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A mechanistic trial of the neurobiology of extinction learning and intraparietal sulcus stimulation

Award Number: R01MH132740
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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A mechanistic trial of the neurobiology of extinction learning and intraparietal sulcus stimulation - Project Summary Posttraumatic stress disorder (PTSD) is associated with alterations in arousal that do not respond well to evidence-based practices. Patients with PTSD tend to fall into one of two groups in extinction training (and in exposure therapy): 1) over-engagers, where arousal is too high; and 2) under-engagers, where patients are so worried about becoming upset that they distract themselves from the task (which prevents learning). In this mechanistic clinical trial, we will evaluate a strategy to augment extinction training with neuromodulation to reduce arousal and improve extinction retention. Augmenting extinction training with continuous theta burst stimulation (cTBS, a type of transcranial magnetic stimulation) delivered to the intraparietal sulcus (IPS) may lead to targeted reductions in arousal. Our team has shown that the IPS is a “connectivity hub” for arousal and that stimulating this region with TMS can reduce excessive arousal in healthy people. The goal for this R01 is to evaluate the main effects of IPS cTBS (versus sham cTBS, a between-subject comparison) and its interaction with extinction training (vs. neutral training) on arousal among patients with PTSD. We hypothesize that reducing parietal hyperexcitability will help patients with PTSD to modulate arousal during extinction training—enough arousal to ensure that they can benefit, but not too much arousal which prevents learning. These results could translate into future opportunities for novel therapeutic targets among patients with PTSD. The specific aims are as follows: Aim 1: To evaluate the optimal dose of IPS cTBS. H1: Attenuation of startle for IPS cTBS vs. sham cTBS will plateau at 1200 pulses, the anticipated optimal cumulative dose. Aim 2: To compare the main effect of IPS cTBS and its interaction with extinction training on arousal (measured by startle response). Using a two (between group: sham vs. IPS cTBS) x 2 (within group: extinction training vs. control/neutral training) randomized controlled design among patients with PTSD (N = 120), we will examine the potential benefit of cTBS and extinction training on reduction in arousal. H2a: IPS cTBS will result in greater reduction in arousal compared to sham cTBS. H2b: Participants who receive IPS cTBS will have a significantly lower difference in retention of extinction learning vs. control/neutral training (indicative of greater retention of extinction learning) compared to participants who receive sham cTBS. Secondary: We will test analogous hypotheses on subjective outcomes and on cognitive outcomes and we hypothesize similar directions of effects. Aim 3: To evaluate neural mechanisms of action of IPS cTBS + extinction training. Participants will complete a resting state fMRI scan on tests of retention of learning experimental visits to evaluate neural changes from training. H3: We will observe attenuated activation (relative to pre-test) of the IPS for participants who received IPS cTBS compared to those who received sham cTBS.


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: 2026 ( Subtotal = $777,889 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	11/28/2025	NON-COMPETING CONTINUATION	$777,889
														Subtotal = $777,889

Issue Date FY: 2025 ( Subtotal = $794,916 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	11/15/2024	NON-COMPETING CONTINUATION	$675,678
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	2	9/18/2025	NON-COMPETING CONTINUATION	$119,238
														Subtotal = $794,916

Issue Date FY: 2024 ( Subtotal = $811,653 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	1	6/6/2024	NEW	$81,165
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	1	1/10/2024	NEW	$730,488
														Subtotal = $811,653

Grand Total All Awards = $2,384,458

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A mechanistic trial of the neurobiology of extinction learning and intraparietal sulcus stimulation

Award Number: R01MH132740

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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