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Objective: The purpose of this study was to use proton magnetic resonance spectroscopy, at 4.0 T, to explore the glutamine and glutamate levels in the anterior cingulate cortex of children and adolescents with bipolar disorder (BPD; medicated and unmedicated) and healthy comparison subjects (HCSs). We hypothesized that unmedicated children with BPD would have reduced glutamine and glutamate levels compared with HCSs and medicated children with BPD. Method: Spectra were acquired from the anterior cingulate cortex in 22 children and adolescents with DSM-IV-TR BPD, type 1 (13 female: age 12.6 ± 4.4 years: 7 of the subjects with BPD were unmedicated at the time of the scan) and 10 HCSs (7 female: age 12.3 ± 2.5 years). Results: Unmedicated subjects with BPD had significantly lower glutamine levels than HCSs or medicated subjects with BPD. There were no differences in glutamate levels between the three groups. Conclusions: These results are consistent with there being an abnormality in anterior cingulate cortex glia in untreated children and adolescents with BPD. The results of this pilot study may be important in helping us better understand the pathophysiology of child and adolescent BPD. In addition, this observation may help to develop better and more targeted treatments, in particular those affecting the metabolism of glutamine, perhaps by regulation of glutamine synthetase activity.

Pediatric bipolar disorder (BPD) is a severe psychiatric illness with significant morbidity whose pathophysiology is largely still unknown. The morbidity associated with this disorder is driven, in part, by the child’s inability to modulate affect and cognition; those affected by the disorder have a diminished ability to control the intensity of a response to the environment and the ease of recovery from the response. For example, even in euthymic individuals with BPD, there are enduring impairments in attention, executive functioning, processing speed, and in working and verbal declarative memory that lead to difficulties in daily life (1). In addition, individuals who are genetically at risk for developing BPD have deficits in verbal declarative memory, selective and sustained attention, and in working memory, suggesting that these domains may serve as cognitive endophenotypic markers of the disorder that in turn could implicate areas of pathophysiology in the brain (1). For example, these domains of cognitive functioning are largely under the control of the cerebral cortex and are highly heritable (2–4). Therefore, in order to contribute to a deeper understanding of the neurobiological correlates that underlie the dysfunction associated with the disorder (5), it is critical to study the cerebral cortex, where brain operations occur that govern cognitive abilities (6). Taken collectively, published neuroimaging (functional, biochemical, and structural) studies indicate that there may be cortical abnormalities in adults and children with BPD (7–12). To understand more fully the differences in the cortex seen in children with BPD, it is critical to assess the lobes of cortical gray matter (GM) and the gyri of each lobe, as different regions of the cortex subserve different cognitive functions. For example, the frontal lobe (FL) is involved in cognition, memory, sensory processing, planning and initiation of voluntary movements, language production, and integration of cognition and affect. The temporal lobe (TL) is integral for auditory processing, language comprehension, semantic memory processing, visual perception, and sensory integration (13). The parietal lobe (PL) is involved in processing tactile and proprioceptive information, language comprehension, speech, writing, and aspects of spatial orientation and perception. The occipital lobe (OL) is involved in visual functions (13). To our knowledge a detailed anatomical assessment of the entire cerebral cortex, using structural magnetic resonance imaging (MRI), has not been carried out in studies in adults with BPD, nor has it been carried out in child studies. Of particular importance is the need to assess the cortex in children with BPD, given that their brains are relatively free from factors known to affect the brain, such as lengthy medication exposure, substance abuse, and electroconvulsive therapies (14). To our knowledge, this is the first structural neuroimaging study to fully assess the entire cortical GM and subsequently the gyri of the lobes of the cortex in pediatric BPD. Based on prior studies (neuroimaging and neuropsychological), we set out to assess expected alterations in cortical volumes, in pediatric BPD, to determine if these youth might show a specific pattern of cortical GM deficits. Given the data from the prior neuroimaging studies (in both children and adults), we hypothesized that children with BPD would show cortical GM deficits, particularly in sections of the FL, similar to adults with the disorder.

Youths with bipolar disorder are ideal for studying illness pathophysiology given their early presentation, lack of extended treatment, and high genetic loading. Adult bipolar disorder MRI studies have focused increasingly on limbic structures and the thalamus because of their role in mood and cognition. On the basis of adult studies, the authors hypothesized a priori that youths with bipolar disorder would have amygdalar, hippocampal, and thalamic volume abnormalities.Forty-three youths 6-16 years of age with DSM-IV bipolar disorder (23 male, 20 female) and 20 healthy comparison subjects (12 male, eight female) similar in age and sex underwent structured and clinical interviews, neurological examination, and cognitive testing. Differences in limbic and thalamic brain volumes, on the logarithmic scale, were tested using a two-way (diagnosis and sex) univariate analysis of variance, with total cerebral volume and age controlled.The subjects with bipolar disorder had smaller hippocampal volumes. Further analysis revealed that this effect was driven predominantly by the female bipolar disorder subjects. In addition, both male and female youths with bipolar disorder had significantly smaller cerebral volumes. No significant hemispheric effects were seen.These findings support the hypothesis that the limbic system, in particular the hippocampus, may be involved in the pathophysiology of pediatric bipolar disorder. While this report may represent the largest MRI study of pediatric bipolar disorder to date, more work is needed to confirm these findings and to determine if they are unique to pediatric bipolar disorder.