Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment

Abstract

OBJECTIVE Deficits in positive affect and their neural bases have been associated with major depression. However, whether reductions in positive affect result solely from an overall reduction in nucleus accumbens activity and fronto-striatal connectivity or the additional inability to sustain engagement of this network over time is unknown. The authors sought to determine whether treatment-induced changes in the ability to sustain nucleus accumbens activity and fronto-striatal connectivity during the regulation of positive affect are associated with gains in positive affect. METHOD Using fMRI, the authors assessed the ability to sustain activity in reward-related networks when attempting to increase positive emotion during performance of an emotion regulation paradigm in 21 depressed patients before and after 2 months of antidepressant treatment. Over the same interval, 14 healthy comparison subjects underwent scanning as well. RESULTS After 2 months of treatment, self-reported positive affect increased. The patients who demonstrated the largest increases in sustained nucleus accumbens activity over the 2 months were those who demonstrated the largest increases in positive affect. In addition, the patients who demonstrated the largest increases in sustained fronto-striatal connectivity were also those who demonstrated the largest increases in positive affect when controlling for negative affect. None of these associations were observed in healthy comparison subjects. CONCLUSIONS Treatment-induced change in the sustained engagement of fronto-striatal circuitry tracks the experience of positive emotion in daily life. Studies examining reduced positive affect in a variety of psychiatric disorders might benefit from examining the temporal dynamics of brain activity when attempting to understand changes in daily positive affect.

Conflict of interest statement

Conflicts of Interest

Dr. Kalin has no conflicts to declare that are directly related to the data presented in this manuscript. However, he does consult to companies (including Wyeth Pharmaceuticals who funded this study) related to the development of new psychotropic agents (see below), has stock options in 2 companies (Corcept and CeNeRx) and is principal owner of a small biotech company aimed at the development of novel antidepressants (Promoter Neurosciences). Consultant or Scientific Advisory Board: Astra Zeneca; Bristol-Myers-Squibb; CeNeRx Biopharma; Corcept; Cyberonics; Forest Laboratories; General Electric Corp; Jazz Pharmaceuticals, Ely Lilly; Neuronetics; Sanofi Syntholabs; Wyeth Pharmaceuticals. Stockholder or Equity: Corcept Biosciences; CeNeRx. Owner: Promoter Neurosciences, LLC. All other authors declare no competing interests.

Figures

Figure 1

Changes in HAMD, self-reported positive affect and negative affect from 0 – 2 months. * = p

Figure 2

For those who completed the trial, those individuals displaying the greatest improvement in sustained nucleus accumbens activity also showed the largest gains in self-reported positive affect. X-axis reflects individual differences in changes in sustained nucleus accumbens activity from pre- to post-treatment (2 month post-treatment(2nd Half – 1st Half) – Pretreatment Baseline(2nd Half – 1st Half)). Y-axis reflects gains in self-reported positive affect. Blue dots represent depressed patients on Venlafaxine, green dots represent patients on Fluoxetine.

Figure 3

A) Increases in sustained nucleus accumbens-middle frontal gyrus (BA 10/46) connectivity is related to gains in self-reported positive affect after controlling for changes in self-reported negative affect. B) For scatter plot, X-axis reflects changes in sustained nucleus accumbens-middle frontal gyrus connectivity from pre- to post-treatment (2 month post-treatment(2nd Half – 1st Half) – Pretreatment Baseline(2nd Half – 1st Half)). Y-axis reflects gains in positive affect after controlling for changes in negative affect. Blue dots represent depressed patients on Venlafaxine, green dots represent patients on Fluoxetine.