Neuromodulation of Motivation and Reward Oscillations (NEMO)

Delta and Theta-Frequency Transcranial Alternating Stimulation Neuromodulation of Motivation and Reward Oscillations in Disorder of Reward Dysfunction.

Cannabis use disorder (CUD) and major depressive disorder (MDD) are among the most prevalent psychiatric conditions in the United States, affecting an estimated 20.6 million and 21 million adults respectively. Both disorders are characterized by anhedonia, diminished motivation, and blunted neural reward sensitivity. This shared dysregulated reward-processing may reflect a common prefrontal oscillatory dysfunction, centralized in mesolimbic dopaminergic reward pathways. This proposed project aims to investigate if transcranial alternating current (tACS) can modulate motivational behaviours and neural reward responsivity in participants with MDD and/or CUD during an effortful reward task. The investigators hypothesize that delta transcranial alternating current stimulation will produce a greater neural reward responsivity (RewP), and motivational behaviour during an effortful reward task.

Study Overview

• Status: Recruiting
• Conditions: Anhedonia; Major Depression; Cannabis Use Disorder; Transcranial Alternating Current Stimulation
• Intervention / Treatment: Device: Transcranial Alternating Current Delta Stimulation.; Device: Transcranial Alternating Current Theta Stimulation; Device: Transcranial Alternating Current Stimulation Sham

Detailed Description

Disrupted reward processing is a transdiagnostic feature that plays a central role in the development, and maintenance of anhedonia in Cannabis Use Disorder (CUD) and Major Depressive Disorder (MDD). Reward positivity (RewP) is an event-related potential (ERP) component derived from electroencephalogram (EEG) data, associated with motivation, reward responsivity and valuation. This neural signature originates in the medial and dorsolateral prefrontal cortexes. In MDD, reduced RewP has been associated with decreased willingness to expend effort for reward. Research of CUD and RewP is scarce, but dampened RewP has been demonstrated across different substances use disorders (SUDs) in response to monetary reward tasks. Taken together, these findings signal an emerging research frontier to establish RewP as a clinical biomarker and create a compelling mandate for causal investigation. Low-frequency neural oscillations are the key mechanisms facilitating long-distance prefrontal connectivity and interregional communication. Delta oscillations (2.5Hz) in medial and left lateral prefrontal cortexes are closely linked to RewP and reward prediction error signaling, while theta oscillations (6Hz) index cognitive control and prefrontal regulatory engagement during reward processing. Disruptions in both bands have been well documented in MDD, to a more limited extent, in cannabis-using populations. The proposed experiment will causally test whether sham, delta, and theta frequency tACS can alter motivation and reward responsivity (behaviourally [Effort behaviour] and neurally [RewP, delta power]), in participants with disorder of reward dysfunction, CUD, MDD, and healthy controls. Findings from the proposed study will aid in mechanistic understanding of prefrontal circuits underlying reward impairment in CUD and MDD, and ultimately enable for the development of novel brain stimulation techniques to target disorder-maintaining anhedonia. The investigators hypothesise that delta tACS will modulate reward responsivity in participants with disorders of reward. Such that, during the EEfRT Task delta stimulation will enhance reward responsive goal directed behaviour (Behavioral H1) and delta phase connectivity between left lateral and medial frontal electrodes (Neural H1) at effort decision period. As well as greater reward positivity (RewP; Neural 2), and win vs. loss delta power and phase coherence at feedback (Neural H3).

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zoe Howell Doctoral Student PI, M.Res.; Phone Number: 850-644-2445; Email: brains@psy.fsu.edu

Study Locations

• United States
  • Florida
    • Tallahassee, Florida, United States, 32306-4301
      • Not yet recruiting
      • The BRAINS Lab at Florida State University
      • Contact: Zoe A Doctoral Student PI, M.Res.; Phone Number: 850-644-2445; Email: brains@psy.fsu.edu
    • Tallahassee, Florida, United States, 32306-4301
      • Recruiting
      • The Riddle Lab at Florida State University
      • Contact: Zoe S Post baccalaureate Researcher, B.A.; Phone Number: (850) 644-9869; Email: RiddleLabFSU@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria (General):

• Aged between 18 - 55 years old.
• Able to provide informed consent
• Have normal to corrected vision
• Willing to comply with all study procedures and be available for the duration of the study
• Speak and understand English.
• Negative THC saliva test and alcohol breathalyzer at all lab visits.
• Negative UTOX for any substance other than THC.

Exclusion Criteria (General):

• Mania history (Bipolar I, or current mania).
• Psychosis history.
• Current suicide intent (score >4 on C-SRSS, or intent >0 on SRA)
• Current moderate-to-severe SUD or AUD (Except CUD and nicotine for NEMO-CUD).
• Current pregnancy.
• Seizure, neurological conditions, or brain surgery history.
• Implanted medical devices (e.g., cochlear implants, cardiac pacemakers).
• Change in psychotropic medication in the past 3 months (i.e., medication needs to be stable for 12 weeks).
• Use of seizure threshold lowering medication (e.g., Stimulants, Benzos, SNRIs, Antipsychotics [Adderall, Vyvanse, Xanax, Wellbutrin, Cymbalta, Lithium] - SSRIs not exclusionary).

Specific CUD Inclusion:

• Avg. 6+ cannabis use days per week over the past 3-months, and 24+ cannabis use days in the past 30 days.
• Primary delta-9 or THC-A cannabis flower or vape concentrate user.
• Current moderate-to-severe CUD (4+ criteria in the past year, at least one criterion other than craving must be met in the past three months).
• Cannabis is the primary substance of use (Nicotine dependence is allowable)
• Not currently receiving treatment for cannabis, planning to immediately quit or reduce use.
• Lifetime history of MDE/PDD must have lifetime anhedonia symptom and/or heavy cannabis user (3+ sessions daily for at least past year including the past 3-months and past 30 days).

Specific MDD Inclusion:

• Current MDE diagnosis.
• No lifetime history of severe SUD.
• No current moderate-to-severe SUD.
• 100% of NEMO-MDD participants elevated anhedonia on TEPS-C (i.e., 32 or lower on TEPS-C subscale).

Specific Control Inclusion:

• No current or historical psychiatric diagnosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Delta tACS; All participants receive delta (2.5 Hz), theta (6 Hz), and sham tACS across three separate sessions, separated by a 7-10 day washout. Session order is randomised and counterbalanced using a balanced Latin square, within each diagnostic group (CUD, MDD, healthy control). Stimulation is interleaved between the 8 blocks of the EEfRT (e.g., block 1 with stimulation, block 2 without, etc.). EEG activity will be recorded throughout the non-stimulation 4 blocks and proceeding interleaved non-stimulation blocks.	Device: Transcranial Alternating Current Delta Stimulation.; Approximately 20-minutes of delta stimulation (2.5Hz) applied to F3 (returns AF7, FC5, FC1) and AFz (returns Fp1, Fp2, F2). Transcranial Alternating Current Stimulation Device is NeuroConn DC-Stimulator MC.
Active Comparator: Theta tACS; All participants receive delta (2.5 Hz), theta (6 Hz), and sham tACS across three separate sessions, separated by a 7-10 day washout. Session order is randomised and counterbalanced using a balanced Latin square, within each diagnostic group (CUD, MDD, healthy control). Stimulation is interleaved between the 8 blocks of the EEfRT (e.g., block 1 with stimulation, block 2 without, etc.). EEG activity will be recorded throughout the non-stimulation 4 blocks and proceeding interleaved non-stimulation blocks.	Device: Transcranial Alternating Current Theta Stimulation; Approximately 20-minutes of theta stimulation (6Hz) applied to F3 (returns AF7, FC5, FC1) and AFz (returns Fp1, Fp2, F2). Transcranial Alternating Current Stimulation Device is NeuroConn DC-Stimulator MC.
Sham Comparator: Sham tACS; All participants receive delta (2.5 Hz), theta (6 Hz), and sham tACS across three separate sessions, separated by a 7-10 day washout. Session order is randomised and counterbalanced using a balanced Latin square, within each diagnostic group (CUD, MDD, healthy control). Stimulation is interleaved between the 8 blocks of the EEfRT (e.g., block 1 with stimulation, block 2 without, etc.). EEG activity will be recorded throughout the non-stimulation 4 blocks and proceeding interleaved non-stimulation blocks.	Device: Transcranial Alternating Current Stimulation Sham; The tACS stimulation is briefly turned on and off over the course of 15-30 seconds.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effort-updating behavior during decision period.	The % of hard effort choices selected following a win versus following a loss.	Baseline (Day 0), Sham Session (Day 1-10, or Day 10-20, or Day 20-30), Theta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30), Delta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30). Specific range depends on particular counterbalanced order.
Delta phase coherence between left lateral and medial frontal electrodes during decision period following a win versus following a loss.	Electrical activity of the brain will be recorded via EEG during performance of the task and neurostimulation. Delta phase connectivity between left lateral and medial frontal electrodes during the decision period following a win versus following a loss.	Baseline (Day 0), Sham Session (Day 1-10, or Day 10-20, or Day 20-30), Theta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30), Delta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30). Specific range depends on particular counterbalanced order.
Reward positivity amplitude	Electrical activity of the brain will be recorded via EEG during performance of the task and neurostimulation. Reward positivity amplitude to wins vs. losses.	Baseline (Day 0), Sham Session (Day 1-10, or Day 10-20, or Day 20-30), Theta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30), Delta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30). Specific range depends on particular counterbalanced order.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delta event-related spectral power	Electrical activity of the brain will be recorded via EEG during performance of the task and neurostimulation. Delta power to wins vs. losses.	Baseline (Day 0), Sham Session (Day 1-10, or Day 10-20, or Day 20-30), Theta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30), Delta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30). Specific range depends on particular counterbalanced order.
Delta intertrial phase coherence	Electrical activity of the brain will be recorded via EEG during performance of the task and neurostimulation. Delta intertrial phase coherence to wins vs. losses.	Baseline (Day 0), Sham Session (Day 1-10, or Day 10-20, or Day 20-30), Theta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30), Delta Stim. Session (Day 1-10, or Day 10-20, or Day 20-30). Specific range depends on particular counterbalanced order.

Collaborators and Investigators

• Sponsor: Florida State University
• Investigators: Principal Investigator: Richard J Macatee, Ph.D., Florida State University

Publications and helpful links

General Publications

• Byrd KJ, Johnston BW, Culp S, Kreutzer KA, Way BM, Phan KL, Gorka SM. Neural reward sensitivity and longitudinal patterns of alcohol and cannabis use in college-aged youth. Drug Alcohol Depend. 2026 Apr 1;281:113079. doi: 10.1016/j.drugalcdep.2026.113079. Epub 2026 Feb 10.
• Proudfit GH. The reward positivity: from basic research on reward to a biomarker for depression. Psychophysiology. 2015 Apr;52(4):449-59. doi: 10.1111/psyp.12370. Epub 2014 Oct 17.
• Murray CH, Glazer JE, Lee R, Nusslock R, de Wit H. Delta9-THC reduces reward-related brain activity in healthy adults. Psychopharmacology (Berl). 2022 Sep;239(9):2829-2840. doi: 10.1007/s00213-022-06164-y. Epub 2022 May 25.
• Joyner KJ, Bowyer CB, Yancey JR, Venables NC, Foell J, Worthy DA, Hajcak G, Bartholow BD, Patrick CJ. Blunted Reward Sensitivity and Trait Disinhibition Interact to Predict Substance Use Problems. Clin Psychol Sci. 2019;7(5):1109-1124. doi: 10.1177/2167702619838480. Epub 2019 Sep 1.
• Riddle J, Alexander ML, Schiller CE, Rubinow DR, Frohlich F. Reward-Based Decision-Making Engages Distinct Modes of Cross-Frequency Coupling. Cereb Cortex. 2022 May 14;32(10):2079-2094. doi: 10.1093/cercor/bhab336.

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: October 26, 2026
• First Submitted That Met QC Criteria: November 3, 2026
• First Posted (Actual): November 9, 2026

Study Record Updates

• Last Update Posted (Actual): November 9, 2026
• Last Update Submitted That Met QC Criteria: November 3, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Cannabis Use Disorder; Neurostimulation; Reward Responsivity
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Behavioral Symptoms; Neurobehavioral Manifestations; Mood Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Depression; Depressive Disorder, Major; Anhedonia
• Other Study ID Numbers: STUDY00007710

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

The IPD will only be shared under reasonable request. The investigators might not share IPD in order to keep participant confidentiality paramount.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No