Olusola Ajilore

Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy

Type 2 diabetes and major depression are disorders that are mutual risk factors and may share similar pathophysiological mechanisms. To further understand these shared mechanisms, the purpose of our study was to examine the biochemical basis of depression in patients with type 2 diabetes using proton MRS. Patients with type 2 diabetes and major depression (n=20) were scanned along with patients with diabetes alone (n=24) and healthy controls (n=21) on a 1.5 T MRI/MRS scanner. Voxels were placed bilaterally in dorsolateral white matter and the subcortical nuclei region, both areas important in the circuitry of late-life depression. Absolute values of myo-inositol, creatine, N-acetyl aspartate, glutamate, glutamine, and choline corrected for CSF were measured using the LC-Model algorithm. Glutamine and glutamate concentrations in depressed diabetic patients were significantly lower (p<0.001) in the subcortical regions as compared to healthy and diabetic control subjects. Myo-inositol concentrations were significantly increased (p<0.05) in diabetic control subjects and depressed diabetic patients in frontal white matter as compared to healthy controls. These findings have broad implications and suggest that alterations in glutamate and glutamine levels in subcortical regions along with white matter changes in myo-inositol provide important neurobiological substrates of mood disorders.

Gray matter prefrontal changes in type 2 diabetes detected using MRI

To examine the volumes of the gray and white matter both globally and regionally in patients diagnosed with type 2 diabetes and controls.

Impaired inter-hemispheric integration in bipolar disorder revealed with brain network analyses.

BACKGROUND This represents the first graph theory-based brain network analysis study in bipolar disorder, a chronic and disabling psychiatric disorder characterized by severe mood swings. Many imaging studies have investigated white matter in bipolar disorder, with results suggesting abnormal white matter structural integrity, particularly in the fronto-limbic and callosal systems. However, many inconsistencies remain in the literature, and no study to date has conducted brain network analyses with a graph-theoretic approach. METHODS We acquired 64-direction diffusion-weighted magnetic resonance imaging on 25 euthymic bipolar I disorder subjects and 24 gender- and age-equivalent healthy subjects. White matter integrity measures including fractional anisotropy and mean diffusivity were compared in the whole brain. Additionally, structural connectivity matrices based on whole-brain deterministic tractography were constructed, followed by the computation of both global and local brain network measures. We also designed novel metrics to further probe inter-hemispheric integration. RESULTS Network analyses revealed that the bipolar brain networks exhibited significantly longer characteristic path length, lower clustering coefficient, and lower global efficiency relative to those of control subjects. Further analyses revealed impaired inter-hemispheric but relatively preserved intra-hemispheric integration. These findings were supported by whole-brain white matter analyses that revealed significantly lower integrity in the corpus callosum in bipolar subjects. There were also abnormalities in nodal network measures in structures within the limbic system, especially the left hippocampus, the left lateral orbitofrontal cortex, and the bilateral isthmus cingulate. CONCLUSIONS These results suggest abnormalities in structural network organization in bipolar disorder, particularly in inter-hemispheric integration and within the limbic system.

Quantitative Tract-Specific Measures of Uncinate and Cingulum in Major Depression Using Diffusion Tensor Imaging

Previous findings suggested the role of the prefrontal cortex, hippocampus, and cingulate gyrus in major depressive disorders (MDD), but the white matter microstructural abnormalities of the fibers connecting these brain structures are not known. The purpose of this study was to test the hypothesis that white matter abnormalities are present in association fibers of the uncinate fasciculus (UF) and cingulum bundle (CB) among MDD subjects. A total of 21 MDD subjects aged between 30 and 65 years and 21 age-matched healthy controls (HC) were recruited. All subjects were right-handed and without history of diabetes or other cardiac diseases. We extracted quantitative tract-specific measures based on diffusion tensor imaging tractography to examine both diffusivity and geometric properties of the UF and CB. Significantly decreased fractional anisotropy (FA) and increased radial diffusivity of the right UF were observed in MDD patients compared with HC (p<0.05), while their geometric characteristics remained relatively unchanged. Among MDD subjects, depression severity had a significant negative correlation with normalized number of fibers (NNF) in the right UF (r=−0.53, p=0.02). We also found significant age effect (old<young) in HC group and laterality effect (L>R) in both groups in the FA measure of the CB. Our study demonstrates novel findings of white matter microstructural abnormalities of the right UF in MDD. In the MDD group, the severity of depression is associated with reduced NNF in the right UF. These findings have implications for both clinical manifestations of depression as well as its pathophysiology.

Brain network dysfunction in late-life depression: a literature review.

As a common psychiatric disorder in the growing geriatric population, late-life depression (LLD) has a negative impact on the cognitive, affective, and somatic domains of the lives of the elderly individuals. Accumulating evidence from the structural and functional imaging studies on LLD supports a “network dysfunction model” rather than a “lesion pathology model” for understanding the underlying biological mechanism in this mental disorder. In this work, we used network dysfunction model as a conceptual framework for reviewing recent neuroimaging findings in LLD. Our focus was on 4 major neurocircuits that have been shown to be involved in LLD: default mood network, cognitive control network, affective/frontolimbic network, and corticostriatal circuits. Findings of LLD-related gray and white matter structural abnormalities and resting-state and task-based functional changes were discussed for each network separately. We extended our review by summarizing the latest works that apply graph theory–based network analysis techniques for testing alterations in whole-brain network properties associated with LLD.

Graph Theory Analysis of Cortical-Subcortical Networks in Late-Life Depression

OBJECTIVES Late-life major depression (LLD) is characterized by distinct epidemiologic and psychosocial factors, as well as medical comorbidities that are associated with specific neuroanatomical differences. The purpose of this study was to use interregional correlations of cortical and subcortical volumes to examine cortical-subcortical structural network properties in subjects with LLD compared with healthy comparison subjects. METHODS This was a cross-sectional neuroimaging study conducted in the general community. We recruited 73 healthy elderly comparison subjects and 53 subjects with LLD who volunteered in response to advertisements. Brain network connectivity measures were generated by correlating regional volumes after controlling for age, gender, and intracranial volume by using the Brain Connectivity Toolbox. RESULTS Results for overall network strength revealed that LLD networks showed a greater magnitude of associations for both positive and negative correlation weights compared with healthy elderly networks. LLD networks also demonstrated alterations in brain network structure compared with healthy comparison subjects. LLD networks were also more vulnerable to targeted attacks compared with healthy elderly comparison subjects, and this vulnerability was attenuated when controlling for white matter alterations. CONCLUSIONS Overall, this study demonstrates that cortical-subcortical network properties are altered in LLD and may reflect the underlying neuroanatomical vulnerabilities of the disorder.

Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression

The purpose of this study was to examine the effect of type 2 diabetes with major depression on cortical gray matter using magnetic resonance imaging and cortical pattern matching techniques. We hypothesized that diabetic subjects and depressed diabetic subjects would demonstrate decreased cortical gray matter thickness in prefrontal areas as compared to healthy control subjects. Patients with type 2 diabetes (n=26) and patients with diabetes and major depression (n=26) were compared with healthy controls (n=20). Gray matter thickness across the entire cortex was measured using cortical pattern matching methods. All subjects with diabetes demonstrated decreased cortical gray matter thickness in the left anterior cingulate region. Additionally, depressed diabetic subjects showed significant cortical gray matter decreases in bilateral prefrontal areas compared with healthy controls. Correlations between clinical variables and cortical gray matter thickness revealed a significant negative relationship with cerebrovascular risk factors across all three groups, most consistently in the left dorsomedial prefrontal cortex. A significant positive relationship between performance on attention and executive function tasks and cortical gray matter thickness predominantly in left hemisphere regions was also seen across all subjects. Depression and diabetes are associated with significant cortical gray matter thinning in medial prefrontal areas.

Glucocorticoids exacerbate the deleterious effects of gp120 in hippocampal and cortical explants.

Abstract: Glucocorticoids (GCs), the adrenal steroids secreted during stress, can compromise the ability of hippocampal neurons to survive numerous necrotic insults. We have previously observed that GCs worsen the deleterious effects of gp120, the glycoprotein of the acquired immune deficiency syndrome virus, which can indirectly damage neurons and which is thought to play a role in the neuropathological features of human immuno‐deficiency virus infection. Specifically, GCs augment gp120‐induced calcium mobilization, ATP depletion, decline in mitochondrial potential, and neurotoxicity in fetal monolayer cultures from a number of brain regions. In the present report, we demonstrate a similar gp120/GC synergy in adult hippocampal and cortical explants. We generated explants from rats that were either adrenalectomized, adrenally intact, or intact and treated with corticosterone to produce levels seen in response to major stressors. Metabolic rates in explants were then indirectly assessed with silicon microphysiometry, and cytosolic calcium concentrations were assessed with fura‐2 fluorescent microscopy. We observed that basal levels of GCs tonically augment the disruptive effects of gp120 on metabolism in the CA1 cell field of the hippocampus and in the cortex. Moreover, raising GC concentrations into the stress range exacerbated the ability of gp120 to mobilize cytosolic calcium in a number of hippocampal cell fields. Finally, we observed that the synthetic GC prednisone had similarly exacerbating effects on gp120. Thus, GCs can worsen the deleterious effects of gp120 in a system that is more physiologically relevant than the fetal monolayer culture and in a region‐specific manner.

In vivo Characterization of 11β-Hydroxysteroid Dehydrogenase in Rat Hippocampus Using Glucocorticoid Neuroendangerment as an Endpoint

11β-Hydroxysteroid dehydrogenase (11β-HSD) is the enzyme responsible for the interconversion of corticosterone (CORT) to 11-dehydrocorticosterone (11-DHC). CORT is an adrenal hormone secreted during the stress response and it has widespread effects in many different target tissues. In addition, CORT can exacerbate damage caused by neurological insults, such as kainic acid-induced seizures. In addition to its protective role in the kidney, 11β-HSD is also thought to play a role in steroid regulation in the brain. However, it is not known whether the enzyme is acting in vivo as a reductase or a dehydrogenase. If the enzyme is working as a reductase, converting 11-DHC to CORT, it has the potential to exacerbate neurotoxicity due to other agents. On the other hand, 11β-HSD could be neuroprotective if the enzyme is acting as a dehydrogenase, deactivating CORT by converting it into 11-DHC. To characterize the enzyme in vivo, we have utilized glucocorticoid neuroendangerment in the hippocampus as an indirect assay of 11β-HSD function. We have shown that 11-DHC can exacerbate kainic acid toxicity in adrenalectomized (ADX) rats and this exacerbation is blocked by the 11β-HSD antagonist, carbenoxolone; these findings suggest that 11β-HSD is working as a reductase in ADX rats. The presumptive reductase activity found in ADX rats was derived from both hippocampal and peripheral forms of the enzyme. In the presence of physiological levels of glucocorticoids, reductase activity was decreased and no dehydrogenase activity was detected. The present study demonstrates that 11β-HSD reductase activity, both in vivo and in vitro, occurs only in the presence of low levels of circulating glucocorticoids.

Focal Subcortical Biophysical Abnormalities in Patients Diagnosed With Type 2 Diabetes and Depression

CONTEXT Major depressive disorder has been consistently identified in patients with type 2 diabetes. Despite its high prevalence and clinical effect, the neurobiological substrates underlying depression in patients with diabetes remain largely unknown. OBJECTIVE To examine the biophysical integrity of proteins in critical white and gray matter regions in patients with type 2 diabetes and major depression to understand the pathophysiology of depression in diabetes. DESIGN A cross-sectional magnetization transfer study using magnetic resonance imaging. Regions examined included the anterior cingulate, corpus callosum, frontal and occipital white matter, and the caudate and lenticular nuclei. SETTING A tertiary care university hospital. PARTICIPANTS We studied 16 patients diagnosed with type 2 diabetes and major depression, 22 patients diagnosed with diabetes without depression (diabetic controls), and 30 controls without diabetes or major depression (healthy controls). MAIN OUTCOME MEASURES Magnetization transfer ratios, a measure of the biophysical structure of proteins in the gray and white matter. RESULTS Magnetization transfer ratios were significantly lower bilaterally in the head of the caudate nucleus in the group with diabetes and depression compared with the other 2 groups (P < .001). Diabetic controls had values between the depressed diabetic and healthy control groups. There were no significant differences in magnetization transfer ratios between groups in the other regions examined. CONCLUSIONS These data indicate that there is an important subcortical biophysical component to depression in patients with type 2 diabetes. This finding has broad implications for the neuronal circuitry underlying mood disorders.