Intrinsic functional neurocircuitry associated with treatment response to transdiagnostic CBT in bipolar disorder with anxiety

Abstract

Background: Anxiety in bipolar disorder (BD) exacerbates emotion dysregulation and reduces treatment response. We recently conducted a pilot trial of transdiagnostic CBT to target anxiety and emotion dysregulation in BD adjunctive to pharmacotherapy. Reductions in depression and anxiety symptoms were significantly predicted by baseline levels of neuroticism and perceived affective control, as well as changes over time in emotion regulation skills. The present study investigates mechanism of treatment response by examining the relationship between baseline emotion regulation-related neural circuitry and trial outcomes.

Methods: Nineteen patients completed baseline resting state fMRI scans prior to treatment randomization. Functional connectivity between the anterior insula (AI) and regions in the salience network (SN), default mode network (DMN), and executive control network (ECN) were examined as predictors of baseline and treatment-related changes in emotion regulation.

Results: Greater improvements in emotion regulation were predicted by weaker right dorsal AI - right ventrolateral prefrontal cortex (VLPFC; SN) and stronger bilateral dorsal AI - bilateral amygdala functional connectivity. Baseline neuroticism was negatively correlated with right dorsal AI- inferior parietal lobule (ECN) functional connectivity, and baseline deficits in perceived affective control were positively associated with ventral AI - bilateral dACC (SN) connectivity.

Limitations: Small sample limits interpretability of treatment-specific effects.

Conclusion: Baseline functional connectivity of emotion-regulation related neural circuitry significantly predicted change in emotion regulation-related dimensions associated with anxiety and depression symptom reduction. Future studies are needed to determine if employing methods such as neuromodulation to rehabilitate relevant neural circuitry may improve ultimate treatment outcomes of transdiagnostic CBT for BD and anxiety.

Keywords: Anterior insula; Anxiety disorders; Bipolar disorder; Emotion regulation; Functional connectivity networks.

Figure 1.

Functional network ROI locations. A) Anterior insula ROIs. Masked clusters include bilateral 2mm spherical masks from dorsal and ventral mid anterior insula, derived from Kelly et al. (2012). Masks available for download at http://fcon_1000.projects.nitrc.org. B) Functional network target regions. ROI masks derived from the Wake Forest University Pickatlas (WFU PickAtlas) Automatic Anatomical Labeling tool using 10mm spherical ROIs. Center of spheres selected from functional network max voxel locations specified in Seeley et al. (2007), listed as MNI coordinates (x, y, z). Salience network (SN): (a) right dACC (6, 22, 30); (b) left dACC (−6, 18, 30); (c) left VLPFC/DLPFC (−38, 52, 10); (d) right VLPFC (42, 46, 0); Frontoparietal executive control network (ECN): (e) right lateral parietal (38, −56, 44), (f) right DLPFC (46, 46, 14); (g) left inferior parietal lobule (−48, −48, 48); (h) left DLPFC (−34, 46, 10). Default mode network (DMN): (i) right vmPFC (2, 36, 10); (j) right posterior cingulate cortex (7, −43, 33); (k) left posterior cingulate cortex (−7, −43, 33); (l) left vmPFC (−2, 36, 10)

Figure 1.

Functional network ROI locations. A) Anterior insula ROIs. Masked clusters include bilateral 2mm spherical masks from dorsal and ventral mid anterior insula, derived from Kelly et al. (2012). Masks available for download at http://fcon_1000.projects.nitrc.org. B) Functional network target regions. ROI masks derived from the Wake Forest University Pickatlas (WFU PickAtlas) Automatic Anatomical Labeling tool using 10mm spherical ROIs. Center of spheres selected from functional network max voxel locations specified in Seeley et al. (2007), listed as MNI coordinates (x, y, z). Salience network (SN): (a) right dACC (6, 22, 30); (b) left dACC (−6, 18, 30); (c) left VLPFC/DLPFC (−38, 52, 10); (d) right VLPFC (42, 46, 0); Frontoparietal executive control network (ECN): (e) right lateral parietal (38, −56, 44), (f) right DLPFC (46, 46, 14); (g) left inferior parietal lobule (−48, −48, 48); (h) left DLPFC (−34, 46, 10). Default mode network (DMN): (i) right vmPFC (2, 36, 10); (j) right posterior cingulate cortex (7, −43, 33); (k) left posterior cingulate cortex (−7, −43, 33); (l) left vmPFC (−2, 36, 10)

Figure 2.

Relationship (Pearson’s r) between A) baseline levels of neuroticism and right dorsal AI – left IPL functional connectivity; and B) baseline levels of perceived affective control and right ventral AI – right dACC functional connectivity. Functional connectivity values reflect r-to-z-transformed scores. Higher NEO-Neuroticism scores reflect higher levels of neuroticism. Higher ACS scores reflect greater deficits in perceived affective control.

Figure 3.

Relationship (Pearson’s r) between slope of change (slope b) in perceived affective control (ACS scores) and baseline functional connectivity between A) left ventral anterior insula – right VLPFC; B) right dorsal anterior insula – right VLPFC; C) right dorsal anterior insula – left amygdala; and D) left dorsal anterior insula – left amygdala. Functional connectivity values reflect r-to-z-transformed scores. Change slope scores represent the slope of change in ACS scores over 6 monthly assessments. Negative change score values represent linear reductions in ACS scores over time. Higher ACS scores reflect greater deficits in perceived affective control. Displayed ß and p-values represent results of linear regression models controlling for age, gender, and medication load. *Result shown is uncorrected; did not survive corrections for multiple comparisons.