MRI study of the cerebellum in young bipolar patients

Abstract

Prior studies demonstrate structural abnormalities of cerebellar vermis in adult bipolar patients. Cerebella of 16 young bipolar patients (mean age ± S.D. = 15.5 ± 3.4) and 21 healthy controls (mean age ± S.D. = 16.9 ± 3.8) were examined using magnetic resonance imaging. The volumes of right, left and total cerebellum, vermis, and areas of vermal regions V1 (lobules I–V), V2 (lobules VI–VII), and V3 (lobules VIII–X) were measured. Analysis of covariance, with age, gender, and intra-cranial brain volume as covariates, revealed no significant differences in cerebellum or vermis measures between patients and controls; however, there was a trend to smaller vermis V2 areas in patients (p = 0.06). The number of previous affective episodes and vermis area V2 were inversely correlated (partial correlation coefficient = − 0.97, P = 0.001) in the male bipolar patient group. Our results are preliminary, but consistent with the findings from studies in adult bipolar patients suggesting the involvement of structural changes in cerebellar vermis in the pathophysiology of bipolar disorder.

Introduction

Bipolar disorder is a common, life-long progressive illness that typically begins in adolescence, with a lifetime prevalence of 1.0% in adolescents (Lewinsohn et al., 1995). Emerging literature suggests that early-onset bipolar disorder is associated with a chronic course, substantial morbidity with repeated hospitalizations, and a mixed symptom presentation with comorbid disruptive disorders (Biederman et al., 2000, Weckerly, 2002). The cerebellum is implicated in the pathophysiology of bipolar disorder (Soares and Mann, 1997, Strakowski et al., 2002). It has connections, largely via thalamus, to many brain areas relevant to cognition and behavior, including the dorsolateral prefrontal cortex, medial frontal cortex, anterior cingulate and the posterior hypothalamus (Rapoport et al., 2000). There are noradrenergic, serotonergic and dopaminergic inputs to the cerebellum from brainstem nuclei (Schmahmann, 1996). Through its connections with limbic areas and cortical associative areas, the cerebellum could be involved in the regulation of sensorial, procedural, linguistic and emotional activities, as well as motor function (Rapoport et al., 2000, Middleton and Strick, 2001). A cerebellar cognitive affective syndrome, characterized by deficits in executive function, spatial cognition, linguistic processing and affect regulation, has been described (Schmahmann and Sherman, 1998). The cerebellar cognitive affective syndrome also occurs in children, where lesions of the vermis, in particular, are associated with dysregulation of affect (Levisohn et al., 2000).

Prior computerized tomography studies revealed smaller total cerebellar size in adult bipolar patients compared to schizophrenia patients and healthy controls (reviewed in Soares and Mann, 1997), but the three published MRI studies, using manual region of interest tracing approaches (DelBello et al., 1999, Brambilla et al., 2001, Mills et al., 2005), did not find significantly smaller cerebellar hemispheres in adult bipolar patients compared with healthy subjects. Brambilla et al. (2001) studied primarily middle-aged adults (mean age: 36 ± 10 y), whereas DelBello et al. (1999) had a younger sample, mean ages for first-episode patients being 24 ± 4 y and for the multiple-episode patients 29 ± 5 y. The age range in the Mills et al. study (2005) was 16–35 y, with patients hospitalized for their first manic episode having a mean age of 22 ± 6 y, and patients with at least two prior manic episodes having a mean age of 25 ± 6 y. In contrast, a recent study by Adler et al. (2007), using voxel-based morphometry (VBM), reported larger bilateral cerebellar gray matter volume in a mixed sample of adolescents and adults (age range 13–41 y) with bipolar I disorder compared to healthy subjects.

Although three out of four published MRI studies report no cerebellar volume abnormalities in bipolar disorder subjects, vermal abnormalities related to repeated illness episodes have been reported. DelBello et al. found that vermis area V3 (the inferior posterior and flocculonodular lobes, lobules VIII–X) is significantly smaller in multiple-episode than in first-episode bipolar patients and healthy volunteers, suggesting that the cerebellar vermis may undergo atrophy during the course of bipolar illness. This finding was supported by Mills et al. (2005) who showed that patients with multiple manic episodes have smaller V3 volumes than healthy subjects, and by Brambilla et al. (2001) who showed a trend (p = 0.075) for an inverse correlation between number of episodes and vermis area V3. In addition, Mills et al. (2005) reported that bipolar patients with multiple episodes have smaller V2 (superior posterior vermis, neocerebellar vermal lobules VI–VII) volumes compared with first-episode patients and healthy subjects. They also noted that patients with multiple manic episodes have significantly smaller V2 volumes than first-episode patients. Taken together, these findings suggest superior posterior (i.e. limbic cerebellum) and possibly flocculonodular vermal abnormalities in bipolar disorder.

In this MRI study, we examined anatomical abnormalities in cerebellum and vermis in young bipolar patients and healthy subjects. We hypothesized that young bipolar disorder patients would not show cerebellar volume abnormalities, but consistent with prior studies in adult bipolar patients, would show vermal abnormalities reflecting possible neurodegeneration with repeated illness episodes. Such a finding in young bipolar patients would suggest that neuropathological processes affecting the vermis are present early in the illness course.