Limbic Cortical Dysregulation Model of Depression

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In an attempt to synthesize the findings described in the previous sections, regions with known anatomical interconnections that also show consistent changes across studies are summarized in a simplified schematic model illustrated in Fig. 7.5 (updated from Mayberg, 1997). Failure of this regional network is hypothesized to explain

Frontal And Posterior Cortical Network

Figure 7.5. Limbic-cortical dysregulation model. Cortical compartment: limbic compartment: subcortical compartment: Arrows: relevant anatomical connections. Numbers: Brodmann designations. Abbreviations: CBT, cognitive behavioral therapy; mFr, medial prefrontal; dFr, prefrontal; pm, premotor; par, parietal; aCg, dorsal anterior cingulate; pCg, posterior cingulate; rCg, rostral cingulate; VTA, ventral tegmental area; LC, locus ceruleus; DR, dorsal raphe; mOF, medial orbital frontal; Cg25, subgenual cingulate; Hth, hypothalamus; Hc, hippocampus; a-ins, anterior insula; amyg, amygdala; p-ins, posterior insula. (Updated from Mayberg, 1997.)

Figure 7.5. Limbic-cortical dysregulation model. Cortical compartment: limbic compartment: subcortical compartment: Arrows: relevant anatomical connections. Numbers: Brodmann designations. Abbreviations: CBT, cognitive behavioral therapy; mFr, medial prefrontal; dFr, prefrontal; pm, premotor; par, parietal; aCg, dorsal anterior cingulate; pCg, posterior cingulate; rCg, rostral cingulate; VTA, ventral tegmental area; LC, locus ceruleus; DR, dorsal raphe; mOF, medial orbital frontal; Cg25, subgenual cingulate; Hth, hypothalamus; Hc, hippocampus; a-ins, anterior insula; amyg, amygdala; p-ins, posterior insula. (Updated from Mayberg, 1997.)

the combination of clinical symptoms seen in depressed patients (i.e., mood, motor, cognitive, vegetative-circadian). Regions are grouped into three main "compartments" or levels: cortical, subcortical, and limbic. The frontal-limbic (dorsal-ventral) segregation additionally identifies those brain regions where an inverse relationship is seen across the different PET paradigms. Sadness and depressive illness are both associated with decreases in cortical regions and relative increases in limbic areas. The model, in turn, proposes that illness remission occurs when there is appropriate modulation of dysfunctional limbic-cortical interactions (solid black arrows)—an effect facilitated by various forms of treatment. It is further postulated that initial modulation of unique subcortical targets by specific treatments facilitates adaptive changes in particular pathways necessary for network homeostasis and resulting clinical recovery. Medial frontal, rostral cingulate, and orbital frontal regions are separated from their respective compartments in the model to highlight their primary role in self-referencing the salience of exogenous emotional events—a phenomenon that differentiates healthy from depressed states.

This working neural systems model can also be used in context of the multidimensional construct illustrated in Figure 7.1. Namely, the functional state of the depressed brain reflects both the initial insult or "functional lesion" and the ongoing process of attempted self-correction or adaptation influenced by such factors as heredity, temperament, early-life experiences, and previous depressive episodes. From this perspective, the net regional activity or sum total of various synergistic and competing inputs is what accounts for the observed clinical symptoms. For instance, if frontal hyperactivity is seen, it might be interpreted as an exaggerated and maladaptive compensatory process, manifesting clinically as psychomotor agitation and rumination, whose purpose is to override, at the cortical level, a persistent negative mood generated by abnormal chronic activity of limbic-subcortical structures. In contrast, frontal hypometabolism would be seen as the failure to initiate or maintain such a compensatory state, with resulting apathy, psychomotor slowness and impaired executive functioning as is common in melancholic patients. In this context, different interventions with varying primary mechanisms of action should be equally effective if the functional integrity of pathways is preserved within the depression circuit overall, perhaps offering a neurobiological explanation for the comparable clinical efficacy of pharmacological and cognitive treatments in randomized controlled trials. Similarly, progressively more aggressive treatments needed to relieve symptoms in some patients may reflect poor adaptive capacity or an actual disintegration of network connections in these patient subgroups. Lastly, unmasking of aberrant adaptive responses within these critical systems with properly targeted provocations might identify preclinical vulnerability or relapse risk. While such a network approach is a deliberate oversimplification, it provides a flexible platform to systematically test these hypotheses, as well as consider the relative contribution of additional genetic and environmental variables in disease pathogenesis and treatment response. Continued development of imaging and multivariate statistical strategies that optimally integrate these factors will be a critical next step in fully characterizing the depression phenotype at the neural systems level.

Acknowledgments. Research by the author described in this chapter was supported by grants from the National Institute of Mental Health, Canada Institute for

Health Research, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Charles A. Dana Foundation, the Theodore and Vada Stanley

Foundation, and Eli Lilly.


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