The neural basis of hot and cold cognition in depressed patients, unaffected relatives, and low-risk healthy controls: An fMRI investigation

Abstract

Background: Modern cognitive neuropsychological models of depression posit that negatively biased emotional ("hot") processing confers risk for depression, while preserved executive function ("cold") cognition promotes resilience.

Methods: We compared neural responses during hot and cold cognitive tasks in 99 individuals: those at familial risk for depression (N = 30 unaffected first-degree relatives of depressed individuals) and those currently experiencing a major depressive episode (N = 39 unmedicated depressed patients) with low-risk healthy controls (N = 30). Primary analyses assessed neural activation on two functional magnetic resonance imaging tasks previously associated with depression: dorsolateral prefrontal cortex (DLPFC) responsivity during the n-back working memory task; and amygdala and subgenual anterior cingulate cortex (sgACC) responsivity during incidental emotional face processing.

Results: Depressed patients exhibited significantly attenuated working memory-related DLPFC activation, compared to low-risk controls and unaffected relatives; unaffected relatives did not differ from low-risk controls. We did not observe a complementary pattern during emotion processing. However, we found preliminary support that greater DLPFC activation was associated with lower amygdala response during emotion processing.

Limitations: These findings require confirmation in a longitudinal study to observe each individual's risk of developing depression; without this, we cannot identify the true risk level of the first-degree relative or low-risk control group.

Conclusions: These findings have implications for understanding the neural mechanisms of risk and resilience in depression: they are consistent with the suggestion that preserved executive function might confer resilience to developing depression in first-degree relatives of depressed patients.

Keywords: Amygdala; DLPFC; Depression; Emotion processing; Working memory.

Fig. 1

Distribution and summary statistics of parameter estimates in the left and right DLPFC ROIs and whole-brain analysis results. The blue dotted line represents the mean; the red line represents the median; light purple patch shows the 95% confidence interval; darker purple patch shows the standard deviation of the mean. In the full ANOVA, there was a significant main effect of group (overall group effect p = 0.012) and laterality (p = 0.006). Depressed patients had significantly lower DLPFC activation compared to both unaffected relatives (mean difference=0.169, p = 0.012, Cohen's d = 0.674) and low-risk controls (mean difference=0.162, p = 0.014, Cohen's d = 0.560) (both significant at corrected threshold of p = 0.0167), and there were no differences in DLPFC activation between controls and unaffected relatives (mean difference=0.007, p = 0.926, Cohen's d = 0.01). DLPFC=dorsolateral prefrontal cortex; ROI=region of interest.

Fig. 2

Distribution and summary statistics of parameter estimates in the left and right amygdala ROIs for the primary contrast (fearful>neutral) for each group. The blue dotted line represents the mean; the red line represents the median; light purple patch shows the 95% confidence interval; darker purple patch shows the standard deviation of the mean. ROI=region of interest; amygd=amygdala.

Fig. 3

Distribution and summary statistics of parameter estimates in the sgACC ROI for the primary contrast (fearful>neutral) for each group. The blue dotted line represents the mean; the red line represents the median; light purple patch shows the 95% confidence interval; darker purple patch shows the standard deviation of the mean. ROI=region of interest; sgACC=subgenual anterior cingulate cortex.

Fig. 4

Association between sgACC deactivation and depression measures. Relationship between subgenual anterior cingulate cortex (sgACC) deactivation to happy vs neutral faces and symptom scores in depressed patients for Beck Depression Inventory (BDI, p = 0.049, non-significant at corrected threshold of p = 0.0063, A) and Hamilton Depression rating scale (HAM-D, p = 0.030, non-significant at corrected threshold of p = 0.0063, B).

Fig. 5

Relationship between amygdala activation to happy faces (average across left and right) and average dorsolateral prefrontal cortex (DLPFC) activation during the n-back task (r=−0.246, p = 0.016, non-significant at corrected threshold of p = 0.0125). DLPFC=dorsolateral prefrontal cortex.