The Emotional Brain in Obsessive-Compulsive Disorder

Background Obsessive-compulsive disorder (OCD) is characterized by distressing obsessions and time-consuming compulsions. The disorder affects 1-3% and can be highly impairing to daily functioning and detrimental to the quality of life. Cognitive behavioral therapy is an effective treatment for 50-75% of people with OCD, leaving a considerable minority who do not benefit from the best available treatments we have today. Neuroimaging has related the disorder to the function and structure of cortico-striato-thalamo-cortical and fronto-limbic circuits. A better understanding of these circuits might contribute to a better understanding of the disorder, how current treatments change the brain, and how we can help non-responders with better treatments in the future. This is likely particularly true for fronto-limbic and affective circuits, given their role in the formation, maintenance, and extinction of fear as well as motivating behavior. The aim of this dissertation was, first, to investigate how OCD is related to brain activation during emotional processing of aversive stimuli. Secondly, we wanted to examine if unaffected siblings of OCD patients showed similar anxiety, brain activation, and connectivity during emotion provocation and regulation as their OCD-affected siblings compared to unrelated healthy controls. Lastly, we wanted to investigate if the resting-state network structure changes in OCD patients directly after the Bergen 4-Day Treatment (B4DT), a concentrated and exposure-based psychological therapy. Methods Paper I was a meta-analysis of 25 functional neuroimaging studies comparing OCD patients and healthy controls during emotion processing, when participants were exposed to aversive or neutral stimuli. In Paper II we used functional magnetic resonance imaging (fMRI) to investigate distress, brain activation, and fronto-limbic connectivity during emotion provocation and regulation of neutral, fear-related, and OCD-related stimuli in 43 unmedicated OCD patients, 19 unaffected siblings, and 38 healthy controls. In Paper III we used resting-state fMRI to study the network structure of 28 OCD patients (21 unmedicated) and 19 healthy controls the day before and three days after B4DT. We examined static and dynamic graph metrics at the global, subnetwork, and regional levels, as well as between-subnetwork connectivity. Results In Paper I, we found that OCD patients showed more activation than healthy controls in the orbitofrontal cortex (OFC), extending into the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC), bilateral amygdala (extending into the right putamen), left inferior occipital cortex, and right middle temporal gyrus during aversive versus neutral stimuli. Meta-regressions showed that medication status and comorbidity moderated amygdala, occipital and ventromedial prefrontal cortex hyperactivation, while symptom severity moderated hyperactivation in medial frontal prefrontal and superior parietal regions. In Paper II we showed that unaffected siblings resembled healthy controls in task-related distress, less amygdala activation/altered timing than OCD patients during emotion provocation. During OCD-related emotion regulation siblings showed no significant difference in dmPFC activation versus either OCD patients or healthy controls, but showed more temporo-occipital activation and dmPFC-amygdala connectivity compared to healthy controls. In Paper III we found that unmedicated OCD patients showed more frontoparietal-limbic connectivity before treatment than healthy controls. This, along with sgACC flexibility, was reduced in OCD patients directly after B4DT. Conclusions OCD patients show hyperactivation of the amygdala and related structures, but this characteristic is not directly shared with unaffected siblings during provocation or regulation of emotional information. However, siblings seem to show compensatory activation and connectivity in other areas. The rapid changes in frontoparietal-limbic connectivity and subgenual ACC flexibility suggests that concentrated treatment leads to a more independent and stable network state. OCD is related to subtle alterations in limbic activation and fronto-limbic connectivity during both emotional tasks and resting-state, which seems to vary with comorbidity and is sensitive to treatment

The Bergen 4-day treatment for panic disorder: adapting to COVID-19 restrictions with a hybrid approach of face-to-face and videoconference modalities

Background The Bergen 4-day treatment (B4DT) is a concentrated exposure-based therapy that has been shown to be effective in the treatment of anxiety disorders. The current study sought to examine the effectiveness of B4DT for panic disorder (PD), when delivered with a combination of face-to-face sessions and videoconferencing. Methods Treatment was delivered to 50 patients from April 2020 to May 2021. Because of regulations during the pandemic, a significant portion of the treatment was conducted via videoconference. The primary outcome measure was the clinician-rated Panic Disorder Severity Scale (PDSS), and secondary measures included patient-rated symptoms of panic disorder, agoraphobia, generalized anxiety, depression, and treatment satisfaction. Changes in symptom levels over time were estimated using multilevel models. Results Patients showed a significant reduction in clinician-rated symptoms of panic disorder (Measured by PDSS) from before treatment to post treatment (d = 2.18) and 3-month follow-up (d = 2.01). At three months follow-up 62% of patients were classified as in remission, while 70% reported a clinically significant response. We also found a reduction in symptoms of depression and generalized anxiety, and the patients reported high satisfaction with the treatment. Conclusion The current study suggests that B4DT delivered in a combination of videoconference and face-to-face meetings may be a useful treatment approach. As the study is uncontrolled, future studies should also include more strictly designed investigations.publishedVersio

Stable inhibition-related inferior frontal hypoactivation and fronto-limbic hyperconnectivity in obsessive–compulsive disorder after concentrated exposure therapy

Response inhibition has previously been suggested as an endophenotype for obsessive–compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it’s unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.publishedVersio

Effects of Bergen 4-Day Treatment on Resting-State Graph Features in Obsessive-Compulsive Disorder

Background Exposure and response prevention is an effective treatment for obsessive-compulsive disorder (OCD), but it is unclear how symptom reduction is related to changes in the brain. We aimed to determine the effects of a 4-day concentrated exposure and response prevention program (Bergen 4-day treatment) on the static and dynamic functional connectome in patients with OCD. Methods Thirty-four patients with OCD (25 unmedicated) underwent resting-state functional magnetic resonance imaging the day before the Bergen 4-day treatment, and 28 (21 unmedicated) were rescanned after 1 week. Twenty-eight healthy control subjects were also scanned for baseline comparisons and 19 of them were rescanned after 1 week. Static and dynamic graph measures were quantified to determine network topology at the global, subnetwork, and regional levels (including efficiency, clustering, between-subnetwork connectivity, and node flexibility in module allegiance). The Yale-Brown Obsessive Compulsive Scale was used to measure symptom severity. Results Twenty-four patients (86%) responded to treatment. We found significant group × time effects in frontoparietal-limbic connectivity (ηp2 = .19, p = .03) and flexibility of the right subgenual anterior cingulate cortex (ηp2 = .18, p = .03), where, in both cases, unmedicated patients showed significant decreases while healthy control subjects showed no significant changes. Healthy control subjects showed increases in global and subnetwork efficiency and clustering coefficient, particularly in the somatomotor subnetwork. Conclusions Concentrated exposure and response prevention in unmedicated patients with OCD leads to decreased connectivity between the frontoparietal and limbic subnetworks and less flexibility of the connectivity of the subgenual anterior cingulate cortex, suggesting a more independent and stable network topology. This may represent less limbic interference on cognitive control subnetworks after treatment.acceptedVersio

Disentangling Within- and Between-Person Effects During Response Inhibition in Obsessive-Compulsive Disorder

Background: Obsessive-compulsive disorder (OCD) has been related to worse performance, abnormal brain activity, and functional connectivity during response inhibition. Whether these findings are indications of stable traits that contribute to the development of the disorder, or whether they are a result of the state severity of obsessions and anxiety, remains unclear since previous research mainly has employed cross-sectional designs. The present study aimed to assess longitudinal between- and within-person relationships between symptoms, task performance, right inferior frontal gyrus brain activation, and connectivity between the right amygdala and the right pre-supplementary motor area in 29 OCD patients before and after concentrated exposure and response prevention treatment. Method: Patients received exposure and response prevention delivered during 4 consecutive days, following the Bergen 4-day Treatment format. Patients performed a Stop Signal Task during 3T functional Magnetic Resonance Imaging the day before treatment, as well as 1 week and 3 months after treatment completion. Multilevel models were used to analyze disaggregated within- and between-person effects over time. Independent variables were scores on the symptom severity scales for OCD, anxiety, depression, and state distress during scanning. Dependent variables were reaction time for go trials, stop signal response time, task-related brain activation and connectivity. Results: A positive between-person effect was found for obsessive-compulsive, anxiety, and depressive symptom severity on go trial reaction time, indicating that patients with higher symptom scores on average respond slower during accurate go trials. We also found no significant between- or within-person relations between symptom severity and task-related activation or fronto-limbic connectivity. Conclusions: The between-person findings may point toward a general association between slower processing speed and symptom severity in OCD. Longitudinal studies should disaggregate between- and within-person effects to better understand variation over time.publishedVersio

Longitudinal changes in neurometabolite concentrations in the dorsal anterior cingulate cortex after concentrated exposure therapy for obsessive-compulsive disorder

Background The dorsal anterior cingulate cortex (dACC) plays an important role in the pathophysiology of obsessive-compulsive disorder (OCD) due to its role in error processing, cognitive control and emotion regulation. OCD patients have shown altered concentrations in neurometabolites in the dACC, particularly Glx (glutamate+glutamine) and tNAA (N-acetylaspartate+N-acetyl-aspartyl-glutamate). We investigated the immediate and prolonged effects of exposure and response prevention (ERP) on these neurometabolites. Methods Glx and tNAA concentrations were measured using magnetic resonance spectroscopy (1H-MRS) in 24 OCD patients and 23 healthy controls at baseline. Patients received concentrated ERP over four days. A subset was re-scanned after one week and three months. Results No Glx and tNAA abnormalities were observed in OCD patients compared to healthy controls before treatment or over time. Patients with childhood or adult onset differed in the change over time in tNAA (F(2,40) = 7.24, ɳ2p= 0.27, p = 0.004): concentrations increased between one week after treatment and follow-up in the childhood onset group (t(39) = -2.43, d = -0.86, p = 0.020), whereas tNAA concentrations decreased between baseline and follow-up in patients with an adult onset (t(42) = 2.78, d = 1.07, p = 0.008). In OCD patients with versus without comorbid mood disorders, lower Glx concentrations were detected at baseline (t(38) = -2.28, d = -1.00, p = 0.028). Glx increased after one week of treatment within OCD patients with comorbid mood disorders (t(30) = -3.09, d = -1.21, p = 0.004). Limitations Our OCD sample size allowed the detection of moderate to large effect sizes only. Conclusion ERP induced changes in neurometabolites in OCD seem to be dependent on mood disorder comorbidity and disease stage rather than OCD itself.publishedVersio

The thalamus and its subnuclei—a gateway to obsessive-compulsive disorder

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T-1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered (https://osf.io/73dvy) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status

The Emotional Brain in Obsessive-Compulsive Disorder

Background Obsessive-compulsive disorder (OCD) is characterized by distressing obsessions and time-consuming compulsions. The disorder affects 1-3% and can be highly impairing to daily functioning and detrimental to the quality of life. Cognitive behavioral therapy is an effective treatment for 50-75% of people with OCD, leaving a considerable minority who do not benefit from the best available treatments we have today. Neuroimaging has related the disorder to the function and structure of cortico-striato-thalamo-cortical and fronto-limbic circuits. A better understanding of these circuits might contribute to a better understanding of the disorder, how current treatments change the brain, and how we can help non-responders with better treatments in the future. This is likely particularly true for fronto-limbic and affective circuits, given their role in the formation, maintenance, and extinction of fear as well as motivating behavior. The aim of this dissertation was, first, to investigate how OCD is related to brain activation during emotional processing of aversive stimuli. Secondly, we wanted to examine if unaffected siblings of OCD patients showed similar anxiety, brain activation, and connectivity during emotion provocation and regulation as their OCD-affected siblings compared to unrelated healthy controls. Lastly, we wanted to investigate if the resting-state network structure changes in OCD patients directly after the Bergen 4-Day Treatment (B4DT), a concentrated and exposure-based psychological therapy. Methods Paper I was a meta-analysis of 25 functional neuroimaging studies comparing OCD patients and healthy controls during emotion processing, when participants were exposed to aversive or neutral stimuli. In Paper II we used functional magnetic resonance imaging (fMRI) to investigate distress, brain activation, and fronto-limbic connectivity during emotion provocation and regulation of neutral, fear-related, and OCD-related stimuli in 43 unmedicated OCD patients, 19 unaffected siblings, and 38 healthy controls. In Paper III we used resting-state fMRI to study the network structure of 28 OCD patients (21 unmedicated) and 19 healthy controls the day before and three days after B4DT. We examined static and dynamic graph metrics at the global, subnetwork, and regional levels, as well as between-subnetwork connectivity. Results In Paper I, we found that OCD patients showed more activation than healthy controls in the orbitofrontal cortex (OFC), extending into the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC), bilateral amygdala (extending into the right putamen), left inferior occipital cortex, and right middle temporal gyrus during aversive versus neutral stimuli. Meta-regressions showed that medication status and comorbidity moderated amygdala, occipital and ventromedial prefrontal cortex hyperactivation, while symptom severity moderated hyperactivation in medial frontal prefrontal and superior parietal regions. In Paper II we showed that unaffected siblings resembled healthy controls in task-related distress, less amygdala activation/altered timing than OCD patients during emotion provocation. During OCD-related emotion regulation siblings showed no significant difference in dmPFC activation versus either OCD patients or healthy controls, but showed more temporo-occipital activation and dmPFC-amygdala connectivity compared to healthy controls. In Paper III we found that unmedicated OCD patients showed more frontoparietal-limbic connectivity before treatment than healthy controls. This, along with sgACC flexibility, was reduced in OCD patients directly after B4DT. Conclusions OCD patients show hyperactivation of the amygdala and related structures, but this characteristic is not directly shared with unaffected siblings during provocation or regulation of emotional information. However, siblings seem to show compensatory activation and connectivity in other areas. The rapid changes in frontoparietal-limbic connectivity and subgenual ACC flexibility suggests that concentrated treatment leads to a more independent and stable network state. OCD is related to subtle alterations in limbic activation and fronto-limbic connectivity during both emotional tasks and resting-state, which seems to vary with comorbidity and is sensitive to treatment

Neurobiology of cognitive remediation therapy for schizophrenia: A systematic review

Cognitive impairment is an important aspect of schizophrenia, where cognitive remediation therapy (CRT) is a promising treatment for improving cognitive functioning. While neurobiological dysfunction in schizophrenia has been the target of much research, the neural substrate of cognitive remediation and recovery has not been thoroughly examined. The aim of the present article is to systematically review the evidence for neural changes after CRT for schizophrenia.The reviewed studies indicate that CRT affects several brain regions and circuits, including prefrontal, parietal, and limbic areas, both in terms of activity and structure. Changes in prefrontal areas are the most reported finding, fitting to previous evidence of dysfunction in this region. Two limitations of the current research are the few studies and the lack of knowledge on the mechanisms underlying neural and cognitive changes after treatment. Despite these limitations, the current evidence suggests that CRT is associated with both neurobiological and cognitive improvement. The evidence from these findings may shed light on both the neural substrate of cognitive impairment in schizophrenia, and how better treatment can be developed and applied

Symptom Dimensions in Obsessive-Compulsive Disorder as Predictors of Neurobiology and Treatment Response

Purpose of review: Specific symptom dimensions of obsessive-compulsive disorder (OCD) have been suggested as an approach to reduce the heterogeneity of obsessive-compulsive disorder, predict treatment outcome, and relate to brain structure and function. Here, we review studies addressing these issues. Recent findings: The contamination and symmetry/ordering dimensions have not been reliably associated with treatment outcome. Some studies found that greater severity of sexual/aggressive/religious symptoms predicted a worse outcome after cognitive behavioral therapy (CBT) and a better outcome after serotonin reuptake inhibitors (SRIs). Contamination symptoms have been related to increased amygdala and insula activation in a few studies, while sexual/aggressive/religious symptoms have also been related to more pronounced alterations in the function and structure of the amygdala. Increased pre-treatment limbic responsiveness has been related to better outcomes of CBT, but most imaging studies show that important limitations and replication in large-scale studies is needed. We review possible reasons for the strong limbic involvement of the amygdala in patients with more sexual/aggressive/religious symptoms, in relation to their sensitivity to CBT. Summary: Symptom dimensions may predict treatment outcome, and patients with sexual/religious/aggressive symptoms are at a greater risk of not starting or delaying treatment. This is likely partly due to more shame and perceived immorality which is also related to stronger amygdala response. Competently delivered CBT is likely to help these patients improve to the same degree as patients with other symptoms