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overview Narrative Description of Research: Schizophrenia is a major public health problem that affects close to 1% of the general population and has devastating effects on the psychological and financial resources of the patient, family, and larger community. Unfortunately there is still no clear understanding of the pathology although recent research has made it increasingly clear that biological factors may play an important role. One promising area of research has focused on the detection of abnormalities in the brains of patients afflicted with schizophrenia. Here, both post-mortem and recent magnetic resonance structural imaging (MRI) studies suggest that temporal lobe and temporal lobe limbic system abnormalities, especially pronounced on the left, may be implicated in the pathophysiology of schizophrenia. The broad goal of Dr. Shenton’s research program (see http://pnl.bwh.harvard.edu) has been to apply new imaging techniques to the study of schizophrenia in order to determine and to localize brain abnormalities which likely underlie the symptoms and disordered behavior observed in patients diagnosed with schizophrenia. Accordingly, this investigator has focused her research efforts in trying to define and to localize further brain abnormalities in the temporal lobe in patients afflicted with schizophrenia. Newly developed image processing techniques, originally developed for the analysis of multichannel remote sensing data (i.e., satellites), have been employed to analyze high spatial resolution magnetic resonance imaging (MRI) scans (1.5-mm and 2-mm slices). The application of these image processing techniques to the investigation of schizophrenia has been particularly helpful because these techniques not only exploit more fully information contained in MR scans, but they also offer more precise and accurate measurements, factors important to schizophrenia where brain abnormalities are often more subtle, and harder to detect, than for other pathophysiological disorders, and where, consequently, precise and accurate measurements become that much more essential. These techniques have now been used by Dr. Shenton and her colleagues to make volumetric measurements of: (1) whole brain for gray matter, white matter and CSF; (2) temporal lobe (gray and white matter); (3) amygdala-hippocampal complex, (4) parahippocampal gyrus, (5) superior temporal gyrus; (6) cingulate gyrus; (7) parietal lobe; and (8) basal ganglia structures. In addition, an analysis of the gyral pattern in the cortical gray matter surface of the temporal lobes has been completed. Results demonstrate that schizophrenic patients, compared to normal controls, show reductions in volume in temporal lobe limbic system structures (amygdala-hippocampal formation and parahippocampal gyrus), and in superior temporal gyrus. These abnormalities were found to be more pronounced on the left, were correlated with each other, and there was an observed correlation between measures of formal thought disorder and left superior temporal gyrus volume. The latter finding suggested to the investigator and her coworkers that there was damage to an interconnected neural network that may be important to verbal associations and verbal memory, which may account for the loose associations so often observed in schizophrenia. This line of research is continuing and newer methods are being developed for analyzing the brain, including warping techniques which may replace the laborious tracing of smaller regions of the brain. Additionally, measures of shape are being applied to brain regions of interest as such measures may be more sensitive than measures of volume alone and they may reflect neurodevelopmental anomalies in the brains of patients diagnosed with schizophrenia. This research has been extended to first onset cases of schizophrenia as well as to individuals diagnosed with schizotypal personality disorder. The former focus is important as it will allow these investigators to discern whether or not brain abnormalities are evident early in the course of the illness, prior to confounding variables such as a chronic illness and long term effects of neuroleptics. The latter focus is important as it will allow these investigators to discern similarities and differences in a disorder that is genetically linked to schizophrenia but where psychosis is not observed. Finally, Dr. Shenton is also working closely with collaborators investigating hippocampal abnormalities in individuals diagnosed with post-traumatic stress disorder (PTSD). Currently, there is a morphometric brain study of the amygdala-hippocampus in monozygotic twins where one twin has PTSD as a result of combat exposure in the Vietnam War, and the other does not. Such studies will help us to understand whether or not some individuals have a predisposition to developing PTSD. Other morphometric studies of brain abnormalities in clinical populations include new studies investigating the cognitive and behavioral correlates of brain abnormalities in William’s Syndrome patients. Work using transcranial magnetic stimulation (TMS) has also been conducted by Dr. Shenton and her colleagues in an attempt to understand further cognitive processes which can be interrupted by TMS, thus affording the opportunity to link processes that occur in the millisecond range with specific loci in the brain. This program of research is being developed to examine motor maps but will be extended to map cortical speech areas in order to determine whether there are differences in language processing between patients with schizophrenia and a normal comparison group. New studies using MR diffusion tensor imaging (DTI) are also being applied to neuropsychiatric disorders. This is a relatively new imaging technique that will be important for examining white matter fiber tracts in the brain in schizophrenia and other neuropsychiatric disorders. More specifically, unlike conventional MRI, where white matter appears uniform and homogeneous, the novel technology of DTI affords an opportunity to investigate and to quantify normal and abnormal white matter fiber tracts in vivo in the human brain. Here Dr. Shenton and her collaborators are focusing on assessing anisotropic diffusion in the uncinate fasciculus, the most prominent white matter fiber tract connecting the frontal and temporal lobe, as well as other fiber tracts likely implicated in schizophrenia. Findings reveal a group by side interaction as well as a lack of normal left greater than right asymmetry in patients with schizophrenia. These findings demonstrate the importance of investigating white matter fiber tracts in vivo in schizophrenia, and support the hypothesis of a disruption in normal connectivity between temporo-frontal brain regions in schizophrenia. Another area of research that Dr. Shenton and her colleagues are conducting is research in the area of traumatic brain injury (TBI). Injury to the brain, especially in concussion or mild TBI, mainly involves diffuse axonal injury, which is best characterized by diffusion imaging techniques. Mild TBI, in fact, is difficult to characterize using conventional CT and MRI because these imaging techniques are not optimal for detecting diffuse axonal injury, particularly as evinced by mild TBI. Diffusion tractography techniques that can quantify damage along fiber tracts is thus an important new area of research that may add to our understanding of TBI. Dr. Shenton and her colleagues are part of a large PTSD and TBI Clinical Consortium supported by the Department of Defense (http://intrust.sdsc.edu/), which includes 10 sites across the country where neuroimaging will be conducted to understand better the neurobiology of TBI. Work is also being conducted with Dr. Robert Stern at Boston University Medical School, Center for Chronic Traumatic Encephalopathy, in evaluating chronic traumatic encephalopathy (CTE) using neuroimaging techniques, applied to a group of National Football Players who are at risk for developing CTE. Work has also been done in investigating subconcussive blows to the head in elite soccer players in Germany with Dr. Inga Koerte. This work was recently published in JAMA. Further, because traumatic brain injury is a heterogeneous disorder, in that where the head is impacted determines where in the brain the injury has occurred, Dr. Shenton has bee working with Dr. Sylvain Bouix in establishing individual profiles of injury in traumatic brain injury using a normative atlas. This work has recently been published in PlosOne. By applying these new techniques to assess heretofore unmeasurable differences between the brains of normal control subjects and clinical populations, Dr. Shenton and her colleagues hope to understand better the pathophysiology of neuropsychiatric disorders.
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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.