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

J Affect Disord. 2024 Sep 15:361:415-424. doi: 10.1016/j.jad.2024.06.025. Epub 2024 Jun 13.

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.

MeSH terms

  • Adult
  • Bipolar Disorder* / diagnostic imaging
  • Bipolar Disorder* / metabolism
  • Bipolar Disorder* / physiopathology
  • Depressive Disorder, Major* / diagnostic imaging
  • Depressive Disorder, Major* / metabolism
  • Depressive Disorder, Major* / physiopathology
  • Emotions* / physiology
  • Fear / physiology
  • Female
  • Humans
  • Magnetic Resonance Imaging*
  • Male
  • Middle Aged
  • Positron-Emission Tomography*
  • Prefrontal Cortex* / diagnostic imaging
  • Prefrontal Cortex* / metabolism
  • Prefrontal Cortex* / physiopathology
  • Receptor, Metabotropic Glutamate 5* / metabolism
  • Young Adult

Substances

  • Receptor, Metabotropic Glutamate 5
  • GRM5 protein, human