Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: a combined positron emission tomography and magnetic resonance imaging study in healthy individuals

Abstract

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control. Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest. Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = –0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05). Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity. Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

Genetic variation in endocannabinoid signaling is associated with differential network‐level functional connectivity in youth

“…In adults, converging evidence across species has observed lower anxiety symptoms and greater resting‐state fronto‐amygdala connectivity in carriers of the A‐allele variant, relative to non‐carriers (Dincheva et al., 2015; Gärtner et al., 2019). Furthermore, recent work found that the strength of fronto‐amygdala connectivity was inversely correlated with amygdalar binding of a FAAH probe, although this study did not find evidence for a relationship between fronto‐amygdala connectivity and the FAAH C385A polymorphism (Green et al, 2021). Other studies have identified A‐allele carriers as having lower threat‐related amygdala reactivity (Hariri et al., 2009), as well as faster amygdala habituation to threat (Gunduz‐Cinar et al., 2013).…”

The influence of FAAH genetic variation on physiological, cognitive, and neural signatures of fear acquisition and extinction learning in women with PTSD

“…Interestingly, administering a FAAH inhibitor is not the only way to examine the effects of elevated AEA on fear conditioning processes - there is also a fairly common functional single nucleotide polymorphism (SNP) in the FAAH gene (C385A; rs324420) that results in lower levels of FAAH protein, and as a result, increased AEA concentrations ( Mayo et al, 2020a , Sipe et al, 2002 , Spagnolo et al, 2016 ). Interestingly, individuals that possess the FAAH C385C → A mutation exhibit elevated AEA concentrations (due to lower FAAH expression) in the amygdala and enhanced fear extinction recall neurocircuitry (i.e., enhanced regulation of amygdala by ventromedial prefrontal cortex; vmPFC), which is in contrast to women with PTSD who typically exhibit altered fear extinction neurocircuitry (e.g., amygdala hyperreactivity, vmPFC and hippocampal hyporeactivity) and poor extinction learning ( Mayo et al, 2021 , Mayo et al, 2020a , Green et al, 2021 ). Similar to FAAH inhibition, in addition to accelerated fear extinction learning ( Dincheva et al, 2015 ), elevated AEA due to this genetic polymorphism has also been linked to decreased anxiety responses following the presentation of stress- and threat-inducing stimuli ( Hariri et al, 2009 ) in healthy humans without a clinical anxiety disorder, and lower hyperarousal symptoms in adults with PTSD ( Spagnolo et al, 2016 ).…”

Higher trait neuroticism is associated with greater fatty acid amide hydrolase binding in borderline and antisocial personality disorders

“…There are very few studies that have explored in vivo measures of personality functioning in ASPD or BPD and none to our knowledge that have specifically assayed components of the ECS, apart from one functional MRI study of healthy individuals that found no relationship between neuroticism and amygdala [ 11 C]CURB λ k 3 35 . Here, we focused on the relationship between FAAH binding and neuroticism in personality disorders.…”