Pregenual Anterior Cingulate Dysfunction Associated with Depression in OCD: An Integrated Multimodal fMRI/1H MRS Study

Abstract

Depression is a commonly occurring symptom in obsessive-compulsive disorder (OCD), and is associated with worse functional impairment, poorer quality of life, and poorer treatment response. Understanding the underlying neurochemical and connectivity-based brain mechanisms of this important symptom domain in OCD is necessary for development of novel, more globally effective treatments. To investigate biopsychological mechanisms of comorbid depression in OCD, we examined effective connectivity and neurochemical signatures in the pregenual anterior cingulate cortex (pACC), a structure known to be involved in both OCD and depression. Resting-state functional magnetic resonance imaging (fMRI) and H magnetic resonance spectroscopy (MRS) data were obtained from participants with OCD (n=49) and healthy individuals of equivalent age and sex (n=25). Granger causality-based effective (directed) connectivity was used to define causal networks involving the right and left pACC. The interplay between fMRI connectivity,H MRS and clinical data was explored by applying moderation and mediation analyses. We found that the causal influence of the right dorsal anterior midcingulate cortex (daMCC) on the right pACC was significantly lower in the OCD group and showed significant correlation with depressive symptom severity in the OCD group. Lower and moderate levels of glutamate (Glu) in the right pACC significantly moderated the interaction between right daMCC-pACC connectivity and depression severity. Our results suggest a biochemical-connectivity-psychological model of pACC dysfunction contributing to depression in OCD, particularly involving intracingulate connectivity and glutamate levels in the pACC. These findings have implications for potential molecular and network targets for treatment of this multi-faceted psychiatric condition.

A connectional hub in the rostral anterior cingulate cortex links areas of emotion and cognitive control

“…This view conforms with and extends the disconnection hypothesis (Catani and ffytche, 2005): Damage to a hub region can cause disconnection between a wide range of functional modalities, and correspondingly, a spectrum of affective and cognitive disorders. The disconnection hypothesis is in line with the broadly observed rACC abnormality in various diseases, including major depression disorder (MDD) (Mayberg et al, 1997; Pizzagalli, 2011), obsessive-compulsive disorder (OCD) (Beucke et al, 2014; Tadayonnejad et al, 2018), attention deficit hyperactivity disorder (Tomasi and Volkow, 2012), and posttraumatic stress disorder (Bryant et al, 2008; Kennis et al, 2015; Patel et al, 2012). Based on the FC areas sending convergent inputs to the hub, dysconnectivity with the hub may be involved in the imbalance between goal directed control, emotion and higher cognition in these disorders.…”

Effects of short‐term cognitive‐coping therapy on resting‐state brain function in obsessive‐compulsive disorder

“…Third, OCD patients who had comorbidity with depression or anxiety were not excluded, as the comorbidity issue is common in the clinically psychiatric diagnosis. Some evidence suggest that OCD patients with comorbidity of depression or anxiety have different neuroimaging results, compared with those without (Cardoner et al., 2007; Kong et al., 2020; Remijnse et al., 2013; Saxena et al., 2001; Tadayonnejad et al., 2018; Thorsen et al., 2018). Our data warranted larger sample size in future studies is needed to examine the effect of CCT on OCD patients with the comorbidity and those without.…”

Sequential multi-locus transcranial magnetic stimulation for treatment of obsessive-compulsive disorder with comorbid major depression: A case series

“…The therapeutic benefit of DLPFC stimulation may be mediated through connections to the subgenual [9] and pregenual [10] anterior cingulate cortex. Interestingly, in Tadayonnejad et al (2018) study, pregenual anterior cingulate cortex was shown to mediate the abnormal interaction between cortico-striatal-thalamo-cortical OCD and frontolimbic MDD circuits. We suggest that DLPFC TMS by modulating pregenual anterior cingulate cortex function not only impacts within (DMN) circuit dynamics but also between (OCD and MDD) circuits interaction.…”

“…Epidemiologic studies have shown that OCD symptoms generally precedes the occurrence of depression, suggesting a causal interacting model in which OCD predisposes to development of depressive symptoms [5]. In line with that causal model, Tadayonnejad et al showed aberrant effective (directional) connectivity between OCD and MDD circuits may be a potential network mechanism of depressive symptom genesis or worsening in OCD-MDD [6]. The challenging nature of this comorbidity necessitates the development of novel, more effective treatments.…”