Deep phenotyping of attention impairments and the 'Inattention Biotype' in Major Depressive Disorder

Abstract

Background: Attention impairment is an under-investigated feature and diagnostic criterion of Major Depressive Disorder (MDD) that is associated with poorer outcomes. Despite increasing knowledge regarding mechanisms of attention in healthy adults, we lack a detailed characterization of attention impairments and their neural signatures in MDD.

Methods: Here, we focus on selective attention and advance a deep multi-modal characterization of these impairments in MDD, using data acquired from n = 1008 patients and n = 336 age- and sex-matched healthy controls. Selective attention impairments were operationalized and anchored in a behavioral performance measure, assessed within a battery of cognitive tests. We sought to establish the accompanying neural signature using independent measures of functional magnetic resonance imaging (15% of the sample) and electroencephalographic recordings of oscillatory neural activity.

Results: Greater impairment on the behavioral measure of selective attention was associated with intrinsic hypo-connectivity of the fronto-parietal attention network. Not only was this relationship specific to the fronto-parietal network unlike other large-scale networks; this hypo-connectivity was also specific to selective attention performance unlike other measures of cognition. Selective attention impairment was also associated with lower posterior alpha (8-13 Hz) power at rest and was related to more severe negative bias (frequent misidentifications of neutral faces as sad and lingering attention on sad faces), relevant to clinical features of negative attributions and brooding. Selective attention impairments were independent of overall depression severity and of worrying or sleep problems.

Conclusions: These results provide a foundation for the clinical translational development of objective markers and targeted therapeutics for attention impairment in MDD.

Trial registration: ClinicalTrials.gov NCT00693849.

Keywords: Attention; EEG; behavioral testing; depression; functional MRI.

Conflict of interest statement

Conflict of interest. Over the past three years, L.M.W has received scientific advisory board fees from Psyberguide of the One Mind Institute and consultancy from Humana and Blackthorn Therapeutics for projects not related to this work.

Figures

Fig. 1.

Selective attention behavior in MDD patients v. healthy controls. Reaction times to Word- and Color-naming conditions of the selective attention task. MDD, Major depressive disorder. Error bars represent bootstrapped 95% confidence intervals.

Fig. 2.

Associations of attention impairments in MDD patients with dysfunction in various large-scale networks. Circuit dysfunction fit scores are calculated independently for each circuit according to hypothesized dysfunction (e.g. fronto-parietal network hypo-connectivity) and standardized to a sample of healthy controls (see Methods and eMethods for more details on circuit fit score quantification). Box plots represent reaction time distributions for healthy controls. ACC, Anterior cingulate cortex; AG, Angular gyrus; al, Anterior insula; alPL, Anterior inferior parietal lobule; amPFC, Anterior medial prefrontal cortex; dACC, Dorsal anterior cingulate cortex; DLPFC, Dorsolateral prefrontal cortex; mPFC, Medial prefrontal cortex; msPFC, Medial superior prefrontal cortex; PCC, Posterior cingulate cortex; PCu, Precuneus; RT, Reaction time; SLEA, Sublenticular extended amygdala; vMPFC, Ventromedial prefrontal cortex.

Fig. 3.

Association of selective attention impairment with average posterior alpha power (EEG) during eyes-closed and eyes-open rest periods. EC-EO, Difference between eyes-closed and eyes-open rest periods; RT, Reaction time.

Fig. 4.

Association of selective attention performance with negative valence bias on the emotional face identification task. (a) Association of selective attention performance with the difference in reaction times between Sad and Neutral faces or Sad and Happy faces on the emotional face identification task. (b) Association of selective attention performance with misidentifications of neutral faces as sad faces. MDD, Major depressive disorder; HC, Healthy controls; RT: Reaction time.

Fig. 5.

Network dysfunction and oscillatory power in an extreme Inattention Biotype group of MDD participants v. age- and sex-matched MDD participants without attention impairment. (a) Fronto-parietal network connectivity and resting posterior alpha power in participants with selective attention impairment v. those without. Error bars represent bootstrapped 95% confidence intervals. *p < 0.05, **p < 0.01. (b) Topography plots of alpha power and time-frequency transforms at the posterior electrode of interest.