Neurobiology of Depression: An Integrated View Of Key Findings

V. Maletic; M. Robinson; T. Oakes; S. Iyengar; S. G. Ball; J. Russell

Disclosures

Int J Clin Pract. 2007;61(12):2030-2040. 

In This Article

Functional and Structural Changes in MDD

Although much information still needs to be attained, imaging and other methods have begun to elucidate the neurobiological abnormalities associated with MDD. In particular, several prefrontal and limbic structures and their interconnected circuits have been implicated in affective regulation. Figure 2 These neuroanatomical areas include the ventromedial prefrontal cortex (VMPFC), lateral orbital prefrontal cortex (LOPFC), dorsolateral prefrontal cortex (DLPFC), anterior cingulated cortex (ACC), ventral striatum (including nucleus accumbens), amygdala and the hippocampus. Abnormalities in these areas have been shown in patients with MDD compared with healthy controls and thus suggest a foundation for the symptomatic expression of MDD.[24,25] However, these deviations may be obscured or not present at the individual patient level and thus, these findings cannot necessarily be considered pathognomic.

Major depressive disorder affects the dynamic connectivity among neuroanatomical structures involved in regulation of mood and stress response. Limbic structures (amygdala, hippocampus and nucleus accumbens) have reciprocal connections with 'para-limbic´ cortical areas, subgenual anterior cingluate and ventromedial prefrontal cortex (VMPFC). Hypothetically, disrupted 'connectivity´ between limbic/para-limbic areas and rostral integrative prefrontal formations, results in compromised feedback regulation of limbic activity. Consequently, dorsal cognitive/executive network is hypoactive while overly active limbic areas continue to stimulate the hypothalamus leading to neuroendocrine dysregulation and sympathetic hyperactivity

As an integrated circuit, the prefrontal cortex, cingulate, amygdala, and hippocampus serves not only mood regulation, but also learning and contextual memory processes. Within the prefrontal cortex, the VMPFC mediates pain, aggression, sexual functioning and eating behaviours whereas the LOPFC assesses risk and modulates maladaptive and perseverative affective states (behaviours). These two areas have a reciprocal pattern of activity with the DLFPC, which maintains executive function, effortful sustained attention, and working memory processes.[26] Subdivisions within the ACC assume diverse roles, with the dorsal ACC being part of the cognitive/executive functioning network and the ventral ACC being involved in assessing emotional and motivational information. The ACC also monitors outcomes of behaviour and cognition and makes adjustments based on changing contingencies.[27,28]

In patients with MDD, regional blood flow studies suggest hyperactivity in the VMPFC and LOPFC and hypoactivity in the DLFPC compared with controls.[24] Given the functions of these regions, as previously described, this abnormal activity pattern may be responsible for the manifestations of symptoms associated with MDD. Hyperactivity of the VMPFC is associated with enhanced sensitivity to pain, anxiety, depressive ruminations and tension whereas hypoactivity of the DLFPC may produce psychomotor retardation, apathy, and deficits in attention and working memory. Using fMRI paradigms, connectivity studies have also suggested a decrement in the 'communication' between amygdala and ACC regions.[29] A consequence of this loss of connectivity could be a failure of the ACC to serve its inhibitory role in emotional regulation,[30] resulting in further motivational and affective disruption.[31]

At the intersection of limbic, cognitive/executive and neuroendocrine regulatory circuits, including the hypothalamic-pituitary-adrenal axis (HPA), the hippocampus may be particularly vulnerable in depression. Imaging studies of hippocampal volume have been of particular interest. In a meta-analysis of 12 studies, hippocampal volume was found to be consistently and significantly reduced in patients with MDD compared with controls, and these reductions occurred bilaterally with a slightly greater decrement in right hippocampal volume.[32] Other studies have shown that the degree of hippocampal reduction is directly proportional to the number and the duration of untreated depressive episodes.[33] Among depressed inpatients, while controlling for the effect of age, hippocampal volume was significantly correlated with duration of illness prior to hospitalisation.[34] Even after remission of an episode,patients with recurrent MDD have continued to show significantly smaller hippocampal volume compared with healthy controls.[35]

Differences in hippocampal volume between patients with depression and healthy controls may not be fully attributable to the disease state. Heritability studies of hippocampal volume suggest both environmental and genetic contributions with heritability estimates of 54% in nonhuman primates and 40% in adult male twins.[36,37] Several genomic imaging studies, comparing patients with MDD and healthy controls, have shown associations between hippocampal volume and specific genes that are implicated in mood disorders.[38,39] In a 1-year prospective study of 30 patients with MDD, hippocampal volume did not significantly change during the study period, but patients whose depression failed to remit had a significantly smaller hippocampus at baseline and at 1 year than did patients who did remit.[40] Combining the evidence from these genetic, cross-sectional, and clinical treatment studies suggests that morphological differences in the hippocampus may be a predisposing factor in MDD, but changes can also accumulate in the course of the disease and thereby create an obstacle to full recovery.

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