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.
"This issue should be further investigated. With these caveats in mind, in this extended sample, we have replicated our results tying human intelligence to pathological worry (Coplan et al., 2006). Patients with generalized anxiety exhibited, along with the expected increase in self-reported worry, relatively high IQ scores and lower white matter choline and choline-containing compounds in comparison to healthy volunteers . "
[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
"In addition, Cr is involved in energy-dependent brain function (Wyss and Kaddurah- Daouk, 2000). Cr decreases are presumably associated with increase in metabolic activity (as discussed in Coplan et al., 2006), As one example, Cr has reportedly been reduced in medial temporal lobe of patients with panic disorder (Massana et al., 2002), raising the possibility that Cr may also vary independently in pathological anxiety states. Increases of baseline NAA ratio measures in right dorsolateral prefrontal cortex of human patients with generalized anxiety disorder (Mathew et al., 2004) and Asperger Syndrome (Murphy et al., 2002), provide precedent for relatively high NAA states, perhaps following excess cleavage of N-acetyl aspartatyl-glutamate (NAAG) into glutamate and NAA. "
[Show abstract][Hide abstract] ABSTRACT: We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA)-an amino acid considered reflective of neuronal density/functional integrity-using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N=10) or control rearing conditions (N=9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted.
Brain research 10/2010; 1358:191-9. DOI:10.1016/j.brainres.2010.08.021 · 2.84 Impact Factor
"Furthermore, a few psychiatric disorders have been successfully treated with Cr. It was shown that patients with disorders related to anxiety have reduced brain Cr content (Coplan et al. 2006). Hence, it is not surprising that Cr supplementation seems to be effective in relieving symptoms, attenuating depression, and improving the quality of sleep in individuals suffering from posttraumatic stress (Amital et al. 2006a). "
[Show abstract][Hide abstract] ABSTRACT: Creatine (Cr) plays a central role in energy provision through a reaction catalyzed by phosphorylcreatine kinase. Furthermore,
this amine enhances both gene expression and satellite cell activation involved in hypertrophic response. Recent findings
have indicated that Cr supplementation has a therapeutic role in several diseases characterized by atrophic conditions, weakness,
and metabolic disturbances (i.e., in the muscle, bone, lung, and brain). Accordingly, there has been an evidence indicating
that Cr supplementation is capable of attenuating the degenerative state in some muscle disorders (i.e., Duchenne and inflammatory
myopathies), central nervous diseases (i.e., Parkinson’s, Huntington’s, and Alzheimer’s), and bone and metabolic disturbances
(i.e., osteoporosis and type II diabetes). In light of this, Cr supplementation could be used as a therapeutic tool for the
elderly. The aim of this review is to summarize the main studies conducted in this field and to highlight the scientific and
clinical perspectives of this promising therapeutic supplement.
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