A Longitudinal Pilot Proton MRS Investigation of the Manic and Euthymic States of Bipolar Disorder

Several lines of evidence implicate dysfunction in brain energy production as a key component of bipolar disorder. In particular, elevated brain lactate levels observed in this condition suggest a shift from aerobic to anaerobic metabolism, possibly as a result of mitochondrial abnormalities. Most prior imaging studies of brain metabolites were performed in either euthymic or depressed bipolar patients or compared different populations in different mood states. We sought to measure brain metabolite concentrations in the same patients in both manic and euthymic states. Given the dramatic changes in clinical state of bipolar disorder patients, we hypothesized that previously observed abnormalities in lactate concentrations in bipolar disorder might show state dependent changes. In this study 15 patients (mean age 36.1 years) diagnosed with bipolar I disorder underwent proton magnetic resonance spectroscopy of the anterior cingulate cortex and parieto-occipital cortex during hospitalization for acute mania (mean Young Mania Rating Scale (YMRS) 22.1). Seven of these subjects returned (mean interval 21.16 months) to have imaging repeated while euthymic (mean YMRS 2.0). A group of age- and gender-matched control participants (N=6) were scanned as well. We report that during mania, bipolar disorder subjects had lactate levels comparable to healthy control subjects but during euthymia these levels were significantly reduced. No significant change was observed for other metabolites. These results implicate mood dependent alterations in energy metabolism in the biology of bipolar disorder. Additionally, this finding has potential use as a biomarker for both evaluating novel treatments as well as diagnostic clarification between mood disorders

Brain Activation During Working Memory Is Altered in Patients With Type 1 Diabetes During Hypoglycemia

OBJECTIVE To investigate the effects of acute hypoglycemia on working memory and brain function in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging during euglycemic (5.0 mmol/L) and hypoglycemic (2.8 mmol/L) hyperinsulinemic clamps, we compared brain activation response to a working-memory task (WMT) in type 1 diabetic subjects (n = 16) with that in age-matched nondiabetic control subjects (n = 16). Behavioral performance was assessed by percent correct responses. RESULTS During euglycemia, the WMT activated the bilateral frontal and parietal cortices, insula, thalamus, and cerebellum in both groups. During hypoglycemia, activation decreased in both groups but remained 80% larger in type 1 diabetic versus control subjects (P < 0.05). In type 1 diabetic subjects, higher HbA1c was associated with lower activation in the right parahippocampal gyrus and amygdala (R2 = 0.45, P < 0.002). Deactivation of the default-mode network (DMN) also was seen in both groups during euglycemia. However, during hypoglycemia, type 1 diabetic patients deactivated the DMN 70% less than control subjects (P < 0.05). Behavioral performance did not differ between glycemic conditions or groups. CONCLUSIONS BOLD activation was increased and deactivation was decreased in type 1 diabetic versus control subjects during hypoglycemia. This higher level of brain activation required by type 1 diabetic subjects to attain the same level of cognitive performance as control subjects suggests reduced cerebral efficiency in type 1 diabetes

Bioenergetic Measurements in Children with Bipolar Disorder: A Pilot 31^{31}P Magnetic Resonance Spectroscopy Study

Background: Research exploring Bipolar Disorder (BD) phenotypes and mitochondrial dysfunction, particularly in younger subjects, has been insufficient to date. Previous studies have found abnormal cerebral pH levels in adults with BD, which may be directly linked to abnormal mitochondrial activity. To date no such studies have been reported in children with BD. Methods: Phosphorus Magnetic Resonance Spectroscopy ($^{31}$P MRS) was used to determine pH, phopshocreatine (PCr) and inorganic phosphate (Pi) levels in 8 subjects with BD and 8 healthy comparison subjects (HCS) ages 11 to 20 years old. Results: There was no significant difference in pH between the patients and HCS. However, frontal pH values for patients with BD increased with age, contrary to studies of HCS and the pH values in the frontal lobe correlated negatively with the YMRS values. Global Pi was significantly lower in subjects with BD compared with HCS. There were no significant differences in PCr between the groups. Global PCr-to-Pi ratio (PCr/Pi) was significantly higher in subjects with BD compared with HCS. Conclusions: The change in Pi levels for the patients with BD coupled with the no difference in PCr levels, suggest an altered mitochondrial phosphorylation. However, our findings require further investigation of the underlying mechanisms with the notion that a mitochondrial dysfunction may manifest itself differently in children than that in adults. Limitations: Further investigations with larger patient populations are necessary to draw further conclusions

Reduced T2* Values in Soleus Muscle of Patients with Type 2 Diabetes Mellitus

Tissue water transverse relaxation times (T2) are highly sensitive to fluid and lipid accumulations in skeletal muscles whereas the related T2* is sensitive to changes in tissue oxygenation in addition to factors affecting T2. Diabetes mellitus (DM) affects muscles of lower extremities progressively by impairing blood flow at the macrovascular and microvascular levels. This study is to investigate whether T2 and T2* are sensitive enough to detect abnormalities in skeletal muscles of diabetic patients in the resting state. T2 and T2* values in calf muscle of 18 patients with type 2 DM (T2DM), 22 young healthy controls (YHC), and 7 age-matched older healthy controls (OHC) were measured at 3T using multi-TE spin echo and gradient echo sequences. Regional lipid levels of the soleus muscle were also measured using the Dixon method in a subset of the subjects. Correlations between T2, T2*, lipid levels, glycated hemoglobin (HbA1c) and presence of diabetes were evaluated. We found that T2 values were significantly higher in calf muscles of T2DM subjects, as were T2* values in anterior tibialis, and gastrocnemius muscles of T2DM participants. However, soleus T2* values of the T2DM subjects were significantly lower than those of the older, age-matched HC cohort $(22.9\pm 0.5 vs 26.7\pm 0.4 ms, p<0.01)$. The soleus T2* values in the T2DM cohort were inversely correlated with the presence of diabetes (t = −3.46, p<0.001) and with an increase in HbA1c, but not with body mass index or regional lipid levels. Although multiple factors may contribute to changes in T2* values, the lowered T2* value observed in the T2DM soleus muscle is most consistent with a combination of high oxygen consumption and poor regional perfusion. This finding is consistent with results of previous perfusion studies and suggests that the soleus in individuals with T2DM is likely under tissue oxygenation stress

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Tissue-specific differences in brain phosphodiesters in late-life major depression

Objective: Late-life depression has been hypothesized to have a neurodegenerative component that leads to impaired executive function and increases in subcortical white matter hyperintensities. Phosphorus magnetic resonance spectroscopy (MRS) can quantify several important phosphorus metabolites in the brain, particularly the anabolic precursors and catabolic metabolites of the constituents of cell membranes, which could be altered by neurodegenerative activity. Methods: Ten patients with late-life major depression who were medication free at time of study and 11 aged normal comparison subjects were studied using P-31 MRS three-dimensional chemical shift imaging at 4 Tesla. Phosphatidylcholine and phosphatidylethanolamine comprise 90% of cell membranes in brain but cannot be quantified precisely with 31P MRS. We measured phosphocholine and phosphoethanolamine, which are anabolic precursors, as well as glycerophosphocholine and glycerophosphoethanolamine, which are catabolic metabolites of phosphatidylcholine and phosphatidylethanolamine. Results: In accordance with our hypotheses, glycerophosphoethanolamine was elevated in white matter of depressed subjects, suggesting enhanced breakdown of cell membranes in these subjects. Glycerophosphocholine did not show any significant difference between comparison and depressed subjects but both showed an enhancement in white matter compared with gray matter. Contrary to our hypotheses, neither phosphocholine nor phosphoethanolamine showed evidence for reduction in late-life depression. Conclusion: These findings support the hypothesis that neurodegenerative processes occur in white matter in patients with late-life depression more than in the normal elderly population.Rogers' Family FoundationNARSADPfizer (K23 MH07728) (R01 MH058681) (R01 DA015116) (R01 AG20654)Harvard CatalystJohnson & Johnson Johnson & Johnson USA Janssen Biotech IncEli LillyOrganonUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA)GlaxoSmithKlineRoche HoldingAspect Medical SystemsForest LaboratoriesUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) (R01MH058681) (K23MH077287)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Aging (NIA) (R01AG020654)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (K24DA015116) (K05DA031247

Behavior in the open field predicts the number of KCl-induced cortical spreading depressions in rats.

Anxiety disorders are known to be comorbid with migraine, and cortical spreading depression (CSD) is the most likely cause of the migraine aura. To search for possible correlations between susceptibility to CSD and anxiety we used the open field test in male Sprague-Dawley rats chronically treated with the preventive anti-migraine drugs valproate or riboflavin. Animals avoiding the central area of the open field chamber and those with less exploratory activity (i.e. rearing) were considered more anxious. After 4 weeks of treatment CSDs were elicited by application of 1M KCl over the occipital cortex and the number of CSDs occurring over a 2h period was compared to the previously assessed open field behavior. Higher anxiety-like behavior was significantly correlated with a higher frequency of KCl-induced CSDs. In saline-treated animals, fewer rearings were found in animals with more frequent CSDs (R=-1.00). The duration of ambulatory episodes in the open field center correlated negatively with number of CSDs in the valproate group (R=-0.83; p<0.005) and in riboflavin treated group (R=-0.69; p<0.05) as well as total time spent in the open field center in both groups (R=-0.75; p<0.05 and R=-0.58; p<0.1 respectively). These results suggest that anxiety symptoms are associated with susceptibility to CSD and might explain why it can be an aggravating factor in migraine with aura