Wade Weber

Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study

BACKGROUND Emerging evidence suggests that docosahexaenoic acid (DHA, 22:6n-3), the principal omega-3 (n-3) fatty acid in brain gray matter, positively regulates cortical metabolic function and cognitive development. However, the effects of DHA supplementation on functional cortical activity in human subjects are unknown. OBJECTIVE The objective was to determine the effects of DHA supplementation on functional cortical activity during sustained attention in human subjects. DESIGN Healthy boys aged 8-10 y (n = 33) were randomly assigned to receive placebo or 1 of 2 doses of DHA (400 or 1200 mg/d) for 8 wk. Relative changes in cortical activation patterns during sustained attention at baseline and endpoint were determined by functional magnetic resonance imaging. RESULTS At 8 wk, erythrocyte membrane DHA composition increased significantly from baseline in subjects who received low-dose (by 47%) or high-dose (by 70%) DHA but not in those who received placebo (-11%). During sustained attention, both DHA dose groups had significantly greater changes from baseline in activation of the dorsolateral prefrontal cortex than did the placebo group, and the low-dose and high-dose DHA groups had greater decreases in the occipital cortex and cerebellar cortex, respectively. Relative to low-dose DHA, high-dose DHA resulted in greater decreases in activation of bilateral cerebellum. The erythrocyte DHA composition was positively correlated with dorsolateral prefrontal cortex activation and was inversely correlated with reaction time, at baseline and endpoint. CONCLUSION Dietary DHA intake and associated elevations in erythrocyte DHA composition are associated with alterations in functional activity in cortical attention networks during sustained attention in healthy boys. This trial was registered at clinicaltrials.gov as NCT00662142.

Progressive neurostructural changes in adolescent and adult patients with bipolar disorder

Lisy ME, Jarvis KB, DelBello MP, Mills NP, Weber WA, Fleck D, Strakowski SM, Adler CM. Progressive neurostructural changes in adolescent and adult patients with bipolar disorder.
Bipolar Disord 2011: 13: 396–405.

Low docosahexaenoic acid status is associated with reduced indices in cortical integrity in the anterior cingulate of healthy male children: A 1H MRS Study

Abstract Docosahexaenoic acid (DHA, 22:6n-3) is the principal omega-3 fatty acid in mammalian brain gray matter, and emerging preclinical evidence suggests that DHA has neurotrophic and neuroprotective properties. This study investigated relationships among DHA status, neurocognitive performance, and cortical metabolism measured with proton magnetic resonance spectroscopy (1H MRS) in healthy developing male children (aged 8–10 years, n = 38). Subjects were segregated into low-DHA (n = 19) and high-DHA (n = 19) status groups by a median split of erythrocyte DHA levels. Group differences in 1H MRS indices of cortical metabolism, including choline (Cho), creatine (Cr), glutamine + glutamate + γ-aminobutyric acid (Glx), myo-inositol (mI), and N-acetyl aspartate (NAA), were determined in the right and left dorsolateral prefrontal cortex (R/L-DLPFC, BA9) and bilateral anterior cingulate cortex (ACC, BA32/33). Group differences in neurocognitive performance were evaluated with the Kaufman Brief Intelligence Test and identical-pairs version of the continuous performance task (CPT-IP). Subjects in the low-DHA group consumed fish less frequently (P = 0.02), had slower reaction times on the CPT-IP (P = 0.007), and exhibited lower mI (P = 0.007), NAA (P = 0.007), Cho (P = 0.009), and Cr (P = 0.01) concentrations in the ACC compared with the high-DHA group. There were no group differences in ACC Glx or any metabolite in the L-DLPFC and R-DLPFC. These data indicate that low-DHA status is associated with reduced indices of metabolic function in the ACC and slower reaction time during sustained attention in developing male children.

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.

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.

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 (1H 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 1H 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.

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.

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.

Abstract 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.

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.