Localization of dysfunction in major depressive disorder: prefrontal cortex and amygdala

Abstract

Despite considerable effort, the localization of dysfunction in major depressive disorder (MDD) remains poorly understood. We present a hypothesis about its localization that builds on recent findings from primate neuropsychology. The hypothesis has four key components: a deficit in the valuation of "self" underlies the core disorder in MDD; the medial frontal cortex represents "self"; interactions between the amygdala and cortical representations update their valuation; and inefficiency in using positive feedback by orbital prefrontal cortex contributes to MDD.

Figure 1

Cytoarchitectonic maps of the medial (top) and orbital (bottom) frontal cortex from humans (A) and macaque monkeys (B), based on the analysis of Price and his colleagues (16, 17). Abbreviations: cc, corpus callosum, ig, induseum griseum, Ia, agranular insular cortex (pl, posterolateral; pm, posteromedial; l, lateral; m, medial; i, inferior); G, gustatory cortex; PL, prelimbic cortex; IL, infralimbic cortex; AC, anterior cingulate cortex.

Figure 2

Regions from which electrical stimulation elicits autonomic effects. The stippling shows the regions of a macaque monkey brain from which autonomic responses can be evoked. Left: A, granular and dysgranular insular cortex; B, anterior insular cortex; C. caudal orbitofrontal cortex; D, inferior temporal cortex, F, temporal pole. Right: A, subgenual anterior cingulate cortex; B, anterior cingulate cortex; C, infralimbic cortex; D, temporal pole. From Kaada et al. (59).

Figure 3

Effect of bilateral ablations or crossed disconnections on the devaluation effect (A) and blood-pressure changes in anticipation of food (B). Abbreviations: PFo, monkeys with bilateral lesions of the orbital prefrontal cortex; Amyg, monkeys with bilateral excitotoxic lesions of the amygdala; PFo x Amyg, monkeys with surgical disconnection of PFo in one hemisphere from the amygdala in the other hemisphere; Control, unoperated monkeys; mmHg, millimeters of mercury.

Figure 4

Effect of bilateral ablations of PFo or amygdala on object-reversal learning (A and B) and conditioned blood pressure changes (C). Abbreviations: PFo, monkeys with bilateral lesions of orbital prefrontal cortex; Amyg, monkeys with bilateral excitotoxic lesions of the amygdala; Control, unoperated monkeys; mmHg, millimeters of mercury; E+1, the trial after an error; EC+1, the trial after a sequence of error-correct; EC(n)+1, the trial after an error trial followed by n correct trials; CS+, conditioned stimulus; R, reversal; Init, initial training on object discrimination.