Decreased choline and creatine concentrations in centrum semiovale in patients with generalized anxiety disorder: relationship to IQ and early trauma.
ABSTRACT We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted left and right CSO CHO concentrations, independent of age, sex, group assignment and PSWQ scores. The CSO may therefore represent a neural substrate that exhibits reductions in CHO and CR metabolite concentrations that are inversely associated with GAD symptomatology and, in the case of CHO, with intelligence. These conclusions are deemed preliminary due to small sample size, with further study of cerebral WM in anxiety disorders suggested.
- SourceAvailable from: Dikoma C Shungu[Show abstract] [Hide abstract]
ABSTRACT: We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ's and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.Frontiers in Evolutionary Neuroscience 01/2011; 3:8. DOI:10.3389/fnevo.2011.00008
- [Show abstract] [Hide abstract]
ABSTRACT: Generalized anxiety disorder (GAD) has undergone a series of revisions in its diagnostic criteria that has moved it, nosologically, away from its original affiliation with panic disorder (PD) and closer to major depressive disorder (MDD). This, together with its high comorbidity and putative shared genetic risk with MDD, has brought into question its place in future psychiatric nosology, prompting the planners of Diagnostic and Statistical Manual-V (DSM-V) and International Classification of Diseases-11 (ICD-11) to set up a workgroup tasked to better understand the relationship between GAD and MDD. This review attempts to summarize the extant data to compare GAD and MDD on a series of research validators to explore this relationship. Although insufficient data currently exist for GAD in several key validator classes, tentative conclusions can be drawn on the diagnostic status of GAD in relation to MDD. Although GAD possesses substantial overlap with MDD in the areas of genetics, childhood environment, demographics, and personality traits, this tends to hold true for other anxiety disorders (ADs) as well, with the strongest evidence for PD. Data from life events, personality disorders, biology, comorbidity, and pharmacology are mixed, showing some areas of similarity between GAD and MDD but some clear differences, again with a moderate degree of nonspecificity. Thus, although the bulk of evidence supports a close underlying relationship between them, the relatively nonspecific nature of these findings provides little more reason to question the nosologic validity of GAD in relation to MDD than that of some other anxiety disorders.Depression and Anxiety 04/2008; 25(4):300-16. DOI:10.1002/da.20491 · 4.29 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Generalized anxiety disorder (GAD) is a common chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically informative research has examined the potential sources of reported brain differences. We acquired spectroscopic, volumetric, and diffusion tensor magnetic resonance imaging data from a pilot study of 34 female subjects selected from monozygotic twin pairs based upon their affection status for GAD, and examined brain regions previously implicated in fear and anxiety for their relationship with affection status and genetic risk. Lifetime GAD associated with increased creatine levels in the amygdala, smaller left hippocampal volume, and lower fractional anisotropy in the uncinate fasciculus which connects amygdala and frontal cortex. In addition, GAD genetic risk predicted increases in myo-inositol in the amygdala and, possibly, glutamate/glutamine/GABA alterations in the hippocampus. The association of lifetime GAD with smaller hippocampal volume was independent of major depression and might represent a common genetic risk marker for internalizing disorders. These preliminary data suggest that GAD and its genetic risk factors are likely correlated with volumetric and spectroscopic changes in fear-related limbic structures and their connections with the frontal cortex.Depression and Anxiety 03/2012; 29(3):202-9. DOI:10.1002/da.20901 · 4.29 Impact Factor