Automated subcortical segmentation using FIRST: test-retest reliability, interscanner reliability, and comparison to manual segmentation.

Multiple techniques exist for the automated segmentation of magnetic resonance images (MRIs). The validity of these techniques can be assessed by evaluating test-retest reliability, interscanner reliability, and consistency with manual segmentation. We evaluate these measures for the FSL/FIRST subcortical segmentation tool. We retrospectively analyzed 190 MRI scans from 87 subjects with mood or anxiety disorders and healthy volunteers scanned multiple times on different platforms (N = 56) and/or the same platform (N = 45, groups overlap), and 146 scans from subjects who underwent both high-resolution and whole brain imaging in a single session, for comparison with manual segmentation of the hippocampus. The thalamus, caudate, putamen, hippocampus, and pallidum were reliably segmented in different sessions on the same scanner (Intraclass correlation coefficient (ICC) > 0.83 scanners and diagnostic groups pooled). In these regions, the range of between platform reliabilities were lower (0.527 < ICC < 0.953), although values below 0.7 were due to systematic differences between platforms or low reliability in the hippocampus between eight- and single-channel coil platforms. Accumbens and amygdala segmentations were generally unreliable within and between scanning platforms. ICC values for hippocampal volumes between automated and manual segmentations were acceptable (ICC > 0.7, groups pooled), and both methods detected significant differences between genders. In addition, FIRST segmentations were consistent with manual segmentations (in a subset of images; N = 20) in the left caudate and bilateral putamen. This retrospective analysis assesses realistic performance of the algorithm in conditions like those found in multisite trials or meta-analyses. In addition, the inclusion of psychiatric patients establishes reliability in subjects exhibiting volumetric abnormalities, validating patient studies.

Habenula volume in post-traumatic stress disorder measured with high-resolution MRI.

BACKGROUND: The habenula plays an important role in regulating behavioral responses to stress and shows increased cerebral blood flow and decreased gray matter volume in patients with mood disorders. Here, we compare the volume of the habenula in unmedicated patients with post-traumatic stress disorder (PTSD) and healthy controls (HC) using MRI. FINDINGS: High-resolution images (resolution of approximately 0.4 mm3) were acquired using a 3T scanner and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. PTSD and HC participants did not differ significantly in absolute or normalized habenula volume. Post hoc analyses controlling for the effects of comorbid major depressive disorder (MDD) and type and age of trauma exposure were not significant. Further, there was no association between PTSD severity and habenula volume. CONCLUSIONS: Our data suggest that PTSD is not associated with robust structural changes in the habenula. The modest size of the PTSD sample may have reduced statistical power thereby accounting for the negative results obtained.

Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study.

BACKGROUND: Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present after death. We conducted the first magnetic resonance imaging analysis of habenula volume in MDD and bipolar disorder (BD). METHODS: High-resolution images (resolution approximately .4 mm(3)) were acquired with a 3T scanner, and a pulse sequence was optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy control subjects (HC) were compared with both medicated (lithium/divalproex, n = 15) and unmedicated, depressed BD (n = 22) patients; unmedicated, depressed MDD patients (n = 28); and unmedicated MDD patients in remission (n = 32). RESULTS: The unmedicated BD patients displayed significantly smaller absolute (p < .01) and normalized (p < .05) habenula volumes than the HC subjects. In post hoc assessments analyzing men and women separately, the currently-depressed women with MDD had smaller absolute (p < .05) habenula volumes than the HC women. None of the other psychiatric groups differed significantly from the HC group. CONCLUSIONS: We provide further evidence for the involvement of the habenula in affective illness but suggest that a reduction in volume might be more pronounced in unmedicated, depressed BD subjects and female currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress and in the suppression of dopamine cell activity after the absence of an expected reward. A reduction in habenula volume might thus have functional consequences that contribute to the risk for developing affective disease.

Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication.

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55 x 0.55 x 0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11+/-10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635.

OBJECTIVE: To assess effects of chronic antidepressant drug treatment on serotonin type-1A receptor (5-HT(1A)R) binding potential (BP) in major depressive disorder. METHODS: Depressed subjects (n = 27) were imaged using PET and [(11)C]WAY-100635 at baseline and following a median of 9.4 weeks of treatment with selective serotonin reuptake inhibitor or dual reuptake inhibitor antidepressant agents. Fifteen subjects had complete pre- and post-treatment scan data. The 5-HT(1A)R BP was derived from the tissue time-radioactivity concentrations from regions-of-interest defined a priori, using a simplified reference tissue model (SRTM), and in a subset of subjects, compartmental modeling (CMOD). RESULTS: Chronic treatment had no effect on pre- or post-synaptic 5-HT(1A)R BP, as confirmed by both the SRTM and CMOD analyses. These results were unaffected by treatment response status and were consistent across brain regions. Among the 22 subjects for whom the clinical response-to-treatment was established, the treatment nonresponders (n = 7) had higher baseline BP values in the left (P = 0.01) and right orbital cortex (P = 0.02) than the responders (n = 15). CONCLUSIONS: Chronic antidepressant drug treatment did not significantly change cerebral 5-HT(1A)R binding, consistent with preclinical evidence that the alterations in serotonergic function associated with antidepressant drug administration are not accompanied by changes in 5-HT(1A)R density. Higher baseline 5-HT(1A)R binding was associated with poorer response to treatment.

Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.

Neurophysiological studies of major depression performed using PET imaging have shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism in multiple prefrontal cortical and limbic structures that have been more generally implicated in emotional processing. The current study investigated the effects of antidepressant drug treatment in these regions using PET measures of glucose metabolism. Subjects with primary MDD (n=27) were imaged while unmedicated and depressed, and, of these, 20 were rescanned following chronic antidepressant drug treatment. Regional metabolism was compared between unmedicated depressives and controls and between the pre- and post-treatment conditions in regions-of-interest (ROI) where metabolism or flow had previously been shown to be abnormal in unmedicated depressives. At baseline, the mean metabolism was increased in the left and right lateral orbital cortex/ventrolateral prefrontal cortex (PFC), left amygdala, and posterior cingulate cortex, and decreased in the subgenual ACC and dorsal medial/dorsal anterolateral PFC in the unmedicated depressives relative to controls, consistent with the results of previous studies. Following treatment, metabolism significantly decreased in the left amygdala and left subgenual ACC, and corresponding changes in the orbital and posterior cingulate cortices approached significance. The metabolic reduction in the amygdala and right subgenual ACC appeared largely limited to those subjects who both responded to treatment and remained well at 6 months follow-up, in whom the reduction in amygdala metabolism tightly correlated with the reduction in HDRS scores. The magnitude of the treatment-associated, metabolic change in the amygdala also correlated positively with the change in the stressed plasma cortisol levels measured during scanning. These data converge with those from other PET studies to indicate that primary MDD is associated with abnormal metabolism in limbic and paralimbic structures of the mesiotemporal and prefrontal cortices. Chronic antidepressant drug treatment reduces metabolism in the amygdala and ventral ACC in subjects showing a persistent, positive treatment response. In contrast, the persistence of the abnormal metabolic deficits in the dorsomedial/dorsal anterolateral PFC in MDD during treatment may conceivably relate to the histopathological changes reported in these regions in post mortem studies of MDD.