scholarly journals 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

2021 ◽  
Vol 46 (2) ◽  
Author(s):  
Duncan G.J. Green ◽  
Jinhee Kim ◽  
Stephen J. Kish ◽  
Rachel F. Tyndale ◽  
Matthew N. Hill ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Prefrontal Cortex ◽  
Functional Connectivity ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Ventromedial Prefrontal Cortex ◽  
Emission Tomography ◽  
Positron Emission ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

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.

scholarly journals Elevated fatty acid amide hydrolase in the prefrontal cortex of borderline personality disorder: a [11C]CURB positron emission tomography study

2020 ◽  
Vol 45 (11) ◽  
pp. 1834-1841 ◽  
Author(s):  
N. J. Kolla ◽  
R. Mizrahi ◽  
K. Karas ◽  
C. Wang ◽  
R. M. Bagby ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Prefrontal Cortex ◽  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Borderline Personality ◽  
Emission Tomography ◽  
Positron Emission ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Abstract Amygdala-prefrontal cortex (PFC) functional impairments have been linked to emotion dysregulation and aggression in borderline personality disorder (BPD). Fatty acid amide hydrolase (FAAH), the major catabolic enzyme for the endocannabinoid anandamide, has been proposed as a key regulator of the amygdala-PFC circuit that subserves emotion regulation. We tested the hypothesis that FAAH levels measured with [11C]CURB positron emission tomography in amygdala and PFC would be elevated in BPD and would relate to hostility and aggression. Twenty BPD patients and 20 healthy controls underwent FAAH genotyping (rs324420) and scanning with [11C]CURB. BPD patients were medication-free and were not experiencing a current major depressive episode. Regional differences in [11C]CURB binding were assessed using multivariate analysis of covariance with PFC and amygdala [11C]CURB binding as dependent variables, diagnosis as a fixed factor, and sex and genotype as covariates. [11C]CURB binding was marginally elevated across the PFC and amygdala in BPD (p = 0.08). In a priori selected PFC, but not amygdala, [11C]CURB binding was significantly higher in BPD (11.0%, p = 0.035 versus 10.6%, p = 0.29). PFC and amygdala [11C]CURB binding was positively correlated with measures of hostility in BPD (r > 0.4; p < 0.04). This study is the first to provide preliminary evidence of elevated PFC FAAH binding in any psychiatric condition. Findings are consistent with the model that lower endocannabinoid tone could perturb PFC circuitry that regulates emotion and aggression. Replication of these findings could encourage testing of FAAH inhibitors as innovative treatments for BPD.

scholarly journals Voxel level quantification of [11C]CURB, a radioligand for Fatty Acid Amide Hydrolase, using high resolution positron emission tomography

PLoS ONE ◽  
2018 ◽  
Vol 13 (2) ◽  
pp. e0192410
Author(s):  
Pablo M. Rusjan ◽  
Dunja Knezevic ◽  
Isabelle Boileau ◽  
Junchao Tong ◽  
Romina Mizrahi ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Fatty Acid ◽  
High Resolution ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Emission Tomography ◽  
Positron Emission ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [11C]CURB

2015 ◽  
Vol 35 (11) ◽  
pp. 1827-1835 ◽  
Author(s):  
Isabelle Boileau ◽  
Pablo M Rusjan ◽  
Belinda Williams ◽  
Esmaeil Mansouri ◽  
Romina Mizrahi ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Fatty Acid ◽  
Human Brain ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Emission Tomography ◽  
Positron Emission ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Positron emission tomography with [11C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test–retest reliability of [11C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test–retest [11C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n = 2 each). The composite parameter γ k3 (an index of FAAH activity, γ = K1/ k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [11C]CURB injection. Oral administration of PF-04457845 reduced [11C]CURB binding to a homogeneous level at all three doses, with γ k3 values decreased by ≥91%. Excellent reproducibility and good reliability (test–retest variability = 9%; intraclass correlation coefficient = 0.79) were observed across all regions of interest investigated. Our findings suggest that γ k3/[11C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.

scholarly journals Lower amygdala fatty acid amide hydrolase in violent offenders with antisocial personality disorder: an [11C]CURB positron emission tomography study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathan J. Kolla ◽  
Isabelle Boileau ◽  
Karolina Karas ◽  
Jeremy J. Watts ◽  
Pablo Rusjan ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Antisocial Personality Disorder ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Reactive Aggression ◽  
Emission Tomography ◽  
Antisocial Personality ◽  
Positron Emission ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

AbstractAntisocial personality disorder (ASPD) imposes a high societal burden given the repetitive reactive aggression that affected individuals perpetrate. Since the brain endocannabinoid system (ECS) has been implicated in ASPD and aggressive behavior, we utilized [11C]CURB positron emission tomography to investigate fatty acid amide hydrolase (FAAH), an enzyme of the ECS that degrades anandamide, in 16 individuals with ASPD and 16 control participants. We hypothesized that FAAH density would be lower in the amygdala for several reasons. First, decreased FAAH expression is associated with increased cannabinoid receptor 1 stimulation, which may be responsible for amygdala hyper-reactivity in reactive aggression. Second, the amygdala is the seat of the neural circuit mediating reactive aggression. Third, other PET studies of externalizing populations show reduced brain FAAH density. Conversely, we hypothesized that FAAH expression would be greater in the orbitofrontal cortex. Consistent with our hypothesis, we found that amygdala FAAH density was lower in the amygdala of ASPD (p = 0.013). Cerebellar and striatal FAAH expression were inversely related with impulsivity (cerebellum: r = −0.60, p = 0.017; dorsal caudate: r = −0.58, p = 0.023; dorsal putamen: r = −0.55, p = 0.034), while cerebellar FAAH density was also negatively associated with assaultive aggression (r = −0.54, p = 0.035). ASPD presents high levels of disruptive behavior with few, if any, efficacious treatment options. Novel therapeutics that increase FAAH brain levels in a region-specific manner could hold promise for attenuating certain symptom clusters of ASPD, although our results require replication.

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