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Sex differences in the neural correlates underlying impairments in response inhibition and salience attribution in cocaine addiction

Award Number: R01DA048301
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Sex differences in the neural correlates underlying impairments in response inhibition and salience attribution in cocaine addiction - National studies show that drug use rates have increased in the last decade among women, comprising a major public health concern in the US. However, women are greatly underrepresented in neuroimaging studies, and the paucity of studies that explicitly target sex comparisons in addicted populations contributes to a gap in the study of the sex specific neurobiological mechanisms underlying drug addiction. Over the last decade, in a series of magnetic resonance imaging (MRI) studies (conducted with previous support including R01DA023579, R01DA020949), we have thoroughly mapped the clinical symptoms of cocaine addiction to the neural networks underlying impairments in Response Inhibition and Salience Attribution (iRISA). This model proposes that the drug assumes heightened salience at the expense of non-drug related reinforcement as associated with abnormalities in reward processing and concomitant decreases in inhibitory control, together increasing addiction severity (including craving, a proxy of relapse) in susceptible individuals. The iRISA model highlights the role of the dopaminergically innervated prefrontal cortex (PFC) and its connections to mesolimbic and striatal subcortical regions as assessed functionally and structurally. However, the majority of this neuroimaging research has been accomplished in male individuals with cocaine use disorders (iCUD). In the current project we aim to expand the reach of iRISA by comparing equal numbers of male to female iCUD; to test this model’s generalizability (vs. drug specificity effects), we will also include individuals with opioid use disorder (iOUD). We will conduct functional MRI during reward processing, inhibitory control and cue-reactivity tasks, and, to inspect generalizability of results beyond task-related activations, during resting-state. Beyond functional activations and connectivity, anatomical scans will assess the underlying gray matter integrity. Across all aims, healthy controls will be included to establish norms. We hypothesize female iCUD to differ from male iCUD, or female controls, in a pattern indicative of enhanced vulnerability to iRISA inclusive of compensatory PFC activations and abnormalities in structural measures; iCUD vs. iOUD comparisons will be exploratory. The novelty of this proposal is further enhanced by an exploratory aim to compare, in a within- subjects design, menstrual cycle (and hormonal) effects and by developing sophisticated machine-learning algorithms to incorporate data from all imaging modalities to yield an automated group classification and addiction severity (including craving) prediction tool. Considering that the majority of research in addiction occurs in males, clarification of the sex differences in the neural underpinnings of iRISA could reinforce the importance of studying both genders and suggest that different treatment strategies may be effective in women (potentially of most impact when timed vis-à-vis menstrual cycle), contributing to the development of tailored (gender-based) treatment options. Including equal numbers of women and men would advance basic studies of drug addiction and ultimately save resources by minimizing cost and adverse effects in future clinical trials.


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: 2024 ( Subtotal = $681,089 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	5	1/25/2024	NON-COMPETING CONTINUATION	$612,979
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	5	4/26/2024	NON-COMPETING CONTINUATION	$68,110
														Subtotal = $681,089

Issue Date FY: 2023 ( Subtotal = $689,316 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	4	2/14/2023	NON-COMPETING CONTINUATION	$689,316
														Subtotal = $689,316

Issue Date FY: 2022 ( Subtotal = $689,316 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	3	2/3/2022	NON-COMPETING CONTINUATION	$620,381
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	3	3/23/2022	NON-COMPETING CONTINUATION	$68,935
														Subtotal = $689,316

Issue Date FY: 2021 ( Subtotal = $689,316 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	2	2/23/2021	NON-COMPETING CONTINUATION	$689,316
														Subtotal = $689,316

Issue Date FY: 2020 ( Subtotal = $689,316 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	1	3/20/2020	NEW	$689,316
														Subtotal = $689,316

Grand Total All Awards = $3,438,353

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Sex differences in the neural correlates underlying impairments in response inhibition and salience attribution in cocaine addiction

Award Number: R01DA048301

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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