Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder

Recent investigations of the neural aspects of emotion have discovered that in addition to regulating motor coordination, balance, and speech, the cerebellum may play an important role in the regulation and monitoring of emotion (1). This is evident by affective disturbances following damage (2) or experimental manipulation (3) to the cerebellum. The cerebellum has rich bidirectional connections to key regions in the cerebral cortex that modulate emotion (4), as suggested by examination of cerebellar projections (5) and demonstration of reduced cerebral gray matter in frontal, parietal, and temporal cortices following cerebellar damage (6). Based on these studies, theories of emotion regulation have involved complex interactions between cortical and cerebellar neural circuits during an emotional experience. In studying the functional topography of the cerebellum, medial portions of lobule VII of the cerebellum appear to be particularly involved in the regulation of certain emotional processes and to connect to limbic circuitry (7). Disruption of the vermis has been associated with a phenomenon called cerebellar cognitive affective syndrome (8), described as a constellation of behavioral and personality changes including flattening of affect or disinhibition. Individuals with this syndrome have been described as being overfamiliar, flamboyant, and impulsive, and as making inappropriate comments or showing regressive and childlike behaviors. These symptoms are similar to those found in individuals with bipolar disorder (BD), a psychiatric syndrome principally characterized by impulsivity and dysregulation of emotion and attention. Moreover, structural and neurochemical imaging investigations have provided evidence of cerebellar abnormalities in populations with BD. Adults with BD between the ages of 18 and 45 years who had experienced multiple episodes of mania have shown reduced V3 vermal volumes compared to participants with first-episode mania and to healthy volunteers (9), suggesting a neurodegenerative process associated with multiple depressive and manic episodes. This finding in the posterior-inferior cerebellar vermis was replicated by the same group and found to extend to the V2 subregion in individuals with multiepisode BD (10). In an adolescent sample, mean V2 subregion volumes were inversely correlated to number of previous affective episodes, particularly in males (11). However, a different study showed enlargement of total vermal volume in adults with BD compared to healthy controls, driven primarily by male gender (12). Increases in left cerebellar vermal size have been found by voxel-based morphometry in healthy relatives of individuals with BD, suggesting that an enlarged vermis may be related to resilience from expression of BD and more adaptive affect regulation (13). The above studies may have shown varying results due to variations in size measurement techniques, sample selection as related to stage of illness, or medication exposure. Nevertheless, macroscopic increases or decreases of the cerebellar size in BD suggest underlying cellular and molecular dysfunction at a microscopic level that warrants further investigation. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive neuroimaging method that provides biochemical data that can be used to quantitatively examine the potential role of the vermis as a biomarker for developing BD. Few studies to date have examined neurochemical processes that may be occurring in the vermis leading to the disrupted emotional processes observed in BD. A promising strategy for understanding the early progression of this illness is to study young subjects who are at familial risk for BD (i.e., have a parent with BD), but do not yet have a mood disorder themselves. Specifically, since offspring studies demonstrate that children with a BD parent have an elevated risk of developing BD or associated symptoms of mood dysregulation (14), such offspring are likely to have brain structural, functional, and chemical characteristics that are critical to the pathogenesis of the disorder. One prior MRS study of BD offspring showed increased orbitofrontal myo-inositol (myo-Ino), a marker for cellular metabolism and related second messenger signaling pathways, and reductions in N-acetyl aspartate (NAA), a healthy nerve cell marker putatively involved in maintaining fluid balance, energy production, and myelin formation in the cerebellar vermis (15). This single investigation of neurochemical characteristics in the cerebellum in familial BD warrants replication in a larger sample to definitively determine the role of the cerebellar vermis in modulating neuronal signaling in individuals who are at familial risk for BD but have not yet developed a fully syndromal manic episode. This line of investigation would help determine whether altered neurochemical processes in the cerebellar vermis are a consequence of disease progression or represent an endophenotype for BD. To address this question, we used 1H-MRS to compare neurochemical levels among children of parents with BD [at-risk offspring with non-bipolar I disorder mood symptoms (AR)] who have some mood symptoms but have not developed a full manic episode and healthy controls (HC). Based on prior studies demonstrating neurometabolite differences in regions involved in emotion regulation, we hypothesized that AR would demonstrate abnormalities in NAA and myo-Ino concentrations in the cerebellar vermis as compared to HC, which would then correlate to more severe subsyndromal mood symptomatology. An additional exploratory aim was to compare vermal glutamate- and choline (Cho)-related metabolite concentrations in these populations given their prior association with bipolar illness (16).