Elsevier

NeuroImage

Volume 30, Issue 2, 1 April 2006, Pages 485-497
NeuroImage

Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry

https://doi.org/10.1016/j.neuroimage.2005.09.029Get rights and content

Abstract

Bipolar disorder (BD) has been associated with abnormalities of brain structure. Specifically, in vivo volumetric MRI and/or post mortem studies of BD have reported abnormalities of gray matter (GM) volume in the medial prefrontal cortex (PFC), amygdala, hippocampal subiculum and ventral striatum. These structures share anatomical connections with each other and form part of a “visceromotor” network modulating emotional behavior. Areas of the lateral orbital, superior temporal and posterior cingulate cortices project to this network, but morphometric abnormalities in these areas have not been established in BD. The current study assessed tissue volumes within these areas in BD using MRI and voxel-based morphometry (VBM).

MRI images were obtained from 36 BD subjects and 65 healthy controls. To account for possible neurotrophic and neuroprotective effects of psychotropic medications, BD subjects were divided into medicated and unmedicated groups. Images were segmented into tissue compartments, which were examined on a voxel-wise basis to determine the location and extent of morphometric changes.

The GM was reduced in the posterior cingulate/retrosplenial cortex and superior temporal gyrus of unmedicated BD subjects relative to medicated BD subjects and in the lateral orbital cortex of medicated BD subjects relative to controls. White matter (WM) was increased in the orbital and posterior cingulate cortices, which most likely reflected alterations in gyral morphology resulting from the reductions in the associated GM.

The morphometric abnormalities in the posterior cingulate, superior temporal and lateral orbital cortices in BD support the hypothesis that the extended network of neuroanatomical structures subserving visceromotor regulation contains structural alterations in BD. Additionally, localization of morphometric abnormalities to areas known to exhibit increased metabolism in depression supports the hypothesis that repeated stress and elevated glucocorticoid secretion may result in neuroplastic changes in BD.

Introduction

Bipolar disorder (BD) is a severe mental illness affecting approximately 1.3–1.6% of the population worldwide. BD is characterized by the presence of both depressive and manic episodes (Drevets and Todd, 1997). There are two diagnostic subtypes, BDI, in which the manic episodes result in pronounced impairment, and BDII, which is characterized by milder periods of hypomania, where elevated mood and activity are present without debilitation (American Psychiatric Association, 2000).

The etiology and pathophysiology of BD are unknown. Nevertheless, both in vivo neuroimaging and post mortem neuropathological studies have shown that individuals with BD have abnormal reductions in gray matter volume in parts of the medial prefrontal cortex (PFC), amygdala, hippocampal subiculum and ventral striatum (reviewed in Drevets et al., 2004, Strakowski et al., 2005). For example, within the medial PFC, morphometric MRI studies found reductions in gray matter volume in the anterior cingulate cortex (ACC) ventral and anterior to the genu of the corpus callosum (termed “subgenual” and “pregenual”, respectively) in BD subjects relative to healthy controls (Drevets et al., 1997, Lochhead et al., 2004, Lyoo et al., 2004, Sassi et al., 2004). The results of these in vivo MRI studies guided post mortem histopathological studies of the subgenual ACC to identify abnormally reductions in neuronal somal size and glial cell counts and increases in neuronal density in BD (Chana et al., 2003), suggesting that the corresponding decrease in gray matter volume was accounted for by reductions in dendritic arborization (Chana et al., 2003, Drevets, 2004). Additionally, in the pregenual ACC and the Brodmann Area (BA) 9 cortex situated anterior to the ACC (anteromedial and dorsal anterolateral PFC), post mortem studies showed abnormal reductions in neuronal and glial cell density in BD subjects relative to controls (Rajkowska et al., 2001, Todtenkopf et al., 2005).

Neuromorphometric abnormalities also have been identified in BD in basal ganglia and mesiotemporal lobe structures that are anatomically related to these medial PFC structures. In the striatum, a post mortem volumetric study found that the left accumbens area, bilateral external pallidum and right putamen were smaller in subjects with BD than in healthy controls (Baumann et al., 1999). In the hippocampal subiculum, BD samples showed abnormal reductions in the density of apical dendritic spines on pyramidal cells (Rosoklija et al., 2000), the concentrations of mRNA for synaptic proteins post mortem (Eastwood and Harrison, 2000) and the gray matter volume (Nugent et al., 2004), although the entire hippocampal volume generally has not been found to differ between BD and control samples. Finally, several neuroimaging studies reported that the amygdala volume is abnormal in BD, although disagreement exists regarding the direction of these differences with respect to healthy controls (reviewed in Drevets, 2004).

The regions implicated by these studies share extensive, monosynaptic, neuronal connections with each other and with the hypothalamus and periaqueductal gray to form a circuit that plays major roles in modulating emotional behavior (Ongur and Price, 2000). This circuit has been characterized as a “visceromotor network” based upon evidence that its projections function to modulate neuroendocrine, autonomic and behavioral responses to threatening, stressful and reward-related stimuli and contexts (Ongur and Price, 2000). Because BD is associated with disturbances in these domains of emotional behavior, the structural abnormalities found within this visceromotor circuit in BD conceivably could play an integral role in this condition's pathogenesis.

Anatomical studies in humans demonstrate that the medial PFC, ventral striatum, subiculum and amygdala regions involved in visceromotor function also share extensive, reciprocal, monosynaptic connections with areas of the orbitofrontal, posterior cingulate and superior temporal cortices (Ongur and Price, 2000, Kondo et al., 2004, Saleem et al., 2004, Price et al., 2004). These anatomical observations converge with neurophysiological data from human brain mapping studies of various emotional states (see Discussion) to suggest that specific orbitofrontal, posterior cingulate and superior temporal areas also may play roles in modulating emotional behavior. Whether morphometric abnormalities also exist in these regions in BD remains unclear, however.

Few post mortem neuropathological studies have assessed orbitofrontal, posterior cingulate or superior temporal cortices in BD, and preliminary results from morphometric MRI studies of BD either await replication or are in disagreement. In the ventral PFC, one voxel-based morphometry (VBM) study reported a reduction in GM density in the lateral orbital cortex situated on the inferior frontal gyrus (Lyoo et al., 2004), while another found a GM reduction located several centimeters away at the ventromedial pole of the superior frontal gyrus (Wilke et al., 2004). In the posterior cingulate cortex (PCC), one VBM study reported widespread deficits in gray matter “density” throughout the cingulate gyrus, including the PCC (Doris et al., 2004), of “poor outcome” BD, although this finding awaits replication and extension to BD subjects who are not poor outcome. Moreover, it remains unclear whether this difference in GM density is associated with a corresponding reduction in GM volume. In the superior temporal gyrus (STG), a post mortem histopathological study observed reduced glial cell density and reduced clustering of neurons into minicolumns in the planum temporale region in BD (Beasley et al., 2005). However, most MRI studies that employed manual segmentation of the entire STG found no significant volumetric differences between BD and control samples (Hirayasu et al., 2000, Schlaepfer et al., 1994, Brambilla et al., 2003, Kasai et al., 2003), although one reported abnormally decreased STG volume in children and adolescents with BD (Chen et al., 2004) and another found abnormally increased right anterior STG volume in adults with BD (Pearlson et al., 1997). These conflicting results regarding STG volume may reflect limitations in the sensitivity for detecting focally distributed differences between BD and control samples using neuromorphometric methods that sample an entire gyrus (see Discussion).

These conflicting results across studies also may reflect differences between the subject samples with respect to medication status or other clinical variables. In recent years, the mood stabilizing drug lithium was found to exert neurotrophic and neuroprotective effects in rodents and humans (Manji et al., 1999), and lithium treatment has been associated with increases in GM in longitudinal studies of BD (Moore et al., 2000a, Moore et al., 2000b). Other agents used for mood stabilization, such as valproic acid preparations, also exert neurotrophic and neuroprotective effects in rodents (Hao et al., 2004). Subjects with BD also are likely to receive antidepressant drugs, which have been associated with neurotrophic effects (Duman, 2004), and antipsychotic agents, which in some cases increase the GM volume of basal ganglia structures (Gur et al., 1998, Corson et al., 1999). The importance of taking such effects into account in neuromorphometric analyses has only recently been suggested by Sassi et al. (2004) and Drevets (2004), who found abnormal volumetric reductions in the ACC only in untreated BD subjects.

The current study is the first VBM study to assess morphometric abnormalities present in BD samples differentiated on the basis of recent medication status. Because the VBM approach is particularly useful for surveying large regions of cortex and revealing inherent differences in tissue volume between groups, this study specifically focused upon orbital and medial prefrontal cortical, PCC and STG regions that constitute the major cortical components of the visceromotor network.

Section snippets

Subjects

Thirty-six subjects (26 female, age = 39 ± 8.1) meeting Diagnostic and Statistical Manual of Mental Disorders-Version IV (DSM-IV) criteria for Bipolar Disorder Type I (n = 7) or II (n = 29) were imaged. Sixty-five healthy controls (46 female, age = 38 ± 11.8) with no personal or family history of psychiatric disorders in first-degree relatives also were imaged. Subjects were drawn from a larger pool of 39 BD subjects and 95 controls based upon having images of sufficient signal homogeneity to

Results

Demographic and clinical information about the subject samples is presented in Table 1. The mean age and gender composition did not differ significantly between groups. All 36 of the BD subjects met criteria for a current major depressive episode at the time of scanning, and all had experienced multiple episodes (>2) of hypomania or mania in the past. Three unmedicated BD subjects and four recently medicated BD subjects were classified as Type I, and the remaining subjects were Type II. The

Discussion

The VBM analysis showed left lateralized reductions in GM in BD patients relative to controls in the PCC, lateral orbital cortex and STG. In the PCC and orbital cortex, local increases in WM were identified in the vicinity of the areas where GM was reduced. The reciprocal pattern of differences between the GM and WM tissue compartments within the PCC and orbital cortex most likely reflects differences in gyral morphology between BD and healthy brains that would be expected to result from the GM

Summary

This study revealed morphometric abnormalities in BD in regions of the medial and orbital PFC, STG and PCC that, together with anatomically related areas of the amygdala, hippocampus, striatum, thalamus, hypothalamus and brain stem, form part of a visceromotor network that regulates the expression and experience of emotion. The separation of the BD subjects on the basis of recent medication status enabled exploration of psychotropic drug effects on these abnormalities that can facilitate the

Acknowledgments

Thanks to Michele Drevets, Joan Williams and Joana-Taylor Tavares for their work on this project. This research was supported by the Intramural Program of the NIH, NIMH.

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