A working model of depression implicating failure of the coordinated interactions of a distributed network of limbic-cortical pathways is proposed. Resting state patterns of regional glucose metabolism in idiopathic depressed patients, changes in metabolism with antidepressant treatment, and blood flow changes with induced sadness in healthy subjects were used to test and refine this hypothesis. Dorsal neocortical decreases and ventral paralimbic increases characterize both healthy sadness and depressive illness; concurrent inhibition of overactive paralimbic regions and normalization of hypofunctioning dorsal cortical sites characterize disease remission. Normal functioning of the rostral anterior cingulate, with its direct connections to these dorsal and ventral areas, is postulated to be additionally required for the observed reciprocal compensatory changes, since pretreatment metabolism in this region uniquely predicts antidepressant treatment response. This model is offered as an adaptable framework to facilitate continued integration of clinical imaging findings with complementary neuroanatomical, neurochemical, and electrophysiological studies in the investigation of the pathogenesis of affective disorders.

https://neuro.psychiatryonline.org/doi/pdfplus/10.1176/jnp.9.3.471

Limbic-cortical dysregulation: a proposed model of depression.

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings.

The anatomy of mood disorders-review of structural neuroimaging studies

Five parallel anatomic circuits link regions of the frontal cortex to the striatum, globus pallidus/substantia nigra, and thalamus. The circuits originate in the supplementary motor area, frontal eye fields, dorsolateral prefrontal region, lateral orbito-frontal area, and anterior cingulate cortex. Open loop structures that provide input to or receive output from specific circuits share functions, cytoarchitectural features, and phylogenetic histories with the relevant circuits. The circuits mediate motor and oculomotor function as well as executive functions, socially responsive behavior, and motivation. Neuropsychiatric disorders of frontal-subcortical circuits include impaired executive function, disinhibition, and apathy; indicative mood disorders include depression, mania, and lability. Transmitters, modulators, receptor subtypes, and second messengers within the circuits provide a chemoarchitecture that can inform pharmacotherapy.

Frontal-subcortical circuits and neuropsychiatric disorders.

Throughout early development, a child spends more time asleep than in any waking activity. Yet, the specific role of sleep in brain maturation is a complete mystery. In this article, the developmental psychobiology of sleep regulation is conceptualized within the context of close links to the control of arousal, affect, and attention. The interactions among these systems are considered from an ontogenetic and evolutionary biological perspective. A model is proposed for the development of sleep and arousal regulation with the following major tenets:1. Sleep and vigilance represent opponent processes in a larger system of arousal regulation.2. The regulation of sleep, arousal, affect, and attention overlap in physiological, neuroanatomical, clinical, and developmental domains.3. Complex interactions among these regulatory systems are modulated and integrated in regions of the prefrontal cortex (PFC).4. Changes at the level of PFC underlie maturational shifts in the relative balance across these regulatory systems (such as decreases in the depth/length of sleep and increased capacity for vigilance and attention), which occur with normal development.5. The effects of sleep deprivation (including alterations in attention, emotions, and goal-directed behaviors) also involve changes at the level of PFC integration across regulatory systems.This model is then discussed in the context of developmental pathology in the control of affect and attention, with an emphasis on sleep changes in depression.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0954579400006945

The regulation of sleep and arousal: Development and psychopathology

We present a consecutive series of 8 patients who developed a manic episode after a brain injury. Five patients had cortical lesions (4 with damage to the right basotemporal region, and 1 with bilateral damage to the orbitofrontal area). While the other 3 patients had subcortical lesions (white matter of the right frontal lobe, right anterior limb of the internal capsule, and right head of the caudate), a fluorodeoxyglucose positron emission tomography scan showed hypometabolism in the right lateral basotemporal region in all 3 patients. These findings suggest a major role for the basal region of the right temporal lobe in the modulation of mood.

Mania after brain injury: neuroradiological and metabolic findings.

Manic-depressive and pure manic states after brain lesions

The interaction between anxiety disorder and major depressive disorder in patients with cerebrovascular lesions was examined in a controlled, 2 x 2 study design. A consecutive series of 24 patients who met criteria for major depression only were compared with 6 patients who met criteria for both major depression and generalized anxiety disorder, and 45 patients who did not meet criteria for either major depression of generalized anxiety. Among patients with positive computed tomographic scans, the anxious-depressed group (n = 19) showed a significantly higher frequency of cortical lesions, while patients with major depression only (n = 15) had a significantly higher frequency of subcortical (basal ganglia) strokes. No significant between-group differences were found in other variables, such as demographic variables, familial and personal history of psychiatric disorders, and neurologic deficits. These findings suggest that, in this mostly black, low-socioeconomic-status population, cortical vs subcortical lesion location may play an important role in determining whether severe anxiety occurs in patients with post-stroke major depression.

Paul Fedoroff

Papers

Mania after brain injury: neuroradiological and metabolic findings.

Manic-depressive and pure manic states after brain lesions

Relationship between anxiety disorders and depressive disorders in patients with cerebrovascular injury.