Ms. Kathy S. Burrows
801 University Blvd SE
Suite 200
Albuquerque, NM 87106
Phone: 505-272-7578
Fax: 505-272-7574
E-mail: kburrows@unm.edu
Number of Human Subjects projects reported: 33
| MIND-02-0108M06981 | "Ultra-high field fMRI and MEG for praxis" |
| MIND-02-MGH 1999-P-008666/19 | "Toward the prevention of schizophrenia: Neurobiological studies of families with schizophrenia" |
| MIND-02-MGH 2000-P-002110 | "The Spatio-Temporal Dynamics of Processing Language Form and Content in Schizophrenia" |
| MIND-02-MGH 2001-P-000257/6 | "Functional and structural neuroimaging studies of higher cognitive function in schizophrenia" |
| MIND-02-MGH2002-P-00580/1 | "Multimodality imaging of cognitive processes in normal subjects" |
| MIND-02-MGHMcCarley | "First episode schizophrenia: an ERP and MEG longitudinal study" |
| MIND-02-MINN 0006M55421 | "Dynamic study of rapid semantic priming in schizophrenia" |
| MIND-02-Minn 0104M95501 | "MRS assessment of glutamate in young patients with schizophrenia" |
| MIND-02-Minn 0206M26761 | "Genomics and white matter abnormalities in schizophrenia." |
| MIND-02-Minn VAMC 2896 | "The neural network of auditory verbal hallucinations" |
| MIND-02-Minn0006M55421 | "MEG Studies of Shcizophrenia" |
| MIND-02-Minn005M50901 | "MEG of visual attention deficits in schizophrenia" |
| MIND-02-Minn0205M25581 | "The Disregulation of Optimized Cognition in Schizophrenia" |
| MIND-02-UNM HRRC 02-051 | "Longitudinal assessment brain neurochemistry early in schizophrenia with high-field proton spectroscopy as a predictor of functional deterioration." |
| MIND-02-UNM HRRC 03-108 | "A Magnetic Resonance Spectroscopy Study of Glutamate Metabolism and Neuronal Integrity in Children and Adolescents with Schizophrenia-Spectrum Disorders" |
| MIND-02-UNM-HRRC 02-267 | "Dynamic Systems Mediating Verbal and Spatial Working Memory Tasks as Characterized by MEG" |
| MIND-03-UNM HRRC 02-502 | "A fMRI Study of Temporal Cognition" |
| MIND-04-IA-01 | "Schizophrenia Consortium Core" |
| MIND-04-MA-01 | "Hippocampal function during transitive influence in Schizophrenia" |
| MIND-04-MA-02 | "Functional imaging of working memory in schizophrenia" |
| MIND-04-MA-03 | "Semantic processing in schizophrenia" |
| MIND-04-MA-04 | "Schizophrenia Research: Functional brain abnormalities in relatives of schizophrenics " |
| MIND-04-MA-05 | "Schizophrenia Research: Multimodal neuroimaging in schizophrenia " |
| MIND-04-MA-06 | "Cognitive Science Research: Various Memory and Language, Visual Object Recognition, and Novelty and Attention Studies " |
| MIND-04-MA-09 | "Schizo Core: Diagnostic, Cognitive, and Clinical Assessment of Chronic Schizophrenic Subjects " |
| MIND-04-MN-01 | "In-Vivo Measurement of Glutamatergic Neurotransmission " |
| MIND-04-MN-02 | "National Consortium Project: Magnetic Resonance Spectroscopy of Glutamate in Young Patients With Schizphrenia" |
| MIND-04-MN-03 | "The Disregulation of Optimized Cognition in Schizophrenia" |
| MIND-04-MN-04 | "Investigating Brain Function, Connectivity and Neurochemistry in Health and Disease: High Field Magnetic Resonance Methodologies" |
| MIND-04-MN-05 | "MEG Studies of Schizophrenia" |
| MIND-04-MN-06 | "MEG Clinical Research Core" |
| MIND-04-NM-01 | "Magnetoencephalographic studies of information processing in normal subjects" |
| MIND-04-NM-02 | "Neural Mechanisms of Temporal Processing Disturbances in Schizophrenia " |
"Ultra-high field fMRI and MEG for praxis"
Principal Investigator: Dr. Apostolos P. Georgopoulos, University of Minnesota
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Minneapolis Veterans Administration Medical Center
Most recent approval: 04/14/04
IRB approval number: FWA00000325
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 9
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: The long-term goal of this research is to elucidate the function of the posterior parietal cortex in maze solving and route following which are typical praxis tasks. For that purpose, the investigators will study the same subjects during performance of the same tasks using (a) single-trial, time-resolved, very high spatial resolution functional magnetic resonance imaging (fMRI) at ultra-high magnetic fields (7 Tesla) and (b) single-trial, very high temporal resolution 248-sensor magnetoencephalography (MEG). The investigators will focus on the spatial representation and dynamic organization of the parietal cortex with respect to visual-spatial functions for which it is essential. It is the understanding of the investigators that this will be the first time that a brain area will be investigated in such spatio-temporal detail and in a single-trial design.
Methodology: Study subjects will be 10 healthy, right-handed persons (five male, five female) between the ages of 20 to 55 with no known disease of the nervous system. All subjects will have an IQ > 85. Subjects will undergo the same maze task during both fMRI and MEG testing. This task will involve using a joystick to navigate a maze.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substance: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: Procedures are listed above. All subjects will give informed consent prior to study participation. The study is voluntary and subjects may withdraw at any time without consequence.
Risks: Risks are minimal as procedures are non-invasive. Subjects will be given breaks to prevent fatigue.
Privacy/Confidentiality/Consent: All information will be kept confidential. The FDA and study sponsor may access study records. In publications resulting from this study names will not be mentioned.
"Toward the prevention of schizophrenia: Neurobiological studies of families with schizophrenia"
Principal Investigator: Dr. Ming T. Tsuang, Massachusetts General Hospital
Project started in: 2002
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hospital
Most recent approval: 05/29/03
IRB approval number: n/a
Explanation of IRB approval:
Project was apparently concluded in 2003 with $96,803 in spending and involving 10 human subjects.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Abstract:
PROJECT CONCLUDED IN 2003.
Objectives: The objective was to better identify the neural substrate of schizophrenia by identifying subsyndromal phenomenology that may be transmitted in persons at risk for this illness. This study focused on temporal-limbic brain regions and their pre-frontal connections that have been identified previously as critical in understanding the nature of schizophrenia. A second aim was to identify the specificity of these hypotheses for schizophrenia compared with persons with bipolar psychotic disorders.
Methodology: Twenty-four persons in each group were studied and 50 normal controls for a total of 146 subjects over three years. Subjects were given diagnostic interviews and cognitive testing to assess IQ, attention span, working and declarative memory, executive function, language domains, and motor function. Patients then participated in functional and structural imaging procedures.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: Subjects were recruited from local hospital clinics and consumer groups (National Alliance for the Mentally Ill). Subjects were given written, informed consent. Subjects did undergo cognitive testing and magnetic resonance imaging (MRI) procedures.
Risks: Subjects may become bored or fatigued during testing. All subjects will be given numerous breaks. All subjects were free to withdraw at any time without consequence.
Privacy/Confidentiality/Consent: Study information will be kept confidential to the extent allowed by law. The FDA and sponsor of the study may access study records. In publications resulting from the study no names will be used.
"The Spatio-Temporal Dynamics of Processing Language Form and Content in Schizophrenia"
Principal Investigator: Dr. Gina Kuperberg, Massachusetts General Hospital
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hospital
Most recent approval: 05/28/04
IRB approval number: 2000-P-002110 CR#4
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 57
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND fiscal year
Type(s) of Human Subjects Involvement:
a. Objectives: The objective is to identify abnormalities in the temporal dynamics of processing language form and content in schizophrenia using event related potentials (ERPs).
b. Methodology: Patients/subjects did undergo magnetoencephalography (MEG) and funtional magnetic resonance imaging (fMRI) studies (at least five weeks apart). They were presented with different stimulus paradigms including neutral versus positive versus negative critical words in sentences and concrete versus abstract critical words in sentences. Both paradigms with half the speakers in each condition will contain a contextual anomoly, and participants will judge whether or not the sentences make sense. Sentences will be presented word by word in the same pseudorandom counterbalanced sequence.
c. Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: None.
d. Involvement of Human Subjects: Subjects will be consented and all study procedures explained. Subjects will be reminded throughout the study that they can withdraw at any time. Subjects will be tested using MEG and fMRI with the above-described cognitive tests. All information will be kept as confidential as possible according to the rules of the institution.
Risks: Subjects may become bored or fatigued during testing. All subjects will be given numerous breaks. All subjects are free to withdraw at any time without consequence.
Privacy/Confidentiality/Consent: Study information will be kept confidential to the extent allowed by law. The FDA and sponsor of the study may access study records. In publications resulting from the study no names will be used.
"Functional and structural neuroimaging studies of higher cognitive function in schizophrenia"
Principal Investigator: Dr. Stephan Heckers, Massachusetts General Hospital
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hospital
Most recent approval: 02/17/04
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 20
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: These projects investigate the cognitive and neuropsychological basis of deficits in higher cognitive function in schizophrenia using structural and functional neuroimaging techniques. In other projects we have established that schizophrenic patients show specific and selective deficits in working memory, declarative memory, and language function. This study will use new methods for the acquisition and analysis of functional and structural data sets, using functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and cortical flat mapping techniques.
Methodology: This study consists of six functional neuroimaging experiments. Men and women aged 18 to 55, right-handed and with a normal verbal IQ, will be studied. Schizophrenic subjects will be recruited as outpatients and must meet inclusion criteria consisting of being on a stable dose of antipsychotic medication for at least six weeks or unmedicated, no substance abuse, and ability to give informed consent. Subjects will be given rating scales to assess symptoms using the Scale to Assess Negative Symptoms, Scale to Assess Posive Symptoms, Simpson-Angus Movement Rating Scale, Global Assessment Scale, Abnormal Involuntary Movement Scale, and Brief Psychiatric Rating Scale instruments.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: Subjects will be recruited and given a series of neuroimaging procedures including fMRI and MEG.
Risks: The risks are minimal as both procedures are non-invasive. Subjects will be given many breaks and may withdraw at any time without consequence.
Privacy/Confidentiality/Consent: Subjects must provide written, informed consent. All information will be kept confidential. The FDA and sponsor of this study may access study files. Any publications resulting from this study will not mention any names.
"Multimodality imaging of cognitive processes in normal subjects"
Principal Investigator: Dr. Caroline West, Massachusetts General Hospital
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hospital
Most recent approval: 06/16/04
IRB approval number: 2002-P-00580
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 18
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: The overall goal is to further understand the neural bases of human cognitive processes in health and disease. A full appreciation of the complex mechanisms that underlie normal cognition is essential to the understanding of cognitive dysfunction. We propose a set of studies in normal subjects to investigate several basic functions known to be disrupted in a number of neurocognitive disorders, particularly schizophrenia. These experiments in normal subjects are a necessary prelude to studies in patient populations. The research described here employs the multi-modal neuroimaging approach developed at Massachusetts General Hospital (MGH). This methodology allows the investigators to explore the localization of cognitive processing mechanisms in the brain, but also to ask questions regarding the time course of those activations. The dynamic spatiotemporal maps of activation that will be obtained from these studies should greatly enhance the understanding of these fundamental cognitive operations. Specifically the investigators seek to (1) Reveal whether there are independent mismatch negativity (MMN) generators in the vicinity of the auditory cortex and whether the MMN can be explained by the effects of lateral inhibition on the N1 component, (2) Identify the spatiotemporal characteristics of attentional processing of novel auditory and visual stimuli, (3) Identify the origin of top-down facilitation in visual object recognition, and (4) Characterize the dynamic structural and functional organization of semantic representations and processing mechanisms.
Methodology: Subjects will undergo functional magnertic imaging (fMRI), magnetoencephalography (MEG), and electroencephalography (EEG) measures.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: Subjects will have MRI, MEG, and EEG measures.
Risks: There is little risk associated with these non-invasive procedures. Persons who should not have MRI scanning will be excluded from the study. These include pregnant women, persons with ear implants or nerve stimulating devices, pacemakers, and aneurysm clips.
Privacy/Confidentiality/Consent: All subjects must give written, informed consent prior to study participation. All study records will be kept confidential. The FDA and the study sponsor may access these records. In any publications resulting from this study, names will not be used.
"First episode schizophrenia: an ERP and MEG longitudinal study"
Principal Investigator: Dr. Robert W. McCarley, Massachusetts General Hospital
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hopsital
Most recent approval: 01/28/04
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 15
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: One of the central questions in schizophrenia is to what extent brain abnormalities occur peri-natally and to what extent these abnormalities occur, or progress, even after the onset of symptoms. This question has been variously posed as a "two-hit" model or as a developmental versus degenerative model, although it is apparent that the mechanisms leading to early developmental abnormalities might also lead to continued alterations after symptom onset. It is also not known whether brain changes occurring after symptom onset might be ameliorated or even halted through proper neuroleptic and psychosocial interventions. To address these important issues, the investigators propose a longitudinal evoked potential study of first episode (hospitalization) schizophrenic and affective psychosis patients, to be followed up as intervals of 1.5 years. Key measures will be electroencephalography (EEG), magnetoencephalography (MEG), and mismatch negativity (MMN) recordings.
Methodology: Subjects will be screened for inclusion/exclusion criteria. These include an IQ above 75, no alcohol or drug dependence or abuse within the last year, and no hearing impairments. Subjects will then be evaluated with diagnostic tools (structured clinical interviews). Clinical measures will include the Scale to Assess Negative Symptoms, Scale to Assess Positive Symptoms, Brief Psychiatric Rating Scale, and Thought Disorder Index. Subjects will also be administered EEG, MEG, and magnetic resonance imaging (MRI) measures.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: Subjects will undergo procedures mentioned above. Subjects will provide written, informed consent prior to any study procedures.
Risks: Subjects may become bored or fatigued during testing. All subjects will be given numerous breaks. All subjects are free to withdraw at any time without consequence.
Privacy/Confidentiality/Consent: Study information will be kept confidential to the extent allowed by law. The FDA and sponsor of the study may access study records. In publications resulting from the study no names will be used.
"Dynamic study of rapid semantic priming in schizophrenia"
Principal Investigator: Dr. Patricia J. Pardo, University of Minnesota
Project started in: 2002
This project ended in fiscal year 2004.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: University of Minnesota
Most recent approval: 09/13/04
IRB approval number: UMN 0006M55421
Additional IRB approvals from other institutions:
Type of Review: Full Board
Approving Institution: Veterans Administration Medical Center
Most recent approval: 09/13/04
IRB approval number: VAMC 2778A
Type of Review: Full Board
Approving Institution: University of Minnesota
Most recent approval: 05/13/04
IRB approval number: UMN 0006M55421
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 13
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: Schizophrenia patients exhibit difficulties in cognitive processing, directly hindering everyday functioning and quality of life. Cognitive behavioral studies have identified aberrant semantic and lexical processing in schizophrenia patients as compared to control subjects. Some of these difficulties have been correlated to the presence of thought disorder (TD). Several studies in semantic priming (facilitation of meaningfully related concepts) in TD schizophrenia patients suggest a dysfunctional organization of semantic memory or retrieval specific in these patients. Other studies have not replicated these findings. Small differences in cognitive task paradigms can yield very different results in both patient and normal control studies, highlighting the need to implement additional tools to discover the dynamic cognitive architecture of both normal and schizophrenic linguistic processing. Whole-head magnetoencephalography (MEG) provides a unique opportunity for dissecting the temporal course and coherence of dynamic cortical responses. The investigators propose to use MEG to identify the time course, magnitude, and coherence of online changes in neuromagnetic flux elicited by rapid, facilitative semantic priming.
The specific aims are: To (1) test the hypothesis that the magnetically recorded neuronal responses to target word trials will elicit substantially different dynamic patterns of cortical response following primed target words in TD schizophrenia patients as compared to non-TD schizophrenia patients and control subjects; and (2) characterize the relationships between components of TD, priming, and neuromagnetic evoked responses. Observing semantic processing in schizophrenia, via directly measuring neuromagnetic responses, should provide unique and meaningful contributions to the field of schizophrenia. Also, findings from this project will lay the groundwork essential for future grant applications to continue this effort.
Methodology: Fourteen adult schizophrenia patients (seven with TD and seven with minimal TD) as measured by the scale for the assessment of thought, language, and communication, along with six matched control subjects will be recruited. Subjects will all be right-handed and 18 to 65 years of age with English as their primary language. Special effort will be made to study unmedicated patients. Subjects will undergo whole-head anatomical magnetic resonance imaging (MRI) scanning. These images will be co-registered with MEG data to facilitate realistic-head modeling. These tests will be conducted while subjects are performing visual word tasks.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: See above.
Risks: The risks are minimal as procedures are non-invasive; subjects will be given breaks.
Privacy/Confidentiality/Consent: Subjects will be consented prior to any study participation. All information will be kept confidential. The FDA and study sponsor may access study records. In publications resulting from this study no names will be used.
"MRS assessment of glutamate in young patients with schizophrenia"
Principal Investigator: Dr. Charles Schulz, University of Minnesota
Project started in: 2002
This project ended in fiscal year 2004.
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Minnesota
Most recent approval: 03/09/04
IRB approval number: 0104M95501
Explanation of IRB approval:
This project appears to have been re-named and is now being carried out as MIND-04-MN-02.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Please go to Project ID: MIND-04-MN-02 for update on this project.
Objectives: The glutamatergic system has been directly and indirectly implicated in schizophrenia from postmortem and functional imaging research. The functional imaging studies from the investigators indicate that the anterior cingulate cortex has shown increased regional cortical blood flow (rCBF) in response to ketamine and is the region where symptoms and rCBF correlate in response to ketamine administration. Several laboratories have studied glutamate and gamma aminobutyric acid (GABA) in postmortem tissue and have described potentially significant changes that accompany the illness. We have the opportunity to use high-strength magnets to separate glutamate, glutamine, and GABA and analyze their concentrations regionally using magnetic resonance spectroscopy (MRS) in the living human person. This study will measure these and other molecules in medicated and unmedicated subjects with schizophrenia and normal volunteers. In addition, we will use functional magnetic resonance imaging (fMRI) to compare the neurochemical distributions of regional cerebral blood flow activations. Our hypothesis is that glutamatergic afferents to the anterior cingulate cortex (ACC) from the hippocampal cortex are hypoactive, resulting in reduced excitation in the ACC and also in other areas of the frontal cortex. This hypothesis can now be directly tested using a high-strength magnet and MRS.
Methodology: Subjects 25 to 45 years of age, who have schizophrenia, will be recruited. Matched controls will also be recruited. Patients will receive structured clinical interviews to confirm diagnosis. Symptoms will be assessed using the positive and negative syndrome scale (PANSS). Patients will not be taken off of their medication for this study. Subjects will be scanned in a 4 Tesla MRI machine for both spectroscopy and fMRI. For fMRI, subjects will be scanned undergoing two tasks (decision and sensory motor control) and in a resting phase.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Does not apply.
Involvement of Human Subjects:
Procedures involving Human Subjects: Procedures are described above.
Risks: The risks are minimal as no procedures are invasive. Subjects may become bored or fatigued during some of the tasks. Breaks will be given to help prevent this. All subjects will provide written, informed consent prior to study participation. Subjects are free to withdraw from the study at any time without consequence.
"Genomics and white matter abnormalities in schizophrenia."
Principal Investigator: Dr. Kelvin O. Lim, University of Minnesota
Project started in: 2002
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Minnnesota
Most recent approval: 11/14/04
Explanation of IRB approval:
Project completed in 2003 with estimated funding of $66,666 and one human subject involved.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Project complete in 2003. This notice is submitted so that report can be removed from roster.
Objectives: The recent availability of gene chip arrays has allowed the efficient examination of gene expression in complex disorders. Postmortem gene expression studies in schizophrenia have recently reported the reduced expression of sets of genes related to myelination. In vivo neuroimaging studies have revealed potential white matter metabolic and microstructural abnormalities in schizophrenia. The overall aim of this proposal is to perform a pilot antimortem study examining the relationship between white matter abnormalities, detected by recently developed in vivo magnetic resonance measures, and selected white matter related candidate genes, identified through completed and ongoing gene expression and other genomic studies. This pilot proposal would be the first to combine in vivo neuroimaging measures with genomics information. The information would be complementary to that obtained through postmortem studies and provide a logical extension of postmortem studies.
Methodology: The investigators plan to study 40 patients with schizophrenia and 48 healthy controls. All subjects will be between 18 and 50 years of age. All subjects will be scanned and blood samples collected.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: See above.
Risks: The risks are minimal. Blood draws can result in bruising at the site where it was drawn. The scan is non-invasive and presents minimal risk. Subjects may become bored or fatigued during some of the tasks. Breaks will be given to help prevent this. All subjects will provide written, informed consent prior to study participation. Subjects are free to withdraw from the study at any time without consequence.
Privacy/Confidentiality/Consent: All information will be kept confidential. The FDA and study sponsor may access study records. In publications resulting from this study, no names will be used.
"The neural network of auditory verbal hallucinations"
Principal Investigator: Dr. Massoud Stephane, Minneapolis Veterans Administration Medical Center
Project started in: 2002
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Minnesota
Most recent approval: 09/13/03
IRB approval number: 2896-A
Explanation of IRB approval:
Project was completed in 2003 and IRB aligned with that time period.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
PROJECT COMPLETED IN 2003.
Objectives: Research focusing on individual psychotic symptoms avoids the diagnostic ambiguity of schizophrenia. Auditory verbal hallucinations (AVH) affect up to 70 percent of schizophrenic patients. AVH research could clarify important aspects of the pathophysiology of schizophrenia. However, this research faces a set of challenges that include:
1) Unpredictability of the occurrence of AVH: this makes direct study a rare opportunity. An abnormal experience is likely to be related to a dysfunction of brain mechanisms underlying normal functions. As AVH arise from a speech disorder, efforts should be made to study language processing in hallucinating patients. Language is linked to a set of distinct, non-overlapping, but interconnected processors. They subserve sublexical, lexical, syntactic, and discourse components and work in concert with other cognitive resources such as attention and working memory. Characterizing language processing in hallucinating patients would shed light on AVH neural mechanisms.
2) Phenomenological variations of AVH: all AVH meet the basic definition - perception of speech in the auditory modality without corresponding external stimuli. However, they vary among multiple phenomenological dimensions, such as repetitive or systematized content, and linguistic complexity (hearing words, sentences, or conversations). There is evidence that the phenomenological variations correspond to variability in the underlying pathophysiology. For example, AVH with repetitive content respond to treatment with antiobsessional agents. A number of positron emission tomography (PET) studies show the activating profile of verbal stimulations varies with the linguistic complexity of the stimuli. Therefore, it is necessary to subgroup AVH according to the phenomenological variables in order to clarify neural substrates.
3) AVH, like most brain dysfunctions and functions, are related to a serial and parallel distributed neural network. Therefore, temporospatial imaging such as magnetoencephalography (MEG) is a particularly suitable method for AVH research. As antipsychotics alter the magnetic signal, studying drug free and naive patients is advantageous.
We hypothesize that AVH result from the dysfunction of a serial and parallel distributed neural network which includes language neural mechanisms. The phonomenological variation of AVH and the associated patterns of cognitive and linguistic deficits are related to pathologies at different locations along this network. The aims are: characterization of cognitive and language processing deficits associated with each phenomenological variable, and characterization of the parallel and serial neural network associated with AVH by MEG.
Methodology: Thirty drug-free or naive patients with a history of AVH and 30 controls will undergo assessment of symptoms and neuropsychological testing. Subjects will then be imaged in resting states and during hallucinations (patients).
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: See above.
Risks: The risks are minimal as no procedures are invasive. Subjects may become bored or fatigued during some of the tasks. Breaks will be given to help prevent this. All subjects will provide written, informed consent prior to study participation. Subjects are free to withdraw from the study at any time without consequence.
"MEG Studies of Shcizophrenia"
Principal Investigator: Dr. Jose Pardo, University of Minnesota and Minnapolis Veterans Admin. Med. Ctr.
Project started in: 2002
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Minnesota
Most recent approval: 06/13/03
Explanation of IRB approval:
Project completed in prior period with final IRB approval date of 06/13/2003.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Other: 01/01/03 to 12/31/03
Explanation:
Final reporting period for project was 01/01/2003 to 12/31/2003 with 10 subjects involved.
Type(s) of Human Subjects Involvement:
PROJECT COMPLETED IN 2003.
Objectives: It has recently been discovered that when schizophrenia patients look at words (simple, common, and concrete nouns) or read them aloud, brain activation spreads abnormally to other language areas that healthy control subjects do not recruit based on the instructions for the task. This spread occurs despite the preserved ability to read aloud. The phenomenon call been termed "spreading neuronal activation" by the investigators. This proposal aims to answer three questions about this abnormality: (1) Does spreading neuronal activation reflect the degree of thought disorder in patients (and will medications alter this pattern)? (2) Is spreading neuronal activation caused by dysfunction in automatic or attentional processing? and (3) What cognitive operations do schizophrenic patients employ to result in such patterns of brain activity (and can healthy subjects also produce such patterns given the right task instructions)? To answer these questions, the investigators will apply functional magnetic resonance imaging (fMRI) to measure brain activation as patients and controls process single nouns under varying instructions (context).
The anticipated outcome of this research is greater understanding of spreading neuronal activation, a process likely to account for disturbances of language and thought so common in schizophrenia. In addition, data from ongoing studies using magnetoencephalography (MEG) to study word processing in schizophrenia have the potential to combine synergistically with these fMRI data using multimodal techniques to visualize both spatial and temporal components of spreading neuronal activation in patients. Such information is pivotal toward understanding the disease mechanisms, which history has proven is essential to design rationally new and effective treatments.
Methodology: Fifteen patients and 15 controls will be recruited. All subjects will be right handed, and controls will be matched for age, gender, and IQ. Subjects will undergo fMRI scanning while completing the known task.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: See above.
Risks: The risks are minimal as no procedures are invasive. Subjects may become bored or fatigued during some of the tasks. Breaks will be given to help prevent this. All subjects will provide written, informed consent prior to study participation. Subjects are free to withdraw from the study at any time without consequence.
Privacy/Confidentiality/Consent: All information will be confidential. The FDA and study sponsor may access study records. Publications resulting from this study will not mention names.
"MEG of visual attention deficits in schizophrenia"
Principal Investigator: Dr. Scott R. Sponheim, Minneapolis Veterans Admin. Med. Ctr. and University of Minnesota
Project started in: 2002
This project ended in fiscal year 2004.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Minneapolis VAMC
Most recent approval: 07/19/04
IRB approval number: VAMC#3187B
Additional IRB approvals from other institutions:
Type of Review: Full Board
Approving Institution: University of Minnesota
Most recent approval: 08/11/04
IRB approval number: MN# 0208M31301
Type of Review: Full Board
Approving Institution: Minneapolis VAMC
Most recent approval: 07/19/04
IRB approval number: VAMC# 3187B
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 17
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: A vast body of evidence indicates that schizophrenia is a brain disorder. Despite powerful techniques for studying the brain, researchers have made limited progress in detailing the expression of schizophrenia in the central nervous system. Perhaps the largest obstacle to uncovering central nervous system etiology in schizophrenia is the limited scientific utility of the disorder's symptom-based definition. Scientists are calling for different ways to define this disorder. Ideally, characterization of schizophrenia would be reliable and simple, near the level of brain structure or function, be stable within individuals over time, and provide a more powerful examination of the disorder's genetic and environmental underpinnings. The marriage of an ongoing family study with a powerful technique for describing brain function using magnetoencephalography (MEG) presents an opportunity to identify functional brain abnormalities evident in schizophrenia that are associated with genetic liability for the disorder. Impaired visual attention is one of the consistently documented cognitive deficits in schizophrenia. Vigilance deficits are relatively stable over disorder course; and vigilance, serial search, and backward masking deficits are present in schizophrenia patients and people at genetic risk for schizophrenia and those in remission for the disorder. Therefore, impaired visual attention is a potentially useful phenotype in examining the etiology of schizophrenia. Although many studies provide behavioral descriptions of impaired visual attention in schizophrenia, little is known about the brain mechanisms underlying the dysfunction. Recent investigations have revealed high frequency oscillations in the visual cortex that may bind information from neurons at both short and long distances in the brain. Recent studies point to the synchrony of gamma oscillations as important to cognitive processing. Gamma activity provides information unique from evoked potentials and possesses the necessary temporal resolution for scientists to test biological models of visual attention deficits in schizophrenia.
Methodology: Five patients, five of their biological siblings, and five non-psychiatric control subjects will complete the MEG protocol. The MEG subjects will be selected based upon their electroencephalogram (EEG) readings. Research staff will administer symptom assessments (Scale to Assess Negative Symptoms, Scale to Assess Positive Symptoms, and Brief Psychiatric Rating Scale) and controls will receive the Structured Interview for Schizotypy, Schizotypal Personality Questionnaire, and Structural Clinical Interview for DSM-II. While MEG is being conducted subjects will undergo visual attention tasks.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: See above.
Risks: The risks of MEG are minimal as it is non-invasive. Subjects will be given breaks to prevent fatigue. Subjects will provide written, informed consent. Participation is voluntary and subjects may withdraw at any time without consequence.
Privacy/Confidentiality/Consent: All information collected is confidential. The FDA and study sponsor may access study records. In publications resulting from this study, no names will be used.
"The Disregulation of Optimized Cognition in Schizophrenia"
Principal Investigator: Dr. Tonya White, University of Minnesota
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Minnesota
Most recent approval: 05/13/04
IRB approval number: FWA00000312
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 140
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: Current theories of schizophrenia explain the considerable heterogeneity in cognitive and clinical symptoms as a result of aberrations in brain connectivity. Studies using structural magnetic resonance imaging (MRI), positron emission tomography (PET), and functional MRI have demonstrated a number of regions implicated as nodes within the circuitry, including the dorsolateral prefrontal cortex, basal ganglia, thalamus, and the cerebellum. Spatial working memory taps into many of these brain regions and has been found to be impaired in schizophrenia. Furthermore, the underlying neuronal circuitry of spatial working memory has also been fairly well defined in both human and infrahuman studies. This provides an opportunity to assess connectivity of brain regions using high-field MR, optimizing both spatial and temporal resolution. The purpose of this study is to evaluate the functional connectivity in adolescents with schizophrenia on a task of spatial working memory compared to a group of gender matched siblings and healthy controls. A time-locked event related paradigm will be utilized to optimize temporal resolution.
Methodology: Three groups of right-handed adolescents between 12 and 17 of age will be recruited to participate in the study. The first group will have been diagnosed with either schizophrenia, schizoaffective disorder, or schizophreniform disorder. Patients who are either neuroleptic naive or undergoing a medication wash will be approached for participation in this study. The second group will be same-sex siblings who are closest in age to the patients who do not have a psychotic disorder. The third group will consist of healthy controls without evidence of a medical or psychiatric disorder. Two tasks to assess spatial working memory will be utilized. Participants will first be tested outside of the scanner to collect data and to assure that they have learned the task prior to being in the scanner (to reduce variability in performance).
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: See above.
Risks: There are minimal risks as these procedures are noninvasive. Participants might become bored or fatigued. Subjects will be given breaks to avoid fatigue.
Privacy/Confidentiality/Consent: Subjects must give informed consent prior to any study procedures. All information will be confidential. The FDA and study sponsor may access study records. Subjects are free to withdraw at any time without consequence.
"Longitudinal assessment brain neurochemistry early in schizophrenia with high-field proton spectroscopy as a predictor of functional deterioration."
Principal Investigator: Dr. Juan Bustillo, MIND Institute/ UNM
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: HRRC 02-051
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: The University of New Mexico
Most recent approval: 01/18/04
IRB approval number: 02-051
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 15
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Objectives: The purpose of the study is to evaluate whether various brain chemicals in persons with schizophrenia change after the person begins treatment with antipsychotic medications.
Despite effective symptom reduction with antipsychotic medications, the majority of schizophrenia patients fail to achieve premorbid status and functional outcomes are generally poor. N-acetylaspartate (NAA), a marker of neuronal viability, is related to cognitive function and may predict functional outcome. NAA is reduced in prefrontal, thalamic, and mesial temporal brain regions in chronically-treated schizophrenia, but may be normal early in the disease. The clinical significance and mechanisms accounting for this NAA reduction are poorly understood. A second line of evidence suggests that glutamine (Gln) may be elevated early in the illness. Glutamine concentrations primarily reflect glutamate (Glu) cleared from the synapse, providing an in-vivo index of glutamatergic neurotransmission. It has been postulated that in schizophrenia there is a progressive excitotoxic process involving hyperglutamatergia, which disrupts neuronal function and accounts for the global cognitive defects and poor psychosocial outcomes of the illness, despite the beneficial symptom reducing effects of antipsychotic medication.
The project uses high-field (4T) 1H-MRS to study NAA, Gln, and Glu in antipsychotic-naïve and minimally-treated schizophrenia. These neurometabolites will be measured in four regions where metabolic abnormalities have been previously reported: anterior cingulate, frontal white matter, medial thalamus, and hippocampus. 1H-MRS assessments will be repeated at 1, 6, and 12 months. Treatment with antipsychotic medications will be standardized and symptoms, side-effects, cognitive, and social function will be assessed prospectively. A group of healthy volunteers will also be followed longitudinally. This project will address three specific pressing issues: (1) the location and temporal evolution of brain NAA reductions during the first year of treatment in schizophrenia; (2) the relationship between NAA reductions and cognitive and social function outcomes; and (3) the relationship between abnormalities in glutamatergic metabolism and NAA reductions during the first year of treatment. Documentation that reductions of NAA are clinically relevant and are preceded and "driven" by hyperglutamatergia would, for example, support the early use of antiglutamatergic agents to prevent functional deterioration in schizophrenia.
Methodology: A special brain study technology called magnetic resonance spectroscopy (MRS) will be used in this study. The antipsychotic medications that may be used in this study include quetiapine, risperidone, haloperidol, and clozapine, all of which have been repeatedly proven to treat the symptoms of schizophrenia. In addition to the MRS, subjects will also receive cognitive assessments.
"A Magnetic Resonance Spectroscopy Study of Glutamate Metabolism and Neuronal Integrity in Children and Adolescents with Schizophrenia-Spectrum Disorders"
Principal Investigator: Dr. Rhoshel Lenroot, MIND Institute/ UNM
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: MIND Institute
Most recent approval: 03/24/04
IRB approval number: 03-108
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 43
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Schizophrenia is widely viewed as related to disturbances in neural development, and schizophrenia which manifests during childhood appears to be a more severe form of the disease. Glutamate (Glu) is a neurotransmitter which plays an important role in normal brain development. Studies in adults with schizophrenia have found evidence of abnormalities in glutamate function, possibly resulting in a neurotoxic effect. However, no studies have been done focusing on glutamate function in children and adolescents with schizophrenia. The overall goal of this study is to obtain preliminary cross-sectional data regarding glutamate metabolism and its relationship to brain structure and function in children and adolescents with schizophrenia. Comparisons will be made with a healthy control group. Measures of glutamate, glutamine (Gln), and N-acetylaspartate (NAA), a marker of neuronal integrity, will be obtained using high-field (4 Tesla) 1 H-MRS. Gln concentrations primarily reflect Glu cleared from the synapse, providing an in-vivo measure of glutamatergic neurotransmission. Nueromatabolites will be examined in three areas with previous evidence of metabolic abnormalities: the anterior cingulate, the medial thalamus, and the hippocampus. Each subject will also have a separate scan to obtain high-resolution structural data for correlation with metabolic measures. Measures of brain function will include a neurocognitive battery and neurological examination. Tanner stages will be obtained as a measure of maturity. This will be the first study of glutamate function in children and adolescents with schizophrenia. Our findings should provide insight into the mechanisms of the disease and help to guide the possible use of medications that affect glutamate function in children.
Methods: We plan to continue to use high-field (4T) single-voxel 1H-MRS to compare glutamate function in children and adolescents with schizophrenia-spectrum disorders and healthy controls. We will also seek to characterize the relationship of glutamate function with measures of NAA, brain structures, cognitive function, and physical maturation. Study procedures will consist of a diagnostic interview based on the scale for affective disorders and schizophrenia (K-SADS) and comprehensive assessment of symptoms and history (CASH), a physical examination including neurological exam and Tanner staging of sexual maturity, a neurocognitive test battery, and two magnetic resonance imaging studies. Measures of brain metabolites including glutamine, glutamate, and N-acetylaspartate will be obtained using a 4 Tesla Varian scanner. High resolution morphometric data will be collected in a separate session on a 1.5 Tesla scanner using a sequence developed by colleagues at the University of Iowa. We are requesting a second year of funding in order to study forty new subjects: twenty children and adolescents with schizophrenia-spectrum disorders and twenty healthy controls.
"Dynamic Systems Mediating Verbal and Spatial Working Memory Tasks as Characterized by MEG"
Principal Investigator: Dr. Cheryl J. Aine, MIND Institute/ UNM
Project started in: 2002
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 02-267
Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: The University of New Mexico
Most recent approval: 07/19/04
IRB approval number: 02-267
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 8
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
Project runs for calendar year
Type(s) of Human Subjects Involvement:
Objectives: One hypothesis concerning the etiology of schizophrenia is that subtle neuropathological changes, such as cell loss or reduced neuropil, occur during development and later manifest in adolescence as a functional disruption in connectivity and communication in neuronal circuits involved in the coordination of mental activity. Most neuroimaging studies examining the neurophysiological basis of schizophrenia have demonstrated that working memory tasks, particularly spatial working memory tasks, are quite effective for revealing deficits in schizophrenic patients. Working memory processes appear to involve a large distributed network of cortical/subcortical areas.
The spatial and verbal working memory (WM) protocols focus on elucidating the brain dynamics associated with working memory and delayed recognition memory in schizophrenic brains and normal controls. Magnetoencephalography (MEG) combined with anatomical magnetic resonance imaging (MRI) are particularly useful for the temporal and spatial separation of sensory activity, encoding, and delayed recognition memory, all within the same WM protocol. In addition, effective use of cross-correlation techniques (cross-correlations in source space) can help identify functional neural circuits involved in encoding and recognition memory processes and the degree to which disparate brain regions respond together as a unit in schizophrenic brains compared to their normative control counterparts.
Method: Ten medicated schizophrenic patients and 10 age-matched controls will participate in two WM tasks (spatial and verbal) using the same physical stimuli. Single digits will be located within each cell of a 4 x 4 grid (16 cells total). All but one of the digits will be displayed in green color while the digit to be attended for future recognition will be displayed in red. A variant of the Sternberg task will be used where either memory set sizes of 1 or 3 will be used in order to examine the effect of memory load. The memory set items are presented sequentially in time. In the spatial task, subjects are instructed to encode the location of the red digit, while in the verbal task, subjects are instructed to encode the digit number itself. Neuromagnetic measurements will be made using a Neuromag 122-channel system at the Veterans Administration Medical Center. Automated analysis of the data will be accomplished by conducting limited searches through the pre-defined head volumes. Source locations will be displayed on the MRIs and their calculated timecourses will be evaluated statistically. It is predicted that schizophrenic patients will reveal a deficit in sustaining activity in the different brain regions involved in the task, which prevent a prefrontal-parietal circuit from communicating effectively between the constituent regions, thus having a negative impact on behavioral performance measures.
"A fMRI Study of Temporal Cognition"
Principal Investigator: Dr. Deborah Harrington, MIND Institute/UNM
Project started in: 2003
Funding for Human Subjects Research: No Funding Sources Reported
This project does not involve the use of multiple protocols/subprojects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: The University of New Mexico
Most recent approval: 08/10/04
IRB approval number: HRRC 02-502
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Other: 01/01/03 to 12/31/03
Explanation:
Last reporting period involving human subjects involvement
Type(s) of Human Subjects Involvement:
Objectives: The mechanisms by which the brain times events and stores them in memory for later use is of great interest. The purpose of this research is to use magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to study the brain systems that control our ability to perceive and remember the amount of time that has passed. The working hypothesis is that the basal ganglia regulate the "timekeeper" mechanism.
Methodology: See above.
Exposure to Ionizing Radiation, Radioactive Substances, and Chemical Substances: Not applicable.
Involvement of Human Subjects:
Procedures involving Human Subjects: Subjects will be asked to perform a variety of tasks to assess the ability to distinguish different intervals of time and different pitches of sound. These involve listening to sounds through earphones and then pressing a button on a keyboard or lifting a finger. These tasks will be performed while the subject is undergoing MEG and the fMRI.
Risks: Subjects will need to lie still in the MRI machine during testing. This test will take up to 90 minutes. Subjects will be given breaks at regular intervals. The MRI machine makes a loud banging noise. Efforts to make subjects comfortable will be made including providing earplugs or other support. Patients with pacemakers, metal in their body, aneurysm clips, ear implants or nerve stimulators will not be able to participate in this study. Pregnant women will also be excluded from participation in this study. All subjects may withdraw from the study at any time without consequence.
Privacy/Confidentiality/Consent: The study records may be made available to the Food and Drug Administration and the University of New Mexico Research and Review Committee. Otherwise, subject records will be kept strictly confidential.
"Schizophrenia Consortium Core"
Principal Investigator: Dr. Beng Ho, University of Iowa
Project started in: 2004
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 3
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Iowa
Most recent approval: 04/20/04
IRB approval number: 8103070
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 8
Reporting period for number of human subjects:
Other: 01/01/04 to 12/17/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Recruit and study 20 first episode, 20 chronic, and 20 demographically matched normal control subjects. First episode patients will be studied twice annually; chronic patients and controls will be studied once. The core will carry out the following tasks with all subjects: informed consent, diagnostic assessment, neuropsychological assessment, clinical assessment (rating scales), and functional and structural neuroimaging. The coordination of the clinical core, clinical assessments, neuropsychological testing, and data management will be performed by a team composed of a half-time neuropsychologist (Core Coordinator, Rosemary Toomey, Ph.D.) and half-time research assistant. Recruitment, consenting, and diagnostic assessment will be performed by two teams, each composed of a half-time research fellow (MD) and full-time research assistant/ recruiter. One team will be based at Minnesota Medical Health Center and one team at Massachusetts General Hospital. Both teams will recruit and establish diagnoses for both first-episode and chronic patients.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Univeristy of Iowa
Most recent approval: 01/27/04
IRB approval number: 1998010017
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 8
Reporting period for number of human subjects:
Other: 01/01/04 to 12/17/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Recruit and study 20 first episode, 20 chronic, and 20 demographically matched normal control subjects. First episode patients will be studied twice annually; chronic patients and controls will be studied once. The core will carry out the following tasks with all subjects: informed consent, diagnostic assessment, neuropsychological assessment, clinical assessment (rating scales), and functional and structural neuroimaging. The coordination of the clinical core, clinical assessments, neuropsychological testing, and data management will be performed by a team composed of a half-time neuropsychologist (Core Coordinator, Rosemary Toomey, Ph.D.) and half-time research assistant. Recruitment, consenting, and diagnostic assessment will be performed by two teams, each composed of a half-time research fellow (MD) and full-time research assistant/ recruiter. One team will be based at Minnesota Medical Health Center and one team at Massachusetts General Hospital. Both teams will recruit and establish diagnoses for both first-episode and chronic patients.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Iowa
Most recent approval: 12/02/03
IRB approval number: 9701024
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 8
Reporting period for number of human subjects:
Other: 01/01/04 to 12/17/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Recruit and study 20 first episode, 20 chronic, and 20 demographically matched normal control subjects. First episode patients will be studied twice annually; chronic patients and controls will be studied once. The core will carry out the following tasks with all subjects: informed consent, diagnostic assessment, neuropsychological assessment, clinical assessment (rating scales), and functional and structural neuroimaging. The coordination of the clinical core, clinical assessments, neuropsychological testing, and data management will be performed by a team composed of a half-time neuropsychologist (Core Coordinator, Rosemary Toomey, Ph.D.) and half-time research assistant. Recruitment, consenting, and diagnostic assessment will be performed by two teams, each composed of a half-time research fellow (MD) and full-time research assistant/ recruiter. One team will be based at Minnesota Medical Health Center and one team at Massachusetts General Hospital. Both teams will recruit and establish diagnoses for both first-episode and chronic patients.
"Hippocampal function during transitive influence in Schizophrenia"
Principal Investigator: Dr. Stephan Heckers, Massachusetts General Hospital
Project started in: 2004
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 1
Identifier or number: 2001P-00258
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: The MIND Institute
Most recent approval: 01/05/04
IRB approval number: 2001P-00258
Additional IRB approvals from other institutions:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 2001P-000446
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 47
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Transitive inference (TI) is the ability to infer relationships about the sequential order of items that have not been studied together. Recent animal studies have provided compelling evidence that this relational memory ability depends on the integrity of the hippocampus (Dusek and Eichenbaum, 1997). In addition, we have recently provided the first evidence that TI judgments are also associated with significant hippocampal activation in humans (Heckers et al., 2003). Thus, TI allows us to study relational memory in humans with a paradigm that can be explored further in animals.
A recent behavioral study has demonstrated selective deficits in TI in subjects with schizophrenia (Titone et al, 2003). While schizophrenia subjects were able to infer relationships between items that did not require a flexible representation of an underlying sequence, they were less accurate when asked to order items that required TI judgments. Taken together, there is compelling evidence that TI is associated with significant hippocampal activation in humans and that this process is impaired in schizophrenia.
METHODS
We will use an event-related study design in a 3T Siemens scanner to study blood oxygen level dependent (BOLD) signal change in the medial temporal lobe in 20 healthy subjects and 20 patients with schizophrenia. Prior to scanning, subjects will be trained on pairs of arbitrary visual stimuli. Some of these pairs are taken from a larger list of sequentially ordered visual stimuli (#1-#6), whereas others are non-overlapping individual pairs (i.e., A-B, C-D, etc.). During scanning, subjects will then be shown novel pairings from either the overlapping or the non-overlapping stimulus sets. Stimulus pairs will be presented in a randomized fashion. Functional images will be analyzed for whole brain activation patterns using the statistical parametric mapping version 2 (SPM2) data processing software package and for medial temporal lobe activation using six individually outlined regions of interest (amygdala, uncus, hippocampal body, entorhinal cortex, perirhinal cortex, and parahippocampal cortex).
"Functional imaging of working memory in schizophrenia"
Principal Investigator: Dr. Dara Manoach, Massachusetts General Hosptial
Project started in: 2004
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: 2002P-000444
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 2002P-000444
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 46
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
With Dr. Stephan Heckers, investigate transitive inference (TI) on the sequential order of items that have not been studied together. Recent animal studies have provided compelling evidence that this relational memory ability depends on the integrity of the hippocampus (Dusek and Eichenbaum, 1997). In addition, we have recently provided the first evidence that TI judgments are also associated with significant hippocampal activation in humans (Heckers et al., 2003). Thus, TI allows us to study relational memory in humans with a paradigm that can be explored further in animals.
A recent behavioral study has demonstrated selective deficits in TI in subjects with schizophrenia (Titone et al, 2003). While schizophrenia subjects were able to infer relationships between items that did not require a flexible representation of an underlying sequence, they were less accurate when asked to order items that required TI judgments. Taken together, there is compelling evidence that TI is associated with significant hippocampal activation in humans and that this process is impaired in schizophrenia.
Methods
We will use an event-related study design in a 3T Siemens scanner to study blood oxygen level dependent (BOLD) signal change in the medial temporal lobe in 20 healthy subjects and 20 patients with schizophrenia. Prior to scanning, subjects will be trained on pairs of arbitrary visual stimuli. Some of these pairs are taken from a larger list of sequentially ordered visual stimuli (#1-#6), whereas others are non-overlapping individual pairs (i.e., A-B, C-D, etc.). During scanning, subjects will then be shown novel pairings from either the overlapping or the non-overlapping stimulus sets. Stimulus pairs will be presented in a randomized fashion. Functional images will be analyzed for whole brain activation patterns using the statistical parametric mapping version 2 (SPM2) data processing software package and for medial temporal lobe activation using six individually outlined regions of interest (amygdala, uncus, hippocampal body, entorhinal cortex, perirhinal cortex, and parahippocampal cortex).
"Semantic processing in schizophrenia"
Principal Investigator: Dr. Gina Kuperberg, Massachusetts General Hosptial
Project started in: 2004
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 2000P-002107
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 32
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Abnormalities of thought and language are core to schizophrenia [1]. In previous MIND supported work, we used functional magnetic resonance imaging (fMRI) and event related potentials (ERPs) to delineate neurocognitive dysfunction in spatial and temporal domains during sentence processing in patients with schizophrenia [2, 3]. We demonstrated specific abnormalities in the modulation of the N400/P600 ERP waveforms and activity within a left lateralized temporal-prefrontal network in schizophrenia. Our studies have thus far focused on semantic and contextual relationships between words within sentences. From a clinical perspective, it has long been known that language and thought disturbances in schizophrenia are particularly severe when themes are negatively emotionally salient or abstract in nature. We now aim to extend our previous findings by examining the effects of emotion and concreteness on neurocognitive function during sentence processing in schizophrenia.
Methods:
Patients and controls will be recruited and assesssed as outlined in the description of the clinical core.
Design:
Paradigm 1 (effects of emotional valence); three main conditions: neutral versus positive versus negative critical words in sentences.
Paradigm 2 (effects of concreteness); two main conditions: concrete versus abstract critical words in sentences.
In both paradigms, half the sentences in each condition will contain a contextual anomaly and participants (right-handed native English speakers; n = 15 in patient and control groups for each paradigm) will judge whether or not the sentences make sense. A Latin-square design will allow for counterbalancing of experimental conditions between subjects. For ERP, fMRI, and magnetoencephalography (MEG) experiments, sentences will be presented word by word (500 ms duration, 100 ms inter-stimulus interval) in the same pseudorandom counterbalanced sequence. ERP and fMRI studies will take place at least five weeks apart, and subjects will view a different stimulus list to minimize practice and repetition priming effects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 2000P-002100
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 59
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
Abnormalities of thought and language are core to schizophrenia [1]. In previous MIND supported work, we used functional magnetic resonance imaging (fMRI) and event related potentials (ERPs) to delineate neurocognitive dysfunction in spatial and temporal domains during sentence processing in patients with schizophrenia [2, 3]. We demonstrated specific abnormalities in the modulation of the N400/P600 ERP waveforms and activity within a left lateralized temporal-prefrontal network in schizophrenia. Our studies have thus far focused on semantic and contextual relationships between words within sentences. From a clinical perspective, it has long been known that language and thought disturbances in schizophrenia are particularly severe when themes are negatively emotionally salient or abstract in nature. We now aim to extend our previous findings by examining the effects of emotion and concreteness on neurocognitive function during sentence processing in schizophrenia.
Methods:
Patients and controls will be recruited and assesssed as outlined in the description of the clinical core.
Design:
Paradigm 1 (effects of emotional valence); three main conditions: neutral versus positive versus negative critical words in sentences.
Paradigm 2 (effects of concreteness); two main conditions: concrete versus abstract critical words in sentences.
In both paradigms, half the sentences in each condition will contain a contextual anomaly and participants (right-handed native English speakers; n = 15 in patient and control groups for each paradigm) will judge whether or not the sentences make sense. A Latin-square design will allow for counterbalancing of experimental conditions between subjects. For ERP, fMRI, and magnetoencephalography (MEG) experiments, sentences will be presented word by word (500 ms duration, 100 ms inter-stimulus interval) in the same pseudorandom counterbalanced sequence. ERP and fMRI studies will take place at least five weeks apart, and subjects will view a different stimulus list to minimize practice and repetition priming effects.
"Schizophrenia Research: Functional brain abnormalities in relatives of schizophrenics"
Principal Investigator: Dr. Larry Seidman, Massachusetts Mental Health Center
Project started in: 2004
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 1999P-008666/20
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 65
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
In 2001 we proposed to collect a sample of 146 persons over a three-year period and carry out functional magnetic resonance imaging (fMRI) with this sample. Funding began on 7/1/02; thus we have had approximately 13 months of data collection, or approximately 1/3 of the data collection period we proposed. During the past year, 45 subjects received functional MRI and other measures funded by other grants (structural MRI and neuropsychological testing). This includes 21 adolescents at high risk (AHR) for schizophrenia (SCZ) or bipolar (BP), 19 age and sex-matched normal controls, and five persons with first episode psychoses. We expect to continue to assess people at the same rate and thus should have a sample of approximately 65 subjects (estimates of 55 AHR subjects and controls and 10 persons with first episode psychoses, by the end of 2003). For the next fiscal year (2004), we propose to continue data collection, as our preliminary data are quite promising.
Methods
Brain Imaging: Functional MRI will be performed using a Siemens 1.5T magnet at the Massachusetts General Hospital Nuclear Magnetic Resonance (MGH NMR) Center. (We use 1.5T because structural data are also collected for morphometric analysis.) The stimuli are viewed through a mirror attached to the head coil. Button-press responses are collected using a magnetic-compatible button box connected to the Macintosh computer via custom USB interface providing both accuracy and response time information. The fMRI data are preprocessed using Statistical Parametric Mapping (SPM) and custom routines in MATLAB.
Two-Back Working Memory (WM) Task: We use a variant of a sequential letter, "N-back" task that has been used in many neuroimaging studies of WM (Cohen et al., 1994). Subjects are instructed to respond to every stimulus using a two-button response box, with one button used to signal targets and the other used to signal non-targets. In the vigilance task, the target is a single pre-specified letter ("X"), and all other stimuli are non-targets. In the two-back condition, the target is any letter that is identical to the one that preceded it two trials back. Subjects respond to each stimulus pressing one button for targets (21 percent of trials) and another for non-targets. Each subject participates in two runs lasting 5.2 minutes each. Each run of trials incorporates a block design with 13 epochs: (1) three 24-second epochs of the vigilance task (Block "A"), (2) three 24-second epochs of the two-back task (Block "B"), and (3) seven 24-second epochs of the "fixation" task, which provide a pre-stimulus baseline and recovery period for the hemodynamic response in between the task blocks (a fixation period will occur between every A and B task). Condition order is randomized across blocks and subjects, with 1/2 receiving ABABAB task order and 1/2 the BABABA task order.
The Verbal Encoding/Declarative Memory Task: The verbal encoding and retrieval paradigm used in Golby et al. (2001) was adapted for use with persons with SCZ. In the encoding task, pairs of common nouns are presented visually during two fMRI scans. In each scan, subjects are presented with 48 stimuli in six blocks of eight stimuli per block. Stimuli are visible for 4,000 ms with an interstimulus interval of 1,000 ms. Prior to starting each scan, subjects are instructed to generate a sentence silently using both words and are explicitly instructed to try to remember the stimuli for a later test. For repeated ("old") nouns, they are told to generate the same sentence each time. Subjects are asked to respond by pressing a button as soon as they completed the sentence-generation task. After scanning, a retrieval task is performed to assess the memory performance. Subjects view 12 previously presented items and 12 foils. Responses ("new", "old") are made by button push. The memory test is administered in the same order as the encoding tasks for each individual.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 2002P-001984
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 12
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
In 2001 we proposed to collect a sample of 146 persons over a three-year period and carry out functional magnetic resonance imaging (fMRI) with this sample. Funding began on 7/1/02; thus we have had approximately 13 months of data collection, or approximately 1/3 of the data collection period we proposed. During the past year, 45 subjects received functional MRI and other measures funded by other grants (structural MRI and neuropsychological testing). This includes 21 adolescents at high risk (AHR) for schizophrenia (SCZ) or bipolar (BP), 19 age and sex-matched normal controls, and five persons with first episode psychoses. We expect to continue to assess people at the same rate and thus should have a sample of approximately 65 subjects (estimates of 55 AHR subjects and controls and 10 persons with first episode psychoses by the end of 2003). In fiscal year 2004, we continued data collection, as our preliminary data are quite promising.
Methods
Brain Imaging: Functional MRI will be performed using a Siemens 1.5T magnet at the Massachusetts General Hospital Nuclear Magnetic Resonance (MGH NMR) Center. (We use 1.5T because structural data are also collected for morphometric analysis.) The stimuli are viewed through a mirror attached to the head coil. Button-press responses are collected using a magnetic-compatible button box connected to the Macintosh computer via custom USB interface providing both accuracy and response time information. The fMRI data are preprocessed using Statistical Parametric Mapping (SPM) and custom routines in MATLAB.
Two-Back Working Memory (WM) Task: We use a variant of a sequential letter, "N-back" task that has been used in many neuroimaging studies of WM (Cohen et al., 1994). Subjects are instructed to respond to every stimulus using a two-button response box, with one button used to signal targets and the other used to signal non-targets. In the vigilance task, the target is a single pre-specified letter ("X"), and all other stimuli are non-targets. In the two-back condition, the target is any letter that is identical to the one that preceded it two trials back. Subjects respond to each stimulus pressing one button for targets (21 percent of trials) and another for non-targets. Each subject participates in two runs lasting 5.2 minutes each. Each run of trials incorporates a block design with 13 epochs: (1) three 24-second epochs of the vigilance task (Block "A"), (2) three 24-second epochs of the two-back task (Block "B"), and (3) seven 24-second epochs of the "fixation" task, which provide a pre-stimulus baseline and recovery period for the hemodynamic response in between the task blocks (a fixation period will occur between every A and B task). Condition order is randomized across blocks and subjects, with 1/2 receiving ABABAB task order and 1/2 the BABABA task order.
The Verbal Encoding/Declarative Memory Task: The verbal encoding and retrieval paradigm used in Golby et al. (2001) was adapted for use with persons with SCZ. In the encoding task, pairs of common nouns are presented visually during two fMRI scans. In each scan, subjects are presented with 48 stimuli in six blocks of eight stimuli per block. Stimuli are visible for 4,000 ms with an interstimulus interval of 1,000 ms. Prior to starting each scan, subjects are instructed to generate a sentence silently using both words and are explicitly instructed to try to remember the stimuli for a later test. For repeated ("old") nouns, they are told to generate the same sentence each time. Subjects are asked to respond by pressing a button as soon as they completed the sentence-generation task. After scanning, a retrieval task is performed to assess the memory performance. Subjects view 12 previously presented items and 12 foils. Responses ("new", "old") are made by button push. The memory test is administered in the same order as the encoding tasks for each individual.
"Schizophrenia Research: Multimodal neuroimaging in schizophrenia"
Principal Investigator: Dr. Steve Stufflebeam, Massachusetts General Hosptial
Project started in: 2004
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Massachusetts General Hosptial
Most recent approval: 01/15/04
IRB approval number: 2002P-001238
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 24
Reporting period for number of human subjects:
Other: 01/01/04 to 12/31/04
Explanation:
MIND Institute fiscal year
Type(s) of Human Subjects Involvement:
The aim of this project is to focus on brain regions where clinical data can be related to functional and structural alterations. The effort builds on and proposes to extend the data in the Progress Report, which furnishes much of the background. There are three main components.
H1. Middle and Inferior Temporal Gyri.
Background: The middle temporal gyrus (MTG) and inferior temporal gyrus (ITG) subserve language and semantic memory processing, visual perception, and multimodal sensory integration.
Predictions:
A. Compared with healthy controls, gray matter in the MTG/ITG will have smaller magnetic resonance imaging (MRI) volumes in first episode schizophrenia (also compared with affective psychosis) and in chronic schizophrenia, and the volume will be inversely correlated with positive symptoms from the scale for the assessment of positive symptoms (SAPS) and hallucinations.
B. Functional MRI (fMRI) studies of semantic processing will show lack of differentiation in schizophrenia of the activation related to semantic processing (abstract vs. concrete word meaning) vs. shallow processing (upper/lower case discrimination) in left superior and middle temporal gyri, with the degree of the fMRI abnormality correlating with the degree of the structural deficit.
H2. Post-onset progression of temporal lobe neocortical gray matter volume reduction in schizophrenia.
A. An enlarged longitudinal sample will continue to show differential post-initial hospitalization progression of gray matter volume reduction in left superior temporal gyrus (STG) in schizophrenia compared with affective psychosis and healthy controls, with most of the change occurring in the first six months following initial hospitalization.
B. Differential post-onset progression of gray matter volume reduction in first episode schizophrenia will also occur in MTG, ITG, and fusiform gyrus, with lesser rates of change and lesser left-lateralization in the more inferior cortical regions.
H3. Fusiform gyrus and face processing.
A. Compared with healthy controls, patients with chronic schizophrenia (> 3 hospitalizations) will show reduction in amplitude of the N170 ERP (event related potentials) evoked by faces, but not the ERP evoked by non-face stimuli.
B. The degree of reduction in the face-related potential will be correlated with the degree of volume reduction in the fusiform gyrus.
Methods
Structural MRI will use high-resolution T1- and T2-weighted scans, mainly on 1.5T (and continued 1.5T on the longitudinal study), but with a beginning of cross-over to 3T. Continued comparisons will be made with manual region of interest (ROI) and more automated methods, including voxel-based morphometry (VBM) and freesurfer. The fMRI will use 3T. ERPs will use a 64-channel array. Subject selection and screening will be as previously described.
Translational Significance
In terms of significance, it hardly needs emphasis that, should our prediction of very rapid progression of ERP and MRI abnormalities in the six months following initial hospitalization for schizophrenia be confirmed, it would immediately form a scientific foundation and moral impetus for studies of the possible preventive effects of medication and psychosocial treatment. We suggest that the post-onset changes mainly reflect a reduction in neuropil related to