Monte S. Buchsbaum, M.D. - US grants

Forty off-medication patients with schizophrenia will receive 18F2-deoxyglucose (2DG) while executing the Continuous Performance Task (CPT), a psychophysical attention assessment. Simultaneous 32-channel topographic evoked potentials (EPs) to CPT stimuli will be obtained. Following uptake of 2DG and labeling of brain structures in the psychophysiological laboratory, the Neuroecat Scanner will obtain slice images with 7.6-7.8 mm in plane and 11.6-12.2 axial resolution assess the metabolic rate of glucose. The 40 patients will be obtained from the Clinical Research Centers of UCLA. Sixteen patients will have adult onset of symptoms (age 18 or later) and sixteen will have childhood onset (age 10 or earlier) but will be currently age 15 or older. The patients will be prescreened for CPT performance and will be selected for extremely poor or good CPT performance. Eight additional adult patients with intermediate CPT scores will allow analysis of positive/negative subtypes. This provides a 2X2 cell design, adult/childhood onset, good/poor attention (n=8 in each of four cells) for within patient group contrasts. Four groups of 16 normal age-and sex-matched normal volunteers will serve as contrasts. The first will be additionally matched on CPT performance to the 16 good attention patients. The second will be naive to CPT instructions and will be asked only to use the stimuli as a fixation point. The third sample will have CPT task difficulty adjusted so that their performance matches the poor schizophrenics. The fourth will only press a button at 4 second intervals. PET images will be converted to units of micromoles glucose/100g/minute and analyzed quantitatively. Analyses will identify specific structures by reference to magnetic resonance scans. A second analysis will examine cortical surface activity obtained from our 3-D reconstruction technique and correlate this with regional evoked potential techniques. In our initial studies with PET, we found schizophrenics to have a diminished anteroposterior metabolic rate gradient with occipital and parietal areas showing higher rates than normal. The current study extends this work using PET with higher resolution, a cognitive task of widely demonstrated salience, topographic EPs covering both hemispheres, and NMR scans to identify anatomic landmarks with greater accuracy.

Positron emission tomography with 18-F deoxyglucose (FDG) will be used to study regional brain metabolic patterns during rapid eye movement (REM) sleep and non-REM sleep in 40 patients with affective disorder and age and sex-matched controls. In Year 1 of this project, we have carried out nighttime PET scans in sleeping normals in REM sleep (n=12), NREM sleep (n=12) and waking (n=12). In this continuation proposal, patients with effective disorder will be studied together with concurrent controls, effective patients would be pre-screened to establish sleep stage timing and identify those with a REM latency between 30 and 60 minutes. Patients ages 21-55, meeting DSM-III criteria for Major Affective Disorder and drawn from the NIMH Clinical Research Center, UCSD, and the Research Unit if the Department of Psychiatry, UC Irvine, will serve as subjects. All patients will be off psychoactive medication a minimum of two weeks, subjects will sleep in a small bedroom with two 10-foot IV lines and polygraph leads extending to a monitoring station outside. We will monitor the polygraphic record and infuse FDG either five minutes after entering Stage 1 or five minutes after entering REM period 2, as in our initial experiments. After 30 minutes of FDG uptake, patients will be scanned, and glucose metabolic rate calculated for cortical and subcortical regions. Twenty patients will be studied in REM sleep and 20 in NREM sleep. controls will be matched to each group. If a second project, patients will be followed and restudied when remitted and again off medication and groups and stages contrasted by repeated measures NOVA. In a third experiment, we will study 20 patients and 20 normals NREM sleep following a night of sleep deprivation. We predict that affective patients may show higher than normal metabolic rates in NREM sleep.

In a series of studies, we and others have found that patients with schizophrenia have relatively reduced metabolic rates in their frontal cortex, temporal lobe and basal ganglia when assessed with positron emi- ssion tomography with 18-F 2-deoxyglucose (FDG). We propose to identify and validate subtypes of schizophrenia based on functional neuroanatomy of these three regions. We will refine our image analysis routines using our MRI template method, assess the accuracy with our new anatomically accurate brain phantom method, replicate findings of a relationship between basal ganglia metabolic rate and neuroleptic response, trace longitudinal change and evaluate familial effects. In Experiment 1, 40 patients with schizophrenia will participate in a 10-week trial of a standard neuroleptic; the design will be a double-- blind, random assignment crossover with PET scans after each five-week period. We will enlarge our current sample of 30 never-medicated patients, and enter as many as possible into the drug trial. In Experiment 2, we will rescan subjects at a five-year followup and evaluate developmental effects with a study of psychotic adolescents and an age-matched depression control group. In Experiment 3, we will scan the siblings of 24 patients with schizophrenia to evaluate familial effects. Patients in all experiments will be evaluated clinically with an expanded life-time version of the Present State Exam structured interview, diagnosed by DSM-III-R criteria, and screened for medical illness. Urine testing will verify drug status. Subjects will perform the degraded Continuous Performance Test during FDG uptake. Following uptake of FDG, the scanner (7.6 mm in plane and 11.6 mm axial resolution) will obtain slice images in micromoles glucose/l00g/ minute. All subjects will receive MRI scans at 5 mm intervals, using the same individually fitted, thermoplastic head holder to allow specific structures to be identified by reference to the anatomic image. Computer algorithms for tracing the caudate, putamen, and other regions will be employed to yield PET templates as well as size and shape assessments.

This project aims to identify brain areas salient to known deficits in the cognitive performance of schizophrenics. Psychophysical tasks known to show performance deficits in schizophrenia, and having adequate reliability and familial similarity will be studied with positron emission tomography with 18 F-2-deoxyglucose (FDG). The tasks include the Wisconsin card sort, smooth pursuit pendulum eye tracking, reaction time, pursuit rotor performance, and the continuous performance test. Adult normal controls will be screened for medical and psychiatric illness by structured schedule (SADS-L), drug use by urine screen, and for family history of psychiatric illness by interview. Sixteen subjects will perform each task during FDG uptake. Following uptake of FDG and labeling of brain structures in the psychophysical laboratory, the NeuroEcat scanner (7.6 mm in plane and 11.6 mm axial resolution) will obtain slice images to assess the metabolic rate of glucose (micromoles glucose/100g/minute). All subjects will receive MRI scans using the same individually fitted thermoplastic head holder to allow specific structures to be identified by reference to the anatomic image. In the first analysis, each group will be compared with a naive reference group (already obtained) viewing continuous performance test stimuli, but with instructions only to use the stimuli as a fixation spot. Brain areas with significantly elevated metabolic rates common to the five tasks will be sought to identify structures key to performance deficits in schizophrenia. In a second analysis, the relationship between task performance and regional metabolic rate will be assessed with correlation coefficients. In the second phase of the project, the task showing the most reliable metabolic rate elevations in structures activated by all tasks, will be tested in a group of unmedicated patients with schizophrenia and a new group of normals for replication.

biomedical equipment purchase; computer graphics /printing; personal computers;

Two cohort of patients will be followed to examine the course of illness in Alzheimer's disease. We will contrast two hypotheses of illness progression: 1) initiation in the medial temporal lobe and spread through the corticocortical projections to the lateral temporal, frontal and parietal lobes and 2) multilocal or global initiation as the variable regional expression of a common underlying diffuse pathological process. In the first cohort (data collected at the University of California, Irvine), 39 patients with mild to moderate Alzheimer's disease received PET Scans and co-registered MRI Scans, neurological examinations, and a battery of neuropsychological assessments in 1989-1990. These patients and their matched elderly normal controls are currently receiving 2-year clinical followup, and will be contacted regularly during the course of the project. These patients have already received a repeat scan. For the second cohort (data to be collected at Mt. Sinai), the ADRC Clinical Research Support Core will recruit and diagnose patients from the Mt.Sinai geriatric programs. We will PET and MRI scan and assess 16 patients each year, eight with memory deficits not meeting NINCDS criteria for AD (Mini-mental more 20 and CDR=0.5; termed "questionable AD") and eight meeting criteria for mild Alzheimer's disease (CDR 0.5 or 1.0) and meet NINCDS ADRDA criteria for AD. Patients will receive a second set of scans after 24 and 48 months; during this funding period not all patients will receive 48 month followup. The ADRC Core will provide followup at six month intervals. Approximately 68% of patients entering the ADRC will come to autopsy. While relatively few will be available in the first five year period, we will have the PET and MRI database for analysis of regional neurofibrillary tangle and plaque counts for the second grant period. From this sample rescanned at regular intervals we will learn if medial temporal lobe change is systematically followed by lateral cortical deficits. The specificity of neuroanatomical sites identified in cohort 1 will be replicated at higher resolution in cohort 2. A complete life span normal control group (ages 20-80) performing the same task during FDG uptake will be available for comparison. Scans will be carried out on our new high-resolution, head dedicated GE 2048 PET Scanner with FDG as the tracer and a verbal memory task. Matching MRI Scans will be obtained for co-registration and assessment of gray/white matter change.

DESCRIPTION (Adapted from applicant's abstract): A large data set of high-resolution coregistered PET/MRI images will be used to develop anatomical and image-processing methods to study the basal forebrain. Seventy rigorously screened healthy adults (5 men and 5 women in each decade from ages 20-90) were imaged while performing a serial verbal learning task. Thirty additional individuals will be imaged to increase statistical power. Scans were obtained with a GE 2048 head-dedicated scanner (4.5-mm resolution in plane, 2.5-3.5M counts) using 18F-deoxyglucose as the tracer. Coronal MRI images (1.2mm thick slices) were coregistered to the PET images. The investigator will focus on the striatum, pallidum and substantia innominata, with special attention to the ventral striatum (nucleus accumbens, striatal bridges into the substantia innominata) and ventral pallidum because they have been less studied (relative to the dorsal caudate and putamen) with MRI in man. A new 3D landmark-morphing method, thin-plate splines, will align and size all images to the same coordinates. The investigator will develop an atlas of basal forebrain anatomical landmarks and variance images for aligning subjects to uniform coordinates. He will test the hypothesis of greater age-related shrinkage and metabolic decrease in areas linked to motor cortex (posterior and dorsal putamen and globus pallidus) than areas linked to the limbic system (e.g., ventral striatum and pallidum). He will extend current correlational methods for understanding the topography of frontal-basal forebrain connectivity and evaluate the similarities between known nonhuman primate topography and human metabolic correlational pattern. Reciprocal compensatory size relationships between basal forebrain structures in the dorsal striatal (putamen to globus pallidus) and ventral (nucleus accumbens to ventral pallidum) systems will be explored to test the hypothesis that individuals with smaller striatal areas will show greater size or functional activity in the structures to which these areas send inhibitory projections. Lastly, the investigator will test realistic phantoms of the basal forebrain to provide accurate empirical measures of PET resolution and examine coronal postmortem cresyl violet and Weigert-stained brain slices to develop coronal slice location coordinates and assess their variation.

Olanzapine is a new medication being used in the treatment of schizophrenia. It combines a selective antagonist effect on mesolimbic dopamine neurons with serotonergic antagonist effects, and alpha1 antagonistic action. Its use in adult patients has been scientifically investigated and clinical accepted. However, child and adolescent psychiatrists are reluctant to use olanzapine for psychotic symptoms, especially as an initial treatment. This project will compare the effects of 2-20 mg haloperidol (standard treatment) with 2.5-20 mg olanzapine in two groups of young schizohrenic patients (n=15 per group), in a double-blind comparison study.

DESCRIPTION (provided by applicant): The thalamus is both a major relay station of sensory and perceptual information to the cortex as well as an important reciprocal participant in cortical action. These roles, both relevant to the sensory processing and executive action deficits in schizophrenia, make the thalamus a leading candidate structure for the defective link in the neural circuits involved in the disease diathesis. During the first 3 years of this project we have developed reliable methods for outlining the medial dorsal nucleus, the pulvinar, and the centromedian nucleus and applied these techniques to the high-resolution MRI of 101 subjects, 41 unmedicated patients with schizophrenia and 60 normal controls and a group of 12 patients with schizotypal personality disorder. This confirmed smaller volumes of the medial dorsal and pulvinar in patients with schizophrenia and the pulvinar alone in patients with schizotypal personality disorder. Coregistered positon emission tomography scans with 18F-doxyglucose were available on the group of 101 and reduced metabolic rates in the medial dorsal and centromedian nuclei were confirmed. We obtained identical MRI on a total of 240 patients with schizophrenia ages 13-65, 78 patients with schizotypal disorder, and 223 normal controls (a total of 541 subjects) and have these images on line and ready for tracing. We carried out 2 functional MRI studies on the thalamus in normal controls with confirmation of functional activation in pulvinar and medial dorsal nucleus in attentional paradigms. In the next 4 years we propose 1) to develop methods for tracing the anterior nucleus of the thalamus, and trace the 4 nuclei in these subjects 2) to examine the relationship of age, sex, illness outcome and symptom patterns to thalamic nuclear volumes 3) contrast fMRI activation in normals and unmedicated and never medicated patients with schizophrenia using MRI templates for regional nuclear assessment and test interregional correlations in volume and activity 4) assess diffusion tensor anisotropy and angle of diffusion orientation in the internal capsule adjacent to the thalamus 5) examine correlations between nuclear volume and volume of regions of the brain that are reciprocally linked including the cingulate gyrus, the caudate and putamen, and the 44 Brodmann areas of the cortex. This project brings together the resources and imaging/anatomical researchers of the Mount Sinai Department of Psychiatry, the Neuroscience PET laboratory and the Department of Radiology.

human therapy evaluation; schizophrenia; antipsychotic agents; haloperidol; adolescence (12-20); mental disorder chemotherapy; drug screening /evaluation; pediatric pharmacology; dopamine; neurons; drug administration rate /duration; sign /symptom; serotonin inhibitor; clinical trials; clinical research; human subject;

Naltrexone has been shown to be of significant benefit in increasing abstinence and decreasing relapse in conjuction with various psychotherapies in alcohol dependent subjects over a 12 week period. There is however a significant number of alcohol dependent subjects that do not respond to natrexone. The serotonin system has been implicated in the pathogenesis of alcoholism and various serotonergic compounds have has tried with modest success in its treatment. The aim of this double blind placebo controlled outpatient trial is to improve the abstinence and relapse rates in alcohol dependent subjects on naltrexone through the addition of sertraline, a serotonin reuptake inhibitor. We propose to recruit 124 non-depressed alcohol dependent subjects from the Substance Abuse Treatment Unit (SATU) at Yale ask them to take naltrexone for one week and then randomize them into two groups. The first group will take naltrexone 50 mg daily plus placebo for 12 weeks, and the other will take naltrexone 50 mg plus sertraline 50 mg daily, increasing to sertraline 100 mg daily after one week, and ontinue at this does, if tolerated, for a further 11 weeks. All subjects will receive weekly relapse prevention group psychotherapy at SATU. Subjects will be monitored weekly for breath alcohol and drug screens, and also for compliance psychopathology and side effects. At the end of the 13 week trial subjects will be sent for appropriate follow up treatment if required. Subjects will be followed up at 6 and 12 months. The investigators hypothesize an increase in abstinence and a decrease in relapse in the alcohol dependent subjects through a synergistic effect of the opiate antagonist and the serotonin reuptake inhibitor.

DESCRIPTION (provided by applicant): A significant body of preclinical and clinical work demonstrates the involvement of the serotonin system in alcoholism. Recent publication of two successful clinical trials of serotonin medications holds significant promise for the field. One study demonstrated a significant effect of the SSRI sertraline in late-onset (type A) alcoholics, while the other demonstrated efficacy of the 5-HT3-antagonist ondansetron in early-onset alcoholics. No other predictors of treatment response have been developed in alcoholism. Neuroimaging, particularly positron emission tomography (PET) scanning, offers a powerful tool to identify specific brain regions that may underlie or be associated with alcoholism. Neuroendocrine, physiological, subjective and recently [18 F] fluoro-deoxy-glucose (FDG) PET scanning responses to the broad spectrum serotonin agonist m-CPP have all been used to examine the serotonin system in alcoholism, and have previously been used to predict the clinical response to serotonin medications in other psychiatric disorders. FDG PET scanning has also recently begun to offer us an understanding of the regional pharmacotherapeutic treatment response to a serotonergic medication in depression, and in other disorders, but has yet to do so in alcoholism. We propose a clinical trial of a serotonergic medication in alcoholism, with the addition of a predictive serotonin neuroimaging and neuroendocrine probe before the study, and a follow up imaging scan at the end of the study. We will take 100 recently abstinent alcoholics, prescribe 200mg of sertraline together with weekly cognitive behavioral psychotherapy, and follow them for a 12-week period. We will perform an m-CPP FDG PET scan and a placebo FDG PET scan on completion of withdrawal prior to the trial, and an FDG PET scan on completion of the trial. Our aims are: firstly, to study changes in regional cerebral metabolism measured by FDG-PET scan induced by serotonin probe m-CPP relative to placebo FDG-PET scans in a group of alcoholics, and compare them with a group of healthy controls; secondly, to correlate the m-CPP induced changes in brain metabolism with the clinical response in a treatment trial of sertraline in the group of alcoholics over a 12-week period; and lastly, to assess the effect of sertraline on changes in placebo FDG- PET scans' regional metabolism, and to correlate changes in brain metabolism with treatment outcome. We hypothesize there will be group of clinical responders and non-responders in response to sertraline, and that the degree of serotonergic response, cerebral regional metabolic, hormonal, physiological or subjective, to the m-CPP challenge prior to the trial will predict the treatment response to sertraline in the trial. We would also hypothesize normalization of the FDG-PET scans in the treatment responsive sertraline group. This study should help identify a group of treatment responders to sertraline, examine whether that treatment response can be predicted using neuroimaging and neuroendocrine techniques, and identify what brain regions are implicated at baseline and in response to treatment.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Using a variety of neuroimaging modalities including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), a substantial number of studies have not shown that changes in activation of the amygdala are common during the acute evocation of fear in normal human subjects (Rauch et al., 2003;Anand &Shekhar, 2003) Furthermore, several imaging studies suggest that patients with anxiety disorders such as panic disorder (PD), posttraumatic stress disorder (PTSD), and social anxiety disorder (SAD) have an altered threshold for amygdala activation compared to normal volunteers. These studies were stimulated by earlier work in rodents and non-human primates thate demonstrates that the lateral and central nuclei of the amygdala are required for both the acuisition and expression of a particular type of fear, conditioned fear, although some studies suggest some division of roles for regions of the central and extended amydala (Davis, 1992). Thus, there is now strong evidence that activation of the amygdala is a phylogentically conserved phenomenon for the experience of a key emotion, fear. The work supporting amygdalar activation in the pathogenesis of pathological fear in patients with anxiety disorder has helped investigators consider the genetic origins of anxiety disorder and likely molecular targets for the development fo novel interventions. Nevertheless, it is widely recognized that activation of the amygdale does not occur in insolation during fear responses. Furthermore, there are obvious limitations in extrapolating from animal models of conditioned fear to anxiety disorders in humans. For examle, conditioned fear can be readily extinguished in experimental animals but anxiety disorders are known o be chronic conditions that do not abate even if a patient has multiple experiences in which previously avoided situations do not result in acute ffear responses. Hences, it is important to consider other areas of the neural circuitry involved in fear responses when attempting to fully understand the neuroanatomy and physiology of anxiety disorders. Recently, a few research groups found that patients with PD, SAD and PSD manifest decreased PFC activity dring the experience of acute anxiety responses. In particular, decreases in activity in the anterior cingulte and in the orbital frontal cortex (OFC) have been cited. Using fMRI, our group found that amygdalar activation in normal volunteers during the presentation of fears cues is blunted when subjects are given a task that demands PFC engagement. Using magnetic resonance spectroscopy, we found decreased concentration of a marker of neuronal viability, N-acetyl aspartate, in the anterior cingulate of adult non-human primates who had been raised under conditions of mild stress dring infancy. In collaboration with colleagues at Cornell University, as part of our Conte Neuroscience Center we recently reported, using fRI, that patients with PD have increased right amygdala and decreased OFC activity during a fear-inducing procedure. Finally, in a pilot study using 15O-PET imaging involving patients with PD and normal controls, we found a marked decrease in OFC blood flow immediately prior to panic attacks induced by the administration of doxapram. This suggests, as some speculations predicts, that reduced PFC activity occurs during the anticipatory anxiety stage immediately prior to a panic attack, thus increasing amygdala activity. Previously, we have shown that in this exact same period prior to panic, patients with PD manifest increased anxiety, increased cortisol level and decreased pCO2 an indication of acute hyperventilation. On the other hand, studies in patients with generalized anxiety disorder (GAD), OCD, and PD also suggest greater activation in regions of the prefrontal cortex than in normal comparison subjects. Hence, there is ambiguity in the literature at present about the way in which the PFC and aygdala interact in PD patients at rest, during anticipatory anxiety, and during panic. Also, in our most recent pilot study using the methods we propose to use in the present study, we found tht following placebo adminitration, when subjects were in an anticipatory anxiety state, patients with PD showed increased aygdalar and increased OFC metabolic rate compared to comparison subjects. During doxapram-induced panic attacks and subtracting out the placebo responses the patients showed further greater increases in amygdalar and OFC metabolic rate compared to controls. Thus, our pilot data show patient control differences in the amygdala that are consistent with our hypotheses, but findings in the PFC that are not. Interestingly, during the placebo infusion we noted an increased left/right ratio in Brodmann area 11 in patients, consistent with psychological theory implicating an anxious anticipatory rather than arousal state. During doxapram infusion, enhanced amygdalar metabolic rate increases in patients are most prominent on the left side, suggesting continuation of anticipatory anxiety into that phase. hence, in the revised application we now include efforts to use instruments sensitive to anxious anticipation and arousal in an attempt to disaggregate these psychological states and better explain the findings. Treatment with cognitive behavioral therapy (CBT) normalized the prefrontal findings in the patients, but had no effect on the amygdala findings. Finally, in exploratory analyses of our pilot data, we uncovered differential relationships between the dorsa___d ventral amygdala and the OFC in patients compared to controls that parallel recent preclinical findings. Taken together, these observations indicate that patients with PD have abnormal patters of regional brain activation compared to controls, some of which may be amenable to improvement with sychoscial intervention, but that studies with expanded sample sizes and rigorous methodology are needed to clarify some of the inconsistencies in the existing literature. We therefore, propose to study this critical aspect of the neurocircuitry of fear by employing a study design that will permit us to image and quantify activity in the OFC and other key brain regions during three conditions of emotional arousal: 1) at rest, experiencing "ordinary" levels of anxiety;2) during anticipatory anxiety;and 3) during panic anxiety, in untreated patients with PD, and then to repeat this after treatment with CBT. We will use panic anxiety, in untreated patients with PD, and then to repeat this after treatment with CBT. We will use doxapram as the "panicogenic" agent in this study because of its high rate of panic induction in PD patients and relatively low rate in normal volunteers and because previous work has shown that panic to doxapram is affedted by "cognitive set." We will employ 18flurodeoxyglucose (FDG) PET imaging instead of 15O-Hs) PET imaging in this study because we wish to measure the metabolic acitvity fo specific brain regions before and during panic attacks. HYPOTHESIS; 1. Prior to treatment, following a saline (placebo) injection but anticipating that they will receive the panicogen doxapram, patients with PD will show altered metabolic activity in the orbital frontal cortex (OFC) as measured by FDG-PET compared to normal comparison subjects and to a separate group of PD patients undergoing FDG-PET scans during a resting condition. 2. There will be significant statistical associations between OFC acitvity, increased anxiety, increased salivary cortisol level, increased heart rate, and increased minute ventilation (the product of respiratory frequency and the tidal volume of breathing) following saline administration (i.e. in the anticipatory state) in PD patients. 3. Prior to treatment, an injection of doxapram will prduce panic attacks in approximately 70% of patients with PD but only 20% of normal comparison subjects. Panicking subjects will show alterred OFC and amygdala metabolic activity compared to non-panicking subjects and to a separate group of PD ptients undergoing FDG-PET scans djuring a resting condition. 4. Prior to treatment, patients with PD will show increased 24-hour urinary cortisol levels, increased variability fo respiration, and decreased heart period variability compared to controls. These will be correlated with OFC metabolic activity during the FDG-PET scans, sggesting coordinated abnormalities between the autonomic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and prefrontal cortical activity in PD patients. 5. Baseline OFC acitvity, anxiety level,cortisol and physiological measures both to saline and doxapram will be correlated with treatment response, and post treatment outcomes measures (PDSS, HAM-A, HAM-D, ASI etc.).

Alterations in connectivity among brain regions such as the frontal lobe, basal forebrain and limbic system have been proposed as network deficits in schizophrenia. The multiregional aspects of the hypothesized problems in connectivity implicate a possible deficit in white matter that could lead to the rerouting or interruption of a number of specific brain circuits. A global deficit in myelin in schizophrenia may also produce a pattern of distributed multiregional deficits compatible with the complex, not clearly localizing, behavioral and cognitive disorganization in schizophrenia. Alteration in numbers, distribution, and ultrastructural integrity of oligodendrocytes, key white matter components, has recently been reported in the prefrontal cortex in schizophrenia, consistent with our original diffusion tensor findings of diminished anisotropy in frontal white matter and our replication of this in the first funding period of this project. To extend our findings of white matter abnormalities in schizophrenia we plan four projects: 1) we will complete a longitudinal sample study with follow-up scans 3 yrs in a cohort of patients with schizophrenia and controls where we have already acquired diffusion tensor and structural images from the already acquired sample of 3T longitudinal sample (240 subjects - 125 patients with schizophrenia and 115 matched controls);2) We will also acquire FDG-PET with absolute glucose quantification on a cohort of 32 unmedicated patients with schizophrenia and 32 age- and sex-matched controls to further develop our initial finding of increased white matter relative metabolic rate in schizophrenia, we will develop exploratory voxelby- voxel correlations between anisotropy and glucose metabolic rate;3) We will exploit our recently developed tract tracing programs to assess the specific tract directions and termination points for cingulate, thalamic, striatal, and callosal fibers in the prefrontal cortex;4) We will share white matter anisotropy and volumetric measures with Projects 1, 2, 3 and 5 and Core B in order to facilitate and inform their potential choice of brain areas to be examined. Taken together, these aims will allow us to obtain the most reliable, valid, functionally different, and informative white matter assessments to confirm specific thalamo-frental, fronto-striatal and cingulate pathway abnormalities in schizophrenia.

Active Follow-up; Age; Anisotropy; Area; Behavioral; Blood Sample; Blood specimen; Brain; Brain region; Brodmann's area; CRISP; Chronic; Clinical; Cognitive; Compatible; Competence; Complex; Computer Retrieval of Information on Scientific Projects Database; Corpus Callosum; Corpus Callosums; Corpus Striatum; Corpus striatum structure; D-Glucose; DNA; Data; Deoxyribonucleic Acid; Dextrose; Diffusion; Encephalon; Encephalons; Fiber; Funding; Genes; Glucose; Grant; Health; Hyperactive behavior; Hyperactivity; Hyperactivity, Motor; Hyperkinesia; Hyperkinesis; Hyperkinetic Movements; Image; Individual; Institution; Interruption; Investigators; Lead; Length; Limbic System; Localized; Measurement; Measures; Medical; Medical Imaging, Positron Emission Tomography; Metabolic; Methods; Myelin; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Numbers; Oligodendrocytes; Oligodendrocytus; Oligodendroglia; Oligodendroglia Cell; PET; PET Scan; PET imaging; PETSCAN; PETT; Pathway interactions; Patients; Pattern; Pb element; Performance; Positron Emission Tomography Scan; Positron-Emission Tomography; Prefrontal Cortex; Programs (PT); Programs [Publication Type]; Proton Magnetic Resonance Spectroscopic Imaging; Rad.-PET; Rate; Recruitment Activity; Relative; Relative (related person); Reporting; Research; Research Personnel; Research Resources; Researchers; Resources; Sampling; Sampling Studies; Scanning; Schizophrenia; Schizophrenic Disorders; Severities; Source; Striate Body; Striatum; Structure; Symptoms; TXT; Testing; Text; Thalamic structure; Thalamus; United States National Institutes of Health; Work; basal forebrain; cohort; dementia praecox; follow-up; frontal cortex; frontal lobe; heavy metal Pb; heavy metal lead; imaging; interest; pathway; programs; recruit; schizophrenic; sex; striatal; substantia alba; thalamic; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alterations in connectivity among brain regions such as the frontal lobe, basal forebrain and limbic system have been proposed as network deficits in schizophrenia. The multiregional aspects of the hypothesized problems in connectivity implicate a possible deficit in white matter that could lead to the rerouting or interruption of a number of specific brain circuits. A global deficit in myelin in schizophrenia may also produce a pattern of distributed multiregional deficits compatible with the complex, not clearly localizing, behavioral and cognitive disorganization in schizophrenia. Alteration in numbers, distribution, and ultrastructural integrity of oligodendrocytes, key white matter components, has recently been reported in the prefrontal cortex in schizophrenia, consistent with our original diffusion tensor findings of diminished anisotropy in frontal white matter and our replication of this in the first funding period of this project. To extend our findings of white matter abnormalities in schizophrenia we plan to: 1) complete a longitudinal sample study with follow-up scans 3 yrs in a cohort of patients with schizophrenia and controls where we have already acquired diffusion tensor and structural images from the already acquired sample of 3T longitudinal sample (240 subjects - 125 patients with schizophrenia and 115 matched controls); 2) acquire FDG-PET with absolute glucose quantification on a cohort of 32 unmedicated patients with schizophrenia and 32 age- and sex-matched controls to further develop our initial finding of increased white matter relative metabolic rate in schizophrenia, we will develop exploratory voxel-by-voxel correlations between anisotropy and glucose metabolic rate; 3) exploit our recently developed tract tracing programs to assess the specific tract directions and termination points for cingulate, thalamic, striatal, and callosal fibers in the prefrontal cortex;4) We will share white matter anisotropy and volumetric measures with Projects 1, 2, 3 and 5 and Core B in order to facilitate and inform their potential choice of brain areas to be examined. Taken together, these aims will allow us to obtain the most reliable, valid, functionally different, and informative white matter assessments to confirm specific thalamo-frontal, fronto-striatal and cingulate pathway abnormalities in schizophrenia.