The findings from our MRS study indicate that offspring of parents with BD show decreases in anterior cingulate glutamate absolute concentrations and trends for decreases in glutamate relative to creatine, but only after they have developed fully syndromal mania. This suggests that for high-risk offspring, altered glutamatergic functioning may represent a marker for a more fully symptomatic clinical course of mania rather than a feature associated with familial risk alone. Exploratory analyses did not reveal any statistically significant differences in any other glutamate-related metabolites among high-risk offspring with BD, high-risk offspring with subsyndromal symptoms, or healthy controls. Moreover, effect sizes for glutamine and Glx were, for the most part, small, suggesting that very large samples would be needed to detect differences that may be biologically relevant.
A signal for decreased glutamate concentrations in high-risk offspring with BD is partially consistent with and adds to several recent studies that have shown state dependent changes in glutamate, its precursor and storage form glutamine, or a combined contribution of glutamate and glutamine (Glx) in individuals with BD. Decreases in glutamine have been found in the ACC in unmedicated children with BD (Moore et al., 2007b
) and in the basal ganglia of healthy adults shortly after they were exposed to subclinical doses of lithium (Shibuya-Tayoshi et al., 2008
). Glx reductions have similarly been found in risperidone-medicated children and adolescents with BD (Moore et al., 2007a
). However, increased Glx concentrations have been found in the basal ganglia and frontal lobes in children 6 to 12 years old with BD (Castillo et al., 2000
), in children with co-occurring BD and attention deficit with hyperactivity disorder (ADHD) (Moore et al., 2006a
), in the grey matter of the cingulate gyrus in unmedicated adults with BD (Dager et al., 2004
). Age and developmental differences across cohorts and variable levels of exposure to medication may account for differences in the direction of change in glutamine and Glx concentrations. Nevertheless, in the presence of fully syndromal BD, these studies collectively suggest altered glutamatergic transmission in prefrontal and subcortical regions.
Interestingly, while we found potential decreases in glutamate concentrations in high-risk offspring with an established history of mania, a decrease in glutamate was not seen in the SS group in spite of similar YMRS scores to the BD group. As the SS group were younger than the BD group and have not yet developed full mania, it is possible that decreases in prefrontal glutamate concentrations reflect the presence of persistent, prolonged, or severe symptoms of mania or depression rather than transient or subsyndromal mood states. Adjusting for age when comparing glutamate concentration between BD and SS groups did not significantly change our results. Further prospective examination of acute and chronic changes of glutamate in the brain and its response to treatment is warranted to understand its relationship to different stages of illness and neurodevelopment.
Some, but not all, prior studies have demonstrated that alterations in other neurometabolite concentrations may occur early during the initial development of BD. NAA, a healthy nerve cell marker putatively involved in maintaining fluid balance, energy production, and myelin formation in the brain has been observed to be decreased in the dorsolateral prefrontal cortex (DLPFC) in pediatric BD (Olvera et al., 2007
) as well as in pediatric high-risk offspring with mania (Chang et al., 2003
), suggesting neurodegenerative changes coincident with the presence of mania. However, further comparisons of NAA levels in bilateral DLPFC in high-risk offspring with and without mania found no statistically significant decrements in NAA, suggesting that decrements of NAA in the DLFPC may not be seen until progression of illness into adulthood (Gallelli et al., 2005
). Another study on symptomatic offspring of BD parents also demonstrated increased orbitofrontal myoinositol (mI), a marker for cellular metabolism and related second messenger signaling pathways (Cecil et al., 2003
). Both NAA and mI appear to change in concentration with lithium treatment in pediatric populations (Davanzo et al., 2003
; Patel et al., 2006
; Patel et al., 2008
). However, these changes in metabolite concentrations have not been replicated in other studies of offspring at high-risk for BD (Gallelli et al., 2005
; Hajek et al., 2008
), including the present study. Diagnostic and developmental heterogeneity, mood state at the time of scan, partial volumes of grey and white matter in the region of interest, and other demographic variables may account for differences across studies.
Several limitations need to be acknowledged for the current study. Voxel placement may have varied slightly across subjects, but was based on anatomical landmarks that provided some framework for reliable placement. Due to limitations in scanning children for prolonged periods of time, scanner drift and the possibility of overlapping resonances due to the short echo time (TE = 35 msec) may have caused sources of variance in our spectral measurements across all groups. We capitalized on the higher 3T field strength used in our study to overcome these issues by providing better peak separation and SNR compared to 1.5 T magnets, although at field strengths greater than 3T, the signal-to-noise ratio and spectral separation for 1
H NMR spectroscopy may be superior (Tkáč et al., 2009
). It is noteworthy that trends for reduced glutamate/Cr ratios were observed, which may not have achieved statistical significance due to additional variance from creatine. Similarly, Glx ratios and absolute concentrations did not achieve statistical significance, possibly due to variance contributed by glutamine, which showed nonsignificant increases across all groups. Although the goal of this study was not to unequivocally differentiate glutamate from glutamine or GABA, a future study using a sequence that provides a less ambiguous measure of glutamate (e.g. CT-PRESS) (Mayer and Spielman, 2005
) would aid in verifying our results.
Sample heterogeneity due to co-occurring diagnoses and medication exposure limit this analysis due to insufficient sample sizes to examine individual effects of these factors. Moreover, adjustments for multiple comparisons in MRS studies can result in null findings (Dickstein et al., 2008
). In the early stages of investigating the relationship between mood disorders and neurochemistry, some accommodation for exploratory analyses should be permitted, particularly since clinical studies have already begun to demonstrate robust and clinically relevant neurochemical responses to pharmacological interventions (DelBello et al., 2006
; Moore et al., 2006b
). Nonetheless, our results did not change even after restricting our analyses to unmedicated subgroups.
To our knowledge, this is the first 1H-MRS study performed as yet investigating glutamatergic neurochemistry in the ACC in children with familial BD and in a population at risk for developing BD due to its familial and symptomatic propensities. Our findings indicate that relative to healthy controls, children at familial risk for BD show in vivo 1H-MRS-detected trends for decreased glutamate concentrations after the onset of fully syndromal mania. This suggests that decreases in glutamate may be a marker for a clinical course that includes the development of frank mania, and requires further investigation for its potential role in the pathophysiology of BD and prefrontal neurodegeneration. These results may be limited by a cross-sectional design, small sample size, co-occurring psychiatric diagnoses, or medication exposure. Nevertheless, glutamatergic function may be an important component to consider in the characterization of risk for developing BD in offspring of bipolar parents. Further longitudinal studies are necessary to determine if early neurochemical changes can predict the development of mania. Improved methods for identifying children with particular neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of fully syndromal BD.