Role of Variation in the Serotonin Transporter Protein Gene (SLC6A4) in Trait Disturbances in the Ventral Anterior Cingulate in Bipolar Disorder

Abstract

Bipolar disorder (BD) is associated with abnormalities of the ventral anterior cingulate cortex (vACC) and its connection sites, including the amygdala, which are key components of a corticolimbic neural system that subserves emotional regulation. Decreased functional connectivity from the vACC to the amygdala in healthy individuals is associated with the short "s" allele-as opposed to the long "l" allele-of a well-known serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4), as are features of BD. This study tests the hypothesis that the s allele influences dysfunction in the vACC-amygdala neural system in BD. Thirty euthymic individuals with BD (20 s carriers, 10 ll) and 48 healthy comparison (HC) participants (34 s, 14 ll) participated in an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, vACC activation was significantly lower in the BD compared to the HC group, and in s carriers compared to ll individuals within both the HC and BD groups, such that BD s carriers exhibited the greatest magnitude of vACC dysfunction. No significant differences were detected in amygdala activation. The findings suggest that the 5-HTTLPR s allele may contribute to a traitrelated, genetically-derived, neurobiological subgroup within BD characterized by prominent vACC dysfunction. Future treatment may be optimized for this BD subgroup by targeting the serotonergic system and the vACC.

Stress Reactivity and Corticolimbic Response to Emotional Faces in Adolescents

“…30,31 In brief, subjects viewed fearful, happy, and neutral human faces from the Ekman series. 32 Each face stimulus was displayed for 2s during which participants were instructed to make a gender judgment using a two-response button box.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Consistent with these behavioral data, brain imaging studies demonstrate an association between the s allele and higher levels of amygdala activation in response to fearful stimuli (Furmark et al, 2004;Hariri et al, 2002;Kobiella et al, 2011;Murphy et al, 2013;Scharinger et al, 2010), reduced grey matter volumes in the dorsolateral PFC, amygdala and the HPC (Atmaca et al, 2011;Frodl et al, 2008;Kobiella et al, 2011;Pezawas et al, 2005), microstructural changes in the uncinate fasciclus, a white matter tract connecting limbic and frontal areas, including the amygdala and anterior cingulate cortex (Pacheco et al, 2009), and decreased coupling of the amygdala-anterior cingulate circuit (Heinz et al, 2005;Lemogne et al, 2011;Pezawas et al, 2005;Roiser et al, 2009;Shah et al, 2009;Volman et al, 2013). Importantly, functional coupling between the anterior cingulate cortex and the amygdala is correlated with trait anxiety (Hahn et al, 2011;Prater et al, 2013).…”

Neural Activation During Facial Emotion Processing in Unmedicated Bipolar Depression, Euthymia, and Mania

“…(18) found decreased left DLPFC activity and elevated striatal activation in response to fearful faces in euthymic participants versus control subjects. Similarly, during fearful face processing, ventral ACC activation was significantly lower in a remitted group compared with control subjects (19). Compared with control subjects, euthymic participants showed hyperactivation in inferior PFC regions but no difference in amygdala activations during a fearful and angry facial emotion processing task (20).…”