1987 — 1991 |
Hoffman, William F |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Drug-Induced Movement Disorders in Schizophrenia @ Oregon Health and Science University
Neuroleptic drugs are crucial elements in the treatment of schizophrenia and other psychoses. Unfortunately, they have several undesirable acute and chronic side effects which limit their effectiveness. Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are common extrapyramidal syndromes (EPS) encountered in chronically neuroleptic treated populations. Both syndromes occur with greater frequency in older persons and may reach prevalances of 50% in this high risk group. Measures of brain dysfunction ("organicity") have been investigated both as risk factors for and correlates of TD and, to a much lesser extent, DIP. There is some evidence of a relationship between cognitive dysfunction and TD, although the data are neither consistent nor conclusive. Other measures of brain structure and function have been even less informative about cerebral correlates of EPS. Neuroleptic and antiparkinson drug treatment may obscure the relationship of TD to other measures of brain function. Usually, neuroleptics suppress TD while antiparkinson agents enhance it. Opposite effects occur for DIP. The effects of concurrent drug treatment on apparent EPS-brain relationships is unknown. The proposed studies will examine the effects of neuroleptic and anticholinergic drug withdrawal on TD, DIP, and measures of brain structure and function. One-hundred-sixty chronic schizophrenics over age 45 will be randomly assigned to equal sized groups who will subsequently be withdrawn from 1) neuroleptics, 2) anticholinergics, 3) both, or 4) neither (control). A baseline CT scan of the brain will be obtained. Neuropsychological function, positive and negative symptoms of schizophrenia, and severity of TD and DIP will be assessed both at baseline and after three weeks drug free. Analysis of group differences before and after withdrawal will provide information critical to the understanding of how current treatment influences the apparent relationship between TD, DIP, and other indicators of brain function. Important issues include: 1) Nature and extent of neuroleptic and anticholinergic influence on the expression of TD and DIP; 2) Nature of specific neuropsychological deficits associated with the movement disorders; 3) Influence of brain atrophy on TD and DIP and its interaction with drug treatment; and 4) Influence of medication or the association of specific patterns of psychiatric symptoms with EPS.
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1994 — 1999 |
Hoffman, William F |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hyperkinesia in Chronic Neuroleptic Naive Schizophrenics @ Oregon Health and Science University
This proposal addresses critical long-standing questions regarding the nature and origin of choreoathetoid movement disorders in schizophrenia by comparing a group of Moroccan schizophrenics who have a long duration of illness but who have never received neuroleptic medication (NM), to matched groups of chronically-medicated (CM) schizophrenics and non- patient controls (NC). (1) Do choreoathetoid movements in schizophrenia appear as a function of the disease process? (2) Do these movement appear as a function of age or duration of illness? (3) Does the appearance of choreoathetoid movements prior to treatment with neuroleptic medications indicate a vulnerability to subsequent development of neuroleptic-induced tardive dyskinesia (TD)? (4) Do schizophrenics who experience long- duration untreated illness show increased cognitive deficits in comparison to patients who have received treatment early in the course of illness? (5) Do schizophrenics who experience long-duration untreated illness show decreased regional brain volumes in comparison to patients who have received treatment early in the course of illness? This study is a unique opportunity to examine a rare population of 100 to 1509 never-medicated DSM-III R schizophrenics as they present for treatment at the Psychiatric Center in Casablanca, Morocco. Prior to treatment, patients will be examined for the presence of choreoathetoid and Parkinsonian movements, and will be given a battery of neuropsychological tests to assess current cognitive functioning. After stabilization on neuroleptic medication, patients will be reexamined for both movements and cognitive function. Patients will also undergo similar reexaminations at one- and two-year intervals. Both Moroccan and U.S. groups will be examined to control for cultural and socioeconomic influences on outcomes. The same battery of examinations given to the never-medicated schizophrenics will also be given to matched comparison groups of chronically-medicated inpatient schizophrenics, recruited form the inpatient wards at the Casablanca Center, the Portland VAMC, and OHSU. Base rates of spontaneous dyskinesias will estimated by applying the same examination to community normal control groups in Casablanca and Portland. All groups will also receive CT scans for volumetric quantification of brain regions. The data will be analyzed by ANOVA, and repeated-measures ANOVA and MANOVA for follow-up data. Planned comparisons showing CM> NM> NC for movement scores will confirm the main hypotheses. Comparisons for cognitive functioning and volumetric analysis are expected to yield NM < CM < NC. Cognitive functioning for NM patients is expected to improve after medication and stabilize below CM levels. The presence of movements in NM patients is expected to predict a vulnerability for subsequent TD.
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2009 — 2010 |
Hoffman, William F |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Cerebral Correlates of Impulsivity in Methamphetamine Addiction @ Oregon Health &Science University
Although methamphetamine has long been endemic to the Portland, Oregon region, its use has reached epidemic proportions nationally. Several studies have reported poor retention of stimulant abusors entering treatment, consistent with the 50% rate of our outpatient clinic. Unfortunately, there is no clinically approved medication to alleviate the severe aversive symptoms that accompany early abstinence from methamphetamine. Recent studies in cocaine abusers entering community day hospital treatment have shown that the beta antagonist propranolol decreases these aversive symptoms while increasing retention and abstinence rates. Hospitalized methamphetamine abusers entering outpatient treatment upon discharge, have comparable or greater amounts of aversive symptomatology. Preclinical stress induced reinstatement studies (in animals whose prior self administration is extinguished pior to stress) hypothesize that beta blockers protect against stress induced relapse. The purpose of the current grant is translational research testing this preclinical hypothesis as well as extending its application from cocaine to methamphetamine in two eighty patient double blind inpatient initiated eight week outpatient trials. Since the preclinical studies model relapse in abstinent patients all patients will be enrolled immediately after a recent hospitalization. Clinical Trial I will evaluate carvedilol, a beta antagonist with additional neuroprotective properties and alpha antagonist properties (believed to be safer in those patients who relapse to methamphetamine while on study medication). In Clinical Trial II, the goal will be translational research based on findings from Years 1-2 utilizing a cholinergic medication identified by Scientific Component 1. In addition, patients will undergo, after four weeks of study medication, a human laboratory evaluation of stressor responsivity. It has been hypothesized that increased stress responsivity is a long term neuroadaptation to drug abuse that may permanently increase the risk of stress-induced relapse.
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2011 — 2012 |
Hoffman, William Franklin |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Neural Phenotypes of Impulsive Choice in Recovery From Alcohol Dependence @ Oregon Health &Science University
DESCRIPTION (provided by applicant): The project has two Specific Aims: SA1. a) Quantify and characterize the parametric variation of cerebral response to delay, probability, and reward magnitude during decision making in AD vs Controls. b) Quantify disruptions of cerebral connectivity as a correlate of increased impulsivity in AD. SA2. Determine the extent to which relapse can be predicted by phenotypic variation in the neural substrates of behavioral impulsivity. METHODS: Eighty recently abstinent AD subjects will be recruited from local residential treatment programs. Forty control subjects will be recruited from the general public and non alcohol dependent friends of the patients. Subjects will be followed for 3 months after their initial sobriety date. They will be evaluated monthly with computerized and questionnaire measures of impulsivity. Patients will keep a drinking diary to allow capture of all elements of relapse during the study period. They will undergo a functional and anatomical MRI evaluation at the initial visit to quantify the neural response to cardinal elements of impulsive choice and to assess the extent of functional and anatomical changes in cerebral connectivity. A statistical model will relate information from brain imaging to the likelihood of relapse. RELEVANCE: The neural profiles defined in this study will improve understanding of the cardinal elements of discounting behavior as a predictor of relapse in AD. Quantitative profiles of mechanisms of choice in AD individuals will provide valuable information for the tailoring of individual treatment regimens. This will directly impact future treatment approaches not only in alcoholism but also for substance abuse and addictive behaviors in general. This knowledge will allow funding for substance abuse treatment programs to be used more effectively. PUBLIC HEALTH RELEVANCE: Alcoholism is a widespread problem that crosses socioeconomic boundaries and is the cause of substantial medical morbidity and economic burden. This project uses functional magnetic resonance imaging to measure individual phenotypic differences in impulsive decision making and relate the cardinal elements of these phenotypic profiles to the likelihood of short-term recovery from alcohol dependence. We predict that development of quantifiable neural profiles will provide valuable information for the tailoring of individual treatment regimens;a deepened understanding of the relationship of brain function to the clinical course of recovery from alcohol dependence has implications for treatment of other addictions and neuropsychiatric disorders.
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2012 — 2016 |
Hoffman, William F |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Mechanism of Impulsive Choice @ Oregon Health & Science University
Specific Aim 1: Quantify and characterize the parametric variation of cerebral response to delay, probability, and reward magnitude during decision making in MA dependent individuals vs Controls. Specific Aim 2: Quantify disruptions in cerebral connectivity as a factor underlying increased impulsivity in MA using functional correlation, diffusion-tensor imaging (DTI) and voxel based morphometry (VBM). Specific Aim 3: Investigate, in humans and rodents, the hypothesis that neuroimmune disruption of network connectivity contributes to impulsive choice in methamphetamine dependence METHODS: Forty-five actively using methamphetamine (MA) dependent individuals, 45 MA dependent patients in early (1 to 6 months) remission and 45 controls will be recruited from local residential treatment programs and by advertisement. Subjects will be evaluated with functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI) and voxel based morphometry (VBM) in order to identify the anatomical and functional networks that underlie impulsive choice. Component 9 will expose mice from two lines selected for high and low MA drinking (Component 9), to chronic MA administration, chronic administration followed by abstinence and saline vehicle (total of 120 mice) and then train them to perform an animal version of the delay discounting task. Component 9 will provide brains of these mice to this component for ex-vivo MRI scanning. We will perform parallel analyses in mouse and human brains. Measures of immune dysregulation and differential gene expression (from Component 8) will be investigated as factors responsible for disruption of decision networks in humans and in animals performing impulsivity tasks.
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2019 — 2020 |
Hoffman, William Franklin |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Effect of Genotype On Resting State Connectivity During Methamphetamine Administration @ Oregon Health & Science University
Project Summary Methamphetamine dependence is a widespread problem that crosses socioeconomic boundaries and causes substantial medical morbidity and economic burden. This project uses genetics and neuroimaging techniques to investigate the neurobiology of addiction to methamphetamine as it relates to the TAAR1 trace amine receptor. We hypothesize that individuals with a common TAAR1 genetic variant (v288v) will have a blunted response to methamphetamine on tests of attention and cognitive control as well as on striato-limbic resting state functional connectivity (RSFC). SA 1. Determine the influence of htaar1 common variant (CV) vs. wild type (WT) genotype on RSFC and craving in chronic MUD. SA 2: Determine the effect of acute oral MA or placebo (PBO) administration on the interaction of htaar1 CV vs. WT genotype on RSFC, craving, cognitive control, attention and subjective experience in MUD. This project will consent and enroll up to 100 subjects who will be screened for TAAR1 genotype and placed into one of two groups: one which will include subjects who are wild type (WT) for the TAAR1 gene and those who are either homozygous or heterozygous for the CV, v288v. Others will be screened out of the study. A partner lab will determine genotype so that study staff and subjects will be blinded to genotype. Subjects will be administered methamphetamine and placebo in a blinded, randomized manner over two visits and evaluated with resting state fMRI, subjective effects and behavioral tasks. RSFC comparisons of meth versus placebo and comparisons of WT versus CV groups will be evaluated.
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