1992 — 1996 |
Swerdlow, Neal R |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Striato-Pallidal Substrates of Deficient Startle Gating @ University of California San Diego
Several disorders may be linked by deficient "gating" or suppression of intrusive thoughts and behaviors, and by dysfunction in neural circuitry linking the limbic system and basal ganglia. This proposal will use an animal model to define the brain substrates of deficient sensorimotor gating, focusing on interactions between the striatum and pallidum in rats and in patients with suspected striatal dysfunction. The overall aim of this proposal is to study the mechanisms that might contribute to deficient sensorimotor gating in Schizophrenia, Obsessive Compulsive Disorder (OCD) and Huntington's Disease (HD). Sensorimotor gating will be defined as the amount that a startle response to a loud noise is inhibited by a weak prestimulus. "Prepulse inhibition" (PPI) is studied in rats and humans with similar parameters and dependent measures. Schizophrenic patients exhibit less PPI of eyeblink startle than do normal controls. In rats, PPI of whole body startle is decreased by drugs that stimulate dopamine (DA) receptors in the nucleus accumbens (NAC) and anteromedial striatum. Preliminary work suggests that the substrates for these deficits include interactions between the hippocampus, striatum and pallidum. First, I propose to study the pharmacology and anatomy of the striatal DAergic control of PPI in rats. In these studies, systemic and intra-striatal injections of selective D1 and D2 agonists and antagonists will be administered to study the role of these DA receptor subtypes in the control of PPI, and 6-hydroxydopamine lesions of presynaptic DA neurons will be used to assess the role of presynaptic DA autoreceptors in the reduction of PPI after intra-striatal DA infusion. Next. I propose to measure PPI in rats after cell-specific ibotenic acid lesions of the NAC, the anterior striatum or the posterior striatum. I will study the role of the pallidum in any striatal lesion-induced loss of PPI, using infusions of muscimol, picrotoxin and GABA into the ventral pallidum or the ventromedial or dorsolateral globus pallidus. To test the validity of this model and its relevance to gating substrates in humans, PPI will be measured in patients with HD, whose degenerative loss of the striato- pallidal GABAergic projection lay lead to deficient motor gating. Finally, PPI will be measured in patients with OCD, to assess whether impaired gating of intrusive thoughts and obsessions is accompanied by deficient PPI, and if so, whether PPI deficits in these patients suggest dysfunction in basal ganglia circuitry. This strategy may identify substrates in limbic system and basal ganglia circuitry where pharmacologic intervention will facilitate the suppression of intrusive thoughts and behaviors in several disorders.
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1 |
1996 — 1997 |
Swerdlow, Neal R |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Sex Differences in Sensorimotor Modulation @ University of California San Diego
DESCRIPTION (Adapted from applicant's abstract): This grant proposes studies of the characteristics and neuroendocrine control of sex differences in sensorimotor modulation of the startle reflex. Sensorimotor modulation is the process by which central inhibitory and facilitatory mechanisms adjust an organism's responsivity to sensory stimuli. This modulation is viewed as protective of some forms of information processing PPI is the normal inhibition of the startle reflex that occurs when the startling stimulus is preceded 30-500 msec by a weak prepulse. At shorter intervals (4-30 msec), very weak prepulses facilitate startle (PPF). The degree to which the weak prepulse inhibits or facilitates the motor response to the starting stimulus is an operational measure of sensorimotor modulation. The startle reflex and its modulation by prepulses have been studied for over 50 years. In an unexpected finding, robust sex differences in PPI and PPF were observed in normal subjects. Women exhibit significantly less PPI than do men, and exhibit PPF at prepulse intervals that are too long to elicit PPF in men. This finding has now been replicated 6 times, in 2 laboratories. No overall sex differences were found in a related measure of visuospatial priming. However, preliminary work suggests that sensorimotor modulation of both startle and visuospatial priming varies across the menstrual cycle, with less inhibition and more facilitation in luteal versus follicular phases. PPI in women was maximal in early follicular phase, and reached its nadir in midluteal phase. PPF was found only in mid-luteal phase. Menstrual patterns were noted in the change in PPI in a single test session: PPI declined across each session in early follicular phase, but this pattern reversed by luteal phase, when PPI increased across each session. Visuospatial priming also exhibited a menstrual pattern, with greater visuospatial facilitation in luteal versus follicular phase. Other recent work suggests that sex differences in PPI are lateralized, evident primarily in right (but not left) eyeblink, in which PPI is regulated largely by the left forebrain. All preliminary work was designed to assess PPI, and thus the stimuli used did not allow a full assessment of PPF. Furthermore, limited resources for these unfunded studies precluded hormonal assays to verify menstrual cycle phase or ovulation. The present studies will fully assess sex and menstrual patterns of inhibition and facilitation of startle and visuospatial priming, using optimal paradigmatic designs and hormonal assays, and bilateral startle measures. PPI, PPF and visuospatial priming will be measured in men, and in women across the menstrual cycle, with documentation of luteal hormone (LH) surge. Neuropsychological measures with reported sex- and menstrual patterns will be assessed, in addition to specific psychometric measures, and results will be correlated with changes in PPI, PPF and visuospatial priming. Sex differences, menstrual cyclicity and laterality of sensorimotor modulation offer a unique opportunity to examine sexual dimorphism in fundamental neurobiological processes that are critical determinants of information processing, and which may be directly relevant to sex differences in the presentation and treatment of psychiatric disorders.
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1 |
1997 — 1999 |
Swerdlow, Neal R |
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. |
Cortico Striatal Substrates of Deficient Startle Gating @ University of California San Diego
DESCRIPTION (Adapted from applicant's abstract): This proposal examines how surgical and pharmacological manipulations of the hippocampus or medial prefrontal cortex (MPFC) in rats produce deficits in basic gating and habituation functions that have been linked to schizophrenia. Both prepulse inhibition (PPI) and habituation of startle responses have been used to demonstrate gating and habituation deficits in schizophrenia patients, and in rats with altered corticostriatal circuitry. The hippocampus and MPFC, via connections with the nucleus accumbens (NAC), appear to modulate startle inhibitory processes. Rats having hippocampal or MPFC lesions exhibit a supersensitive response to the PPI-disruptive effects of dopamine (DA) agonists. These inhibitory deficits will be studied to test hypotheses about neural circuitry that is implicated in the pathophysiology of schizophrenia. Specific Aim 1 will assess critical variables in the development of the "supersensitive" DA-mediated loss of sensorimotor gating produced by excitotoxin lesions of the hippocampus in rats. Studies will assess behavioral effects of receptor-specific agonists, lesions of hippocampal subregions, and the time-course of lesion effects on both PPI and DA receptor measures in the NAC. Aim 2 will identify the neural substrates of the "supersensitive" DA-mediated loss of PPI produced by hippocampal lesions by examining changes in PPI after infusions of DA receptor agonists into the NAC core and shell subregions. Aim 3 will determine the neural circuitry that mediates the reduction in PPI produced by glutamatergic stimulation of the hippocampal. Studies will examine the ability of manipulations of the NAC, or the hippocampal-accumbens projection, to reverse the PPI disruptive effects of intra-hippocampal infusion of N-methyl-D-Aspartate. Aim 4 will characterize the "supersensitive" DA-mediated loss of PPI after excitotoxin lesions of the MPFC, using studies similar to those of Specific Aim 1. Aim 5 will identify the specific neural substrates of the "supersensitive" DA-mediated loss of PPI produced by MPFC lesions in rats. Studies will examine MPFC lesion-induced changes in PPI after infusion of DA receptor agonists into the NAC core and shell. Aim 6 will identify the neural circuitry mediating deficits in PPI produced by reductions in DA function in the MPFC. Studies will test the ability of manipulations of the NAC or ventral tegmentum to reverse the PPI-disruptive effects of MPFC 6-OHDA lesions or intra-MPFC infusion of DA receptor antagonists. In total, these studies will systematically characterize cortico-striatal circuitry regulating critical inhibitory functions that are deficient in schizophrenia.
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1 |
1997 — 2006 |
Swerdlow, Neal R |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Neural Circuitry of Sensorimotor Gating Across Species @ University of California San Diego
DESCRIPTION (provided by applicant): This K02 proposal is for renewed career development support for Dr. Neal Swerdlow, to extend a period of intensive focus on his longstanding research goal: to increase our understanding of the substrates of specific mental disorders by elucidating the neural circuitry regulating aspects of behavioral plasticity in animals and humans. For over 20 years, the PI has studied functional and anatomical interactions in limbic cortico-striato-pallido-thalamic (CSPT) circuitry that regulate sensorimotor gating of the startle reflex. This proposal describes three exciting new lines of inquiry - two in laboratory animals and one in humans - that provide the focus for the next phase of his evolving career. These studies will enhance the convergence of animal and human studies of sensorimotor gating, and will thereby maximize the full power of this cross-species approach to neurobehavioral analysis. Ultimately, this work will help to delineate the functional connections within limbic CSPT circuitry and the genetic regulation of this circuitry, and will make substantive progress towards understanding the contributions of CSPT dysfunctions to the pathophysiology of certain neuropsychiatric disorders. In one line of inquiry, the PI will examine functional interactions between regions of limbic cortex and ventral striatum that regulate sensorimotor gating in rats. Prepulse inhibition (PPI) of acoustic startle will be measured in rats after surgical and pharmacological manipulations of the hippocampus, medial prefrontal cortex and nucleus acumens. These studies will test the hypothesis that changes in sensorimotor gating of the startle reflex after manipulations of the limbic cortex in rats reflect identifiable changes in dopaminergic and glutamatergic activity within the nucleus accumbens. A second line of inquiry will use strain differences in PPI sensitivity to understand the genetic regulation of CSPT circuitry in rats. A third line of inquiry will assess the dopaminergic regulation of PPI in normal humans. Bilateral eye blink startle and PPI will be measured after administration of several different dopaminergic agents, in dose-response and agonist-antagonist studies. This proposal will provide critical new information that will facilitate the design and interpretation of future studies of sensorimotor gating in psychiatric populations, and will help us to interpret sensorimotor gating abnormalities in psychiatric patients at the levels of their underlying neural and genetic substrates.
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1 |
1999 — 2013 |
Swerdlow, Neal R |
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. |
Dopaminergic Substrates of Startle Gating Across Species @ University of California San Diego
DESCRIPTION (provided by applicant): This application seeks renewed support for MH59803, Dopaminergic substrates of startle gating across species. For 20 years, systematic studies in rodents have identified specific neural substrates regulating prepulse inhibition (PPI) of startle. These limbic cortico-striatal-pallido-pontine (CSPP) substrates regulating PPI are relevant to several neuropsychiatric disorders, and are implicated in the reinforcing properties of drugs of abuse. One major challenge is to develop the capacity to probe and understand this PPI-regulatory circuitry in humans, and to identify genes that regulate its function and dysfunction. If neural circuit and genetic information, derived from animal studies, could be translated across species, PPI could become an important, new tool for understanding this biology in normal and neuropsychiatric disordered populations. MH59803 has identified areas of convergence and divergence in the effects of dopamine (DA) and glutamate manipulations on PPI and related measures in rats vs. normal human subjects. These studies also identified both rat and human phenotypes associated with distinct PPI-altering effects of several drugs, including the DA releaser, amphetamine (AMPH). The present proposal extends this translational approach to assess genes associated with PPI-reducing vs. increasing effects of AMPH in inbred rats and normal humans. The expression and its functional consequences of 5 specific genes in three brain regions that regulate PPI -- the nucleus accumbens, medial prefrontal cortex and ventral hippocampus -- will be assessed in inbred rat strains that exhibit PPI-reducing effects of AMPH (PreA) vs. PPI-increasing effects of AMPH (PieA). Analyses will focus on 5 genes based on their association with both PreA vs. PieA phenotypes in outbred rats and PPI phenotypes in 2 separate schizophrenia cohorts; their expression in these 3 brain regions will facilitate a functional circuit-based analyses of gene effects. Specific genes associated with PPI AMPH- sensitivity in rats, together with others associated with human phenotypes that moderate PPI AMPH sensitivity, will be interrogated as predictors of PPI AMPH effects in normal human subjects, based on their response to placebo vs. 20 mg p.o. AMPH in a double-blind, cross-over design. In total, these studies will leverage new information generated in the past funding period, to discover genetic and neurobiological substrates regulating sensorimotor gating across species. Strong inference would then link these substrates to causative factors in the loss of sensorimotor gating in schizophrenia and other disorders, and to therapeutic interventions to remedy these deficits and their associated functional consequences.
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1 |
1999 |
Swerdlow, Neal R |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Iii International Symposium On Tourette Syndrome @ Tourette Syndrome Association, Inc
DESCRIPTION: Since the time of the first NINDS-sponsored International Scientific Symposium on Tourette Syndrome (TS), clinicians and basic scientist alike have been challenged with the task of better defining TS and understanding the pathophysiology of this disorder. The overall purposes of both the First and Second International Scientific Symposia on TS were to stimulate new research and improve care for patients with this disorder, and, as such, both were tremendously successful. The investigator proposes, therefore, a Third International Symposium to specifically address the following topics: issues of rating scales and data concerning the natural course of TS, a review of recent studies of co-morbid conditions, neuropathological examinations of TS brain, review of comparison data of specific cognitive tasks with sensitive neuroimaging measures of brain activity, the pharmacotherapeutic interventions for TS, and examination of new research data concerning non-pharmacologic treatments for this disorder.
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0.913 |
2001 — 2010 |
Swerdlow, Neal R |
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. |
Cortico-Striatal Substrates of Deficient Startle Gating @ University of California San Diego
DESCRIPTION: The first three years of the project included studies to understand how experimental manipulations of the hippocampus or medial prefrontal cortex (MPFC) in rats produce deficits in basic gating and habituation functions that are linked to schizophrenia. Both prepulse inhibition (PPI) and habituation of startle responses have been used to demonstrate gating and habituation deficits in schizophrenia patients and in rats with altered cortico-striatal circuitry. The ventral hippocampus (VH) and MPFC appear to modulate startle inhibitory processes via connections with the nucleus accumbens (NAC). Rats with VH or MPFC lesions exhibit an enhanced sensitivity to the PPI-disruptive effects of dopamine (DA) agonists. This proposal seeks continued support to test specific hypotheses about neural circuitry that is implicated in the pathophysiology of schizophrenia, and to understand the role of this circuitry in schizophrenia-linked gating deficits. Aim 1 will assess the importance of VH lesions (excitotoxic and electrolytic) versus NAC de-efferentation in the development of the enhanced DA-mediated loss of sensorimotor gating, using septal undercuts to interrupt the rostral fornix. To enhance our understanding of the neurochemical basis for the effects VH lesions on PPI, studies will also assess changes in the PPI-disruptive effects of NMDA antagonists and 5HT agonists after VH lesions, and the PPI-restorative effects of antipsychotics. Aim 2 will assess the neural basis for VH lesion effects on PPI, by measuring changes in PPI after DA infusions into NAC subregions. Studies will also test the hypothesis that the effects of VH lesions on PPI are accompanied by changes in DAergic substrates in the MPFC or orbital cortex. Aim 3 will examine the ability of glutamatergic manipulations of the NAC, or transection of the VH-NAC projection, to reverse the PPI-disruptive effects of intra-VH infusion of NMDA. Aim 4 will assess the enhanced DA-mediated loss of PPI after cell or ablative lesions of the MPFC, across post-lesion intervals and via DA receptor subtype-specific agonists, and with measures of forebrain DA receptors. Aim 5 will examine MPFC lesion-induced changes in PPI after infusion of DA agonist into NAC subregions. Aim 6 will test the ability of manipulations of the NAC or ventral tegmentum to reverse the PPI-disruptive effects of MPFC 6-OHDA lesions or intra-MPFC infusion of DA antagonists. In total, these studies will systematically characterize cortico-striatal circuitry regulating critical inhibitory functions that are deficient in schizophrenia. Specific circuit mechanisms responsible for DA-mediated gating deficits after VH or MPFC lesions - revealed by these studies - will continue to be the basis for innovative models of the pathophysiology of schizophrenia and related disorders, and for prospective strategies for novel drug development.
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1 |
2003 — 2010 |
Swerdlow, Neal R |
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. |
Neural Basis of Heritable Da-Mediated Gating Deficits @ University of California San Diego
DESCRIPTION (provided by applicant): Abstract this proposal seeks 3 years of renewed support to determine the neural basis for heritable differences in the regulation of sensorimotor gating by dopamine (DA) activity in rats. Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is impaired in schizophrenia patients and other inherited neuropsychiatric disorders. The phenotype of deficient PPI in these disorders reflects abnormalities in brain mechanisms that regulate PPI. PPI is also impaired in rats by DA agonists e.g. apomorphine (APO) and amphetamine (AMPH) - and sensitivity to these effects appears to be genetically determined in rats, with robust and reliable innate differences across strains and substrains. Strain differences in the PPI-disruptive effects of DA agonists have large effect sizes even across common outbred strains - and reflect differences in CNS effects, and not in drug metabolism or distribution. Because the neurobiology of PPI is well understood in rats, it is possible to determine the neural basis for these inherited differences in the DA-regulation of PPI, and thereby to identify candidate substrates responsible for deficient PPI in neuropsychiatric disorders. Studies in PY 1-4 identified heritable components of PPI DA sensitivity in Sprague Dawley (SD) and Long Evans (LE) rats and their F1 and N2 progeny, building on past findings of strain differences in sensitivity to the PPI-disruptive effects of DA agonists. Studies determined that one neural basis for this phenotype is distal to DA release and D2 receptors in the nucleus accumbens core, but proximal to ventral pallidum (VP) GABA efflux, and is strongly associated with DA-stimulated G-protein activity. Studies proposed for the next 3 years will interrogate specific steps in the intracellular G-protein cAMP signaling pathway that might control heritable differences in DA agonist sensitivity in SD, LE and F1 rats. Dependent measures will include PPI as well as neurochemical (VP GABA efflux) and cellular (cFOS expression) markers of forebrain function. In total, studies will identify molecules that will be targets of strong inference for novel antipsychotic development. The potential contribution of these molecules to gating deficits in heritable brain disorders will be tested in new and existing animal models, and in ongoing studies of the genetic determinants of PPI deficits in schizophrenia. Ultimately, this project will identify neural, biochemical and genetic determinants of impaired sensorimotor gating in specific inherited brain disorders, at a level that will bring clarity to models of pathophysiology, and stimulate the development of new treatments. PUBLIC HEALTH RELEVANCE: Normal brain mechanisms suppress or "gate" the impact of irrelevant stimuli on sensory, cognitive and motor processes. In several inherited neuropsychiatric disorders, like schizophrenia and Toilette syndrome, a loss of these normally protective gating mechanisms leads to an intrusion of information that is experienced as unwanted and often distressing sensations, thoughts and movements. The main goal of this project is to use a well characterized animal model to identify the neural basis for an inherited vulnerability of these gating mechanisms, at a level that will reveal new targets for medications to restore gating and thereby reduce symptoms in neuropsychiatric disorders.
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1 |
2004 — 2007 |
Swerdlow, Neal R |
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. |
A Simple Measure For Studying Sensory Gating Deficits @ University of California San Diego
DESCRIPTION (provided by applicant): This 4 year project will develop, in a resource-efficient manner, a direct, stable, reliable and quantitative measure of sensory gating, and determine whether this measure detects gating deficits in clinical populations. Several disorders are characterized by symptoms that suggest the intrusion into consciousness of unwanted sensory information. Failures in the normal suppression ("gating") of sensory information are associated with cognitive disturbances in schizophrenia, and with sensory tics and premonitory urges in Tourette Syndrome (TS). The biological basis for deficient sensory gating has been studied by "surrogate" measures, in which a first stimulus inhibits (gates) the electrophysiological or motor response to a second stimulus (P50 gating, and prepulse inhibition of startle (PPI), respectively). These measures detect deficits in clinical populations, and are valuable in experimental models. Nonetheless, these surrogate measures do not directly assess the perceptual impact of deficient sensory gating as it is experienced by patients. In fact, little data supports the assumption that either P50 gating or PPI directly assess processes linked to an individual's perception of sensory information, or that deficits in these measures reflect dysfunction responsible for clinical symptoms. A measure that more directly assesses sensory gating, as it impacts perceptual experience, was first reported in 1939, and is termed "prepulse inhibition of perceived stimulus intensity" (PPIPSI). PPIPSI is assessed by a direct report of the perceived intensity of a stimulus, in the presence and absence of a prestimulus. Under appropriate conditions, subjects report that they perceive an intense abrupt stimulus - a 118 dB noise burst, a 40 psi air puff, or a 170 V cutaneous shock - to be less intense if it is preceded by a weak prepulse. PPIPSI has received little attention as a measure of sensory gating, compared to more complex, surrogate measures (P50 suppression and PPI). This application will establish important, new information about PPIPSI, that will allow its use in systematic studies of sensory gating in normal and disordered populations. Studies will assess important features of PPIPSI, including: 1) stimulus parameters that elicit a full range of gating effects; 2) test-retest stability; 3) reliability across experimental settings; 4) generalizability across sensory modalities; 5) its sensitivity in children; and 6) the impact of attentional manipulations. Finally, preliminary studies will assess the utility of this measure in detecting deficits in patients with schizophrenia or TS - disorders characterized by symptoms of deficient sensory and motor inhibition, and by deficits in PPI.
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1 |
2004 |
Swerdlow, Neal R |
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. |
Psychophysiological Correlates of Sensorimotor Function @ University of California San Diego
psychomotor function; psychophysiology; neural inhibition; neural information processing; sensorimotor system; sensory feedback; cognition; startle reaction; behavioral /social science research tag; human subject; clinical research;
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1 |
2005 — 2010 |
Swerdlow, Neal R |
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. |
Human Psychophysiological Correlates of Sensorimotor Functioning @ University of California San Diego
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We will use prepulse inhibition of the acoustic startle reflex as an operational measure of sensorimotor gating. We study the acoustic startle reflex, including prepulse inhibition (PPI) and prepulse facilitation of startle, in Psychiatric and Neurologic patients (Obsessive Compulsive Disorder, Huntington's Disease, Schizophrenia, Impulse Control Disorders, Tourette's Syndrome, and Attention Deficit Disorder), and in appropriate control comparison populations. .
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1 |
2005 — 2006 |
Swerdlow, Neal R |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Neuroscience At the Boundaries of Neurology and Psychiatry @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): [unreadable] This application responds to RFA #MH-05011, "Course Development in the Neurobiology of Disease," to seek support for the implementation of a course, "Neuroscience at the Boundaries of Psychiatry and Neurology" (NBPN). This course addresses the requirements of this RFA, providing an educational experience for graduate students that "will span a breadth of diseases and disorders affecting the nervous system, emphasizing links and common themes across diseases/disorders, and addressing both pathology of these diseases/disorders and their basic science underpinnings." NBPN is a 2-quarter (22-week) course that will educate future physician-scientists on the clinical and basic neurosciences of 11 brain disorders: Obsessive Compulsive Disorder, Tourette Syndrome, Stroke, Huntington's Disease, Substance Dependence, Autism, Schizophrenia, Seizure Disorders, Parkinson's Disease, Alzheimer's Disease and Neuropsychiatric manifestations of HIV-1/AIDS. Introductory didactic material will include lectures on diagnosis in Psychiatry and Neurology, and "core" topics including neuroanatomy, neurodevelopment, neuroimmunology, neuroimaging, electrophysiology, clinical trial design, drug development, and bioethics. Each disorder is covered in a 3- session unit, with an overview lecture, a patient interview session, and a presentation from an invited expert in a related area of "cutting edge" translational neuroscience research. The curriculum emphasizes phenomenological and mechanistic links and common biological themes across these disorders. The educational value of NBPN will be enhanced by the integration of resources from 6 existing training programs at UCSD (5 existing T32 programs (GM007198, AG000216, DC0041-13, MH020002, MH018399), and a sixth under review (UCSD Neurosciences Graduate Training Program)), a process that will also permit both administrative and fiscal efficiency. The Principal Investigator (PI) and Co-Investigator have assembled a team of world-class clinical and basic neuroscientists and educators, many of whom will also serve as an advisory group that will assist in the development, monitoring and evaluation of this teaching program. The contents of NBPN will be disseminated nationally via internet postings. In total, NBPN will achieve the goal of the NIH "blueprint", to educate young physician-scientists in areas of translational neuroscience research, to accelerate the process of translating basic science discoveries into clinical understanding and interventions. [unreadable] [unreadable]
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1 |
2009 — 2010 |
Swerdlow, Neal R |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Genetics of Individual Differences in Amphetamine Effects On Startle Gating @ University of California San Diego
DESCRIPTION (provided by applicant): This application responds to RFA-DA-09-016, "Behavioral Pharmacology and Genetics: Translating and Targeting Individual Differences," and describes studies that will determine the genetic basis for individual differences in the effects of amphetamine (AMPH) on sensorimotor gating in clinically normal subjects. The operational measure of sensorimotor gating in these studies is prepulse inhibition of startle (PPI): the ability of a weak sensory event (prepulse) to inhibit the motor reflex response to a startling noise pulse. For 20 years, systematic studies in rodents have identified specific neural substrates regulating PPI. These limbic cortico- striatal-pallido-pontine substrates regulating PPI are implicated in the hedonic properties of drugs of abuse. PPI is a quantitative endophenotype, showing strong heritability in humans and rodents. The PI has identified heritable strain differences in the effects of the stimulant, d-amphetamine (AMPH), on PPI in rats, and individual differences in the effects of AMPH on PPI in human cohorts distinguished by physiological (level of baseline PPI) and psychological (levels of novelty seeking and sensation seeking) phenotypes. Both the strain differences and human phenotypes are also linked to neural and genetic determinants of forebrain dopaminergic function implicated as a powerful moderator of addiction liability. The goal of this application is to identify genes associated with individual differences in the effects of AMPH on PPI in humans. Candidates of strong inference for association studies will be: 1) genes associated with PPI AMPH sensitivity in rodents, and 2) genes associated with personality dimensions that characterize individuals who differ in PPI AMPH sensitivity. Based on our published findings, approximately 400 single nucleotide polymorphisms (SNPs) will be examined, allowing the interrogation of 20 different genes. Through the use of this quantitative, laboratory-based endophenotype, this application will identify genes that regulate individual differences in physiological, molecular and psychological moderators of addiction. PUBLIC HEALTH RELEVANCE: The goal of this application is to identify genes associated with individual differences in the effects of the psychostimulant, amphetamine, on sensorimotor gating in humans. Efforts will focus on genes associated with amphetamine effects on sensorimotor gating in rodents, and on genes associated with personality dimensions that characterize individuals who differ in amphetamine gating sensitivity. Through the use of this approach, this application will identify genes that regulate individual differences in physiological, molecular and psychological moderators of addiction.
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1 |
2009 — 2021 |
Swerdlow, Neal R |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Psychiatric Research Residency Training Track @ University of California, San Diego
Abstract: In response to PAR-17-081, this application seeks renewed support for MH101072, to enable the UCSD Dept. of Psychiatry to sustain and expand a Research Resident Training Track (RRTT). UCSD has maintained a Psychiatry RRTT since 1987, primarily via internal funding. A newly designed RRTT was developed by the current Program Director and first received R25 support in 2013. Over the past 4 years, this RRTT has surpassed its goals in recruitment, training and career development of outstanding Residents, including trainees from traditionally under-represented groups. This renewal application builds on the strengths of the past 4 years and the scientific expertise of the UCSD faculty, and sustains an RRTT that is both substantive and innovative. MH101702 will achieve the goals of the NIMH Council report, ?Investing in the Future,? and of this FOA, by expanding the pool of Psychiatrist researchers - a crucial step towards improving treatment and outcome for mental disorders. Specifically, this application will achieve 2 Aims and one Exploratory Aim (E-1): Aim 1. To recruit and educate the highest caliber future psychiatric researchers. Trainees complete a 4-year RRTT (PGY I-IV); protected research time increases from 17% (PGY-II) to 40% (PGY-III) to 70% (PGY- IV). Rigorous didactics in PGY-III?IV weekly seminars prepare trainees to fulfill the NIMH strategic plan. Seminars provide a comprehensive grounding in the fundamentals of research design, data analysis, manuscript preparation, dissemination of findings, bioethics and the responsible conduct of research. Trainees acquire academic survival skills and receive careful supervision and personalized career mentorship. The ?core? curriculum, described in detail in this application, is designed to strengthen and sustain Psychiatry RRTT trainees' career connection with mental health research, and with the core missions of academic psychiatry. Aim 2. To increase the number of research psychiatrists from under-represented backgrounds. Diversity representation in our RRTT grew from 0% in the 10 years prior to this R25, to 44.4% in the current class. This renewal builds on this success with new URM faculty and advisers, an expanded Summer Fellow- ship program, and new efforts towards URM outreach made possible by recent successes in URM recruitment. Aim E-1. A ?pilot? integrated Adult / Child Psychiatry RRTT (3 trainees/5 y) will include Child Psychia- try-relevant PGY-II-IV research (17-40-70%) and didactics, and 30% dedicated PGY-V-VI research time. With 5 years of renewed R25 support, UCSD will admit 2 RRTT trainees/yr and graduate 10 trainees (6 current + 4 new). At the end of 5 years, 8 R25-funded trainees will still be in the ?pipeline,? distributed (2 per year) across PGYs-I?IV. These 8 trainees will complete their RRTT via renewed R25 or Departmental support, bringing the total yield of this R25 to 10+8 =18 RRTT trainees. UCSD will provide careful, individualized oversight of each trainee, in an innovative format that will accelerate their path towards fellowships, faculty positions and NIH research funding, and thereby achieve the goal of this NIMH Research Education Program.
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1 |
2011 — 2013 |
Swerdlow, Neal R |
R34Activity Code Description: To provide support for the initial development of a clinical trial or research project, including the establishment of the research team; the development of tools for data management and oversight of the research; the development of a trial design or experimental research designs and other essential elements of the study or project, such as the protocol, recruitment strategies, procedure manuals and collection of feasibility data. |
Biomarker Strategies For Medication-Enhanced Cognitive Training in Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): This R34 application responds to PAR-09-173, to achieve the first goal of this FOA by supporting: "the development and/or pilot testing of new or adapted interventions." The two overarching goals of this application are: 1) to test the effects of the acute administration of the NMDA antagonist, memantine (MEM), on sensorimotor gating and working memory (WM) in schizophrenia (SZ) patients, and 2) to assess the feasibility of using MEM to predictably enhance the therapeutic benefits of cognitive training in SZ. The pharmacotherapy of SZ has been dominated by antidopaminergic drugs with limited clinical impact. Some forms of psychosocial rehabilitation, such as cognitive training (CT), appear to effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CT in SZ might be enhanced by drugs that increase specific cognitive abilities, including WM, even if these pro-cognitive drugs lack clinical impact when administered without CT. The main goal of this application is to develop an innovative intervention strategy that enhances the clinical benefits of CT in SZ through administration of a pro-cognitive agent to biomarker-identified sensitive patients. We reported that a single dose of the widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of the startle reflex in healthy subjects. PPI-enhancing effects of MEM in healthy subjects are associated with: 1) increased WM;and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is consistently impaired in SZ patients;lowest levels of PPI in patients are associated with: 1) poor functional outcome;and 2) the Val/Val COMT genotype. If our MEM findings in healthy subjects are reproduced in SZ patients, we will detect MEM-associated improvements in PPI and WM, particularly among Val/Val patients. We will then be positioned to test the hypothesis that acute PPI and WM- enhancing effects of MEM predict therapeutic benefit of MEM in SZ patients undergoing CT. This application has two aims: Aim 1 will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 60 SZ patients, to test the prediction that MEM will increase PPI and enhance WM in SZ patients, particularly in those characterized by low basal PPI levels and/or the Val/Val COMT genotype. Mismatch negativity and gamma band synchronization will also be assessed as potentially informative MEM-sensitive and functionally relevant biomarkers. Aim 2 will assess the feasibility of testing the therapeutic benefit of MEM as an adjunct to CT in SZ patients, and the feasibility of testing the primary hypothesis that such benefit will be predicted by increased PPI and/or WM in SZ patients after the Aim 1 single dose MEM challenge. It is predicted that subject recruitment and completion in both arms of a controlled 12-week CT trial in SZ out- patients among subjects completing Aim 1 will be appropriate for testing both the overall effectiveness of MEM as an adjunct to CT and the ability to predict this effectiveness among biomarker-identified patient subgroups. PUBLIC HEALTH RELEVANCE: Cognitive training is moderately effective at reducing symptoms and improving life function in schizophrenia patients. The present application develops a strategy for increasing the effectiveness of cognitive training through the use of pro-cognitive medications. Specific biomarkers will be studied that identify patients most sensitive to these pro-cognitive medications, to test the feasibility of using these biomarkers in a large clinical trial of medication-enhanced cognitive training in schizophrenia.
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2012 — 2020 |
Swerdlow, Neal R |
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. |
Memantine Effects On Sensorimotor Gating and Neurocognition in Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): This R01 will establish the biological basis for a novel treatment strategy for schizophrenia (SZ), by identifying biomarkers that predict pro-cognitive drug effects in SZ patients. These pro-cognitive effects would be utilized to specifically enhance the clinical impact of cognitive therapies (CTs) for SZ; similar strategies are being effectively advanced for the treatment of anxiety disorders. This application will test the effects of a challenge dose of the low-affinity NMDA antagonist, memantine (MEM), on sensorimotor gating and neuro- cognition in SZ patients; specific hypotheses will be tested in relation to the moderating impact of physiological and genetic biomarkers on these MEM effects. Predictors of positive effects of MEM will be used to identify enriched MEM-sensitive SZ patient cohorts for trials using MEM to augment the therapeutic effects of CTs. The pharmacotherapy of SZ has been dominated by drugs with limited clinical impact. Some forms of CTs, including the broader formats of cognitive rehabilitation and cognitive training, effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CTs in SZ might be enhanced by drugs that increase specific cognitive abilities, including working memory (WM), even if these pro-cognitive drugs lack clinical impact when administered without CT. The main goal of this application is to develop an innovative intervention strategy that enhances the clinical benefits of CT in SZ through administration of pro-cognitive agents to biomarker-identified sensitive patients. We recently reported that a single dose of the safe, neuroprotective, widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of startle in healthy subjects. These PPI-enhancing effects of MEM are associated with: 1) increased WM; and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is impaired in SZ patients; lowest levels of PPI in patients are associated with: 1) poor functional outcome; and 2) the Val/Val COMT genotype. If our MEM findings in healthy subjects are reproduced in SZ patients, we will detect MEM-associated increases in PPI and WM, particularly among Val/Val patients. We will then be positioned to test the hypothesis that acute PPI and WM-enhancing effects of MEM predict therapeutic benefit of MEM in SZ patients undergoing CT. This application will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 80 SZ patients and 80 healthy subjects, to test the prediction that MEM will increase PPI and enhance WM in SZ patients, particularly in those characterized by low basal PPI levels and/or the Val/Val COMT genotype. Mismatch negativity and gamma band synchronization will also be assessed as potentially informative MEM-sensitive and functionally relevant biomarkers. Findings from this study will guide future clinical trials testing the overall effectiveness of MEM as an adjunct to CT by identifying biomarker-defined patients most likely to benefit from this therapeutic regimen; the feasibility of such trials is now being tested by the PI's R34 MH093453. PUBLIC HEALTH RELEVANCE: Cognitive therapies are moderately effective at reducing symptoms and improving life function in schizophrenia patients. The present application aims to develop a strategy for increasing the effectiveness of cognitive therapies in schizophrenia through the use of pro-cognitive medications. Specific biomarkers will be studied that identify patients most sensitive to these pro-cognitive medications, based on suggestive findings in healthy controls, with the future aim of using these biomarkers in a large clinical trial of medication-enhanced cognitive interventions in schizophrenia.
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2014 — 2018 |
Swerdlow, Neal R |
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. |
Pharmacologic Augmentation of Neurocognition and Cognitive Training in Psychosis @ University of California San Diego
DESCRIPTION (provided by applicant): This application proposes the first test of a novel therapeutic model, in which a pro-cognitive agent augments the impact of a cognitive therapy for schizophrenia (SZ). Pharmacologic Augmentation of Cognitive Therapy (PACT) for SZ, first proposed by the PI in 2010 and first tested in this application, funda- mentally challenges existing approaches to enhancing function in SZ patients, both in theory and practice. To date, MH59803 has investigated the neural regulation of laboratory-based measures of deficient information processing in SZ patients, using preclinical rodent and healthy human models to explicate the biology of these deficits, and to establish a rational basis for developing novel therapies for SZ. MH59803 studies of the neural regulation of prepulse inhibition (PPI) of startle in rats initially probed basic anatomical, neurochemical and molecular mechanisms. These studies then moved from bench-to-bedside, focusing on dopamine (DA) agonist effects on PPI and neurocognition in healthy human subjects (HS), and their regulation by genes identified in cross-species studies. In the process, MH59803 detected biomarkers that predict PPI- enhancing and pro-cognitive effects of the DA releaser, amphetamine (AMPH). These findings have led to specific predictions of AMPH effects on PPI and neurocognition in antipsychotic (AP)-medicated SZ patients that, if confirmed in the present application, could help transform therapeutic approaches to SZ. This renewal application reflects a logical progression of studies at systems and molecular levels, translated next to HS, and now to experimental models in SZ patients. The path of bench-to-bedside progress in MH59803 has helped generate a critical paradigm shift in therapeutic models for SZ, which will directly address the need for more effective treatments for this devastating disorder. In Aim 1, the effects of AMPH (placebo (PBO) vs. 10, or PBO vs. 20 mg, p.o.) will be tested on PPI, neurocognition (assessed with the MATRICS Consensus Cognitive Battery (MCCB)) and computerized Targeted Cognitive Training (TCT) performance in 120 AP-treated SZ patients and 40 HS, in a double-blind, randomized, PBO-controlled cross-over design. Moderating roles on AMPH effects will be assessed for both behavioral (low baseline performance) and genetic (single nucleotide polymorphisms for catechol-O-methyl- transferase (COMT)) biomarkers. In Aim 2, parallel animal model studies will inform Aim 1 results in AP- medicated SZ patients by testing the effects of systemic APs and D1 antagonism on: 1) AMPH-potentiated PPI, and 2) AMPH effects on new cross-species paradigms assessing MCCB-like measures of a 5-choice continuous performance task and a TCT-like sensory discrimination task in rats. In total, Aim 1 findings will generate strong, testable predictions about the ability of AMPH to safely enhance the benefits of cognitive therapies in biomarker-identified SZ patients; Aim 2 will establish informative animal models to explicate the neural basis of Aim 1 findings, setting the stage for future advances in this novel approach to SZ therapeutics.
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2018 — 2021 |
Swerdlow, Neal R |
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. |
Biomarker Predictors of Memantine Sensitivity in Patients With Alzheimer's Disease @ University of California, San Diego
Abstract This application responds to PAR-16-365: ?Pilot Clinical Trials for the Spectrum of Alzheimer's Disease ...?, and its calls for ?Studies to define and refine the target population? and ?address heterogeneity of response? identification of specific individuals? more [vs.] less likely to benefit from the intervention(s).? Alzheimer's Disease (AD) is a severe neurodegenerative brain disorder, with limited therapeutic options. The NMDA receptor antagonist, memantine (MEM) is approved for treatment of moderate-to-severe AD; its mechanisms are not well understood, but may include a blunting of glutamate-mediated neurotoxicity. While meta-analyses confirm MEM's effectiveness in delaying the progression of cognitive and behavioral disturbances in AD, the clinical response to MEM is modest, short-lived and highly heterogeneous, with many AD patients showing no gains even with an extended MEM trial. The utility of MEM in AD might be greatly enhanced if patients could be identified as ?MEM-sensitive? vs. ?MEM-insensitive? in advance of a therapeutic trial, using a predictive biomarker. For the past decade, the PI has studied the acute neurophysiological effects of MEM in laboratory animals, healthy human subjects (HS) and schizophrenia (SZ) patients. These studies demonstrated that a single ?challenge dose? of MEM (20 mg) significantly enhanced specific laboratory measures of early auditory information processing (EAIP) in HS and SZ patients: prepulse inhibition (PPI), mismatch negativity (MMN) and gamma band auditory steady-state response (ASSR; including gamma power and synchronization). This application will determine whether the EAIP response to an acute MEM-challenge can be used to predict a positive therapeutic response to MEM in patients with mild-to-moderate AD, over a 24 week trial. Aim 1 tests the hypothesis (H1) that a single dose of MEM (20 mg vs. placebo (PBO)) will significantly enhance EAIP measures in patients with mild-to-moderate severity AD (n=88). Assessed across the full cohort of patients, PPI, MMN and ASSR should be significantly greater after MEM vs. PBO. However, the magnitude of this ?MEM effect? (MEM minus PBO) will vary across measures and patients. Aim 2 will leverage this response heterogeneity to test the hypothesis (H2) that patients exhibiting a larger ?MEM effect? on EAIP will experience a significantly greater clinical response to MEM, compared to patients with a smaller ?MEM effect? on EAIP. After Aim 1 testing, MEM treatment will be initiated and titrated to 10 mg bid in all patients. Clinical outcome measures will be assessed at baseline, 8, 16 and 24 weeks. Analyses will determine whether MEM effects on EAIP measures (individually, and in composite scores) predict the magnitude of the clinical response to MEM in these patients. Moderating factors will be tested, including specific single nucleotide polymorphisms known to moderate MEM sensitivity. This application leverages a unique set of empirical laboratory findings with MEM to develop a novel biomarker predicting sensitivity to MEM's therapeutic impact in patients with AD.
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2020 — 2021 |
Swerdlow, Neal R |
R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
Pharmacologic Augmentation of Targeted Cognitive Training in Schizophrenia @ University of California, San Diego
In response to RFA-MH-18-705, this application develops a novel treatment strategy for chronic psychotic disorders, via Pharmacologic Augmentation of Cognitive Therapies (PACTs), and thereby directly addresses a critical need for more effective treatments for these devastating brain disorders. Despite 60 years as the major therapeutic tool for chronic psychotic disorders, including schizophrenia, antipsychotics may not significantly alter the course or real-life functional impact of these disorders. Modest clinical benefits in these patients can be achieved via specific cognitive therapies (CTs), including ?bottom-up? sensory-based targeted cognitive training (TCT), but such treatments are time- and resource-intensive, and responses are incomplete and variable. This application seeks a practical way to augment the benefits of TCT in schizophrenia patients. We hypothesize that specific pro-cognitive agents will augment the clinical gains from TCT in schizophrenia patients, and that this PACT approach will be particularly effective in biomarker-defined subgroups of patients. Preliminary support for this hypothesis comes from the PI's studies (MH59803): in antipsychotic-medicated schizophrenia patients, the pro-attention drug, d-amphetamine, significantly enhanced learning in an auditory discrimination task (Posit Science ?Sound Sweeps?). ?Sound Sweeps? is a key component of a TCT program known to produce clinical gains in schizophrenia patients. Amphetamine- enhanced gains in auditory processing speed (APS) learning in schizophrenia patients were associated with baseline (pre-drug) levels of specific neurophysiological biomarkers. Dose-response and time course studies identified optimal amphetamine dose (5 mg po) and time (1 h pre-TCT) for maximal pro-learning effects. Consistent with a large literature, amphetamine was safe and well tolerated in this patient population. This application conducts a careful assessment of this PACT strategy for schizophrenia in 3 Aims: Aim 1) Confirmation of target engagement: 54 well-characterized schizophrenia patients will be tested to confirm that amphetamine (5 mg po) enhances APS learning; Aim 2) Efficient pilot testing: Subjects from Aim 1 are randomized into 2 treatment arms (n=27/arm) for a double-blind PBO-controlled 30-session clinical trial of amphetamine+TCT vs. PBO+TCT, to determine whether amphetamine augments the magnitude, rate and/or durability of TCT-induced gains, and whether these gains are associated with target engagement, using specific Go/No-Go criteria and outcome measures of symptoms, neurocognition and real-life function; Aim 3) Identify biomarker predictors of the PACT response, based on neurocognitive, electrophysiological, psychophysiological and performance-based measures assessed pre- and post-TCT. This is a highly novel, high-risk high-reward application to develop a novel treatment paradigm and thereby relieve suffering in patients with chronic psychotic disorders.
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