Neural basis of abnormal response to negative feedback in unmedicated mood disorders.

Depressed individuals show hypersensitivity to negative feedback during cognitive testing, which can precipitate subsequent errors and thereby impair a broad range of cognitive abilities. We studied the neural mechanisms underlying this feedback hypersensitivity using functional magnetic resonance imaging (fMRI) with a reversal learning task that required subjects to ignore misleading negative feedback on some trials. Thirteen depressed subjects with major depressive disorder (MDD), 12 depressed subjects with bipolar disorder (BD) and 15 healthy controls participated. The MDD group, but not the BD group, demonstrated enhanced sensitivity to negative feedback compared to controls, as indicated by the rates of rule reversal following misleading negative feedback. In the control and BD groups, hemodynamic activity was significantly higher in the dorsomedial and ventrolateral prefrontal cortices during reversal shifting, and significantly lower in the right amygdala in response to negative feedback. The extent to which the amygdala showed less activity during negative feedback correlated inversely with the behavioral tendency to reverse after misleading feedback. This effect was not present in the MDD group, who also failed to recruit the prefrontal cortex during behavioral reversal. Hypersensitivity to negative feedback is present in unmedicated depressed patients with MDD. Disrupted top-down control by the prefrontal cortex of the amygdala may underlie this abnormal response to negative feedback in unipolar depression.

Distinct profiles of neurocognitive function in unmedicated unipolar depression and bipolar II depression.

BACKGROUND: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. Few studies have directly compared depressed subjects with major depressive disorder (MDD) and bipolar disorder (BD), and many are confounded by medication status across subjects. In this study, we compared the performance of unmedicated currently depressed MDD and BD groups on a battery of neuropsychological tests that included measures of risk taking and reflection impulsivity. METHODS: Twenty-two MDD, seventeen BDII, and 25 healthy control subjects (HC), matched for age and IQ, were assessed on a battery of neuropsychological tests. RESULTS: The depressed groups showed comparable ratings of depression severity and age of illness onset. The MDD group was impaired on tests of spatial working memory and attentional shifting, sampled less information on a test of reflection impulsivity, and was oversensitive to loss trials on a decision-making test. The BDII subjects were generally intact and did not differ significantly from control subjects on any test. CONCLUSIONS: These data indicate differing profiles of cognitive impairment in unmedicated depressed MDD versus BDII subjects. Moderately depressed BDII subjects displayed relatively intact cognitive function, whereas MDD subjects demonstrated a broader range of executive impairments. These cognitive deficits in depression were not attributable to current medication status.

Frontal cerebral vulnerability and executive deficits from raised intracranial pressure in child traumatic brain injury.

In severe pediatric traumatic brain injury (TBI), a common focus of treatment is raised intracranial pressure (ICP). The aim of this investigation was to test whether raised ICP is associated with later prefrontal executive deficits and regional brain tissue loss, consistent with an anterior vascular compartment syndrome. Thirty-three participants were assigned to one of two severe TBI groups based on whether or not they had increased ICP complicating their critical illness. At follow-up (average 3.9 years), the participants underwent magnetic resonance imaging and a battery of neuropsychological testing focused on prefrontal function. The ICP group had white matter loss that was diffuse as well as regional in the corpus callosum, periventricular tissue, and frontal region. Loss of gray matter in the ICP group was more regionally specific, with bilateral loss in the caudate nuclei and frontal regions, including the right dorsolateral region, right supplementary motor area, and the left orbitofrontal cortex. Both groups had normal intelligence quotients (IQs), but the ICP group showed long-term deficits on various measures of attention and executive function such as working memory, decision-making, and impulsivity. These findings suggest that raised ICP leads to diffuse brain injury and a predilection to hypoperfusion in, at least, the distribution of the anterior cerebral artery. Furthermore, since voxel-based morphometry (VBM) and measures of attention and executive function are sensitive to the phenomenon of raised ICP, we consider that these techniques warrant inclusion in trials assessing ICP-directed therapy.