Louise Emsell

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Limbic and callosal white matter changes in euthymic bipolar I disorder: an advanced diffusion magnetic resonance imaging tractography study.

BACKGROUND White matter microstructural changes detected using diffusion tensor imaging have been reported in bipolar disorder. However, findings are heterogeneous, which may be related to the use of analysis techniques that cannot adequately model crossing fibers in the brain. We therefore sought to identify altered diffusion anisotropy and diffusivity changes using an improved high angular resolution fiber-tracking technique. METHODS Diffusion magnetic resonance imaging data was obtained from 35 prospectively confirmed euthymic bipolar disorder type 1 patients (age 22-59) and 43 control subjects (age 22-59) drawn from a sample of 120 age- and gender-matched demographically similar case-control pairs. Tractography using a constrained spherical deconvolution approach to account for crossing fibers was implemented. Changes in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity between patient and control groups in subdivisions of the corpus callosum, cingulum, and fornix were measured as indicators of trait differences in white matter microstructural organization in bipolar disorder. RESULTS Patients had significantly reduced fractional anisotropy and increased mean diffusivity and radial diffusivity in all divisions of the corpus callosum, left fornix, and subgenual cingulum compared with control subjects. Axial diffusivity was increased in the fornix bilaterally and right dorsal-anterior cingulum. CONCLUSIONS By using an improved fiber-tracking method in a clinically homogeneous population, we were able to localize trait diffusivity changes to specific subdivisions of limbic fiber pathways, including the fornix. Our findings extend previous reports of altered limbic system microstructural disorganization as a trait feature of bipolar disorder.

The structural neuroimaging of bipolar disorder

There is an increasing body of literature fuelled by advances in high-resolution structural MRI acquisition and image processing techniques which implicates subtle neuroanatomical abnormalities in the aetiopathogenesis of bipolar disorder. This account reviews the main findings from structural neuroimaging research into regional brain abnormalities, the impact of genetic liability and mood stabilizing medication on brain structure in bipolar disorder, and the overlapping structural deviations found in the allied disorders of schizophrenia and depression. The manifold challenges extant within neuroimaging research are highlighted with accompanying recommendations for future studies. The most consistent findings include preservation of total cerebral volume with regional grey and white matter structural changes in prefrontal, midline and anterior limbic networks, non-contingent ventriculomegaly and increased rates of white matter hyperintensities, with more pronounced deficits in juveniles suffering from the illness. There is increasing evidence that medication has observable effects on brain structure, whereby lithium status is associated with volumetric increase in the medial temporal lobe and anterior cingulate gyrus. However, research continues to be confounded by the use of highly heterogeneous methodology and clinical populations, in studies employing small scale, low-powered, cross-sectional designs. Future work should investigate larger, clinically homogenous groups of patients and unaffected relatives, combining both categorical and dimensional approaches to illness classification in cross-sectional and longitudinal designs in order to elucidate trait versus state mechanisms, genetic effects and medication/illness progression effects over time.

The effect of template selection on diffusion tensor voxel-based analysis results.

Diffusion tensor imaging (DTI) is increasingly being used to study white matter (WM) degeneration in patients with psychiatric and neurological disorders. In order to compare diffusion measures across subjects in an automated way, voxel-based analysis (VBA) methods were introduced. In VBA, all DTI data are transformed to a template, after which the diffusion measures of control subjects and patients are compared quantitatively in each voxel. Although VBA has many advantages compared to other post-processing approaches, such as region of interest analysis or tractography, VBA results need to be interpreted cautiously, since it has been demonstrated that they depend on the different parameter settings that are applied in the VBA processing pipeline. In this paper, we examine the effect of the template selection on the VBA results of DTI data. We hypothesized that the choice of template to which all data are transformed would also affect the VBA results. To this end, simulated DTI data sets as well as DTI data from control subjects and multiple sclerosis patients were aligned to (i) a population-specific DTI template, (ii) a subject-based DTI atlas in MNI space, and (iii) the ICBM-81 DTI atlas. Our results suggest that the highest sensitivity and specificity to detect WM abnormalities in a VBA setting was achieved using the population-specific DTI atlas, presumably due to the better spatial image alignment to this template.

Altered Interhemispheric and Temporal Lobe White Matter Microstructural Organization in Severe Chronic Schizophrenia

Diffusion MRI investigations in schizophrenia provide evidence of abnormal white matter (WM) microstructural organization as indicated by reduced fractional anisotropy (FA) primarily in interhemispheric, left frontal and temporal WM. Using tract-based spatial statistics (TBSS), we examined diffusion parameters in a sample of patients with severe chronic schizophrenia. Diffusion MRI data were acquired on 19 patients with chronic severe schizophrenia and 19 age- and gender-matched healthy controls using a 64 gradient direction sequence, (b=1300 s/mm2) collected on a Siemens 1.5T MRI scanner. Diagnosis of schizophrenia was determined by Diagnostic and Statistical Manual for Mental Disorders 4th Edition (DSM-IV) Structured Clinical Interview for DSM disorder (SCID). Patients were treatment resistance, having failed to respond to at least two antipsychotic medications, and had prolonged periods of moderate to severe positive or negative symptoms. Analysis of diffusion parameters was carried out using TBSS. Individuals with chronic severe schizophrenia had significantly reduced FA with corresponding increased radial diffusivity in the genu, body, and splenium of the corpus callosum, the right posterior limb of the internal capsule, right external capsule, and the right temporal inferior longitudinal fasciculus. There were no voxels of significantly increased FA in patients compared with controls. A decrease in splenium FA was shown to be related to a longer illness duration. We detected widespread abnormal diffusivity properties in the callosal and temporal lobe WM regions in individuals with severe chronic schizophrenia who have not previously been exposed to clozapine. These deficits can be driven by a number of factors that are indistinguishable using in vivo diffusion-weighted imaging, but may be related to reduced axonal number or packing density, abnormal glial cell arrangement or function, and reduced myelin.

Characterizing the microstructural basis of "unidentified bright objects" in neurofibromatosis type 1: A combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis.

Introduction The histopathological basis of “unidentified bright objects” (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1. Methods 3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO–cNAWM pairs. Results No significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered. Conclusion Our results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in ‘extracellular-like’, intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo.

White matter differences in euthymic bipolar I disorder: a combined magnetic resonance imaging and diffusion tensor imaging voxel‐based study

A broad range of subtle and markedly heterogenous neuroanatomical abnormalities of grey matter and white matter have been reported in bipolar disorder. Euthymic bipolar disorder patients represent a clinically homogenous group in which to identify trait‐based biomarkers of bipolar disorder. In this study, we sought to clarify the nature and extent of neuroanatomical differences in a large, clinically homogeneous group of euthymic bipolar disorder patients.

White matter microstructural abnormalities in families multiply affected with bipolar I disorder: a diffusion tensor tractography study

BACKGROUND White matter (WM) abnormalities are proposed as potential endophenotypic markers of bipolar disorder (BD). In a diffusion tensor imaging (DTI) voxel-based analysis (VBA) study of families multiply affected with BD, we previously reported that widespread abnormalities of fractional anisotropy (FA) are associated with both BD and genetic liability for illness. In the present study, we further investigated the endophenotypic potential of WM abnormalities by applying DTI tractography to specifically investigate tracts implicated in the pathophysiology of BD. METHOD Diffusion magnetic resonance imaging (MRI) data were acquired from 19 patients with BD type I from multiply affected families, 21 of their unaffected first-degree relatives and 18 healthy volunteers. DTI tractography was used to identify the cingulum, uncinate fasciculus (UF), arcuate portion of the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), corpus callosum, and the anterior limb of the internal capsule (ALIC). Regression analyses were conducted to investigate the effect of participant group and genetic liability on FA and radial diffusivity (RD) in each tract. RESULTS We detected a significant effect of group on both FA and RD in the cingulum, SLF, callosal splenium and ILF driven by reduced FA and increased RD in patients compared to controls and relatives. Increasing genetic liability was associated with decreased FA and increased RD in the UF, and decreased FA in the SLF, among patients. CONCLUSIONS WM microstructural abnormalities in limbic, temporal and callosal pathways represent microstructural abnormalities associated with BD whereas alterations in the SLF and UF may represent potential markers of endophenotypic risk.

Longitudinal Assessment of Chemotherapy-Induced Alterations in Brain Activation During Multitasking and Its Relation With Cognitive Complaints

PURPOSE To examine whether cognitive complaints after treatment for breast cancer are associated with detectable changes in brain activity during multitasking. PATIENTS AND METHODS Eighteen patients who were scheduled to receive chemotherapy performed a functional magnetic resonance imaging multitasking task in the scanner before the start of treatment (t1) and 4 to 6 months after finishing treatment (t2). Sixteen patients who were not scheduled to receive chemotherapy and 17 matched healthy controls performed the same task at matched intervals. Task difficulty level was adjusted individually to match performance across participants. Statistical Parametric Mapping 8 (SPM8) software was used for within-group, between-group, and group-by-time interaction image analyses. RESULTS Voxel-based paired t tests revealed significantly decreased activation (P < .05) from t1 to t2 at matched performance in the multitasking network of chemotherapy-treated patients, whereas no changes were noted in either of the control groups. At baseline, there were no differences between the groups. Furthermore, in contrast to controls, the chemotherapy-treated patients reported a significant increase in cognitive complaints (P < .05) at t2. Significant (P < .05) correlations were found between these increases and decreases in multitasking-related brain activation. Moreover, a significant group-by-time interaction (P < .05) was found whereby chemotherapy-treated patients showed decreased activation and healthy controls did not. CONCLUSION These results suggest that changes in brain activity may underlie chemotherapy-induced cognitive complaints. The observed changes might be related to chemotherapy-induced damage to the brain or reduced connectivity between brain regions rather than to changes in effort or changes in functional strategy. To the best of our knowledge, this is the first longitudinal study providing evidence for a relationship between longitudinal changes in cognitive complaints and changes in brain activation after chemotherapy.

The functional neuroanatomy of multitasking: combining dual tasking with a short term memory task.

Insight into the neural architecture of multitasking is crucial when investigating the pathophysiology of multitasking deficits in clinical populations. Presently, little is known about how the brain combines dual-tasking with a concurrent short-term memory task, despite the relevance of this mental operation in daily life and the frequency of complaints related to this process, in disease. In this study we aimed to examine how the brain responds when a memory task is added to dual-tasking. Thirty-three right-handed healthy volunteers (20 females, mean age 39.9 ± 5.8) were examined with functional brain imaging (fMRI). The paradigm consisted of two cross-modal single tasks (a visual and auditory temporal same-different task with short delay), a dual-task combining both single tasks simultaneously and a multi-task condition, combining the dual-task with an additional short-term memory task (temporal same-different visual task with long delay). Dual-tasking compared to both individual visual and auditory single tasks activated a predominantly right-sided fronto-parietal network and the cerebellum. When adding the additional short-term memory task, a larger and more bilateral frontoparietal network was recruited. We found enhanced activity during multitasking in components of the network that were already involved in dual-tasking, suggesting increased working memory demands, as well as recruitment of multitask-specific components including areas that are likely to be involved in online holding of visual stimuli in short-term memory such as occipito-temporal cortex. These results confirm concurrent neural processing of a visual short-term memory task during dual-tasking and provide evidence for an effective fMRI multitasking paradigm.