Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder

Abstract

Background: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD.

Methods: Positron emission tomography (PET) with [¹⁸F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25).

Results: Consistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028).

Limitations: The modest sample size is the primary limitation.

Conclusions: Deficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

Keywords: Bipolar disorder; Dorsolateral prefrontal cortex; Functional magnetic resonance imaging; Metabotropic glutamate receptor 5; Orbitofrontal cortex; Positron emission tomography.

Figure 1.. Regions of hyperactivation during implicit processing of fearful affect in BD.

[A] Significant clusters (voxel p<0.005, cluster p<0.05) identified in a voxel-wise ANOVA testing for an overall main effect of group are visualized in common space in the axial orientation. Each of the five clusters is indicated by an arrowhead in a color that coordinates with colored text on Table 2 and [B] bar graph x-axis labels. Bar graph displays extracted individual subject β-weights (line at group mean) and pairwise group comparisons for each cluster [post hoc tests with Bonferroni’s (family-wise error, FWE) correction for multiple comparisons]: * p_FWE <0.05; ** p_FWE <0.01; *** p_FWE <0.001 relative to BD.

Figure 2.. Negative correlations between prefrontal mGlu5 receptor availability and FEAR BOLD response in BD.

Significant clusters (voxel p<0.005, cluster p<0.05) identified in a voxel-wise ANCOVA testing for correlations between [A] dlPFC and [B] OFC mGlu5 receptor availability ([¹⁸F]FPEB V_T) and brain activation during implicit processing of fearful facial expressions (fMRI FEAR BOLD β) among individuals with BD are visualized in common space in the axial orientation. Each of the significant clusters is indicated by an arrowhead in a color that coordinates with colored text on Table 3. Negative relationships between [¹⁸F]FPEB V_T values and ANCOVA-identified cluster mean FEAR BOLD β weights are shown for [C] dlPFC and [D] OFC.

Figure 3.. Correlations with clinical features in BD.

Significant positive correlation between clusters of hyper-activation in the BD group (FEAR BOLD β) and [A] impulsiveness as measured by the Barratt Impulsiveness Scale (BIS), and [B] negative correlations with verbal memory as assessed by the International Shopping List Delayed Recall (ISLR) task. Exact Pearson’s r and associated p-values are provided in Table 3. Significant correlations between dlPFC and OFC mGlu5-related FEAR BOLD and [C] psychomotor function, as measured by the Detection Test (DET), and [D] attentional difficulties assessed by the Identification Test (IDN). [E] Exact Pearson’s r and associated p-values are provided in the table. Abbreviations: dorsolateral prefrontal cortex (dlPFC); left (L); orbitofrontal cortex (OFC); right (R); supramarginal gyrus (SMG); Rolandic operculum (R operc.)