Martha Elizabeth Shenton

Abnormalities of the left temporal lobe and thought disorder in schizophrenia : a quantitative magnetic resonance imaging study

BACKGROUND Data from postmortem, CT, and magnetic resonance imaging (MRI) studies indicate that patients with schizophrenia may have anatomical abnormalities of the left temporal lobe, but it is unclear whether these abnormalities are related to the thought disorder characteristic of schizophrenia. METHODS We used new MRI neuroimaging techniques to derive (without knowledge of the diagnosis) volume measurements and three-dimensional reconstructions of temporal-lobe structures in vivo in 15 right-handed men with chronic schizophrenia and 15 matched controls. RESULTS As compared with the controls, the patients had significant reductions in the volume of gray matter in the left anterior hippocampus-amygdala (by 19 percent [95 percent confidence interval, 3 to 36 percent]), the left parahippocampal gyrus (by 13 percent [95 percent confidence interval, 3 to 23 percent], vs. 8 percent on the right), and the left superior temporal gyrus (by 15 percent [95 percent confidence interval, 5 to 25 percent]). The volume of the left posterior superior temporal gyrus correlated with the score on the thought-disorder index in the 13 patients evaluated (r = -0.81, P = 0.001). None of these regional volume decreases was accompanied by a decrease in the volume of the overall brain or temporal lobe. The volume of gray matter in a control region (the superior frontal gyrus) was essentially the same in the patients and controls. CONCLUSIONS Schizophrenia involves localized reductions in the gray matter of the left temporal lobe. The degree of thought disorder is related to the size of the reduction in volume of the left posterior superior temporal gyrus.

Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia

We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.

Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder

This study used quantitative volumetric magnetic resonance imaging techniques to explore the neuroanatomic correlates of chronic, combat-related posttraumatic stress disorder (PTSD) in seven Vietnam veterans with PTSD compared with seven nonPTSD combat veterans and eight normal nonveterans. Both left and right hippocampi were significantly smaller in the PTSD subjects compared to the Combat Control and Normal subjects, even after adjusting for age, whole brain volume, and lifetime alcohol consumption. There were no statistically significant group differences in intracranial cavity, whole brain, ventricles, ventricle:brain ratio, or amygdala. Subarachnoidal cerebrospinal fluid was increased in both veteran groups. Our finding of decreased hippocampal volume in PTSD subjects is consistent with results of other investigations which utilized only trauma-unexposed control groups. Hippocampal volume was directly correlated with combat exposure, which suggests that traumatic stress may damage the hippocampus. Alternatively, smaller hippocampi volume may be a pre-existing risk factor for combat exposure and/or the development of PTSD upon combat exposure.

DTI and MTR abnormalities in schizophrenia: Analysis of white matter integrity

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.

Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus (CG), may play a role in the pathophysiology of schizophrenia; however, the cingulum bundle (CB), the white matter tract furnishing both input and output to CG, and the most prominent white matter fiber tract in the limbic system, has not been evaluated in schizophrenia using the new technology of diffusion tensor imaging (DTI). We used line scan DTI to evaluate diffusion in the CB in 16 male schizophrenia patients and 18 male control subjects, group-matched for age, parental socioeconomic status, and handedness. We acquired 4-mm-thick coronal slices through the entire brain. Maps of fractional anisotropy (FA) were generated to quantify diffusion within the left and right CB on eight slices that included the central portion of the CB. Results showed group differences, bilaterally, in area and mean FA for CB, where patients showed smaller area and less anisotropy than controls. For patients, decreased left CB correlated significantly with attention and working memory measures as assessed by the Wisconsin Card Sorting Test. These data provide strong evidence for CB disruptions in schizophrenia, which may be related to disease-related attention and working memory abnormalities.

Voxel-Based Morphometric Analysis of Gray Matter in First Episode Schizophrenia

Voxel-based morphometry (VBM) may afford a more rapid and extensive survey of gray matter abnormalities in schizophrenia than manually drawn region of interest (ROI) analysis, the current gold standard in structural MRI. Unfortunately, VBM has not been validated by comparison with ROI analyses, nor used in first-episode patients with schizophrenia or affective psychosis, who lack structural changes associated with chronicity. An SPM99-based implementation of VBM was used to compare a group of 16 patients with first-episode schizophrenia and a group of 18 normal controls and, as a further comparison, 16 first-episode patients with affective psychosis. All groups were matched for age and handedness. High spatial resolution structural images were normalized to the SPM99 template and then segmented, smoothed, and subjected to an ANCOVA. Schizophrenia vs control group comparisons: Voxel-by-voxel comparison of gray matter densities showed that only the left STG region was significantly different when corrected for multiple comparisons (P <.05), consistent with our previously reported manual ROI results. Analysis of the extent of voxel clusters, replicated with permutation analyses, revealed group differences in bilateral anterior cingulate gyri and insula (not previously examined by us with manually drawn ROI) and unilateral parietal lobe, but not in medial temporal lobe (where our ROI analysis had shown differences). However, use of a smaller smoothing kernel and a small volume correction revealed left-sided hippocampal group differences. Affective psychosis comparisons: When the same statistical thresholding criteria were used, no significant differences between affective psychosis patients and controls were noted. Since a major interest was whether patients with affective psychosis shared some anatomical abnormalities with schizophrenia, we applied a small volume correction and searched within the regions that were significantly less dense in schizophrenia compared to control subjects. With this statistical correction, the insula showed, bilaterally, the same pattern of differences in affective disorder subjects as that in schizophrenic subjects, whereas both left STG and left hippocampus showed statistical differences between affectives and schizophrenics, indicating the abnormalities specific to first-episode schizophrenia. These findings suggest both the promise and utility of VBM in evaluating gray matter abnormalities. They further suggest the importance of comparing VBM findings with more traditional ROI analyses until the reasons for the differences between methods are determined.

Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.

A digital brain atlas for surgical planning, model-driven segmentation, and teaching

We developed a three-dimensional (3D) digitized atlas of the human brain to visualize spatially complex structures. It was designed for use with magnetic resonance (MR) imaging data sets. Thus far, we have used this atlas for surgical planning, model-driven segmentation, and teaching. We used a combination of automated and supervised segmentation methods to define regions of interest based on neuroanatomical knowledge. We also used 3D surface rendering techniques to create a brain atlas that would allow us to visualize complex 3D brain structures. We further linked this Information to script files in order to preserve both spatial information and neuroanatomical knowledge. We present here the application of the atlas for visualization in surgical planning far model-driven segmentation and for the teaching of neuroanatomy. This digitized human brain has the potential to provide important reference information for the planning of surgical procedures. It can also serve as a powerful teaching tool, since spatial relationships among neuroanatomical structures can be more readily envisioned when the user is able to view and rotate the structures in 3D space. Moreover, each element of the brain atlas is associated with a name tag, displayed by a user controlled pointer. The atlas holds a major promise as a template for model-driven segmentation. Using this technique, many regions of interest can be characterized simultaneously on new brain images.

White matter hemisphere asymmetries in healthy subjects and in schizophrenia: a diffusion tensor MRI study

Hemisphere asymmetry was explored in normal healthy subjects and in patients with schizophrenia using a novel voxel-based tensor analysis applied to fractional anisotropy (FA) of the diffusion tensor. Our voxel-based approach, which requires precise spatial normalization to remove the misalignment of fiber tracts, includes generating a symmetrical group average template of the diffusion tensor by applying nonlinear elastic warping of the demons algorithm. We then normalized all 32 diffusion tensor MRIs from healthy subjects and 23 from schizophrenic subjects to the symmetrical average template. For each brain, six channels of tensor component images and one T2-weighted image were used for registration to match tensor orientation and shape between images. A statistical evaluation of white matter asymmetry was then conducted on the normalized FA images and their flipped images. In controls, we found left-higher-than-right anisotropic asymmetry in the anterior part of the corpus callosum, cingulum bundle, the optic radiation, and the superior cerebellar peduncle, and right-higher-than-left anisotropic asymmetry in the anterior limb of the internal capsule and the anterior limbs prefrontal regions, in the uncinate fasciculus, and in the superior longitudinal fasciculus. In patients, the asymmetry was lower, although still present, in the cingulum bundle and the anterior corpus callosum, and not found in the anterior limb of the internal capsule, the uncinate fasciculus, and the superior cerebellar peduncle compared to healthy subjects. These findings of anisotropic asymmetry pattern differences between healthy controls and patients with schizophrenia are likely related to neurodevelopmental abnormalities in schizophrenia.

γ-Band Auditory Steady-State Responses Are Impaired in First Episode Psychosis

BACKGROUND In chronic schizophrenia and chronic bipolar disorder, gamma band (30-100 Hz) auditory steady-state electroencephalogram responses (ASSRs) are reduced in power and phase locking, likely reflecting neural circuit dysfunction. Here we examined whether gamma ASSR deficits are also present at first hospitalization for psychosis. METHODS Subjects were 16 first episode schizophrenia patients (SZ), 16 first episode affective disorder patients (AFF) (13 with bipolar disorder), and 33 healthy control subjects (HC). Stimuli were 20-, 30-, and 40-Hz binaural click trains. The ASSR phase locking and evoked power were analyzed with the Morlet wavelet transform. RESULTS At 40-Hz stimulation, SZ and AFF had significantly reduced phase locking compared with HC. This deficit was more pronounced over the left hemisphere in SZ. Evoked power at 40 Hz was also reduced in the patients compared with HC. At 30-Hz stimulation phase locking and evoked power were reduced in both patient groups. The 20-Hz ASSR did not differ between groups, but phase locking and evoked power of the 40-Hz harmonic of the 20-Hz ASSR were reduced in both SZ and AFF. Phase locking of this 40-Hz harmonic was correlated with total positive symptoms in SZ. CONCLUSIONS The gamma ASSR deficit is present at first hospitalization for both schizophrenia and affective disorder but shows a left hemisphere bias in first hospitalized SZ. Some of the neural circuitry abnormalities underlying the gamma ASSR deficit might be common to psychoses in general, whereas others might be specific to particular disorders.