Toward a functional neuroanatomy of dysthymia: A functional magnetic resonance imaging study

Abstract

Background

Dysthymia is a common mood disorder. Recent studies have confirmed the neurobiological and treatment response overlap of dysthymia with major depression. There are no previous published studies of functional magnetic resonance imaging (fMRI) in dysthymia.

Method

fMRI was used to compare neural processing of 17 unmedicated dysthymic patients with 17 age, sex, and education-matched control subjects in a mood induction paradigm using the International Affective Pictures System (IAPS).

Results

Using a random effects analysis to compare the groups, the results revealed that the dysthymic patients had significantly reduced activation in the dorsolateral prefrontal cortex compared to controls. The dysthymic patients exhibited increased activation in the amygdala, anterior cingulate and insula compared to controls and these differences were more evident when processing negative than positive images.

Limitations

This study included both early and late subtypes of dysthymia, and participants were only imaged at one time point, which may limit the generalizability of the results.

Conclusions

The findings suggest the involvement of the prefrontal cortex, anterior cingulate, amygdala, and insula in the neural circuitry underlying dysthymia. It is suggested that altered activation in some of these neural regions may be a common substrate for depressive disorders in general while others may relate specifically to symptom characteristics and the chronic course of dysthymia. These findings are particularly striking given the history of this deceptively mild disorder which is still confused by some with character pathology.

Introduction

Dysthymic disorder (low-grade chronic depression), with a prevalence as high as 6% in the general population (Kessler et al., 1994), is distinguished from major depressive disorder largely based on severity and course, with dysthymia following a milder but chronic course. Both conditions share common symptoms, significant functional impairment, as well as some common biological diathesis, including genetic predisposition, and response to antidepressant treatment (Akiskal and Cassano, 1997).

Dysthymia was once considered a “character” disorder. Despite converging evidence from a variety of external validating strategies for mood disorder (see Akiskal and Cassano, 1997), it occupies an ambiguous position in the DSM-IV-TR (American Psychiatric Association, 2000) as evidenced by its location on both Axis I (as a subthreshold chronic mood disorder) and Axis II (as a proposed depressive personality disorder). Evidence for brain pathology, such as sleep neurophysiologic findings observed in major depressive conditions (Akiskal et al., 1980), was historically important in upholding the affective thesis. The present contribution on functional brain imaging is conceived to further bolster this thesis.

Previous functional neuroimaging studies have clearly demonstrated that the frontal limbic neural circuitry plays a major role in the regulation of normal emotion (Matthews et al., 2008, Seminowicz et al., 2004, Siegle et al., 2007). Furthermore, Phillips et al. (2003) distinguish between two fronto-limbic emotional circuitries: A ventral circuit, comprised of the amygdala, insula, ventral striatum and ventral regions of the anterior cingulate and prefrontal cortex, and responsible for assigning emotional significance to a stimulus and producing an affective state in response; and a dorsal circuit, including the hippocampus and the anterior cingulate and prefrontal cortex, which is implicated in the regulation of affective states.

Neuroimaging studies in patients with major depression have reported altered activations and laterality differences in this circuitry, especially the prefrontal cortex, anterior cingulate, amygdala and hippocampus, among other regions (Davidson et al., 2003, Matthews et al., 2008, Seminowicz et al., 2004, Siegle et al., 2007). It has been suggested that prefrontal hypoactivity may be a common feature of many subtypes of depression, including unipolar, bipolar and treatment-refractory depression (Aihara et al., 2007, Kennedy et al., 2001, Seminowicz et al., 2004). The reduction in activation in the left dorsolateral prefrontal cortex (DLPFC) seen in depressed patients is believed to be a function of gray matter volume reduction in this region, and was found to increase following successful antidepressant treatment (Davidson et al., 2002). Increased activation of the amygdala, which is involved in the processing of aversive emotional stimuli (e.g. fear), and of the insula, which has a key role in affective modulation, have been reported in depressive and anxiety disorders (Etkin and Wager, 2007, Keedwell et al., 2005, Matthews et al., 2008, Paulus and Stein, 2006). Altered activation of the cingulate (Beauregard et al., 1998, Buchsbaum et al., 1997), a region critical to integrating attention and emotion, has been reported with implications for therapeutic response (Davidson et al., 2002, Matthews et al., 2008). In general, major depression is said to be associated with increased activation of regions responsible for emotional processing, and hypoactivity of structures implicated in cognitive function (Baxter et al., 1989, Harvey et al., 2005).

To our knowledge, there are no previous fMRI studies of primary dysthymia subjects. In this study it was hypothesized that dysthymic patients would differ from matched healthy controls in having distinct patterns of activation in the frontal limbic circuitry. Furthermore, it was anticipated that such patterns of activation may overlap with those reported in major depression, but with some differences that may be more specific to dysthymia.