Anatomical MRI study of basal ganglia in major depressive disorder

Abstract

The basal ganglia form a part of the brain neuroanatomic circuits that may be involved in mood regulation. Decreases in basal ganglia volumes have been previously reported in major depressive disorder patients in comparison to healthy controls. In this study, we measured caudate, putamen, and globus pallidus volumes in 25 patients with major depressive disorder (4 M; age±S.D.=41±11 years) and 48 healthy controls (29 M; age±S.D.=35±10 years), using high-resolution magnetic resonance imaging (MRI), in an attempt to replicate prior findings. Unlike most previous studies, we did not find significant differences between patient and control groups in basal ganglia volumetric measures. Nonetheless, there was a significant interaction between diagnosis and cerebral hemisphere, with MDD patients showing decreased asymmetry in globus pallidus volumes in comparison with healthy controls. Furthermore, in the patient group, left putamen volumes correlated inversely with length of illness, and left globus pallidus volume correlated directly with number of prior depressive episodes. These findings suggest that abnormalities in lateralization and possibly neurodegenerative changes in basal ganglia structures participate in the pathophysiology of major depressive disorder.

Introduction

Major depressive disorder (MDD), the most common psychiatric disorder (Kessler et al., 1994), is foreseen to be the second most frequent cause of disability by the year 2020 (Murray and Lopez, 1996). Although MDD has no established etiology or pathophysiology, the study of its biological aspects has acquired a prominent role, especially in the last three decades.

Fronto-subcortical circuits have been described as important networks of the brain, participating directly in brain–behavior interactions. They are named accordingly with their function or the region they are efferent from. Although each of them constitutes a closed loop where dedicated neurons remain segregated from the parallel networks, they have ‘open’ afferent and efferent components that establish connections with ‘open components’ from other circuits, sharing specific functions with them (Mega and Cummings, 1994). At least two interconnected frontal-subcortical circuits, the limbic-striatal-pallidal-thalamic and the limbic-thalamo-cortical, appear to play an important role in MDD pathophysiology (Drevets et al., 1992). Other studies suggest that circuits involving prefrontal cortex, amygdala, basal ganglia, and thalamus are probably disturbed in MDD. Increasing evidence suggests dysfunction in various elements of these circuits, even though the precise mechanisms involved have not been elucidated (Drevets et al., 1992, Cummings, 1993, Guze and Gitlin, 1994, Mayberg, 1997, Soares and Mann, 1997a, Soares and Mann, 1997b).

Although it is very difficult to assess systematically complex brain–behavior interaction as observed in MDD, studies addressing neurological disorders that present a high prevalence of depression during their course have provided some important insights. In this sense, mood disturbances can be observed in animals with limbic lesions; motivation and pleasurable sensation appear to be related to hypothalamus and upper brain stem stimulation; feelings of helplessness and worthlessness frequently observed in depressed patients may derive from frontal lobe dysfunction; and motor manifestations such as alteration in gait and posture observed in depressive states may derive from basal ganglia dysfunction (Cummings, 1993).

New strategies for testing pathophysiological theories in mental disorders have arisen with the development of neuroimaging techniques, which permit in vivo visualization and quantification of the gross anatomy, physiology and neurochemistry of the brain. In fact, they represent an invaluable advance when compared to postmortem anatomical studies, since the latter suffer interference from many factors related to the death process rather than the psychiatric illness per se. In vivo neuroimaging techniques can be classified into two major groups: functional (PET, SPECT, fMRI and MRS) and structural (CT and MRI). Despite the belief that ‘episodic illnesses’ would involve only biochemical rather than histopathological abnormalities, MDD, like epilepsy, has been shown to involve both anatomical and functional abnormalities (Guze and Gitlin, 1994, Soares and Mann, 1997a, Soares and Mann, 1997b).

Decreased metabolic activity in dorsolateral and medial prefrontal cortex areas has been reported by most but not all PET (positron emission tomography) studies involving depressed patients (Baxter et al., 1989, Bench et al., 1992, Biver et al., 1994, Mayberg, 1997). Other PET and SPECT (single photon emission computed tomography) studies have found reduced metabolism/blood flow in the basal ganglia of depressed patients compared to healthy controls (Austin et al., 1992, Baxter et al., 1985, Buchsbaum et al., 1986, Mayberg et al., 1994). Additionally, some investigators have reported a significant increase in blood flow or glucose metabolism of the basal ganglia associated with recovery in MDD (Scott et al., 1994, Henry et al., 2001).

Magnetic resonance imaging (MRI) is virtually the only structural neuroimaging technique available to investigate basal ganglia abnormalities, since computed tomographic (CT) brain scans do not provide reliable distinction between gray and white matter, and neuropathologic studies have generally utilized small and heterogeneous samples (Baumann et al., 1999, Baumann and Bogerts, 1999). Some but not all structural neuroimaging studies have also found differences between unipolar depressive patients and healthy controls, with patients showing reduced volumes of the caudate and putamen nuclei (Husain et al., 1991, Krishnan et al., 1992, Krishnan, 1993, Dupont et al., 1995, Parashos et al., 1998).

Data from several studies that involved patients suffering from basal ganglia illnesses have also suggested an important role for these structures in MDD pathophysiology. Krishnan (1993) reported a significant correlation between the degree of atrophy in the neostriatum and the presence of depression in Huntington's disease; Murphy et al. (1992) reported basal ganglia lesions in up to 50% of late-onset depressed patients; and other studies have demonstrated an elevated prevalence of depression prior to the onset of motor symptoms in Huntington's disease, a known basal ganglia degenerative illness (Krishnan et al., 1992, Krishnan, 1993).

The main objective of the present MRI study was to investigate possible abnormalities in basal ganglia volumes of MDD patients. In addition, we investigated a possible effect of age and clinical variables on these volumes. We hypothesized that depressed patients would have smaller basal ganglia volumes compared to healthy controls and that the volumes of these structures would inversely correlate with the length of illness, severity of the current episode and the number of previous episodes.