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

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-HT 1A [(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-HT 1A 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-HT 1A 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.

Mechanisms of rumination change in adolescent depression (RuMeChange): study protocol for a randomised controlled trial of rumination-focused cognitive behavioural therapy to reduce ruminative habit and risk of depressive relapse in high-ruminating adolescents

“…Preliminary data and published studies include targeted seed-based analyses of connectivity between PCC (DMN node) and left inferior temporal gyrus (CCN node) [ 46 , 47 , 58 , 60 , 62 , 64 – 69 ]. Connectivity of PCC to inferior frontal gyrus (also CCN) was considered.…”

“…The CCN is a distinct network of distributed neural nodes that broadly supports integrative executive functions such as inhibitory control, working memory, and sustained complex attention [ 59 ]. One function of inhibitory control is its ability to modulate negative affective processes, including rumination [ 46 , 60 , 61 ]. Consistent with a CCN disruption hypothesis of elevated rumination, rs-fMRI studies have reported that disrupted/elevated DMN-CCN connectivity (and decreased within CCN connectivity) is associated with increased rumination and decreased inhibitory control [ 46 , 61 , 62 ].…”

Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model

“…Likewise, the neural, cognitive, information processing, and psychological patterns discussed above have broad transdiagnostic relevance, particularly with respect to other disorders of negative affect (e.g., anxiety, trauma-related conditions) 140 -that likewise respond to pharmacologic interventions with plasticity-enhancing properties 141,142 . Equally noteworthy, however, is the marked heterogeneity of depressed patients, which is evident at the neural network 143,144 , cognitive 145 , information processing 145,146 , and clinical 147 levels, and may help to explain the fact that no known intervention strategy is effective for all depressed patients. Rather than assuming a unitary etiology, and a correspondingly uniform pathway to recovery from depression, a focus on establishing correlations across levels of analysis-both before and after administering plasticity-enhancing interventions-will help to clarify the degree to which an integrative neuroplasticity model may be relevant to some individual forms of depression and negative affect, but not others 140 .…”

Neuropsychological Functioning in Users of Serotonergic Psychedelics – A Systematic Review and Meta-Analysis

“…Furthermore, tryptamines involve more 5-HT 1a R agonism than phenethylamines ( Halberstadt and Geyer, 2011 ). The 5-HT 1a R has been shown to play a role in cognitive control in both humans ( Langenecker et al, 2019 ) and animals ( Baba et al, 2015 ). In addition, use of a 5-HT 1a agonist over the course of 6 weeks has been shown to increase executive functioning in patients with schizophrenia ( Sumiyoshi et al, 2001 ).…”