantly higher in the OCD patients with MDD comorbidity (OCD+MDD) compared to those without MDD (OCD-MDD) (p<0.001). Zonulin and occludin levels also rose significantly as disease severity increased in the OCD patient group (respectively; p<0.001, p=0.001). The levels of both increased in line with the severity of depression based on HDRS scores in the OCD+MDD group (p<0.001). A positive correlation was determined between the duration of OCD and zonulin and occludin levels. Evaluation of the entire OCD group revealed a moderate positive correlation between Y-BOCS and HDRS scores and zonulin and occludin. Zonulin and occludin levels in this research were significantly higher in the patients with OCD than in the healthy controls. That elevation was positively correlated with disease duration and severity, and the increase was significantly more pronounced in OCD with MDD comorbidity. These findings point to a possible disorder in the intestinal barrier and blood-brain barrier in OCD patients.

Objective To investigate the regulatory effect of cognitive behavioral therapy (CBT) on the functional connectivity of cognitive control network in untreated obsessive-compulsive disorder (OCD) patients, so as to provide evidence for understanding the neurobiological mechanism of CBT. Methods A total of 45 OCD patients and 45 matched normal controls were recruited at the outpatient clinic in Beijing Anding Hospital. Four therapists provided 14 times of CBT treatment for OCD patients. All subjects underwent clinical symptom assessment and magnetic resonance imaging at baseline and at the end of 12 weeks. The clinical symptoms were assessed by the psychiatrists using Y-BOCS, HAMD17 and HAMA. The clinical symptoms of OCD patients before and after CBT treatment were compared. The GRETNA software package was used to preprocess the resting-state fMRI data. The whole brain function network was constructed with the template of Power 264 functional brain area as the network node. The function connection intensity outside the cognitive control network was calculated, and the function connection of 2 groups of brain networks at two timepoints were compared by repeated measurement of variance analysis. Results A total of 41 patients completed CBT. The scores of obsessive-compulsive symptoms, anxiety symptoms and depressive symptoms decreased at the end of 12th week, of which 32 patients were improved (Y-BOCS reduction ≥35%). Single factor repeated analysis of variance and post hoc tests were performed between patients with improvement and normal controls. At baseline, the functional connection between the cingulo-opercular network and the salience network of OCD patients was lower than that of the normal control (0.172±0.060 vs. 0.215±0.076, t=1.731, P=0.040), it increased after treatment (0.186±0.171 vs. 0.172±0.060, t=2.480, P=0.010). At baseline, the functional connection of cingulo-opercular network and subcortical network in OCD patients was lower than that of normal control (0.119±0.081 vs. 0.129±0.070, t=1.640, P=0.040), and it increased after treatment (0.130±0.161 vs. 0.119±0.081, t=2.421, P=0.020). At baseline, the functional connection between the frontal-parietal network and subcortical network was lower than that of normal controls (-0.004±0.039 vs. 0.021±0.054, t=2.280, P=0.020), and it increased after treatment (0.020±0.042 vs.-0.004±0.039, t=-2.300 P=0.020). Conclusions CBT could effectively improve obsessive-compulsive symptoms accompanying with improvement of the external functional connectivity of cognitive control network in OCD patients. Key words: Obsessive-compulsive disorder; Cognitive therapy; Cognitive control network; Functional connectivity

Chronic tics and Tourette syndrome in patients with obsessive–compulsive disorder

Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness with complex clinical manifestations. Cognitive dysfunction may underlie OC symptoms. The frontoparietal network (FPN) is a key region involved in cognitive control. However, the findings of impaired FPN regions have been inconsistent. We employed meta-analysis to identify the fMRI-specific abnormalities of the FPN in OCD. PubMed, Web of Science, Scopus, and EBSCOhost were searched to screen resting-state functional magnetic resonance imaging (rs-fMRI) studies exploring dysfunction in the FPN of OCD patients using three indicators: the amplitude of low-frequency fluctuation/fractional amplitude of low-frequency fluctuation (ALFF/fALFF), regional homogeneity (ReHo) and functional connectivity (FC). We compared all patients with OCD and control group in a primary analysis, and divided the studies by medication in secondary meta-analyses with the activation likelihood estimation (ALE) algorithm. A total of 31 eligible studies with 1359 OCD patients (756 men) and 1360 healthy controls (733 men) were included in the primary meta-analysis. We concluded specific changes in brain regions of FPN, mainly in the left dorsolateral prefrontal cortex (DLPFC, BA9), left inferior frontal gyrus (IFG, BA47), left superior temporal gyrus (STG, BA38), right posterior cingulate cortex (PCC, BA29), right inferior parietal lobule (IPL, BA40) and bilateral caudate. Additionally, altered connectivity within- and between-FPN were observed in the bilateral DLPFC, right cingulate gyrus and right thalamus. The secondary analyses showed improved convergence relative to the primary analysis. OCD patients showed dysfunction FPN, including impaired local important nodal brain regions and hypoconnectivity within the FPN (mainly in the bilateral DLPFC), during the resting state. Moreover, FPN appears to interact with the salience network (SN) and default mode network (DMN) through pivotal brain regions. Consistent with the hypothesis of fronto-striatal circuit dysfunction, especially in the dorsal cognitive circuit, these findings provide strong evidence for integrating two pathophysiological models of OCD.

Obsessive-compulsive disorder (OCD) is an anxiety disorder with significant morbidity whose pathophysiology is not fully understood. Neuroimaging studies have characterized OCD in terms of elevated striatal and prefrontal reactivity to emotion provocation. This neural model may be informed by investigation of functional connectivity in OCD, identifying alterations in how sensory information is integrated into frontostriatal regions. The current study employed functional magnetic resonance imaging (fMRI) to compare neural activity and connectivity in 31 OCD patients (12 washing and 19 checking subtypes) and 17 healthy volunteers in an emotion provocation paradigm using visual stimuli. OCD status was associated with hyper-activation of the posterior cingulate (PCg) in response to emotion provocation. Additionally, OCD patients demonstrated elevated PCg functional connectivity with the visual cortices and frontostriatal regions. Exploratory analyses suggested that stimulus-provoked activity and connectivity was elevated for checking subtypes in motor cortices, and elevated in washing subtypes in the anterior insula and orbitofrontal cortex. The PCg's role in moderating connectivity between the visual cortex and frontolimbic regions is muted in OCD, consistent with the PCg's suggested role in regulating attention towards emotional stimuli. Exploratory analyses suggest distinct PCg connectivity profiles in OCD subtypes, with checking linked to motor activation, but washing linked to a network supporting emotional salience. The study was not powered to fully investigate the effects of medication, patients often endorsed secondary symptom subtypes that muddied washing/checking distinctions, and the emotion provocation paradigm was of limited intensity compared to life stressors.

Background and AimsRecent studies have challenged the anxiety-avoidance model of obsessive–compulsive disorder (OCD), linking OCD to impulsivity, risky-decision-making and reward-system dysfunction, which can also be found in addiction and might support the conceptualization of OCD as a behavioral addiction. Here, we conducted an exploratory investigation of the behavioral addiction model of OCD by assessing whether OCD patients are more impulsive, have impaired decision-making, and biased probabilistic reasoning, three core dimensions of addiction, in a sample of OCD patients and healthy controls.MethodsWe assessed these dimensions on 38 OCD patients and 39 healthy controls with the Barratt Impulsiveness Scale (BIS-11), the Iowa Gambling Task (IGT) and the Beads Task.ResultsOCD patients had significantly higher BIS-11 scores than controls, in particular on the cognitive subscales. They performed significantly worse than controls on the IGT preferring immediate reward despite negative future consequences, and did not learn from losses. Finally, OCD patients demonstrated biased probabilistic reasoning as reflected by significantly fewer draws to decision than controls on the Beads Task.ConclusionsOCD patients are more impulsive than controls and demonstrate risky decision-making and biased probabilistic reasoning. These results might suggest that other conceptualizations of OCD, such as the behavioral addiction model, may be more suitable than the anxiety-avoidance one. However, further studies directly comparing OCD and behavioral addiction patients are needed in order to scrutinize this model.

In economics, models of decision-making under risk are widely investigated. Since many empirical studies have shown patterns in choice behavior that classical models fail to predict, several descriptive theories have been developed. Due to an evident phenotypic heterogeneity, obsessive compulsive disorder (OCD) patients have shown a general deficit in decision making when compared to healthy control subjects (HCs). However, the direction for impairment in decision-making in OCD patients is still unclear. Hence, bridging decision-making models widely used in the economic literature with mental health research may improve the understanding of preference relations in severe patients, and may enhance intervention designs. We investigate the behavior of OCD patients with respect to HCs by means of decision making economic models within a typical neuropsychological setting, such as the Cambridge Gambling Task. In this task subjects have to decide the amount of their initial wealth to invest in each risky decision. To account for heterogenous preferences, we have analyzed the micro-level data for a more informative analysis of the choices made by the subjects. We consider two influential models in economics: the expected value (EV), which assumes risk neutrality, and a multiple reference points model, an alternative formulation of Disappointment theory. We find evidence that (medicated) OCD patients are more consistent with EV than HCs. The former appear to be more risk neutral, namely, less sensitive to risk than HCs. They also seem to base their decisions on disappointment avoidance less than HCs.

Obsessive compulsive disorder (OCD) is a serious mental disease highly associated with the dysfunctional dynamics of brain networks. The default mode network (DMN) is an essential brain network responding to various cognitive functions, which has been reported the abnormality in OCD patients. However, the underlying evolutions of temporal-spatial neurodynamics in fast-changing DMN activity of OCD remains largely unclear. In the present work, we tried to address this issue by tracking the neurodynamic structure of electrophysiological DMN activity in OCD patients during the resting state. To achieve this purpose, we reconstructed the DMN source activity from the scalp EEG signal with the exact low-resolution brain electromagnetic tomography (LORETA) algorithm, and applied coactive micropattern (CAMP) analysis developed by our previous studies to characterize DMN dynamics. We observed three CAMPs with distinct spatial structures in DMN dynamics for the normal subjects, while there were four different CAMPs in OCD patients. More interestingly, the temporal features of CAMPs which displayed similar spatial structures in two groups were also significantly altered in OCD patients compared with those in normal subjects, implying an abnormal DMN dynamic structure for OCD. Moreover, stronger DMN source connectivity in different CAMP networks emerged in OCD patients, where the posterior cingulate cortex and frontal cortex might be two hub regions with more increased connectivity. Overall, our results showed pathological alterations in the dynamic configuration of the DMN in OCD patients and revealed the neural brain network mechanism for OCD. All these findings could deepen our understanding of the neural pathology of OCD and might provide potential electrophysiological markers for diagnosing OCD patients clinically.

Altered connectivity within and between the default mode, central executive, and salience networks in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a common psychiatric illness characterised by recurrent, intrusive thoughts and repetitive, stereotyped behaviours. There is converging evidence that OCD is associated with a specific cognitive deficit related to organising and manipulating information in working memory. There is also evidence that OCD is associated with certain pre-morbid personality traits. However, further research is needed to elucidate whether these cognitive deficits and personality traits are specific to OCD or are present in other anxiety disorders and/or individuals with sub-clinical levels of obsessive-compulsive (OC) symptoms. In this thesis, 20 OCD patients were compared to 20 patients with panic disorder, 20 subjects with sub-clinical OC symptoms and 20 healthy control subjects on tests of working memory and the Five-Factor Model of personality. To measure different aspects of working memory, participants completed three delayed matching-to-sample (DMS) tasks and two continuous performance working memory tasks (n-back tasks). The DMS tasks assessed the ability to actively maintain different types of information in working memory (irregular objects; geometric objects; spatial locations). The n-back tasks assessed the ability to update and temporally order verbal and spatial stimuli in working memory. The OCD patients were less accurate than the healthy control subjects on the memory trials of the spatial DMS task, the 3- back trials of the spatial n-back task, and the 2-back and 3-back trials of the verbal n-back task. The OCD patients were also less accurate than patients with panic disorder and sub-clinical OC subjects on the verbal 3-back task. The results indicated that OCD patients were impaired on cognitive tasks requiring the maintenance of spatial stimuli and the updating and temporal ordering of verbal and spatial stimuli in working memory. The OCD patients were not impaired on tasks requiring the maintenance of object information in working memory. To measure normal personality traits, subjects completed the Revised NEO Personality Inventory (NEO PIR). Compared to healthy controls, OCD patients reported being highly emotional and introverted, less open to new experiences, and lacking confidence in their own abilities. The OCD patients were similar to the panic disorder patients on most of the domains and facets of the NEO PI-R, however, they were distinguished by their lower openness to experiencing new activities, and being less diligent and purposeful. Compared to the sub-clinical OC subjects, OCD patients reported being more prone to feelings of depression, more vulnerable to stress, less likely to experience positive emotions, more humble and sincere and less able to carry tasks through to completion. Overall, the thesis provided further evidence that OCD patients are impaired on cognitive tasks requiring the organisation and manipulation of information in working memory. However, it is still unclear whether this deficit arises due to capacity constraints being exceeded in working memory systems, or some other executive dysfunction such as excessive error monitoring. Future research, combining neuropsychological testing with neuroimaging techniques, is required to better understand the neural mechanisms underlying the impaired performance of OCD patients on tests of working memory. The present thesis also found that normal personality traits - as measured by the NEO PI-R - were able to distinguish OCD patients from healthy controls, patients with panic disorder and individuals with sub-clinical levels of OC symptoms. The results have implications for sub-clinical OC research and the clinical management of OCD.