Defining biotypes for depression and anxiety based on large-scale circuit dysfunction: a theoretical review of the evidence and future directions for clinical translation

Abstract

Complex emotional, cognitive and self-reflective functions rely on the activation and connectivity of large-scale neural circuits. These circuits offer a relevant scale of focus for conceptualizing a taxonomy for depression and anxiety based on specific profiles (or biotypes) of neural circuit dysfunction. Here, the theoretical review first outlines the current consensus as to what constitutes the organization of large-scale circuits in the human brain identified using parcellation and meta-analysis. The focus is on neural circuits implicated in resting reflection (default mode), detection of "salience," affective processing ("threat" and "reward"), "attention," and "cognitive control." Next, the current evidence regarding which type of dysfunctions in these circuits characterize depression and anxiety disorders is reviewed, with an emphasis on published meta-analyses and reviews of circuit dysfunctions that have been identified in at least two well-powered case:control studies. Grounded in the review of these topics, a conceptual framework is proposed for considering neural circuit-defined "biotypes." In this framework, biotypes are defined by profiles of extent of dysfunction on each large-scale circuit. The clinical implications of a biotype approach for guiding classification and treatment of depression and anxiety is considered. Future research directions will develop the validity and clinical utility of a neural circuit biotype model that spans diagnostic categories and helps to translate neuroscience into clinical practice in the real world.

Keywords: anxiety/anxiety disorders; biological markers; brain; depression; functional MRI; imaging/neuroimaging; mood disorders.

Figure 1

Large-scale intrinsic and task-evoked circuits identified in the extant literature Abbreviations: ACC, Anterior Cingulate Cortex; AG, Angular Gyrus; aI, Anterior Insula, aIPL, Anterior Inferior Parietal Lobule; amPFC, Anterior Medial Prefrontal Cortex; dACC, Dorsal Anterior Cingulate Cortex; DLPFC*, Dorsolateral Prefrontal Cortex + Anterior Prefrontal Cortex + Inferior Frontal Cortex; DPC, Dorsal Parietal Cortex; Hipp, Hippocampus; LPFC, Lateral Prefrontal Cortex; mPFC, Medial Prefrontal Cortex; msPFC, Medial Superior Prefrontal Cortex; OFC, Orbitofrontal Cortex; PCC, Posterior Cingulate Cortex; PCG, Precentral Gyrus; PCu, Precuneus; SLEA, Sublenticular Extended Amygdala; vMPFC, Ventromedial Prefrontal Cortex

Figure 2

Types of neural circuit dysfunction underlying phenotypes of depression and anxiety, based on current knowledge. These dysfunctions are described in terms of both the neural circuit involved (e.g., “reward”) and the clinical phenomenology (e.g., “anhedonia”) related to each dsyfunction. Abbreviations: ACC, Anterior Cingulate Cortex; AG, Angular Gyrus; aI, Anterior Insula, aIPL, Anterior Inferior Parietal Lobule; amPFC, Anterior Medial Prefrontal Cortex; dACC, Dorsal Anterior Cingulate Cortex; DLPFC*, Dorsolateral Prefrontal Cortex + Anterior Prefrontal Cortex + Inferior Frontal Cortex; DPC, Dorsal Parietal Cortex; Hipp, Hippocampus; LPFC, Lateral Prefrontal Cortex; mPFC, Medial Prefrontal Cortex; msPFC, Medial Superior Prefrontal Cortex; OFC, Orbitofrontal Cortex; PCC, Posterior Cingulate Cortex; PCG, Precentral Gyrus; PCu, Precuneus; SLEA, Sublenticular Extended Amygdala; vMPFC, Ventromedial Prefrontal Cortex

Figure 3

An illustration of theoretical profiles envisioned for future clinical translation and use of neural circuit dsyfunctions at the individual patient level.