phosphocreatine and Bipolar-Disorder

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.

Topics: Animals; Bipolar Disorder; Brain; Clinical Studies as Topic; Creatine; Depressive Disorder, Major; Energy Metabolism; Humans; Nutritional Support; Phosphocreatine

Mitochondrial dysfunction is implicated in bipolar disorder based on the following lines of evidence: 1) Abnormal brain energy metabolism measured by 31P-magnetic resonance spectroscopy, that is, decreased intracellular pH, decreased phosphocreatine (PCr), and enhanced response of PCr to photic stimulation. 2) Possible role of maternal inheritance in the transmission of bipolar disorder. 3) Increased levels of the 4977-bp deletion in mitochondrial DNA (mtDNA) in autopsied brains. 4) Comorbidity of affective disorders in certain types of mitochondrial disorders, such as autosomal inherited chronic progressive external ophthalmoplegia and mitochondrial diabetes mellitus with the 3243 mutation. Based on these findings, we searched for mtDNA mutations/ polymorphisms associated with bipolar disorder and found that 5178C and 10398A polymorphisms in mtDNA were risk factors for bipolar disorder. The 5178C genotype was associated with lower brain intracellular pH. mtDNA variations may play a part in the pathophysiology of bipolar disorder through alteration of intracellular calcium signaling systems. The mitochondrial dysfunction hypothesis, which comprehensively accounts for the pathophysiology of bipolar disorder, is proposed.

Topics: Adenosine Triphosphate; Basal Ganglia; Bipolar Disorder; Brain; Calcium Channels; DNA, Mitochondrial; Gene Deletion; Humans; MELAS Syndrome; Mitochondria; Phosphocreatine; Point Mutation; Signal Transduction

Bipolar disorder may be associated with mitochondrial dysfunction. Therefore, agents that enhance mitochondrial functioning may be efficacious in bipolar disorder. We performed a randomized placebo-controlled trial of the mitochondrial enhancers acetyl-L-carnitine (ALCAR) and α-lipoic acid (ALA) in patients with bipolar depression, and assessed markers of cerebral energy metabolism using phosphorus magnetic resonance spectroscopy.. We administered ALCAR (1000-3000 mg daily) plus ALA (600-1800 mg daily) or placebo for 12 weeks to 40 patients with bipolar depression and obtained imaging data at baseline, week 1, and week 12 of treatment in 20 patients using phosphorus 3-dimensional chemical-shift imaging at 4 T. Statistical analysis used random effects mixed models.. We found no significant difference between ALCAR/ALA and placebo on change from baseline in the Montgomery-Asberg Depression Rating Scale in both the longitudinal (mean difference [95% confidence interval], -1.4 [-6.2 to 3.4], P = 0.58) and last-observation-carried-forward (-3.2 [-7.2 to 0.9], P = 0.12) analyses. ALCAR/ALA treatment significantly reduced phosphocreatine levels in the parieto-occipital cortex at week 12 (P = 0.002). Reduction in whole brain total nucleoside triphosphate levels from baseline to week 1 was associated with reduction in Montgomery-Asberg Depression Rating Scale scores (P = 0.02) in patients treated with ALCAR/ALA. However, this was likely a chance finding attributable to multiple statistical comparisons.. Treatment with ALCAR and ALA at the dose and duration used in this study does not have antidepressant effects in depressed bipolar patients and does not significantly enhance mitochondrial functioning in this patient group.

Topics: Acetylcarnitine; Adult; Antidepressive Agents; Bipolar Disorder; Brain; Chi-Square Distribution; Drug Therapy, Combination; Energy Metabolism; Female; Humans; Linear Models; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Phosphocreatine; Psychiatric Status Rating Scales; Thioctic Acid; Time Factors; Treatment Outcome

Eleven patients with bipolar depression were given doses of up to 18 g per day of triacetyluridine (TAU) over 6 weeks to test the effect of uridine on symptoms of depression via Montgomery-Asberg Depression Rating Scale (MADRS; Asberg, Montgomery, Perris, Schalling, & Sedvall, 1978) scores and on cellular bioenergetics using phosphorus magnetic resonance spectroscopic imaging (31P-MRSI). All patients and comparison participants (n = 9) completed baseline 31P-MRSI scans, and 9 patients completed posttherapy scans. The percentage changes for MADRS scores (Week 2, -23.8; Week 3, -34.9; Week 4, -42.5) and the time effects of TAU on MADRS scores (Week 2, z = -2.07, p = .039; Week 3, z = -4.28, p < .001; Week 4, z = -4.54, p < .001) may reflect TAU effects on early symptom improvement. TAU responders (patients who had a 50% or greater reduction in MADRS scores from baseline at any time) demonstrated a significant difference from nonresponders in pH changes from baseline (effect size = 150). These results suggest that TAU treatment may decrease symptoms of depression and improve mitochondrial functioning.

Topics: Acetates; Adult; Antidepressive Agents; Bipolar Disorder; Brain Chemistry; Depressive Disorder; Female; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Neuropsychological Tests; Phosphocreatine; Psychiatric Status Rating Scales; Uridine

Increasing numbers of youth are presenting for psychiatric evaluation with markedly irritable mood plus "hyperarousal" symptoms. Diagnostically homeless in current nosology, the syndrome (as well as its underlying neurobiology) is little understood. To address this problem, we conducted an exploratory proton magnetic resonance spectroscopy (MRS) study in a large sample of youth with chronic, functionally disabling irritability accompanied by hyperarousal, a clinical syndrome known as "severe mood dysregulation" (SMD), which may represent a broad phenotype of pediatric bipolar disorder. Medication-free SMD youth (N=36) and controls (N=48) underwent 1.5 Tesla MRS in four regions of interest. The following three neurometabolites, relative to creatine (Cr), were quantified with LCModel Software: (a) myo-inositol (mI), a marker of intra-cellular second messengers linked to the neurobiology of bipolar disorder; (b) glutamate/glutamine (GLX), a marker of the major excitatory neurotransmitter glutamate; and (c) N-acetyl aspartate (NAA), a marker of neuronal energetics. SMD subjects had significantly lower temporal mI/Cr versus controls. However, this difference did not survive correction for multiple comparisons. Given studies implicating mI in lithium's action in BD adults and youth, further work is necessary to determine potential therapeutic implications of our present finding and how SMD youth differ pathophysiologically from those with strictly defined BD.

Topics: Antimanic Agents; Arousal; Aspartic Acid; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Brain Mapping; Cerebral Cortex; Chronic Disease; Creatine; Diagnosis, Differential; Dominance, Cerebral; Double-Blind Method; Glutamine; Humans; Image Processing, Computer-Assisted; Inositol; Irritable Mood; Lithium Compounds; Magnetic Resonance Spectroscopy; Mood Disorders; Phosphocreatine

Previous studies have found that treatment with lithium over a 4-week period may increase the concentration of N-acetyl-aspartate (NAA) in both bipolar patients and controls. In view of other findings indicating that NAA concentrations may be a good marker for neuronal viability and/or functioning, it has been further suggested that some of the long term benefits of lithium may therefore be due to actions to improve these neuronal properties. The aim of the present study was to utilize H magnetic resonance spectroscopy ( H MRS) to further examine the effects of both lithium and sodium valproate upon NAA concentrations in treated euthymic bipolar patients. In the first part of the study, healthy controls (n =18) were compared with euthymic bipolar patients (type I and type II) who were taking either lithium (n =14) or sodium valproate (n =11), and NAA : creatine ratios were determined. In the second part, we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n =9) and compared these to age- and sex-matched healthy controls (n =11), and we quantified the exact concentrations of NAA using an external solution. The results from the first part of the study showed that bipolar patients chronically treated with lithium had a significant increase in NAA concentrations but, in contrast, there were no significant increases in the sodium valproate-treated patients compared to controls. The second part of the study also found no effects of sodium valproate on NAA concentrations. These findings are the first to compare NAA concentrations in euthymic bipolar patients being treated with lithium or sodium valproate. The results support suggestions that longer-term administration of lithium to bipolar patients may increase NAA concentrations. However, the study suggests that chronic administration of sodium valproate to patients does not lead to similar changes in NAA concentrations. These findings suggest that sodium valproate and lithium may not share a common mechanism of action in bipolar disorder involving neurotrophic or neuroprotective effects.

Topics: Adult; Antidepressive Agents; Antimanic Agents; Aspartic Acid; Bipolar Disorder; Cerebral Cortex; Choline; Creatine; Drug Administration Schedule; Female; Humans; Inositol; Lithium; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Valproic Acid

Few studies have examined the neurochemical abnormalities that might be associated with pediatric bipolar disorder. The aim of this study was to use magnetic resonance spectroscopy to evaluate several brain regions implicated in bipolar disorder in children with a mood disorder and a familial risk for bipolar disorder. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. Specifically, decreased N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr) of the prefrontal cortex and cerebellar vermis would reflect impairments in neuronal function and cellular metabolism, and elevated myo-inositol (mI) would reflect impaired phosphoinositide metabolism, potentially representing early markers of neurophysiologic changes that might underlie the development of bipolar disorder.. Children with a mood disorder and at least one parent with bipolar disorder (n = 9) and healthy children (n = 10) group matched for age (8-12 years), race, sex, education, and Tanner stage were evaluated using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. Proton magnetic resonance spectroscopy was acquired using 8-cc volumes within the frontal cortex, frontal white matter, and the cerebellar vermis. Metabolite ratios (NAA/Cr, cholines (Cho)/Cr, mI/Cr, NAA/Cho, NAA/mI, and Cho/mI) and concentrations (NAA, Cr, Cho, and mI) were calculated and compared between groups.. The trend in concentration levels of NAA and Cr was approximately 8% lower for children with a mood disorder than healthy children within the cerebellar vermis. The frontal cortex in children with a mood disorder revealed elevated mI concentration levels, approximately 16% increased, compared with healthy children.. Similar to findings in adults with bipolar disorders, neurochemical abnormalities within the frontal cortex and the cerebellar vermis were present in this preliminary comparison of children with a mood disorder and a familial risk for bipolar disorder. Larger sample sizes are needed to replicate these findings.

Topics: Aspartic Acid; Bipolar Disorder; Brain Chemistry; Cerebellum; Child; Family; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Mood Disorders; Phosphocreatine; Protons; Psychiatric Status Rating Scales; Risk; Wechsler Scales

To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode.. Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects.. There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects.. We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

Topics: Adolescent; Adult; Affective Symptoms; Bipolar Disorder; Child; Child of Impaired Parents; Creatine; Female; Gyrus Cinguli; Humans; Longitudinal Studies; Male; Phosphocreatine; Prefrontal Cortex; Proton Magnetic Resonance Spectroscopy; Risk Assessment

Increased oxidative stress in cerebral mitochondria may follow exposure to the systemic hypobaric hypoxia associated with residing at higher altitudes. Because mitochondrial dysfunction is implicated in bipolar disorder (BD) pathophysiology, this may impact the cerebral bioenergetics in BD. In this study, we evaluated the cerebral bioenergetics of BD and healthy control (HC) subjects at two sites, located at sea level and at moderate altitude.. Forty-three veterans with BD and 33 HC veterans were recruited in Boston (n = 22) and Salt Lake City (SLC; n = 54). Levels of phosphocreatine, β nucleoside triphosphate (βNTP), inorganic phosphate, and pH over total phosphate (TP) were measured using phosphorus-31 magnetic resonance spectroscopy in the following brain regions: anterior cingulate cortex and posterior occipital cortex, as well as bilateral prefrontal and occipitoparietal (OP) white matter (WM).. A significant main effect of site was found in βNTP/TP (Boston > SLC) and phosphocreatine/TP (Boston < SLC) in most cortical and WM regions, and inorganic phosphate/TP (Boston < SLC) in OP regions. A main effect analysis of BD diagnosis demonstrated a lower pH in posterior occipital cortex and right OP WM and a lower βNTP/TP in right prefrontal WM in BD subjects, compared to HC subjects.. The study showed that there were cerebral bioenergetic differences in both BD and HC veteran participants at two different sites, which may be partly explained by altitude difference. Future studies are needed to replicate these results in order to elucidate the dysfunctional mitochondrial changes that occur in response to hypobaric hypoxia.

Topics: Adenosine Triphosphate; Adult; Aged; Altitude; Bipolar Disorder; Boston; Brain; Case-Control Studies; Energy Metabolism; Female; Gyrus Cinguli; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Occipital Lobe; Parietal Lobe; Phosphates; Phosphocreatine; Phosphorus Isotopes; Prefrontal Cortex; Utah; Veterans; White Matter

Brain energy metabolism is critical for supporting synaptic function and information processing. A growing body of evidence suggests abnormalities in brain bioenergetics in psychiatric disorders, including both bipolar disorder (BD) and schizophrenia.. We studied 20 patients experiencing a first episode of BD and 28 healthy control participants at 4T and quantified creatine kinase forward reaction rate constant using. We found a significant reduction in creatine kinase forward reaction rate constant in the BD group (F = 4.692, p = .036), whereas brain ATP and phosphocreatine concentrations, as well as brain parenchymal pH, were normal.. These results pinpoint a specific molecular mechanism underlying our previous observation of an inability to replenish brain ATP during times of high energy demand in BD.

Topics: Adenosine Triphosphate; Adolescent; Adult; Bipolar Disorder; Brain; Case-Control Studies; Creatine Kinase; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Photic Stimulation; Young Adult

Despite the diagnostic challenges in categorizing bipolar disorder subtypes, bipolar I and II disorders (BD-I and BD-II respectively) are valid indices for researchers. Subtle neurobiological differences may underlie clinical differences between mood disorder subtypes. The aims of this study were to investigate neurochemical differences between bipolar disorder subtypes.. There were significant differences between groups in terms of glutamate [F = 6.27, p = 0.003], glutamate + glutamine [F = 6.08, p = 0.004], inositol containing compounds (Ino) (F = 9.25, p < 0.001), NAA [F = 7.63, p = 0.001] and creatine + phosphocreatine [F = 11.06, p < 0.001] in the left hemisphere and Ino [F = 5.65, p = 0.005] in the right hemisphere. Post-hoc comparisons showed that the BD-I disorder group had significantly lower metabolite levels in comparison to the BD-II and the HC groups.. This was a cross-sectional study with a small sample size. In addition, patients were on various psychotropic medications, which may have impacted the results.. Neurochemical levels, in the superior temporal cortices, measured with

Topics: Adult; Bipolar Disorder; Creatine; Cross-Sectional Studies; Cyclothymic Disorder; Female; Glutamic Acid; Humans; Magnetic Resonance Imaging; Male; Phosphocreatine; Proton Magnetic Resonance Spectroscopy; Temporal Lobe; Young Adult

We previously reported that higher body mass index (BMI) was associated with greater hippocampal glutamate+glutamine in people with bipolar disorder (BD), but not in non-BD healthy comparator subjects (HSs). In the current report, we extend these findings by examining the impact of BD diagnosis and BMI on hippocampal volumes and the concentrations of several additional neurochemicals in 57 early-stage BD patients and 31 HSs. Using 3-T magnetic resonance imaging and magnetic resonance spectroscopy, we measured bilateral hippocampal volumes and the hippocampal concentrations of four neurochemicals relevant to BD: N-acetylaspartate+N-acteylaspartylglutamate (tNAA), creatine+phosphocreatine (Cre), myoinositol (Ins) and glycerophosphocholine+phosphatidylcholine (Cho). We used multivariate factorial analysis of covariance to investigate the impact of diagnosis (patient vs HS) and BMI category (normal weight vs overweight/obese) on these variables. We found a main effect of diagnosis on hippocampal volumes, with patients having smaller hippocampi than HSs. There was no association between BMI and hippocampal volumes. We found diagnosis and BMI effects on hippocampal neurochemistry, with patients having lower Cre, Ins and Cho, and overweight/obese subjects having higher levels of these chemicals. In patient-only models that controlled for clinical and treatment variables, we detected an additional association between higher BMI and lower tNAA that was absent in HSs. To our knowledge, this was the first study to investigate the relative contributions of BD diagnosis and BMI to hippocampal volumes, and only the second to investigate their contributions to hippocampal chemistry. It provides further evidence that diagnosis and elevated BMI both impact limbic brain areas relevant to BD.

Topics: Adolescent; Adult; Aspartic Acid; Bipolar Disorder; Body Mass Index; Brain; Case-Control Studies; Creatine; Dipeptides; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Inositol; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Obesity; Organ Size; Overweight; Phosphatidylcholines; Phosphocreatine; Young Adult

To investigate tissue-dependent cerebral energy metabolism by measuring high energy phosphate levels in unmedicated adolescents diagnosed with bipolar I disorder.. Phosphorus-31 magnetic resonance spectroscopic imaging data were acquired over the entire brain of 24 adolescents with bipolar I disorder and 19 demographically matched healthy comparison adolescents. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP, determined from the γ-resonance) in homogeneous gray and white matter in the right and left hemispheres of the cerebrum of each subject were obtained by extrapolation of linear regression analyses of metabolite concentrations vs. voxel gray matter fractions.. Multivariate analyses of variance showed a significant effect of group on high energy phosphate concentrations in the right cerebrum (p=0.0002) but not in the left (p=0.17). Post-hoc testing in the right cerebrum revealed significantly reduced concentrations of PCr in gray matter and ATP in white matter in both manic (p=0.002 and 0.0001, respectively) and euthymic (p=0.004 and 0.002, respectively) bipolar I disorder subjects relative to healthy comparisons.. The small sample sizes yield relatively low statistical power between manic and euthymic groups; cross-sectional observations limit the ability to determine if these findings are truly independent of mood state.. Our results suggest bioenergetic impairment - consistent with downregulation of creatine kinase - is an early pathophysiological feature of bipolar I disorder.

Topics: Adenosine Triphosphate; Adolescent; Affect; Biomarkers; Bipolar Disorder; Brain; Case-Control Studies; Cerebrum; Child; Cross-Sectional Studies; Energy Metabolism; Female; Gray Matter; Humans; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Phosphorus Isotopes; White Matter; Young Adult

Neurochemical changes are responsible for bipolar disorder (BD) pathophysiology. Despite current progress in BD research, mood- and trait-related alterations in BD continue to elicit further investigation.. In this study, we report a longitudinal proton magnetic resonance spectroscopy study evaluating dorsomedial prefrontal cortex (DMPFC) metabolites N-acetylaspartate (NAA), creatine plus phosphocreatine (total creatine [tCr]), phosphorylcholine plus glycerophosphocholine, myo-inositol, and glutamate plus glutamine levels of manic and euthymic adult BD type I patients (n=48) treated with standard antimanic medicines, compared to matching healthy controls (n=44).. DMPFC NAA values and NAA/tCr ratio were significantly lower in euthymic BD patients when compared with healthy controls with similar levels of other metabolites in all groups, indicating a trait-related NAA abnormality in euthymic BD patients.. of our study include a relatively low (1.5T) magnetic resonance field strength and variable drugs administered to achieve euthymia despite the best efforts to standardize the open fashion treatment.. Our study contributes to the integrating models of trait-related metabolite alterations observed in euthymia since NAA is considered as a marker of neuronal viability and mitochondrial energy metabolism. In light of supporting and conflicting results reported previously, future studies with longitudinal designs and larger patient groups are warranted to better define both state- and trait-related cerebral metabolic alterations associated with BD pathophysiology.

Topics: Adult; Antimanic Agents; Aspartic Acid; Bipolar Disorder; Choline; Cyclothymic Disorder; Female; Frontal Lobe; Gyrus Cinguli; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Phosphocreatine; Prefrontal Cortex

To identify abnormalities in high energy phosphate cerebral metabolism in euthymic bipolar disorder.. Phosphorus-31 magnetic resonance spectroscopic imaging ((31)P MRSI) data were acquired from the entire brain of 9 euthymic adults with bipolar disorder and 13 healthy adults. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP) in homogeneous gray and white matter were obtained by tissue regression analysis.. Analyses of covariance revealed the effect of age to be significantly different between bipolar and healthy groups for concentrations of PCr (p=0.0018) and ATP (p=0.013) in gray matter. These metabolites were negatively correlated with age in gray matter in bipolar subjects while PCr was positively correlated with age in gray matter of healthy subjects. Additionally, age-corrected concentrations of PCr in gray matter were significantly elevated in bipolar subjects (p=0.0048).. Given that this cross-sectional study possessed a small sample and potentially confounding effects of medication status, we recommend a larger, longitudinal study to more robustly study relationships between bioenergetic impairment and duration of disease.. Our results suggest bioenergetic impairment related to mitochondrial function may be progressive in multi-episode bipolar subjects as they age.

Topics: Adenosine Triphosphate; Adult; Aging; Bipolar Disorder; Cerebral Cortex; Cross-Sectional Studies; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphates; Phosphocreatine; Phosphorus; White Matter

Converging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using (31)P magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.

Topics: Adenosine Triphosphate; Adult; Bipolar Disorder; Brain; Case-Control Studies; Creatine Kinase; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Photic Stimulation

The aim of the present study was to measure brain phosphorus-31 magnetic resonance spectroscopy ((31) P MRS) metabolite levels and the creatine kinase reaction forward rate constant (kf ) in subjects with bipolar disorder (BD).. Subjects with bipolar euthymia (n = 14) or depression (n = 11) were recruited. Healthy comparison subjects (HC) (n = 23) were recruited and matched to subjects with BD on age, gender, and educational level. All studies were performed on a 3-Tesla clinical magnetic resonance imaging system using a (31) P/(1) H double-tuned volume head coil. (31) P spectra were acquired without (1) H-decoupling using magnetization-transfer image-selected in vivo spectroscopy. Metabolite ratios from a brain region that includes the frontal lobe, corpus callosum, thalamus, and occipital lobe are expressed as a percentage of the total phosphorus (TP) signal. Brain pH was also investigated.. Beta-nucleoside-triphosphate (β-NTP/TP) in subjects with bipolar depression was positively correlated with kf (p = 0.039, r(2) = 0.39); similar correlations were not observed in bipolar euthymia or HC. In addition, no differences in kf and brain pH were observed among the three diagnostic groups. A decrease in the ratio of phosphomonoesters to phosphodiesters (PME/PDE) was observed in subjects with bipolar depression relative to HC (p = 0.032). We also observed a trend toward an inverse correlation in bipolar depression characterized by decreased phosphocreatine and increased depression severity.. In our sample, kf was not altered in the euthymic or depressed mood state in BD. However, decreased PME/PDE in subjects with bipolar depression was consistent with differences in membrane turnover. These data provide preliminary support for alterations in phospholipid metabolism and mitochondrial function in bipolar depression.

Topics: Adult; Bipolar Disorder; Corpus Callosum; Depression; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Mitochondria; Phosphocreatine; Phospholipids; Phosphorus Isotopes; Psychiatric Status Rating Scales; Thalamus

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.. 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.. 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.. 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.. Further investigations with larger patient populations are necessary to draw further conclusions.

Topics: Adolescent; Bipolar Disorder; Child; Energy Metabolism; Female; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Male; Nuclear Magnetic Resonance, Biomolecular; Phosphates; Phosphocreatine; Young Adult

To compare the concentrations of high-energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC).. We used in vivo phosphorus-31 magnetic resonance spectroscopy ((31) P-MRS) at 3 Tesla to measure phosphocreatine (PCr), beta-nucleoside triphosphate (β-NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs.. Analysis of covariance, including age as a covariate, revealed differences in PCr (p=0.037), Pi (p=0.017), and PCr/Pi (p=0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post-hoc Tukey-Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p=0.038) and medicated BD (24%; p=0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p=0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p=0.013) and with medicated BD (39%; p=0.002). No differences in β-NTP or pH were observed.. Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n-acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD.

Topics: Adolescent; Bipolar Disorder; Case-Control Studies; Depression; Energy Metabolism; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Spectroscopy; Male; Mitochondria; Phosphates; Phosphocreatine; Phosphorus Isotopes; Polyphosphates

The few studies applying single-voxel ¹H spectroscopy in children and adolescents with bipolar disorder (BD) have reported low N-acetyl-aspartate (NAA) levels in the dorsolateral prefrontal cortex (DLPFC), and high myo-inositol / phosphocreatine plus creatine (PCr+Cr) ratios in the anterior cingulate. The aim of this study was to evaluate NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr in various frontal cortical areas in children and adolescents with BD. We hypothesized that NAA levels within the prefrontal cortex are lower in BD patients than in healthy controls, indicating neurodevelopmental alterations in the former.. We studied 43 pediatric patients with DSM-IV BD (19 female, mean age 13.2 ± 2.9 years) and 38 healthy controls (19 female, mean age 13.9 ± 2.7 years). We conducted multivoxel in vivo ¹H spectroscopy measurements at 1.5 Tesla using a long echo time of 272 ms to obtain bilateral metabolite levels from the medial prefrontal cortex (MPFC), DLPFC (white and gray matter), cingulate (anterior and posterior), and occipital lobes. We used the nonparametric Mann-Whitney U test to compare neurochemical levels between groups.. In pediatric BD patients, NAA and GPC+PC levels in the bilateral MPFC, and PCr+Cr levels in the left MPFC were lower than those seen in the controls. In the left DLPFC white matter, levels of NAA and PCr+Cr were also lower in BD patients than in controls.. Lower NAA and PCr+Cr levels in the PFC of children and adolescents with BD may be indicative of abnormal dendritic arborization and neuropil, suggesting neurodevelopmental abnormalities.

Topics: Adolescent; Aspartic Acid; Bipolar Disorder; Brain Chemistry; Child; Diagnostic and Statistical Manual of Mental Disorders; Female; Glycerylphosphorylcholine; Humans; Inositol; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Phosphorylcholine; Prefrontal Cortex; Protons

Alcoholism is highly prevalent among bipolar disorder (BD) patients, and its presence is associated with a worse outcome and refractoriness to treatment of the mood disorder. The neurobiological underpinnings that characterize this comorbidity are unknown. We sought to investigate the neurochemical profile of the dorsolateral prefrontal cortex (DLPFC) of BD patients with comorbid alcoholism. A short-TE, single-voxel (1)H spectroscopy acquisition at 1.5T from the left DLFPC of 22 alcoholic BD patients, 26 non-alcoholic BD patients and 54 healthy comparison subjects (HC) were obtained. Absolute levels of N-acetyl aspartate, phosphocreatine plus creatine, choline-containing compounds, myo-inositol, glutamate plus glutamine (Glu+Gln) and glutamate were obtained using the water signal as an internal reference. Analysis of co-variance was used to compare metabolite levels among the three groups. In the primary comparison, non-alcoholic BD patients had higher glutamate concentrations compared to alcoholic BD patients. In secondary comparisons integrating interactions between gender and alcoholism, non-alcoholic BD patients presented significantly higher glutamate plus glutamine (Glu+Gln) than alcoholic BD patients and HC. These results appeared to be driven by differences in male subjects. Alcoholic BD patients with additional drug use disorders presented significantly lower myo-inositol than BD patients with alcoholism alone. The co-occurrence of BD and alcoholism may be characterized by neurochemical abnormalities related to the glutamatergic system and to the inositol second messenger system and/or in glial pathology. These abnormalities may be the neurochemical correlate of an increased risk to develop alcoholism in BD, or of a persistently worse clinical and functional status in BD patients in remission from alcoholism, supporting the clinical recommendation that efforts should be made to prevent or early diagnose and treat alcoholism in BD patients.

Topics: Adult; Age Factors; Alcoholism; Analysis of Variance; Aspartic Acid; Bipolar Disorder; Brain; Comorbidity; Creatine; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Sex Factors

Topics: Adenosine Triphosphate; Bipolar Disorder; Brain; DNA, Mitochondrial; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Mitochondrial Diseases; Phosphocreatine

While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy ((1)H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N-acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr).. Thirty-two medication-free BD subjects (33.8 +/- 10.2 years) and 32 matched controls (33.8 +/- 9.0 years) underwent a short echo-time (TE = 30 ms) (1)H MRS. An 8-cm(3) single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo-inositol, and glutamate were obtained, using the water signal as an internal reference.. BD subjects had lower Cr + PCr [F((1,62)) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [F((1,62)) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites.. These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.

Topics: Adult; Analysis of Variance; Aspartic Acid; Bipolar Disorder; Case-Control Studies; Creatine; Energy Metabolism; Female; Functional Laterality; Humans; Magnetic Resonance Spectroscopy; Male; Mental Status Schedule; Middle Aged; Phosphocreatine; Phospholipids; Prefrontal Cortex; Protons; Severity of Illness Index

Increasing evidence suggests abnormalities in the structure, function, and neurochemistry of the frontal cortex in pediatric bipolar (BP) patients. We conducted a single-voxel proton magnetic resonance spectroscopy ((1)H MRS) of the left dorsolateral prefrontal cortex (DLPFC) of pediatric BP patients, expecting lower N-acetyl-aspartate (NAA) levels within that brain region compared to healthy comparison subjects.. We studied 35 pediatric BP (23 BP type I, 12 BP type II; mean age +/- SD = 13.2 +/- 2.9 years; 18 females) and 36 healthy controls (mean age +/- SD = 13.7 +/- 2.6 years, 17 females). A short echo time, single-voxel (1)H spectroscopy approach point-resolved spectroscopy (PRESS) sequence, measurements of metabolites was performed on a 1.5T Philips MR system.. BP subjects had significantly lower NAA levels in the left DLPFC compared to healthy controls (F = 4.21, df = 1, 68, p = 0.04). There was not a significant difference between groups for phosphocreatine + creatine (PCr+Cr), glycerolphosphocholine + phosphocholine (GPC + PC), myo-inositol (mI), or glutamate. Further analyses revealed a significant reduction of NAA in our early puberty group compared to controls (Mann-Whitney U-test statistic = 52.00, p = 0.014), but not for BP versus controls in other pubertal groups.. BP subjects have lower NAA levels in the left DLPFC compared to healthy subjects, suggesting neuronal dysfunction in this region.

Topics: Adolescent; Aspartic Acid; Bipolar Disorder; Child; Creatine; Female; Glycerylphosphorylcholine; Humans; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Phosphorylcholine; Prefrontal Cortex; Puberty

Brain-derived neurotrophic factor val66met polymorphism has been implicated in the pathophysiology of bipolar disorder. We investigated the neurochemistry of the left dorsolateral prefrontal cortex of bipolar disorder and healthy participants in relation to the brain-derived neurotrophic factor val66met polymorphism using H-magnetic resonance spectroscopy. Absolute N-acetyl-aspartate, phosphocreatine+creatine (PCr+Cr), choline-containing compounds, myo-inositol, and glutamate levels were measured. Bipolar disorder met-carriers had lower PCr+Cr levels than bipolar disorder val/val patients, and bipolar disorder val/val patients had higher PCr+Cr levels than val/val healthy controls. These results indicate that bipolar disorder met-carriers have abnormal energy metabolism in the left dorsolateral prefrontal cortex.

Topics: Adult; Amino Acid Substitution; Aspartic Acid; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Creatine; Energy Metabolism; Female; Genotype; Humans; Magnetic Resonance Spectroscopy; Male; Methionine; Phosphocreatine; Polymorphism, Genetic; Prefrontal Cortex; Psychiatric Status Rating Scales; Valine

The authors' goal was to investigate phosphatidylinositol and glutamatergic metabolism in the anterior cingulate cortex of children and adolescents with attention deficit hyperactivity disorder (ADHD) alone, children with ADHD plus bipolar disorder, and children with no axis I diagnosis.. Proton spectra were acquired from a 4.8-ml voxel placed in the anterior cingulate cortex of 30 subjects who were 6 to 13 years old. Fifteen subjects had ADHD and no comorbid disorder, eight had ADHD plus bipolar disorder, and seven were healthy comparison subjects.. Children with ADHD had a significantly higher ratio of glutamate plus glutamine to myo-inositol-containing compounds than children with ADHD plus bipolar disorder and healthy children.. myo-Inositol-containing compounds may provide information on the action of antimanic treatments such as lithium, valproate, and carbamazepine. Glutamate and glutamine are measures of glutamatergic neurotransmission and thus may also reflect changes in serotonin and dopamine pathways.

Topics: Adolescent; Age Factors; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Brain Chemistry; Child; Comorbidity; Creatine; Dopamine; Glutamic Acid; Glutamine; Gyrus Cinguli; Humans; Inositol; Magnetic Resonance Spectroscopy; Phosphocreatine; Protons; Serotonin; Tissue Distribution

Bipolar disorder (BPD) affects more than 2 million adults in the USA and ranks among the top 10 causes of worldwide disabilities. Despite its prevalence, very little is known about the etiology of BPD. Recent evidence suggests that cellular energy metabolism is disturbed in BPD. Mitochondrial function is altered, and levels of high-energy phosphates, such as phosphocreatine (PCr), are reduced in the brain. This evidence has led to the hypothesis that deficiencies in energy metabolism could account for some of the pathophysiology observed in BPD. To further explore this hypothesis, we examined levels of creatine kinase (CK) mRNA, the enzyme involved in synthesis and metabolism of PCr, in the hippocampus (HIP) and dorsolateral prefrontal cortex (DLPFC) of control, BPD and schizophrenia subjects.. Tissue was obtained from the Harvard Brain Tissue Resource Center. Real-time quantitative polymerase chain reaction (HIP, DLPFC) and gene expression microarrays (HIP) were employed to compare the brain and mitochondrial 1 isoforms of CK.. Both CK isoforms were downregulated in BPD. Furthermore, mRNA transcripts for oligodendrocyte-specific proteins were downregulated in the DLPFC, whereas the mRNA for the neuron-specific protein microtubule-associated protein 2 was downregulated in the HIP.. Although some of the downregulation of CK might be explained by cell loss, a more general mechanism seems to be responsible. The downregulation of CK transcripts, if translated into protein levels, could explain the reduction of high-energy phosphates previously observed in BPD.

Topics: Adult; Aged; Animals; Bipolar Disorder; Creatine Kinase; Female; Gene Expression Regulation, Enzymologic; Hippocampus; Humans; Male; Middle Aged; Mitochondria; Phosphocreatine; Polymerase Chain Reaction; Prefrontal Cortex; Protein Array Analysis; Rats; Rats, Sprague-Dawley; RNA, Messenger

Several neurochemical abnormalities have been reported in bipolar disorder (BD), but the exact mechanisms that underlie its pathophysiology remain to be elucidated. Proton magnetic resonance spectroscopy (1HMRS) allows in vivo measurements of certain neurometabolites in the human brain. 1HMRS was used to investigate the dorsolateral prefrontal cortex (DLPFC) in bipolar subjects during a manic or mixed phase. N-acetyl-L-aspartate (NAA), choline-containing molecules (Cho), creatine plus phosphocreatine (Cr) and myoinositol (Ino) were measured.. Ten bipolar patients (nine manic, one mixed), diagnosed by a semi-structured clinical interview (SCID), and ten age- and gender-matched healthy volunteers were studied. Absolute neurometabolites levels were measured from two 8 cm3 voxels placed in left and right DLPFC using a short TE 1HMRS method at 1.5 T. T1- and T2-weighted anatomical magnetic resonance imaging was performed to exclude any neuroanatomical abnormality.. No significant differences were found for NAA, Cho, Cr, Ino, NAA/Cr, Cho/Cr or Ino/Cr between patients and controls. Manic/mixed patients had significantly higher left-to-right myoinositol ratios in DLPFC (p = 0.044).. Increased left-to-right myoinositol ratios in the DLPFC in bipolar patients during acute mania may represent a dysfunction in the phosphoinositide-signaling pathway. Longitudinal studies with larger samples of unmedicated patients assessing pre- and post-treatment times will be required for further clarification of the time course of these abnormalities and the relationship with treatment effects.

Topics: Acute Disease; Adult; Antimanic Agents; Antipsychotic Agents; Aspartic Acid; Bipolar Disorder; Choline; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Inositol; Magnetic Resonance Imaging; Male; Middle Aged; Patient Selection; Phosphocreatine; Prefrontal Cortex

Magnetic resonance spectroscopy studies (MRS) reported abnormally low levels of N-acetylaspartate (NAA, a marker of neuronal integrity) in dorsolateral prefrontal cortex (DLPFC) of adult bipolar patients, suggesting possible neuronal dysfunction. Furthermore, recent MRS reports suggested possible lithium-induced increase in NAA levels in bipolar patients. We examined with in vivo (1)H MRS NAA levels in the DLPFC of adult bipolar patients.. Ten DSM-IV bipolar disorder patients (6 lithium-treated, 4 drug-free) and 32 healthy controls underwent a short echo-time 1H MRS session, which localized an 8 cm3 single-voxel in the left DLPFC using a STEAM sequence.. No significant differences between the two groups were found for NAA, choline-containing molecules (GPC+PC), or phosphocreatine plus creatine (PCr+Cr) (Student t-test, p > 0.05). Nonetheless, NAA/PCr+Cr ratios were significantly increased in lithium-treated bipolar subjects compared to unmedicated patients and healthy controls (Mann-Whitney U-test, p < 0.05).. Relatively small sample size may have reduced the statistical power of our analyses and the utilization of a single-voxel approach did not allow for the examination of other cortical brain areas.. This study did not find abnormally reduced levels of NAA in left DLPFC of adult bipolar patients, in a sample of patients who were mostly on medications. However, elevated NAA/PCr+Cr ratios were shown in lithium-treated bipolar patients. Longitudinal 1H MRS studies should further examine NAA levels in prefrontal cortex regions in untreated bipolar patients before and after mood stabilizing treatment.

Topics: Adult; Aspartic Acid; Bipolar Disorder; Case-Control Studies; Creatine; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Prefrontal Cortex; Radiography

Converging evidence implicates prefrontal circuits in the pathophysiology of bipolar disorder. Proton spectroscopy studies performed in adult bipolar patients assessing prefrontal regions have suggested decreased levels of N-acetylaspartate (NAA), a putative marker of neuronal integrity. In order to examine whether such abnormalities would also be found in younger patients, a 1H spectroscopy study was conducted that focused on the dorsolateral prefrontal cortex of children and adolescents with bipolar disorder.. The authors examined the levels of NAA, creatine plus phosphocreatine, and choline-containing molecules in the left dorsolateral prefrontal cortex of 14 bipolar disorder patients (mean age=15.5 years, SD=3, eight female) and 18 healthy comparison subjects (mean age=17.3, SD=3.7, seven female) using short echo time, single-voxel in vivo 1H spectroscopy. Absolute metabolite levels were determined using the water signal as an internal reference.. Bipolar patients presented significantly lower NAA levels and a significant inverse correlation between choline-containing molecules and number of previous affective episodes. No differences were found for other metabolites.. These findings suggest that young bipolar patients have decreased NAA levels in the dorsolateral prefrontal cortex, similar to what was previously reported in adult patients. Such changes may reflect an underdevelopment of dendritic arborizations and synaptic connections. These neuronal abnormalities in the dorsolateral prefrontal cortex of bipolar disorder youth are unlikely to represent long-term degenerative processes, at least in the subgroup of patients where the illness had relatively early onset.

Topics: Adolescent; Adult; Age Factors; Aspartic Acid; Bipolar Disorder; Child; Choline; Creatine; Female; Humans; Magnetic Resonance Spectroscopy; Male; Nerve Degeneration; Phosphocreatine; Prefrontal Cortex; Recurrence

While several studies have suggested a relationship between the hippocampus and psychosis in schizophrenia, fewer studies have specifically investigated the presence of psychosis in mood disorders from a neurobiological perspective. Moreover, a limitation of these earlier studies is that the majority of them were performed in chronic patients. The present proton magnetic resonance spectroscopic imaging (1H-MRSI) study assessed neuronal integrity (as assessed with N-acetylaspartate, NAA) in the hippocampus of patients with a first episode of mood disorders with psychotic symptoms. We studied 17 patients and 17 healthy subjects matched for age and sex. Subjects underwent 1H-MRSI, and measures of NAA, choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in 11 brain regions were obtained, i.e. hippocampus (HIPPO), dorsolateral prefrontal cortex, superior temporal gyrus, inferior frontal gyrus, occipital cortex, anterior and posterior cingulate, centrum semiovale, prefrontal white matter, thalamus and putamen. NAA/CRE ratios in HIPPO of patients were significantly lower than in controls. Sporadic and non-hypothesis-driven results were found in occipital cortex and prefrontal white matter as a main effect of diagnosis, and in superior temporal gyrus as a hemisphere by diagnosis interaction. These results would not survive a Bonferroni correction for the number of ROIs. No correlations were found with the available demographic and clinical data. Therefore, hippocampal neuronal abnormalities are present at the onset of mood disorders with psychotic symptoms. These data suggest that neuronal abnormalities in HIPPO may be associated with psychosis in mood disorders. Since these data were obtained in patients at first episode, they cannot be explained by chronicity of illness or pharmacological treatment.

Topics: Adolescent; Adult; Aspartic Acid; Bipolar Disorder; Cerebral Cortex; Choline; Creatine; Depressive Disorder, Major; Dominance, Cerebral; Female; Gyrus Cinguli; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Neurons; Phosphocreatine; Psychiatric Status Rating Scales; Putamen; Reference Values; Thalamus

The diagnosis of bipolar disorder in juveniles is controversial. This study was designed to compare proton magnetic resonance spectroscopy ((1)H MRS) in patients with bipolar disorder or intermittent explosive disorder, two groups with symptomatic overlap but categorical distinction. Children with intermittent explosive disorder designate patients whose illness clinically resembles pediatric bipolar disorder but does not satisfy DSM-IV criteria for mania. Based on the authors' previous report of higher levels of (1)H MRS cingulate myo-inositol/creatine in youngsters with bipolar disorder than in normal comparison subjects, they hypothesized that patients with bipolar disorder would have higher cingulate myo-inositol/creatine-phosphocreatine measurements than patients with intermittent explosive disorder and normal comparison subjects.. Myo-inositol levels were measured with a 2x2x2 cm(3) voxel placed in the anterior cingulate for acquisition of (1)H MRS in 10 patients with bipolar disorder, 10 patients with intermittent explosive disorder, and 13 normal comparison subjects. N-Acetylaspartate, choline moieties, creatine-phosphocreatine, and glutamate-glutamine metabolite levels were also measured.. The patients with bipolar disorder showed significantly higher anterior cingulate myo-inositol/creatine-phosphocreatine and myo-inositol (mmol/liter) levels than the patients with intermittent explosive disorder and the normal comparison subjects. No significant differences were found across groups for myo-inositol or other metabolites in the occipital cortex.. These data provide evidence that differences in the concentration of myo-inositol (mmol/liter) in the anterior cingulate cortex in (1)H MRS may differentiate these two populations. Follow-up studies involving larger samples may conclusively estimate the biological specificity between pediatric bipolar disorder and other disorders, which overlap clinically.

Topics: Adolescent; Age Factors; Aspartic Acid; Bipolar Disorder; Child; Choline; Creatine; Diagnosis, Differential; Disruptive, Impulse Control, and Conduct Disorders; Female; Gyrus Cinguli; Humans; Inositol; Magnetic Resonance Spectroscopy; Male; Occipital Lobe; Phosphocreatine

Previous 31P-MRS (magnetic resonance spectroscopy) studies suggested altered brain energy metabolism in bipolar disorder. This study characterized brain energy metabolism in lithium-resistant bipolar disorder using the photic-stimulation paradigm.. Subjects were 19 patients with DSM-IV bipolar disorder (nine responders and 10 nonresponders, 13 with bipolar I and six with bipolar II) in the euthymic state and 25 healthy volunteers. Energy metabolism in the occipital region was examined by 31P-MRS during photic stimulation (PS). Six 31P-MR spectra were obtained, one was before PS (Pre), two during 12 min of PS (PS1, PS2), and three after the PS (Post 1, Post 2, Post 3).. Significant effect of diagnosis (lithium-responsive bipolar disorder, lithium-resistant bipolar disorder, and control) was found for the phosphocreatine peak area ratio during the course of the photic stimulation (P < 0.05 by repeated measures ANOVA). The phosphocreatine peak area ratio was significantly decreased at Post 1 and Post 2 compared with Pre in lithium-resistant bipolar patients (P = 0.01 and P = 0.01 by Dunnett's multiple comparison).. The finding that phosphocreatine decreased after photic stimulation may be compatible with mitochondrial dysfunction. It is possible that mitochondrial function is impaired in lithium-resistant bipolar disorder.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Brain; Drug Resistance; Female; Humans; Light; Lithium Carbonate; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Phosphorus Isotopes; Photic Stimulation

Alterations in choline and myo-inositol metabolism have been noted in bipolar disorder, and the therapeutic efficacy of lithium in mania may be related to these effects. We wished to determine the relationship between anterior cingulate cortex choline and myo-inositol levels, assessed using proton magnetic resonance spectroscopic imaging (MRSI), and mood state in subjects with bipolar disorder.. Serial assessments of anterior cingulate cortex choline and myo-inositol metabolism were performed in nine subjects with bipolar disorder, taking either lithium or valproate, and 14 controls. Each bipolar subject was examined between one and four times (3.1 +/- 1.3). On the occasion of each examination, standardized ratings of both depression and mania were recorded.. In the left cingulate cortex, the bipolar subjects' depression ratings correlated positively with MRSI measures of Cho/Cr-PCr. In the right cingulate cortex, the Cho/Cr-PCr ratio was significantly higher in subjects with bipolar disorder compared with control subjects. In addition, bipolar subjects not taking antidepressants had a significantly higher right cingulate cortex Cho/Cr-PCr ratio compared with patients taking antidepressants or controls. No clinical or drug-related changes were observed for the Ino/Cr-PCr ratio.. The results of this study suggest that bipolar disorder is associated with alterations in the metabolism of cytosolic, choline-containing compounds in the anterior cingulate cortex. As this resonance arises primarily from phosphocholine and glycerophosphocholine, both of which are metabolites of phosphatidylcholine, these results are consistent with impaired intraneuronal signaling mechanisms.

Topics: Adult; Affect; Bipolar Disorder; Brain Mapping; Choline; Dominance, Cerebral; Female; Gyrus Cinguli; Humans; Inositol; Lithium Carbonate; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Psychiatric Status Rating Scales; Valproic Acid

Using 31P and 1H magnetic resonance spectroscopy (MRS) we previously reported that phosphocreatine was decreased in the left frontal lobe and choline-containing compounds were increased in the basal ganglia in the depressive state in patients with bipolar disorder. We applied quantitative 1H-MRS for further characterization of biochemical alteration in the frontal lobes of bipolar patients.. Twenty-three bipolar patients and 20 normal controls were examined by 1H-MRS with a 1.5T MR system. All patients were examined in the euthymic state, and eight patients were also examined in the depressive state. Volumes of interest of 2.5 x 2.5 x 2.5 cm were selected in the left and right frontal lobes. Absolute concentrations of N-acetyl-1-aspartate, creatine plus phosphocreatine, and choline-containing compounds were calculated from each metabolite peak.. Creatine concentration in the left frontal lobe in bipolar patients in the depressive state was significantly lower than that in the euthymic state. Creatine concentration in the right frontal lobe in the male patients was significantly higher than that in the female patients and a similar trend was also found in the control subjects.. We found a state-dependent change of creatine metabolism in the left frontal lobe of bipolar patients. The present results are compatible with our previous report of decreased phosphocreatine measured by 31P-MRS in the left frontal lobe in bipolar disorder. We also found an effect of gender on the creatine concentration. There may be a gender difference in creatine transport function into the brain.

Topics: Adult; Aged; Bipolar Disorder; Choline; Female; Frontal Lobe; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phosphocreatine

Sleep deprivation (SD) has an antidepressant effect in some, but not all, patients with depression, although its biological mechanisms have not yet been characterized. We previously reported altered brain phosphorus metabolism measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in patients with bipolar depression. We preliminarily examined effects of SD on phosphorus metabolism in the frontal lobes of 15 normal subjects using 31P-MRS. No significant differences of membrane phospholipid metabolism, high-energy phosphate metabolism and intracellular pH were found between before and after SD in these subjects. Further studies will be necessary to elucidate the physiological mechanism of SD for depressive patients.

Topics: Adolescent; Adult; Bipolar Disorder; Circadian Rhythm; Depressive Disorder; Frontal Lobe; Humans; Magnetic Resonance Spectroscopy; Male; Membrane Lipids; Phosphates; Phosphocreatine; Phospholipids; Phosphorus; Reference Values; Sleep Deprivation

Proton magnetic resonance spectra were recorded from a subcortical region containing the basal ganglia in 40 patients with affective disorders (18 with bipolar disorder and 22 with major depression) and in 20 normal controls. The absolute concentration of the choline-containing compounds (Cho) in the patients with bipolar disorder in the depressive state was significantly higher than that in the normal controls. The patients with bipolar disorder had significantly higher levels of the Cho/creatine + phosphocreatine (Cr) and Cho/N-acetly-1-aspartate (NAA) peak ratio compared with the normal controls in both the depressive and euthymic states, with a tendency to higher levels in the depressive state. The Cho/NAA peak ratio was also significantly higher in the patients with major depression compared with the normal controls. These results suggest that the membrane phospholipid metabolism in the basal ganglia is altered in affective disorders.

Topics: Adult; Aspartic Acid; Basal Ganglia; Bipolar Disorder; Choline; Creatine; Depressive Disorder; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mood Disorders; Phosphocreatine

Effect of photic stimulation (PS) on energy metabolism in the human occipital cortex was examined by using phosphorus-31 magnetic resonance spectroscopy in 9 normal subjects. Phosphocreatine (PCr)/total phosphorus signal peak area ratio significantly decreased from 12.3% to 10.9% during the 12 minutes of PS (P < 0.05). PCr once returned to a normal level after PS (11.9%) but significantly decreased again 12-18 minutes after PS (10.8%; P < 0.05). Intracellular pH increased from 7.08 to 7.16 during PS, although this increase was not significant. These results suggest that functional alteration of energy metabolism in the brain is different from that in muscles.

Topics: Adult; Bipolar Disorder; Brain; Energy Metabolism; Female; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Photic Stimulation; Schizophrenia

High energy phosphate metabolites were measured using phase-encoded in vivo phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in both the left and right frontal lobes of 25 patients with bipolar disorder. Eleven patients were examined in the depressive state, 12 in the manic state, and 21 in the euthymic state. Twenty-one age-matched normal volunteers were also examined. The phosphocreatine (PCr) peak area percentage in the left frontal lobe in the patients in the depressive state was decreased compared with that in the normal controls. It was significantly negatively correlated with the Hamilton Rating Scale for Depression score evaluated at the time of 31P-MRS examination. The PCr peak area percentage in the right frontal lobe in the patients in the manic and the euthymic states was decreased compared with that in the controls. These results are compatible with previous reports describing reduction of glucose metabolism in the left frontal lobe in depressive patients with bipolar disorder and trait-dependent right hemisphere dysfunction in bipolar disorder.

Topics: Arousal; Bipolar Disorder; Blood Glucose; Brain Mapping; Depressive Disorder; Dominance, Cerebral; Energy Metabolism; Frontal Lobe; Humans; Magnetic Resonance Spectroscopy; Phosphocreatine

In vivo [31P]magnetic resonance spectroscopic imaging ([31P]MRSI) was performed on 12 unmedicated, euthymic bipolar patients and 14 control subjects to determine if there were alterations in high-energy P metabolism in the temporal lobes of bipolar patients. Compared with the control group, the patients with bipolar disorder demonstrated significantly lower phosphomonoesters (PME) in both the left and right temporal lobes. No other group differences in P metabolites or lateralized asymmetries were noted. This preliminary study provides support for altered temporal lobe phospholipid metabolism in bipolar disorder.

Topics: Adenosine Triphosphate; Adult; Bipolar Disorder; Dominance, Cerebral; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Organophosphates; Personality Assessment; Phosphates; Phosphocreatine; Reference Values; Temporal Lobe

Brain phosphorus metabolism was measured by 31P-MRS in 15 patients with bipolar II disorder (BP II) and 14 patients with bipolar I disorder (BP I). Phosphocreatine (PCr)levels were significantly lower in patients with BP II in all three psychiatric states compared to 59 normal controls (PCr (%) was 13.5 +/- 1.5 (mean +/- SD) for controls, and 12.2 +/- 1.7, 12.1 +/- 1.3, 12.0 +/- 1.9 for hypomanic, euthymic and depressed bipolar II patients respectively). High values of phosphomonoester (PME) were found in BP II patients in the hypomanic and depressive states, but PME values in the euthymic state did not differ significantly from controls. Intracellular pH of BP II patients in all three psychiatric phases was similar to control values, whereas euthymic BP I patients had lower pH values. These results suggest that brain high energy phosphate metabolism may be impaired in BP II and that there may be pathophysiological differences between BP I and BP II.

Topics: Adenosine Triphosphate; Adult; Aged; Analysis of Variance; Bipolar Disorder; Creatine; Creatine Kinase; Female; Humans; Hydrogen-Ion Concentration; Intracellular Fluid; Magnetic Resonance Spectroscopy; Male; Middle Aged; Models, Biological; Phosphocreatine; Phosphoric Monoester Hydrolases

Water-suppressed 1H magnetic resonance spectra were recorded from two brain regions of psychiatric patients and normal volunteers. The two regions studied were (a) the basal ganglia structures surrounding the anterior horn of the lateral ventricle and (b) the occipital cortex. N-Acetylaspartate (NAA), phosphocreatine-creatine (PCr-Cr), choline and inositol resonances were seen in both regions. Ratios of metabolite peak integrals to PCr-Cr peak integral were calculated for each spectrum. To control for partial volume effects, comparisons between patients and controls were made only from identical regions i.e. basal ganglia vs basal ganglia, and likewise for occipital cortex. Metabolite ratios from the occipital region of patients were similar to those from the occipital region of normal subjects. Bipolar patients being treated with lithium had elevated NAA/PCr-Cr in the basal ganglia region when compared to normals. These patients also demonstrated elevated choline/PCr-Cr and inositol/PCr-Cr ratios in the basal ganglia region.

Topics: Adult; Aspartic Acid; Basal Ganglia; Bipolar Disorder; Choline; Creatine; Depressive Disorder; Energy Metabolism; Female; Humans; Image Processing, Computer-Assisted; Inositol; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Occipital Lobe; Phosphates; Phosphocreatine; Protons; Schizophrenia; Schizophrenic Psychology

Lithium specifically and potentially inhibits membrane transport of choline. However, the effect of lithium on human neuronal choline content is unknown. This study was performed to determine if lithium alters the human brain choline concentration in vivo. In vivo proton magnetic resonance spectroscopy was used to compare the relative brain concentration of choline-containing compounds in seven lithium-treated patients and six lithium-free controls. No significant difference was observed in the mean relative choline resonance between the patient and control groups. Lithium treatment did not appear to alter the overall brain content of choline-containing compounds. It remains possible that a component of these compounds, particularly free choline, is elevated during lithium treatment.

Topics: Adult; Aspartic Acid; Bipolar Disorder; Brain; Choline; Corpus Callosum; Humans; Lithium Carbonate; Magnetic Resonance Spectroscopy; Male; Parietal Lobe; Phosphocreatine

Brain phosphorus metabolism was measured in 22 patients with depressive disorders. Ten of them had DSM-III-R bipolar disorder, and 12 had major depression. In bipolar patients, phosphomonoester (PME) and intracellular pH were significantly increased in the depressive state than in the euthymic state, while those values in the euthymic state were significantly low as compared to age-matched normal controls. Phosphocreatine (PCr) was significantly decreased in severely depressed patients compared to mild depressives. These findings suggest that high energy phosphate metabolism, intracellular pH and membrane phospholipid metabolism are altered in depressive disorders.

Topics: Adenosine Triphosphate; Adult; Bipolar Disorder; Brain; Depressive Disorder; Energy Metabolism; Female; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Phosphorus