Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder

Objective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder.

Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.

Subjective response to alcohol: Associated alcohol use and orbitofrontal gray matter volume in bipolar disorder.

BACKGROUND: Alcohol use disorders (AUDs) are highly prevalent in bipolar disorder, however the developmental etiology of this comorbidity remains unknown. Structural differences in the orbitofrontal cortex (OFC) have been linked to problematic drinking in bipolar disorder and typically developing youth, with evidence implicating variations in OFC in differential subjective response to alcohol in typical development. METHODS: Subjective response to alcohol, recent alcohol use, impulsivity, and variation in OFC gray matter volume were investigated in 48 emerging adults (24 with bipolar disorder, 24 typically developing). On average 1.5 years later, drinking patterns were reassessed and relations between subjective response and changes in alcohol use were explored. RESULTS: Groups did not differ in baseline alcohol use or subjective response. At baseline, decreased subjective response to alcohol was associated with increased alcohol use in both groups. Lower gray matter volume in medial OFC in bipolar disorder was associated with increased subjective response to alcohol, whereas lower gray matter volume in OFC in typically developing participants was associated with decreased subjective response to alcohol. Increase in alcohol use (baseline to follow-up) was associated with increased baseline subjective response to alcohol in bipolar disorder, and decreased baseline subjective response in the typically developing group. LIMITATIONS: Preliminary study with a small sample size. CONCLUSION: Underlying OFC biology may contribute to differences in alcohol sensitivity in bipolar disorder which may also relate to prospective changes in alcohol use patterns. Future studies are needed to examine how these factors prospectively relate to development of AUDs in bipolar disorder.

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder.

OBJECTIVE: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). METHODS: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. RESULTS: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). CONCLUSIONS: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Discrete patterns of cortical thickness in youth with bipolar disorder differentially predict treatment response to quetiapine but not lithium.

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.

White matter volumes in youth offspring of bipolar parents.

BACKGROUND: Studying youth at high risk of developing bipolar disorder may clarify neurobiological factors associated with vulnerability to this illness. We present here a baseline characterization of brain structure in youth at-risk for bipolar disorder. METHODS: Magnetic resonance images were obtained from 115 child and adolescent offspring of bipolar disorder type I subjects and 57 healthy child and adolescent offspring of healthy parents (healthy control offspring). Offspring of parents with bipolar disorder were divided into healthy bipolar offspring (n=47) or symptomatic bipolar offspring (n=68), according to presence or absence of childhood-onset psychopathology. All bipolar offspring were free of major mood and psychotic disorders. Gray (GM) and white matter (WM) volumes were compared between groups using voxel-based morphometry. RESULTS: No differences in GM volumes were found across groups. Healthy bipolar offspring presented with decreased WM volumes in areas of the right frontal, temporal and parietal lobes, and in the left temporal and parietal lobes compared to healthy control offspring. Symptomatic bipolar offspring did not present with any differences in WM volumes compared to either healthy bipolar offspring or healthy control offspring. LIMITATIONS: Cross-sectional design and heterogeneous sample of symptomatic bipolar offspring. CONCLUSIONS: WM volume decreases in areas of the frontal, occipital, and parietal lobes are present in bipolar offspring prior to the development of any psychiatric symptoms, and may be a correlate of familial risk to bipolar disorder. In this large cohort, we have not found evidence for regional GM volume abnormalities as an endophenotype for bipolar disorder.

Docosahexaenoic acid biostatus is associated with event-related functional connectivity in cortical attention networks of typically developing children.

OBJECTIVE: Although extant preclinical evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is important for neurodevelopment, little is known about its role in human cortical structural and functional maturation. In the present cross-sectional study, we investigated the relationship between DHA biostatus and functional connectivity in cortical attention networks of typically developing children. METHODS: Male children (aged 8-10 years, n = 36) were divided into 'low-DHA' (n = 18) and 'high-DHA' (n = 18) biostatus groups by a median split of erythrocyte DHA levels. Event-related functional connectivity during the performance of a sustained attention task (identical pairs continuous performance task (CPT-IP)) was conducted using functional magnetic resonance imaging. A voxelwise approach used the anterior cingulate cortex (ACC) as the seed-region. RESULTS: Erythrocyte DHA composition in the low-DHA group (2.6 ± 0.9%) was significantly lower than the high-DHA group (4.1 ± 1.1%, P ≤ 0.0001). Fish intake frequency was greater in the high-DHA group (P = 0.003) and was positively correlated with DHA levels among all subjects. The low-DHA group exhibited reduced functional connectivity between the ACC and the ventrolateral prefrontal cortex, insula, precuneus, superior parietal lobule, middle occipital gyrus, inferior temporal gyrus, and lingual gyrus compared with the high-DHA group (P < 0.05; corrected). The low-DHA group did not exhibit greater ACC functional connectivity with any region compared with the high-DHA group. On the CPT-IP task, the low-DHA group had slower reaction time (P = 0.03) which was inversely correlated with erythrocyte DHA among all subjects. DISCUSSION: These data suggest that low-DHA biostatus is associated with reduced event-related functional connectivity in cortical attention networks of typically developing children.

Neural Function Before and After Mindfulness-Based Cognitive Therapy in Anxious Adolescents at Risk for Developing Bipolar Disorder.

OBJECTIVE: We sought to evaluate the neurophysiology of mindfulness-based cognitive therapy for children (MBCT-C) in youth with generalized, social, and/or separation anxiety disorder who were at risk for developing bipolar disorder. METHODS: Nine youth (mean age: 13 ± 2 years) with a generalized, social, and/or separation anxiety disorder and a parent with bipolar disorder completed functional magnetic resonance imaging (fMRI) while performing a continuous processing task with emotional and neutral distractors (CPT-END) prior to and following 12 weeks of MBCT-C. RESULTS: MBCT-C was associated with increases in activation of the bilateral insula, lentiform nucleus, and thalamus, as well as the left anterior cingulate while viewing emotional stimuli during the CPT-END, and decreases in anxiety were correlated with change in activation in the bilateral insula and anterior cingulate during the viewing of emotional stimuli (p < 0.05, uncorrected; p < 0.005 corrected; cluster size, 37 voxels). CONCLUSIONS: MBCT-C treatment in anxious youth with a familial history of bipolar disorder is associated with increased activation of brain structures that subserve interoception and the processing of internal stimuli-functions that are ostensibly improved by this treatment.

Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study.

OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H MRS) to investigate the effects of fish oil (FO) supplementation on cortical metabolite concentrations in adolescents with major depressive disorder (MDD). METHODS: Metabolite concentrations were determined by (1)H MRS in the anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC) of adolescents with MDD before and following 10-week open-label supplementation with low (2.4 g/day, n = 7) or high (16.2 g/day, n = 7) dose FO. Depressive symptom severity scores and erythrocyte fatty acid levels were also determined. RESULTS: Baseline erythrocyte eicosapentaenoic acid (EPA) composition was positively correlated, and arachidonic acid (AA) and the AA/EPA ratio were inversely correlated, with choline (Cho) concentrations in the right DLPFC. Docosahexaenoic acid (DHA) composition was inversely correlated with myo-inositol (mI) concentrations in the left DLPFC. Erythrocyte EPA and DHA composition increased, and AA decreased, significantly following low-dose and high-dose FO supplementation. In the intent-to-treat sample, depressive symptom severity scores decreased significantly in the high-dose group (-40%, P < 0.0001) and there was a trend in the low-dose group (-20%, P = 0.06). There were no significant baseline-endpoint changes in metabolite levels in each voxel. In the low-dose group there were changes with large effect sizes, including a decrease in mI in the left DLPFC (-12%, P = 0.18, d = 0.8) and increases in glutamate + glutamine (Glx) (+12%, P = 0.19, d = 0.8) and Cho (+15%, P = 0.08, d = 1.2) in the right DLPFC. In the high-dose group, there was a trend for increases in Cho in the right DLPFC (+10%, P = 0.09, d = 1.2). DISCUSSION: These preliminary data suggest that increasing the LCn-3 fatty acid status of adolescent MDD patients is associated with subtle changes in Glx, mI, and Cho concentrations in the DLPFC that warrant further evaluation in a larger controlled trial.

Tissue-dependent cerebral energy metabolism in adolescents with bipolar disorder.

OBJECTIVES: To investigate tissue-dependent cerebral energy metabolism by measuring high energy phosphate levels in unmedicated adolescents diagnosed with bipolar I disorder. METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: Our results suggest bioenergetic impairment - consistent with downregulation of creatine kinase - is an early pathophysiological feature of bipolar I disorder.

Neurofunctional effects of quetiapine in patients with bipolar mania.

OBJECTIVES: Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood. METHODS: Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans. RESULTS: At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003). CONCLUSIONS: These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex--restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.

Neurofunctional changes in adolescent cannabis users with and without bipolar disorder.

AIMS: To compare regional brain activation among adolescents with bipolar disorder and co-occurring cannabis use disorder. DESIGN: Cross-sectional study. SETTING: Cincinnati, OH, USA. PARTICIPANTS: Adolescents with bipolar disorder (BP, n = 14), adolescents with cannabis use disorder (MJ, n = 13), adolescents with co-occurring cannabis use and bipolar disorders (BPMJ, n = 25) and healthy adolescents (HC, n = 15). MEASUREMENTS: Cannabis craving, substance use, Blood Oxygenation Level Dependent (BOLD) signal assessed by the Marijuana Craving Questionnaire (MCQ), Teen-Addiction Severity Index (T-ASI) and a cannabis cue-reactivity task during a functional magnetic resonance imaging (fMRI) session, respectively. FINDINGS: The BP group exhibited significantly greater brain activation than the BPMJ group in the right amygdala (F = 4.14, P = 0.046), left nucleus accumbens (F = 3.8, P = 0.02), left thalamus (F = 3.8, P < 0.05) and the right thalamus (F = 6.2, P = 0.02). The BP group exhibited significantly greater activation than the HC group in the left nucleus accumbens (F = 11.5, P = 0.0001), right thalamus (F = 4.9, P = 0.03) and the left striatum (F = 3.6, P = 0.04). Left amygdala activation of the BPMJ group trended towards being significantly negatively correlated with the number of joints smoked (R = -0.4, P = 0.06). CONCLUSIONS: Bipolar adolescents with comorbid cannabis use do not exhibit the same over-activation of the regions involved in emotional processing as seen in adolescents with bipolar disorder alone. The absence of these findings in patients with comorbid bipolar and cannabis use disorders suggests that these individuals may have a unique endophenotype of bipolar disorder or that cannabis use may alter brain activation uniquely in bipolar disorder patients who use cannabis.

N-acetyl aspartate levels in adolescents with bipolar and/or cannabis use disorders.

OBJECTIVE: Bipolar and cannabis use disorders commonly co-occur during adolescence, and neurochemical studies may help clarify the pathophysiology underlying this co-occurrence. This study compared metabolite concentrations in the left ventral lateral prefrontal cortex among adolescents with bipolar disorder (bipolar group; n = 14), adolescents with a cannabis use disorder (cannabis use group; n = 13), adolescents with cannabis use and bipolar disorders (bipolar and cannabis group; n = 25), and healthy adolescents (healthy controls; n = 15). We hypothesized that adolescents with bipolar disorder (with or without cannabis use disorder) would have decreased N-acetyl aspartate levels in the ventral lateral prefrontal cortex compared to the other groups and that the bipolar and cannabis group would have the lowest N-acetyl aspartate levels of all groups. METHODS: N-acetyl aspartate concentrations in the left ventral lateral prefrontal cortex were obtained using proton magnetic resonance spectroscopy. RESULTS: Adolescents with bipolar disorder showed significantly lower left ventral lateral prefrontal cortex N-acetyl aspartate levels, but post hoc analyses indicated that this was primarily due to increased N-acetyl aspartate levels in the cannabis group. The cannabis use disorder group had significantly higher N-acetyl aspartate levels compared to the bipolar disorder and the bipolar and cannabis groups (p = .0002 and p = .0002, respectively). Pearson correlations revealed a significant positive correlation between amount of cannabis used and N-acetyl aspartate concentrations. CONCLUSIONS: Adolescents with cannabis use disorder showed higher levels of N-acetyl aspartate concentrations that were significantly positively associated with the amount of cannabis used; however, this finding was not present in adolescents with comorbid bipolar disorder.

Neurochemical effects of quetiapine in patients with bipolar mania: a proton magnetic resonance spectroscopy study.

Although the neurophysiology underlying pharmacotherapy for bipolar disorder remains poorly understood, recent studies suggest that therapeutic mechanisms may be reflected in changes in concentrations of N-acetylaspartate (NAA), a putative measure of neuronal integrity and metabolism. In this study, we used magnetic resonance spectroscopy (MRS) to examine prefrontal NAA in patients receiving quetiapine for bipolar mania. On the basis of previous findings, we hypothesized that remission would be associated with increased NAA concentrations in the prefrontal cortex. Thirty-one manic bipolar patients and 13 healthy subjects were recruited to participate in this prospective study. All subjects participated in MRS at baseline and after 8 weeks of treatment. Bipolar subjects received open-label quetiapine monotherapy (mean dose [SD], 584 [191] mg). Fourteen patients remitted (Young Mania Rating Scale ≤ 12) ("remitters"), 11 patients did not ("nonremitters"), and 6 patients were lost to follow-up. Bipolar and healthy subjects did not significantly differ in baseline NAA or degree of change during the 8 weeks. Remitters showed greater mean baseline NAA concentrations in the right ventrolateral prefrontal cortex compared with nonremitters (P < 0.05). In the anterior cingulate, remitters showed near significantly decreased baseline NAA concentrations at baseline (P < 0.06), and significant differences in NAA change during the 8 weeks of treatment (P < 0.03). Manic patients who remitted with quetiapine treatment in the course of this study exhibited distinct patterns of baseline prefrontal NAA concentration, coupled with decreased NAA in the anterior cingulate with treatment; the latter possibly reflecting disparate effects of quetiapine on neuronal metabolism. These data support suggestions that therapeutic effects of quetiapine involve metabolic effects on specific prefrontal regions.

A pilot study of alterations in high energy phosphoryl compounds and intracellular pH in unmedicated adolescents with bipolar disorder.

BACKGROUND: Several lines of evidence suggest that mitochondrial dysfunction underlies the pathophysiology of bipolar disorder, including prior studies indicating abnormalities in phosphometabolites. We examined abnormalities in biomarkers of cellular metabolism including adenosine triphosphate and adenosine diphosphate as well as the pH levels in the anterior cingulate (ACC) and left ventrolateral prefrontal cortices (VLPFC) of adolescents with bipolar disorder. METHOD: Nineteen unmedicated manic and 14 unmedicated euthymic bipolar adolescents as well as 20 healthy adolescents underwent (1)H and (31)P magnetic resonance spectroscopy scans. Intracellular pH levels and concentrations of phosphometabolites were compared among groups. RESULTS: A significant reduction in pHi was found in the ACC of manic adolescents compared to healthy subjects (p=0.03) but not in the left VLPFC. There was no difference in concentration of adenosine triphosphate in the ACC or the left VLPFC among groups. However, compared to healthy subjects, adenosine diphosphate was significantly lower in manic subjects in the ACC (p=0.01) and in euthymic subjects in the left VLPFC (p=0.02). LIMITATIONS: This was a cross-sectional study with a modest sample size. A longitudinal study of a larger number of bipolar adolescents who are treatment naïve would clarify the impact of mood state on metabolic function. CONCLUSION: These results are suggestive of abnormal cellular metabolism and mitochondrial dysfunction in the pathophysiology of bipolar disorder.

A pilot study of anterior cingulate cortex neurochemistry in adolescents with generalized anxiety disorder.

BACKGROUND/AIMS: This study used proton magnetic resonance spectroscopy (¹H MRS) to evaluate the neurochemistry of the anterior cingulate cortex (ACC) in adolescents with generalized anxiety disorder (GAD). METHODS: Adolescents with GAD (n = 10) and healthy subjects (n = 10) underwent a ¹H MRS scan at 4 T. Glutamate (Glu), N-acetyl aspartate, creatine (Cr) and myo-inositol concentrations were measured in the ACC and were compared between untreated adolescents with GAD and age- and sex-matched healthy subjects. RESULTS: Glu/Cr ratios in the ACC correlated with the severity of both generalized anxiety symptoms on the Pediatric Anxiety Rating Scale and with total anxiety symptom severity as measured by the Hamilton Anxiety Rating Scale, but did not differ between adolescents with GAD and healthy subjects. In addition, no differences in N-acetyl aspartate, Cr, or myo-inositol were detected between groups. CONCLUSION: These findings suggest that Glu/Cr in untreated adolescents with GAD may relate to the severity of anxiety symptoms and raise the possibility that dysregulation of Glu within the ACC may be linked to the pathophysiology of pediatric GAD.

Neurocircuitry of generalized anxiety disorder in adolescents: a pilot functional neuroimaging and functional connectivity study.

BACKGROUND: Dysfunction of neural systems responsible for the processing of emotional stimuli is hypothesized to be involved in the pathophysiology of generalized anxiety disorder (GAD) in adolescents. We used standard fMRI and functional connectivity analyses to examine the functional neurocircuitry of GAD in adolescents. METHODS: Ten adolescents with GAD and 10 healthy comparison subjects underwent fMRI while performing a continuous performance task with emotional and neutral distractors. Standard event-related voxel-wise fMRI and steady-state functional connectivity analyses were performed. RESULTS: Increased activation was observed in the left medial prefrontal cortex and right ventrolateral prefrontal cortex (VLPFC) in response to emotional images compared to neutral imagines in youth with GAD. Connectivity analyses using the right VLPFC seed region suggested decreased connectivity between this region and the bilateral medial prefrontal cortex. Connectivity analyses using the right amygdala seed region revealed decreased correlation with the posterior cingulate cortex in adolescents with GAD. The left amygdala seed region demonstrated increased connectivity with the ipsilateral precuneus in youth with GAD compared to healthy subjects. CONCLUSIONS: In addition to increased activation of the medial prefrontal cortex and right VLPFC, we observed altered connectivity between the amygdala or VLPFC and regions, which subserve mentalization (e.g. posterior cingulate cortex, precuneus, and medial prefrontal cortex). This suggests that structures that regulate emotion and affect interact abnormally with key structures that are involved in mentalization, a process known to be disrupted in GAD.

Progressive neurostructural changes in adolescent and adult patients with bipolar disorder.

OBJECTIVES: Several lines of evidence suggest that bipolar disorder is associated with progressive changes in gray matter volume (GMV), particularly in brain structures involved in emotional regulation and expression. The majority of these studies however, have been cross-sectional in nature. In this study we compared baseline and follow-up scans in groups of bipolar disorder and healthy subjects. We hypothesized bipolar disorder subjects would demonstrate significant GMV changes over time. METHODS: A total of 58 bipolar disorder and 48 healthy subjects participated in structural magnetic resonance imaging (MRI). Subjects were rescanned 3-34 months after their baseline MRI. MRI images were segmented, normalized to standard stereotactic space, and compared voxel-by-voxel using statistical parametrical mapping software (SPM2). A model was developed to investigate differences in GMV at baseline, and associated with time and episodes, as well as in comparison to healthy subjects. RESULTS: We observed increases in GMV in bipolar disorder subjects across several brain regions at baseline and over time, including portions of the prefrontal cortex as well as limbic and subcortical structures. Time-related changes differed to some degree between adolescent and adult bipolar disorder subjects. The interval between scans positively correlated with GMV increases in bipolar disorder subjects in portions of the prefrontal cortex, and both illness duration and number of depressive episodes were associated with increased GMV in subcortical and limbic structures. CONCLUSIONS: Our findings support suggestions that widely observed progressive neurofunctional changes in bipolar disorder patients may be related to structural brain abnormalities in anterior limbic structures. Abnormalities largely involve regions previously noted to be integral to emotional expression and regulation, and appear to vary by age.