Wednesday, January 15, 2025 1/15/2025

Targeting Inflammation-Induced Changes in Brain Reward Signaling and Motivational Deficits in Patients with Schizophrenia Using an Anti-Inflammatory Challenge

Award Number: R01MH131910
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The CNS mechanisms underlying motivational deficits in patients with schizophrenia are poorly understood. These deficits significantly contribute to negative symptoms, which are strongly related to poor functional outcomes and nonresponse to antipsychotic therapies. Data from our group and others have shown that increased peripheral inflammatory markers, such as tumor necrosis factor (TNF), are associated with motivational deficits and negative symptoms in patients with schizophrenia. Regarding the mechanisms involved, our data indicate that in patients with schizophrenia, TNF is associated with decreased activation in ventral striatum in response to reward anticipation as well as increased activation in anterior insula in response to increasing perceived effort. These data are consistent with previous results from individuals administered inflammatory stimuli and from patients with depression that indicate that inflammation targets ventral striatum and anterior insula to lead to downstream changes in reward processing and motivation-related behaviors. Taken together, these findings support the hypothesis that inflammation plays a role in motivational deficits and negative symptoms in patients with schizophrenia through effects on the ventral striatum and anterior insula. Nevertheless, the cause and effect nature of this relationship remains unclear. Work from our group and others suggest that reducing inflammation with the TNF antagonist infliximab improves motivated-related behaviors in patients with depression and high inflammation, and our preliminary data indicate that infliximab improves effort-based motivation in depression through effects on ventral striatum. However, previous studies of anti- inflammatories, including cytokine antagonists, in patients with schizophrenia have been limited by a lack of specificity for patients with increased inflammation and a lack of focus on inflammation-related behavioral changes (e.g. amotivation). Herein, we propose a mechanistic clinical trial in which patients with schizophrenia with high inflammation and motivational deficits will be randomized to an anti-inflammatory challenge with infliximab or placebo. We will then test the hypothesis that infliximab (vs placebo) will increase ventral striatal activation in response to reward anticipation and decrease activation of the anterior insula in response to increasing effort using fMRI. In addition, we will assess the response of objective and clinical measures of motivation. Thus, the goals of the proposed research are to use a biomarker-driven approach to determine whether inhibition of TNF with infliximab (compared to placebo) increases activation of the ventral striatum and decreases activation of the anterior insula during an effort-based reward task (Aim 1), while improving objective and clinical measures of motivation (Aim 2) and exploring infliximab’s effects on other brain regions and behaviors to address specificity (Aim 3). In sum, this study will reveal CNS mechanisms of amotivation in schizophrenia and provide biomarkers and targets that will focus future research and support development of precision therapies for amotivation and ultimately negative symptoms in relevant schizophrenia subgroups.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $497,418 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	3	12/11/2024	NON-COMPETING CONTINUATION	$497,418
														Subtotal = $497,418

Issue Date FY: 2024 ( Subtotal = $585,197 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	001	2	5/13/2024	NON-COMPETING CONTINUATION	$58,519
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	2	12/22/2023	NON-COMPETING CONTINUATION	$526,678
														Subtotal = $585,197

Issue Date FY: 2023 ( Subtotal = $547,034 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	1	2/23/2023	NEW	$547,034
														Subtotal = $547,034

Grand Total All Awards = $1,629,649

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Targeting Inflammation-Induced Changes in Brain Reward Signaling and Motivational Deficits in Patients with Schizophrenia Using an Anti-Inflammatory Challenge

Award Number: R01MH131910

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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