Disrupted white matter integrity of corticopontine-cerebellar circuitry in schizophrenia

Evidence for white matter abnormalities in patients with schizophrenia is increasing. Decreased fractional anisotropy (FA) in interhemispheric commissural fibers as well as long-ranging fronto-parietal association fibers belongs to the most frequent findings. The present study used tract-based spatial statistics to investigate white matter integrity in 35 patients with schizophrenia and 35 healthy volunteers. We found that patients exhibited significantly decreased FA relative to healthy subjects in the corpus callosum, the cerebral peduncle, the left inferior fronto-occipital fasciculus, the anterior thalamic radiation, the right posterior corona radiata, the middle cerebellar peduncle, and the right superior longitudinal fasciculus. Increased FA was detectable in the inferior sections of the corticopontine-cerebellar circuit. Present data indicate extended cortical-subcortical alterations of white matter integrity in schizophrenia using advanced data analysis strategies. They corroborate preceding findings of white matter structural deficits in mainly long-ranging association fibers and provide first evidence for neuroplastic changes in terms of an increased directionality in more inferior fiber tracts.     

White matter integrity of the whole brain is disrupted in first-episode schizophrenia

Diffusion tensor imaging studies in schizophrenia have demonstrated lower diffusion anisotropy within white matter that provides information about brain white matter integrity. We have examined whether white matter is abnormal in first-episode schizophrenia by using diffusion tensor imaging. Twenty-one schizophrenic patients and healthy controls underwent diffusion tensor imaging scans that analyzed by using a rigorous voxel-based approach. We found that fractional anisotropy in white matter of the patients was lower than that in controls at the cerebral peduncle, frontal regions, inferior temporal gyrus, medial parietal lobes, hippocampal gyrus, insula, right anterior cingulum bundle and right corona radiata. These results suggested that white matter integrity of the whole brain was disrupted in early illness onset of schizophrenia.     

A voxel-based meta-analysis of diffusion tensor imaging in mild traumatic brain injury

Microstructural damage to white matter and resultant abnormal structural connectivity are a potential underlying pathophysiological mechanism of mild traumatic brain injury (mTBI). Many Tract-Based Spatial Statics studies have investigated the pathophysiology of mTBI, but they yielded inconsistent results potentially due to insufficient statistical power in spite of methodological homogeneity. We used anisotropic effect size signed differential mapping (AES-SDM) to integrate previous studies that recruited patients without a psychiatric history. AES-SDM revealed that fractional anisotropy values were significantly lower in mTBI patients than in control in three clusters. The peak of the largest cluster was in the left thalamus and the cluster extended to the splenium of the corpus callosum and to the anterior thalamic radiation. The second largest cluster was situated in the left forceps minor, and the third largest cluster was in the right superior longitudinal fasciculus III. These results suggest that the pathophysiology of mTBI includes abnormal structural connectivity between the thalamus and the prefrontal cortex, and abnormal intra- and inter-hemispheric structural connectivity involving the prefrontal cortex.     

Correlations between MRI-assessed volumes of the thalamus and cortical Brodmann's areas in schizophrenia

BACKGROUND: We compared the thalamic-cortical volumetric correlational patterns in patients with schizophrenia and normal comparison subjects, and evaluated their relations to outcome. METHODS: High-resolution MR images were acquired in patients with schizophrenia (n=106) and normal comparison subjects (n=42). Patients were divided into good-outcome (n=52) and poor-outcome (Kraepelinian, n=54) subtypes based on their ability for self-care. Correlations between the relative gray and white matter volumes of the individual cortical Brodmann's areas and five dorsoventral levels of the thalamus were assessed. RESULTS: Compared to normal subjects, schizophrenia patients lacked significant thalamic gray matter volume correlations with the prefrontal and medial temporal cortical regions in the right hemisphere, and with frontal, cingulate, posterior parietal and occipital regions in the left hemisphere, while normal white matter volume cortical-thalamic correlations along the cingulate gyrus and in the temporal lobe were not found in schizophrenia patients in both hemispheres. In contrast to both normal comparison subjects and good-outcome group, schizophrenia patients with poor outcomes showed significant bilateral gray matter volume correlations between the dorsal thalamus and ventral prefrontal cortex, while the group differences in the white matter volume correlations were mostly restricted to the cingulate arch. CONCLUSIONS: Whereas patients with schizophrenia exhibit deficiencies in cortical-thalamic correlational patterns, poor outcome is associated with abnormal interregional correlations not observed in either normal subjects or patients with good outcomes. This latter finding may be explained by a core neurodevelopmental disturbance that results in aberrant cortical-thalamic connectivity in poor-outcome schizophrenia.     

Reliability and psychometric properties of the Greek translation of the State-Trait Anxiety Inventory form Y: Preliminary data

We acquired diffusion tensor and structural MRI images on 103 patients with schizophrenia and 41 age-matched normal controls. The vector data was used to trace tracts from a region of interest in the anterior limb of the internal capsule to the prefrontal cortex. Patients with schizophrenia had tract paths that were significantly shorter in length from the center of internal capsule to prefrontal white matter. These tracts, the anterior thalamic radiations, are important in frontal-striatal-thalamic pathways. These results are consistent with findings of smaller size of the anterior limb of the internal capsule in patients with schizophrenia, diffusion tensor anisotropy decreases in frontal white matter in schizophrenia and hypothesized disruption of the frontal-striatal-thalamic pathway system.     

White matter damage is related to ataxia severity in SCA3

Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.     

Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder

CONTEXT Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. OBJECTIVES To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. DESIGN Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. SETTING University magnetic resonance imaging facility. PARTICIPANTS Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. MAIN OUTCOME MEASURES The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. RESULTS Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. CONCLUSIONS Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.     

Some observations on the course and composition of the cingulum bundle in the rhesus monkey

The course and composition of the cingulum bundle was examined by using the autoradiographic tracer technique in the rhesus monkey. The cingulum bundle is observed to consist of three major fiber components originating from thalamus, cingulate gyrus, and cortical association areas. Following isotope injections in the anterior and lateral dorsal thalamic nuclei, labelled fibers form an arch in the white matter behind the cingulate sulcus and occupy the ventral sector of the cingulum bundle. The fibers from the anterior thalamic nucleus coursing in the cingulum bundle extended rostrally to the frontal cortex and caudally to area 23 and the retrosplenial cortex. In contrast, the fibers from lateral dorsal nucleus reached the retrosplenial cortex as well as the parahippocampal gyrus and presubiculum. Efferent fibers from the cingulate gyrus occupy a dorsolateral sector of the cingulum bundle. Those fibers from area 24 of the cingulate gyrus are directed to the premotor and prefrontal regions as well as area 23 and retrosplenial cortex. The fibers from area 23 extend rostrally to the prefrontal cortex and caudoventrally to the presubiculum and parahippocampal gyrus. Finally, an association component originates mainly from prefrontal cortex and posterior parietal region. These fibers occupy a more dorsal and lateral periphery in the cingulate white matter. Cingulum bundle fibers from the prefrontal cortex extend up to the retrosplenial cortex while those from the posterior parietal cortex extend caudally to the parahippocampal gyrus and presubiculum, and rostrally up to the prefrontal cortex.     

Associations of White Matter Integrity and Cortical Thickness in Patients With Schizophrenia and Healthy Controls

Typical brain development includes coordinated changes in both white matter (WM) integrity and cortical thickness (CT). These processes have been shown to be disrupted in schizophrenia, which is characterized by abnormalities in WM microstructure and by reduced CT. The aim of this study was to identify patterns of association between WM markers and cortex-wide CT in healthy controls (HCs) and patients with schizophrenia (SCZ). Using diffusion tensor imaging and structural magnetic resonance imaging data of the Mind Clinical Imaging Consortium study (130 HC and 111 SCZ), we tested for associations between (a) fractional anisotropy in selected manually labeled WM pathways (corpus callosum, anterior thalamic radiation, and superior longitudinal fasciculus) and CT, and (b) the number of lesion-like WM regions (“potholes”) and CT. In HC, but not SCZ, we found highly significant negative associations between WM integrity and CT in several pathways, including frontal, temporal, and occipital brain regions. Conversely, in SCZ the number of WM potholes correlated with reduced CT in the left lateral temporal gyrus, left fusiform, and left lateral occipital brain area. Taken together, we found differential patterns of association between WM integrity and CT in HC and SCZ. Although the pattern in HC can be explained from a developmental perspective, the reduced gray matter CT in SCZ patients might be the result of focal but spatially heterogeneous disruptions of WM integrity.Key words: cortical thickness, fractional anisotropy, structural MRI, DTI, schizophrenia     

White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study

OBJECTIVE: To investigate abnormalities in the structural integrity of brain white matter as suggested by diffusion tensor imaging in adolescents with early-onset schizophrenia (onset of psychosis by age 18). METHOD: Twenty-six patients with schizophrenia and 34 age- and gender-matched healthy volunteers received diffusion tensor imaging and structural magnetic resonance imaging examinations. Fractional anisotropy maps were compared between groups in the white matter using a voxelwise analysis after intersubject registration to Talairach space. RESULTS: Compared with healthy volunteers, patients demonstrated lower fractional anisotropy values in the left anterior cingulate region in close proximity to the caudate nucleus (95% confidence interval of schizophrenic-healthy: -66 to -20). Using regression analysis, the rate of change in fractional anisotropy differed significantly between groups in this region across the age span examined (10-20 years), after adjusting for group differences in premorbid intellectual capacity and parental socioeconomic status. There were no areas of significantly higher fractional anisotropy in patients compared with healthy volunteers. CONCLUSIONS: These data suggest that early-onset schizophrenia is associated with a disruption in the structural integrity of white matter tracts in the anterior cingulate region. These structural abnormalities may contribute to the deficits in motivation, attention, memory, and higher executive functions in adolescents with schizophrenia.     

Inferior frontal white matter anisotropy and negative symptoms of schizophrenia: a diffusion tensor imaging study

OBJECTIVE: The purpose of this study was test the hypothesis that abnormalities of inferior frontal white matter are related to the negative symptoms of schizophrenia. METHOD: Fractional anisotropy of white matter tracts in the prefrontal area of 10 schizophrenic patients was determined by diffusion tensor imaging. Patients were also assessed for severity of negative symptoms by using the Schedule for the Assessment of Negative Symptoms (SANS). RESULTS: Inferior frontal white matter fractional anisotropy was significantly inversely correlated with the SANS global ratings of negative symptoms. CONCLUSIONS: These data, while preliminary, suggest that impaired white matter integrity in the inferior frontal region may be associated with the severity of negative symptoms in schizophrenia.     

A diffusion tensor imaging study of fasciculi in schizophrenia

OBJECTIVE: Cognitive models propose that the symptoms and psychological impairments associated with schizophrenia arise as a consequence of impaired communication between brain regions, especially the prefrontal cortex and the temporal and parietal lobes. Functional imaging and electrophysiological data have provided evidence of functional dysconnectivity, but it is unclear whether this reflects an underlying problem with anatomical connectivity. This study used diffusion tensor imaging to examine the integrity of the major white matter fasciculi, which connects the frontal and temporal-parietal cortices, and the corpus callosum in patients with schizophrenia. METHOD: A 1.5-T magnetic resonance scanner was used to acquire diffusion tensor images giving whole brain coverage at an isotropic 2.5-mm voxel size. Fractional anisotropy was measured in 33 patients with schizophrenia and 40 healthy comparison subjects with an automated voxel-based method of analysis. RESULTS: There was reduced fractional anisotropy in patients with schizophrenia in regions corresponding to the superior longitudinal fasciculi bilaterally and in the genu of the corpus callosum. However, within the patient group, the propensity to experience auditory hallucinations was associated with relatively increased fractional anisotropy in superior longitudinal fasciculi and in the anterior cingulum. CONCLUSIONS: Schizophrenia is associated with altered white matter integrity in the tracts connecting the frontal cortex with the temporal and parietal cortices and with the contralateral frontal and temporal lobes. The severity of these changes may vary with the pattern of symptoms associated with the disorder.     

Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia.

BACKGROUND: The anterior limb of the internal capsule (ALIC) contains the anterior thalamic peduncle connecting the medial and anterior thalamic nuclei with the prefrontal cortex and the cingulate gyrus. The purpose of this study was to detect the volumetric changes in the ALIC in view of the putative abnormal frontothalamic connectivity in schizophrenia. METHODS: High-resolution, three-dimensional magnetic resonance imaging was acquired from 53 schizophrenia patients and 48 age- and gender-matched control subjects. Volumetric analysis was performed using consecutive 1-mm-thick coronal slices rostral to the anterior commissure, on the ALIC, caudate nucleus, and lentiform nucleus. White matter concentration over the whole brain was compared using the voxel-based morphometry (VBM) with Statistical Parametric Mapping 99. RESULTS: The patients had significantly decreased volumes in the bilateral ALIC and showed significantly increased right-greater-than-left asymmetry of the ALIC; VBM revealed a reduction in white matter concentration of the bilateral internal capsule in patients. No volumetric difference was found in the rostral part of the caudate and lentiform nucleus between groups. CONCLUSIONS: Decreased volume found in the ALIC supports the hypothesis of abnormal frontothalamic connectivity in schizophrenia. Increased asymmetry of the internal capsule seems consistent with the notion of predominantly left-side pathology of schizophrenia.     

Microstructural changes in white matter associated with freezing of gait in Parkinson's disease

In Parkinson's disease (PD), freezing of gait (FOG) is associated with widespread functional and structural gray matter changes throughout the brain. Previous study of freezing‐related white matter changes was restricted to brainstem and cerebellar locomotor tracts. This study was undertaken to determine the spatial distribution of white matter damage associated with FOG by combining whole brain and striatofrontal seed‐based diffusion tensor imaging. Diffusion‐weighted images were collected in 26 PD patients and 16 age‐matched controls. Parkinson's disease groups with (n = 11) and without freezing of gait (n = 15) were matched for age and disease severity. We applied tract‐based spatial statistics to compare fractional anisotropy and mean diffusivity of white matter structure across the whole brain between groups. Probabilistic tractography was used to evaluate fractional anisotropy and mean diffusivity of key subcortico‐cortical tracts. Tract‐based spatial statistics revealed decreased fractional anisotropy in PD with FOG in bilateral cerebellar and superior longitudinal fascicle clusters. Increased mean diffusivity values were apparent in the right internal capsule, superior frontal cortex, anterior corona radiata, the left anterior thalamic radiation, and cerebellum. Tractography showed consistent white matter alterations in striatofrontal tracts through the putamen, caudate, pallidum, subthalamic nucleus, and in connections of the cerebellar peduncle with subthalamic nucleus and pedunculopontine nucleus bilaterally. We conclude that FOG is associated with diffuse white matter damage involving major cortico‐cortical, corticofugal motor, and several striatofrontal tracts in addition to previously described cerebello‐pontine connectivity changes. These distributed white matter abnormalities may contribute to the motor and non‐motor correlates of FOG. © 2015 International Parkinson and Movement Disorder Society     

Increased <Emphasis Type="SmallCaps">d</Emphasis>-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples.     

精神分裂症患者全脑白质纤维弥散张量成像的初步研究

目的运用能够提示白质纤维(white matter,WM)完整性的弥散张量成像(diffusion tensor imaging,DTI)技术,探讨精神分裂症患者全脑白质纤维是否受到损害。方法对21例精神分裂症患者(患者组)和21名健康人(对照组)进行全脑DTI扫描,用SPM2(Statistical Parametric Maps,SPM)软件对图像进行处理,采用以像素为基础的分析方法(voxel-based analysis,VBA)对两组的分数各向异性(fractional anisotropy,FA)值进行组间比较。结果患者组下列脑区的FA值显著低于对照组(P<0·001):左侧额眶区和右侧额中回的白质、双侧颞下回白质、双侧顶叶内侧白质、右侧前扣带、双侧海马、双侧大脑脚、双侧岛叶、右侧放射冠和右侧小脑上脚。结论精神分裂症多个部位脑白质纤维的完整性受到破坏。     

N-acetylaspartate reductions in the mediodorsal and anterior thalamus in men with schizophrenia verified by tissue volume corrected proton MRSI

OBJECTIVE: Deficits in the mediodorsal and anterior nuclei of the thalamus may contribute to the psychopathological symptoms of schizophrenia. These thalamic nuclei have been found to be abnormal in schizophrenia and have close connections with other brain structures implicated in the disorder. We therefore examined schizophrenia-related alterations in brain metabolite levels specifically in the mediodorsal and anterior thalamic subregions. METHOD: We used in vivo proton magnetic resonance spectroscopic imaging ((1)H MRSI) to measure N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine+phosphocreatine (Cr) in the mediodorsal and anterior thalamus in 22 male patients with schizophrenia and 22 male controls. Magnetic resonance imaging (MRI) tissue segmentation and thalamic volume mask techniques were performed to distinguish the thalamus, extrathalamic gray and white matter, and CSF within the spectroscopic voxels. RESULTS: Compared to healthy subjects, patients with schizophrenia had significantly lower NAA in the mediodorsal and anterior thalamus bilaterally. No significant differences in Cho or Cr levels were seen. NAA was significantly higher in the left thalamus relative to the right in both groups. We found a strong negative correlation between left thalamic NAA and duration of illness, even after partialling out the effect of age. Tissue segmentation and thalamic volume mask techniques detected no group or lateralized differences in tissue type or CSF percentages, demonstrating that the metabolite reductions were not an artifact of spectroscopic voxel heterogeneity. CONCLUSIONS: These findings suggest diminished function and/or structure in the mediodorsal and anterior thalamus in male patients with schizophrenia and support earlier research demonstrating schizophrenia-related abnormalities in the thalamus and its circuitry.     

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

Objectives:  Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.
Methods:  DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.
Results:  Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.
Conclusions:  Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.     

Thalamic volumes in patients with first-episode schizophrenia

OBJECTIVE: The thalamus, a highly evolved sensory and motor gateway to the cortex, has been implicated in the pathophysiology of several illnesses, including schizophrenia. Several studies have suggested thalamic volume differences in patients with schizophrenia, although only a few studies have examined thalamic structure in new-onset patients. METHOD: The authors used magnetic resonance imaging to measure thalamic volumes in previously untreated patients with first-episode schizophrenia (N=16) relative to those of healthy comparison subjects (N=25). The age range of the patients and comparison subjects was 15 to 45 years of age. Thalamic volumes in the right and left hemispheres were segmented and analyzed, both separately and as total thalamic volume, by a rater blind to clinical data. The thalamus was further segmented into regions that roughly reflected individual thalamic nuclei. Analysis of covariance was used to control for intracranial volume. RESULTS: Right, left, and total thalamic volumes of the patients with schizophrenia were significantly smaller than those of the comparison subjects. Significantly smaller volumes were found in the left central medial subdivision of the patients as well as a smaller volume in the right central medial subdivision that approached significance. These regions primarily comprised the dorsomedial nucleus, a thalamic nucleus thought to be an important component of aberrant circuitry in schizophrenia. Significant volume differences were also seen in the left anterior, right anterior, and right posterior medial subdivisions. CONCLUSIONS: These findings suggest significant thalamic volumetric differences between patients with newly diagnosed schizophrenia and healthy comparison subjects. Future analysis of individual thalamic nuclei may reveal important, specific relationships between thalamic abnormalities and schizophrenia.     

Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD

Background: Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI. Method: A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms "DTI" or "diffusion tensor;" "whole brain" or "voxel-based;" and "depress*." Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region. Results: We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum. Limitations: The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences. Conclusion: Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This isstrong evidence for the involvement of these neural circuits in the pathology of MDD.