Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression

Abstract

Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.

Self-related awareness and emotion regulation

“…In the context of emotion regulation, the amygdala was found to be a major recipient of activation associated with intended cognitive control of emotions mediated by medial prefrontal cortex areas leading to attenuation of amygdala activity (Herwig et al, 2007a;Johnstone et al, 2007;Phan et al, 2005). This is thought to result in reduced amygdala output towards midbrain and brainstem areas and accordingly in less physiological, for instance sympathetic activation (Bishop, 2009;Ochsner and Gross, 2005;Quirk et al, 2003).…”

“…This is thought to result in reduced amygdala output towards midbrain and brainstem areas and accordingly in less physiological, for instance sympathetic activation (Bishop, 2009;Ochsner and Gross, 2005;Quirk et al, 2003). Disturbed emotion processing in the amygdala is also considered to be a pathophysiological feature of depression and anxiety (Bishop, 2009;DeRubeis et al, 2008), with implications of an impaired top-down control of amygdala activity (Johnstone et al, 2007).…”

“…Main theories concerning the neural underpinnings of emotion regulation promote a neural system comprising medial and ventrolateral prefrontal cortical activations that exert control over basal emotion processing and emotion generating areas such as within the amygdala (Ochsner and Gross, 2005). This is well supported by neuroanatomical evidence (Quirk et al, 2003) and by functional neuroimaging (Johnstone et al, 2007;Ochsner and Gross, 2005;Phan et al, 2005). This system is also considered to form a basis for functional models of emotional disturbances in affective disorders such as depression and anxiety (Bishop, 2009;DeRubeis et al, 2008).…”

“…The model mainly concerns external events and intended regulation, and it was derived from respective studies (e.g. Johnstone et al, 2007;Ochsner and Gross, 2005;Phan et al, 2005). However, unpleasant emotions often arise without an explicit external trigger and are experienced as internally generated, which is also the case in depression and anxiety.…”

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

“…[21][22][23][24] . In contrast, both the size and the activity of the amygdala, a structure critical for fear-associated memories, are increased in depressed patients [25][26][27][28] .Consistent with brain imaging studies, depressed patients exhibit deficits in hippocampus-dependent memory tasks and are more sensitive to stressful events [24,29,30] . Changes in neurotransmitter levels, receptors, and serotonin reuptake transporters have also been found in depressed patients, such as increased glutamate, decreased serotonin 1A receptors and impaired serotonergic neurotransmission [31][32][33][34][35] .…”