Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder.

Scott A Langenecker,David Goldman,Stanley J Watson,Huda Akil,Tiffany M Love,Peter Eichhammer,Susan E Kennedy,Robert A Koeppe,Saulo M Ribeiro,Brian J Mickey,Jon-Kar Zubieta,David T Hsu,Kathleen H Elverman,Mary M Heitzeg,Margit Burmeister,Srijan Sen

doi:10.3389/fpsyg.2019.00691

Abstract

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.

Highlights

An enduring, but incomplete observation in MDD (Major Depressive Disorder) is of serotonin dysfunction
We further investigated relationships of fMRI BOLD responses during a Cognitive Control task based upon 5-HT1A binding potential (BP) in the MDD sample, including fMRI BOLD responses based upon degree of 5-HT1A BPND in the MDD sample [Hyp 4 of lowered 5-HT1A BPND correlated with lowered activation in Cognitive Control region(s)]
Half of the MDD group was below the 5th percentile of 5-HT1A BPND for the Z normed average of the regions of significant effects (RSEs) relative to the healthy comparison (HC) group

Summary

Introduction

But incomplete observation in MDD (Major Depressive Disorder) is of serotonin dysfunction. Functional loci at genes that mediate serotonergic function have been implicated in MDD both alone, and via interaction with early life stress (Hariri et al, 2002, 2006; Sen et al, 2004; Neumeister et al, 2006; Surtees et al, 2006; Gotlib et al, 2008; Mak et al, 2013) Fourth, some of these functional variants in genes (modulating serotonin function) alter brain responses to emotion and brain connectivity (Dannlowski et al, 2008; Kalin et al, 2008; Elton et al, 2014; Wessa and Lois, 2015). A short review of the relevant links of serotonin dysfunction in MDD and of potential multimodal intermediate phenotypes [IPs (Burmeister et al, 2008; Kalin et al, 2008; Tan et al, 2008; Langenecker et al, 2010; Webb et al, 2016)] is conducted to integrate these separate lines of inquiry

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Discussion

Conclusion