Anatomy and Function of the Thalamus in Schizophrenia
Monte S. Buchsbaum, P.I.

Contact persons for unmedicated patients with schizophrenia age 18-60:

The thalamus is a major relay station of sensory and perceptual information to the cortex as well as an important reciprocal participant in cortical action. These roles make the thalamus a leading candidate structure for the defective link in the neural circuits involved in the diathesis of schizophrenia. In this project, we developed reliable methods for outlining the medial dorsal nucleus, the pulvinar, and the centromedian nucleus and applied these techniques to the high-resolution MRI scans of 101 subjects, 41 unmedicated schizophrenia patients, 12 patients with schizotypal personality disorder, and 60 normal controls. Smaller volumes of the medial dorsal nucleus and the pulvinar were found in schizophrenia, as well as decreased volume of the pulvinar alone in schizotypal personality disorder. PET studies in the 101 subjects revealed reduced metabolic rates in the medial dorsal and centromedian nuclei in schizophrenia. MRI studies of the thalamus are now being extended to a large sample of 240 patients with schizophrenia ages 13-65, 78 patients with schizotypal disorder, and 223 normal controls (a total of 541 subjects). In a complementary project with a different imaging technique, we carried out two functional MRI studies on the thalamus in normal controls that showed functional activation in the pulvinar and the medial dorsal nucleus during the performance of attentional tasks. The fMRI paradigm is being extended to patients with schizophrenia. Our overall goals are 1) to develop methods for tracing the anterior nucleus of the thalamus, and trace the four nuclei in these subjects; 2) to examine the relationship of age, sex, illness outcome and symptom patterns to thalamic nuclear volumes; 3) to contrast fMRI activation in normal controls with that in unmedicated patients with schizophrenia; 4) to assess diffusion tensor anisotropy and angle of diffusion orientation in the internal capsule adjacent to the thalamus; 5) to examine correlations between nuclear volume and volume of regions of the brain that are reciprocally linked to the thalamus, including the cingulate gyrus, the caudate, the putamen, and the frontal cortex.

Contact persons for unmedicated patients with panic disorder age 18-50:

The response of the amygdala and orbitofrontal cortex (OFC) is examined in patients with panic disorder (PD) to anticipatory anxiety and panic states using FDG-PET. Preclinical research has demonstrated that the amygdala is a crucial brain structure for the acquisition and expression of conditioned fear. Preliminary data showed that PD patients demonstrated increased amygdala activation, relative to controls, during administration of the panicogenic agent doxapram, but unexpectedly also showed increased OFC metabolic rate. We speculate that cognitive behavioral therapy (CBT) modifies prefrontal cortical activity, thereby restoring normal interaction with the amygdala. In this ongoing project, PD patients and matched normal comparison subjects undergo FDG PET scans during resting, placebo, and doxapram administration. Hypotheses are as follows: While anticipating panic, patients will show altered OFC metabolic rate compared with controls. During doxapram administration, panicking patients will show altered amygdala activation compared with non-panicking subjects. Correlations between these brain metabolic analyses and changes in autonomic, neuroendocrine, and subjective anxiety measures are also examined. Patients will then be treated with CBT and the PET scans repeated. We predict that successful treatment will lead to a normalization in OFC metabolism and doxapram-induced amygdala activity. The study aims to further understanding of the neuroanatomical substrate of panic attacks and to establish a possible mechanism of action for successful CBT.

Harold W. Koenigsberg, M.D., P.I.

Contact person for unmedicated patients with schizophrenia or schizotypal personality disorder:

Schizophrenia is characterized by substantial cognitive impairments which, in addition to compromising the individual's ability to perform essential cognitive functions, contribute to the thought disorder and social maladaptations of schizophrenia. These deficits are less responsive to pharmacotherapy than the positive symptoms of schizophrenia, yet may be even more disabling over the long term. This study takes advantage of a partially overlapping disorder, schizotypal personality disorder (SPD), which shares many genetic, phenomenologic and neuropsychological features with schizophrenia, but is characterized by less severe cognitive impairments and the absence of overt psychotic symptoms, to learn more about the neurobiology of the cognitive impairment in schizophrenia and possible mechanisms that may protect SPD patients from the degree of cognitive dysfunction seen in schizophrenia. Identifying such protective factors could lead to new strategies to improve cognitive functioning in schizophrenia by suggesting new pharmacologic or cognitive remediation approaches. This study uses functional magnetic resonance imaging to compare regional brain activation among patients with schizophrenia, patients with SPD, and healthy control subjects as they carry out a cognitive task that relies on visuospatial working memory (VSWM). By comparing activation in specific regions of interest in the frontal cortex, this study will test the hypothesis that schizophrenic and SPD patients have decreased activation in a region traditionally associated with visuospatial working memory in healthy subjects and that SPD patients, but not schizophrenic subjects, are able to recruit another frontal region to compensate for the decreased functional activity in the region utilized for VSWM in healthy subjects.

Joseph D. Buxbaum, P.I.

Project 4: Structure and function of white matter in schizophrenia
Monte S. Buchsbaum, P.I.

Contact persons for unmedicated patients with schizophrenia age 18-60:

The Mount Sinai Center for the Neuroscience of Mental disorders (CCNMD) is designed to remain a highly focused effort to elucidate the role of white matter, oligodendrocytes and myelin in schizophrenia. This proposal is informed by increasing evidence of white matter, myelin and oligodendrocyte abnormalities in schizophrenia in a variety of areas of scientific exploration. A failure in connectivity has been demonstrated to have a role in schizophrenia. Myelination and those factors that affect myelination, such as the function of oligodendrocytes, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendrocytes and myelin in schizophrenia. Imaging, neuroanatomical, genetic and gene expression studies have all supported abnormalities in these cells and processes and contribute to our hypothesis that oligodendrocyte dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome. A broad set of methodologies and expertise will be brought to bear on the questions the CCNMD will pursue, including neuroanatomy, neuroimaging, molecular biology, molecular genetics, animal models neuropsychology, phenomenology, statistics, and data management. The CCNMD comprises five core projects. Project 4 (Buchsbaum) studies the structure and function of white matter in schizophrenia, and relates findings to functional outcome in schizophrenia.

Erin A. Hazlett, Ph.D., P.I.

Emotional dysregulation or reactivity to environmental events, particularly events such as separations, frustrations, or losses, is considered a defining feature of borderline personality disorder (BDP). The neural correlates of abnormal emotional processing in BBD are not understood. Startle eyeblink modification (SEM) methodology provides a non-verbal, quantitative tool for the study of emotional processing. When a brief startle stimulus is presented during an unpleasant stimulus, the amplitude of the startle response is potentiated; a pleasant stimulus occasions a relative inhibition of the startle response; and a neutral stimulus is intermediate. This study uses SEM and functional neuroimaging (event-related fMRI and FDG-PET) to explore the intensity, time course, habituation and functional neuroanatomy of emotional responses in three rigorously screened groups: 26 BPD patients, 26 patients with schizotypal personality disorder, and 26 healthy controls. During both the fMRI and PET scans, participants view an intermixed series of unpleasant (e.g., hate), pleasant (e.g., happy) and neutral (e.g., view) words. SEM amplitude difference scores (e.g., unpleasant - pleasant) measured during simultaneous FDG uptake will provide a measure of the intensity, time course, and habituation of emotional processing of unpleasant stimuli and be correlated with regional glucose metabolism. fMRI BOLD response difference scores in key brain regions will provide measurement of the intensity and time course of brain activation. We focus on three brain regions thought to be involved in emotional processing: amygdala, anterior cingulate, and prefrontal cortex (orbitofrontal and dorsolateral). These regions are part of a brain circuit hypothesized to mediate emotional experience and play a significant role in the expression of BPD symptoms. This combination of a psychophysiological and functional neuroanatomy approach holds the potential to provide much-needed information on normative aspects of emotional processing and insights into the neuroanatomy underlying the emotional dysregulation observed in BPD.

This study is in the data analysis phase and new patients are not being enrolled currently.

A significant body of preclinical and clinical work demonstrates the involvement of the serotonin system 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. In this project, a clinical trial of a serotonergic medication is carried out in alcoholism, with a predictive serotonin neuroimaging and neuroendocrine probe before the study, and a follow-up imaging scan at the end of the study. A total group of 100 recently abstinent alcoholics are prescribed 200 mg of sertraline, together with weekly cognitive behavioral psychotherapy, and followed for a 12-week period. A PET scan with the serotonin probe m-CPP and a placebo scan are performed before treatment trial, and a PET scan is also carried out on completion of the trial. Analyses will focus on prediction of clinical response to sertraline based on pre-treatment cerebral regional metabolic response to the serotonin probe m-CPP. This study should help identify a group of treatment responders to sertraline, examine whether that treatment response can be predicted using neuroimaging techniques, and identify what brain regions are implicated at baseline and in response to treatment.

Antonia S. New, M.D., P.I.

This study is in the data analysis phase and new patients are not being enrolled currently.

The neurobiological underpinnings of borderline personality disorder (BPD) are explored. Impulsive aggression is a particularly troubling attribute of BPD and also forms a type of behavior that can be measured objectively. This study will use a laboratory model, the Point Subtraction Aggression Paradigm, to provoke aggression in 40 BPD patients with impulsive aggression and 40 normal controls. The brain-activity differences between BPD patients and normal controls during aggression provocation are examined with positron emission tomography (PET), with a focus on inhibitory regions, including anterior cingulate gyrus and ventromedial orbital cortex. If BPD patients are unable to recruit inhibitory brain regions to control aggression, then this provides a very clinically meaningful explanation to patients about why they seem to struggle with self-control. It also provides a biological model that can be used to characterize a behavior that is only manifest under certain circumstances. BPD patients can appear in many situations to be completely normal, and yet this is a disorder associated with severe functional impairment, with a high rate of suicide and with frequent acts of aggression. Because this disorder is somewhat elusive to clinicians in short-term contacts, it is especially important to provide a way of characterizing the disorder that captures the pathology clearly. Specific aims of the project are as follows: 1) To identify and clinically characterize 40 impulsive/aggressiveBPD patients (20 males, 20 females) and 40 normal controls (20 males, 20 females). 2) To measure regional glucose metabolism with PET in the impulsive-aggressive BPD patients and normal controls during provocation with the Point Subtraction Aggression Paradigm.

Serge A. Mitelman, M.D., P.I.

We have identified and followed-up for a period of 4 years a cohort of schizophrenia patients with poor functional outcome, incapable of independent living for at least 5 years and aged more than 55 years at the study outset. Structural and diffusion-tensor magnetic resonance imaging were employed twice, at baseline and at the 4-year follow-up, to evaluate the course of both gray and white matter changes in association with functional and cognitive decline. These longitudinal changes in the poor-outcome patient group are being compared to progressive imaging data in both matched healthy control subjects and schizophrenia patients with good outcomes, i.e. capable of independent living in the community. This comparison is expected to yield novel information on the underlying neural basis of the observed rapid functional and cognitive decline in patients with poor outcomes, which may then be used in further theorizing on the nature of the late-life dementia complicating their course of illness. Moreover, the study will produce comparative neuroimaging data on scarcely documented illness progression in a better-outcome group of schizophrenia patients late in life in comparison to the changes seen with normal aging.

Cindy J. Aaronson, Ph.D.
Mount Sinai School of Medicine

PET Imaging of Orbitofrontal Cortex and Amygdala in Panic Disorder after Cognitive Behavior Therapy (CBT) (See NIMH-supported project, PET Imaging of OFC and Amygdala in Panic Disorder, above)

The aim of this study is to establish a possible mechanism of action for successful psychosocial therapy, specifically CBT compared to a normal control group. Patients will receive free Cognitive and Behavioral therapy and a second set of PET scans. See project “PET Imaging of OFC and Amygdala in Panic Disorder” above for details.

The proposed study will capitalize on the data already acquired on the sample of 106 schizophrenia patients (52 with good outcomes; 54 with poor outcomes) and 42 sex- and age-matched normal subjects. These data include volumetric MR and diffusion-tensor (DTI) images obtained on the whole sample at baseline as well as follow-up scans in a subsample of 51 patients and 20 controls. The follow-up images were acquired at 4-7-year intervals after the original scan, employing original sequences and hardware. The DTI and the 5-year follow-up data were collected without direct grant support as part of a VA MERIT project on anatomical MRI, which is now over. This is the only longitudinal DTI data in subjects with schizophrenia available to date.

Serge A. Mitelman, M.D.
Mount Sinai School of Medicine

Five-Year Longitudinal Diffusion-Tensor Imaging Assessment of White Matter in Schizophrenia (See NIMH-supported project, 5-Year DTI/MRI Follow-Up in Schizophrenia, above)

The proposed study will capitalize on the data already acquired on the sample of 106 schizophrenia patients (52 with good outcomes; 54 with poor outcomes) and 42 sex- and age-matched normal subjects. These data include volumetric MR and diffusion-tensor (DTI) images obtained on the whole sample at baseline as well as follow-up scans in a subsample of 51 patients and 20 controls. The follow-up images were acquired at 4-7-year intervals after the original scan, employing original sequences and hardware. The DTI and the 5-year follow-up data were collected without direct grant support as part of a VA MERIT project on anatomical MRI, which is now over. This is the only longitudinal DTI data in subjects with schizophrenia available to date.

Traumatic Brain Injuries

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Forensic studies of a patients suffering from a wide variety of traumatic brain injuries are a special interest of the Neuroscience PET Laboratory. Findings of metabolic abnormalities in brain-injured patients are correlated with neuropsychological and structural imaging (CT, MRI) findings in the same individuals. Proximate causes of trauma vary widely, from automobile accidents, electrocution, chemical exposure, and damage by blunt objects.