Neuropsychological studies of subjects with bipolar disorder suggest impairment of working memory not only in acute mood states, but also while subjects are euthymic. Using fMRI to probe working memory regions in bipolar subjects in different mood states, we sought to determine the functional neural basis for these impairments. Typical working memory areas in normal populations include dorsolateral prefrontal cortex (BA9/46) and the posterior parietal cortex (BA40). We evaluated the activation in these regions using an n-back task in 42 bipolar subjects (13 manic, 15 euthymic and 14 depressed subjects) and 14 control subjects. While both control and bipolar subjects performed similarly on the task, bipolar subjects in all three mood states showed a significant reduction in activation in right BA9/46 and right BA40. Patients with bipolar disorder exhibit significantly attenuated neural activation in working memory circuits, independent of mood state. The reduction of neural activation may suggest a trait-related deficit. Subjects with bipolar disorder activated other additional frontal and temporal regions, perhaps as a compensatory mechanism, but this remains to be further explored.

A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.

A decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies.

Researchers using experimental paradigms to examine cognitive processes have demonstrated that Major Depressive Disorder (MDD) is associated not with a general deficit in cognitive functioning, but instead with more specific anomalies in the processing of negatively valenced material. Indeed, cognitive theories of depression posit that negative biases in the processing of information play a critical role in influencing the onset, maintenance, and recurrence of depressive episodes. In this paper we review findings from behavioral studies documenting that MDD is associated with specific difficulties in attentional disengagement from negatively valenced material, with tendencies to interpret information in a negative manner, with deficits in cognitive control in the processing of negative material, and with enhanced memory for negative material. To gain a better understanding of the neurobiological basis of these abnormalities, we also examine findings from functional neuroimaging studies of depression and show that dysfunction in neural systems that subserve emotion processing, inhibition, and attention may underlie and contribute to the deficits in cognition that have been documented in depressed individuals. Finally, we briefly review evidence from studies of children who are at high familial risk for depression that indicates that abnormalities in cognition and neural function are observable before the onset of MDD and, consequently, may represent a risk factor for the development of this disorder. By integrating research from cognitive and neural investigations of depression, we can gain a more comprehensive understanding not only of how cognitive and biological factors interact to affect the onset, maintenance, and course of MDD, but also of how such research can aid in the development of targeted strategies for the prevention and treatment of this debilitating disorder.

Objective Several lines of evidence implicate gray matter abnormalities in the prefrontal cortex and anterior cingulate cortex in patients with bipolar disorder. Findings however, have been largely inconsistent across studies. Differences in patients’ medication status or mood state, or the application of traditional volumetric methods that are insensitive to subtle neuroanatomic differences may have contributed to these inconsistent findings. Given this, we used magnetic resonance imaging (MRI) in conjunction with cortical pattern matching methods to assess cortical thickness abnormalities in euthymic bipolar subjects who were not treated with lithium. Method Sixty-five subjects, including 34 lithium-free euthymic subjects with bipolar (type I) disorder and 31 healthy subjects were scanned using magnetic resonance imaging (MRI). Data were processed to measure cortical gray matter thickness. Cortical pattern matching methods associated homologous brain regions across subjects. Spatially normalized thickness maps were analyzed to assess illness effects and associations with clinical variables. Results Relative to healthy subjects, euthymic bipolar I subjects had significantly thinner gray matter in bilateral prefrontal cortex (Brodmann Areas 11, 10, 8 and 44) and left anterior cingulate cortex (Brodmann Areas 24/32). Additionally, thinning in these regions was more pronounced in patients with a history of psychosis. No areas of thicker cortex were detected in bipolar subjects versus healthy subjects. Conclusions Using a technique that is highly sensitive to subtle neuroanatomic differences, significant regional cortical thinning was found in euthymic subjects with bipolar disorder. Clinical implications are discussed.

Both elevated and blunted levels of cortisol secretion during childhood and adolescence have been linked to the subsequent onset of Major Depressive Disorder (MDD). These mixed findings may be due to developmental changes in HPA-axis functioning, which have not been previously assessed in the context of risk. In the present study, therefore, we examined whether pubertal development moderated the influence of cortisol secretion on the subsequent development of MDD. Eighty-nine never-disordered girls ages 9-15 years, many of whom were at high risk for depression by virtue of having a maternal history of the disorder, completed a laboratory stress task. To index cortisol reactivity, salivary cortisol samples were collected at baseline and 15 minutes following the onset of the stressor. Girls' levels of pubertal development were measured using Tanner staging. All participants were followed through age 18 in order to assess the subsequent development of MDD. Pubertal stage moderated the effects of cortisol stress reactivity on the development of MDD. Specifically, the onset of MDD was predicted by cortisol hyporeactivity in girls who were earlier in pubertal development (Tanner stage ≤ 2), but by cortisol hyperreactivity in girls who were later in pubertal development (Tanner stage ≥ 3.5). Conclusions These findings demonstrate that girls' cortisol stress reactivity predicts the subsequent onset of MDD, and further, that the nature of this effect depends on the girls' level of pubertal development. Results are discussed in the context of clarifying previous findings, and directions for future research are offered.

The basal ganglia, interacting with the cortex, play a critical role in a range of behaviors. Output from the basal ganglia to the cortex is thought to relay through the thalamus, yet an intriguing alternative is that the basal ganglia may directly project to, and communicate with, the cortex. We explored an efferent projection from the globus pallidus externa (GPe), a key hub in the basal ganglia system, to the cortex of rats and mice. Anterograde and retrograde tracing revealed projections to the frontal premotor cortex, especially the deep projecting layers, originating from GPe neurons that receive axonal inputs from the dorsal striatum. Cre-dependent anterograde tracing in GPe Vgat-ires-cre mice confirmed that the pallidocortical projection is GABAergic, and in vitro optogenetic stimulation in the cortex of these projections produced a fast inhibitory postsynaptic current in targeted cells that was abolished by bicucculine. The pallidocortical projections targeted GABAergic interneurons and, to a lesser extent, pyramidal neurons. This GABAergic pallidocortical pathway directly links the basal ganglia and cortex and may play a key role in behavior and cognition in normal and disease states.

BackgroundBipolar disorder (BD) is a chronic mental illness characterized by severe disruptions in mood and cognition. Diffusion tensor imaging (DTI) studies suggest that white matter (WM) tract abnormalities may contribute to the clinical hallmarks of the disorder. Using DTI and whole brain voxel-based analysis, we mapped the profile of WM anomalies in BD. All patients in our sample were euthymic and lithium free when scanned.MethodsDiffusion-weighted and T1-weighted structural brain images were acquired from 23 lithium-free euthymic subjects with bipolar I disorder and 19 age- and sex-matched healthy control subjects on a 1.5 T MRI scanner. Scans were processed to provide measures of fractional anisotropy (FA) and mean and radial diffusivity (MD and RD) at each WM voxel, and processed scans were nonlinearly aligned to a customized brain imaging template for statistical group comparisons.ResultsRelative to controls, the bipolar group showed widespread regions of lower FA, including the corpus callosum, cortical and thalamic association fibers. MD and RD were abnormally elevated in patients in many of these same regions.ConclusionsOur findings agree with prior reports of WM abnormalities in the corpus callosum and further link a bipolar diagnosis with structural abnormalities of the tapetum, fornix and stria terminalis. Future studies assessing the diagnostic specificity and prognostic implications of these abnormalities would be of interest.