Hippocampal Memory Circuits in Delusions

Study Overview
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Brief Summary
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This study will investigate dentate gyrus (DG) and hippocampal CA3 sub field function, using the pattern separation paradigm, as reflected by the difference in brain activation in response to same-as-previously- seen (OLD) vs. similar-to-previously-seen (SIM) objects in first episode psychosis (FEP) subjects before and after anti psychotic treatment and in matched healthy controls (HC). The current study uses three novel high-resolution task-based and post-encoding resting fMRI measures to probe hippocampal circuitry in delusions. It will also study CA1 function, using a sequential associative mismatch paradigm, as reflected by activation of CA1 in response to mismatching information compared to memory of that stimulus in FEP subjects before and after antipsychotic treatment and in matched HC. Finally, this study will evaluate plasticity of hippocampal intrinsic functional connectivity (IFC) in response to memory consolidation, using an encoding-plasticity paradigm, in FEP subjects before and after anti psychotic treatment and in matched HC. For each of the three imaging projects, a total of 50 FEP subjects and 50 matched healthy controls (HC) will be studied; hence, 300 subjects will be studied over 5 years. Within each paradigm, medication-naive FEP subjects will be studied at baseline and 8 weeks after starting anti psychotic medication. HC participants will be studied at baseline and 8 weeks later but will not receive any treatment.

Official Title
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Hippocampal Memory Circuits in Delusions

Conditions
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Psychosis

Intervention / Treatment
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* Diagnostic Test: Pattern Separation Paradigm
* Diagnostic Test: Sequential Associative Mismatch Paradigm
* Diagnostic Test: Encoding Plasticity Paradigm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females 16 to 35 years of age, inclusive, at the time of informed consent Right-handed Must have experienced a first episode of non-affective psychosis over the past five years Must exhibit a persistence of delusions for at least 4 days per week for at least 4 weeks in the absence of psychotomimetic substance use or other potential organic etiologies, including epilepsy or significant head trauma. Must score at least a 2 (mild to moderate) on the Amount of preoccupation with delusions and Conviction items on the Psychotic Symptom Rating Scale (PSYRATS). Exclusion Criteria: Diagnosis of major mood disorder or other Axis I disorder other than Schizophrenia, Schizoaffective Disorder or Schizophreniform Disorder. Significant medical or neurological illness by history or physical exam including seizure disorder, history of loss of consciousness related to head trauma or developmental disorder including mental retardation. Metal implants, pacemaker, or other metal in the body or medicinal patch. History of claustrophobia. Currently taking any anti psychotic medication (within 4 weeks).

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Controls<br>Matched Healthy Controls | Diagnostic Test: Pattern Separation Paradigm<br>* Will be used to investigate dentate gyrus (DG) and hippocampal CA3 subfield as reflected by the difference in brain activation in response to same as previously seen (OLD) vs similar to previously seen (SIM) objects in first episode (FEP) subjects before and after treatment.<br>Diagnostic Test: Sequential Associative Mismatch Paradigm<br>* used to reflect activation of CA1 in response to mismatching information compared to memory of the stimulus in FEP subjects before and after antipsychotic treatment and in matched Healthy Control (HC).<br>Diagnostic Test: Encoding Plasticity Paradigm<br>* Used to evaluate plasticity of hippocampal Intrinsic Functional Connectivity (IFC) in response to memory consolidation in FEP subjects before and after antipsychotic treatment and in matched HC.<br>|
| Firt Episode Psychosis (FEP)<br>subjects before and after antipsychotic treatment | Diagnostic Test: Pattern Separation Paradigm<br>* Will be used to investigate dentate gyrus (DG) and hippocampal CA3 subfield as reflected by the difference in brain activation in response to same as previously seen (OLD) vs similar to previously seen (SIM) objects in first episode (FEP) subjects before and after treatment.<br>Diagnostic Test: Sequential Associative Mismatch Paradigm<br>* used to reflect activation of CA1 in response to mismatching information compared to memory of the stimulus in FEP subjects before and after antipsychotic treatment and in matched Healthy Control (HC).<br>Diagnostic Test: Encoding Plasticity Paradigm<br>* Used to evaluate plasticity of hippocampal Intrinsic Functional Connectivity (IFC) in response to memory consolidation in FEP subjects before and after antipsychotic treatment and in matched HC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference in CA1 activation between a mismatch and an intact trial in FEP subjects after 8 weeks of antipsychotic treatment and the correlation of this change with change in delusions as measured by the Psyrats-D total score. |  | 8 Weeks | 
| Change in hippocampus-to-VTA (hip-VTA) IFC and hip-to-lateral occipital complex (hip-LO) IFC, from pre- to post- encoding during the encoding-plasticity paradigm, between FEP and HC. |  | 8 Weeks | 
| Change in (a) hip-VTA IFC and (b) hip-LO IFC, from pre- to post- encoding during the encoding-plasticity paradigm |  | 8 Weeks | 
| correlation of change (a) hip-VTA IFC and (b) hip-LO IFC with change in delusional severity measured by the Psyrats-D total score. |  | 8 Weeks |