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

Functional connectivity is frequently used to quantify the complex synchronous distributed fluctuations in neuronal activity derived from functional Magnetic Resonance Imaging and to generate network representations of human brain function. Such "functional connectomes" have great promise for mechanistic studies and for clinical translation. However, we do not know to what extent a functional connectome is stable over time for an individual. In the present work, we evaluate the short-term test-retest reliability of functional connectomes in a large publicly available sample of healthy participants (N=833) scanned on two consecutive days. We also assess the consequences on reliability of three methodological procedures for which a clear guideline in the community is lacking: atlas choice, global signal regression and thresholding. By adopting the intraclass correlation coefficient as a reliability metric, we demonstrate that a relatively small portion of the intrinsic functional connectome is characterized by good (4-6%) to excellent (0.08-1%) stability over time. In particular, connectivity between prefrontal, parietal and temporal areas appears to be especially stable over short timescales. Also, while unreliable edges of the functional connectome are generally weak in terms of average functional connectivity, reliable edges are not necessarily strong. Methodologically, we demonstrate that multimodal parcellation and averaging of connections within known networks are practices that improve reliability. Harnessing this knowledge, for example by honing in on the reliable portion of the connectome, offers one way forward for studies of trait-like features within the normative connectome and for discovery of biomarkers in clinical cohorts.

Psychopathy is a personality disorder characterized by antisocial behavior, lack of remorse and empathy, and impaired decision making. The disproportionate amount of crime committed by psychopaths has severe emotional and economic impacts on society. Here we examine the neural correlates associated with psychopathy to improve early assessment and perhaps inform treatments for this condition. Previous resting-state functional magnetic resonance imaging (fMRI) studies in psychopathy have primarily focused on regions of interest. This study examines whole-brain functional connectivity and its association to psychopathic traits. Psychopathy was hypothesized to be characterized by aberrant functional network connectivity (FNC) in several limbic/paralimbic networks. Group-independent component and regression analyses were applied to a data set of resting-state fMRI from 985 incarcerated adult males. We identified resting-state networks (RSNs), estimated FNC between RSNs, and tested their association to psychopathy factors and total summary scores (Factor 1, interpersonal/affective; Factor 2, lifestyle/antisocial). Factor 1 scores showed both increased and reduced functional connectivity between RSNs from seven brain domains (sensorimotor, cerebellar, visual, salience, default mode, executive control, and attentional). Consistent with hypotheses, RSNs from the paralimbic system-insula, anterior and posterior cingulate cortex, amygdala, orbital frontal cortex, and superior temporal gyrus-were related to Factor 1 scores. No significant FNC associations were found with Factor 2 and total PCL-R scores. In summary, results suggest that the affective and interpersonal symptoms of psychopathy (Factor 1) are associated with aberrant connectivity in multiple brain networks, including paralimbic regions.

This study is the first to examine the anatomical specificity of thalamo-cortical connectivity disturbances in MDD. Subjects with MDD demonstrated altered thalamo-cortical connectivity characterized by a complex pattern of region-dependent hypo- or hyperconnectivity. We therefore speculate that selectively modulating the connectivity of thalamo-cortical circuitry may be a potential novel therapeutic mechanism for MDD.