Cerebellar Involvement in Alcohol Use Disorder (AUD)

Official title

Investigation of Cerebellar Involvement in AUD

Overview

The goal of this observational and interventional study is to better understand the involvement of the cerebellum in the brain reward system in persons with alcohol use disorder (AUD). The main questions it aims to answer are: 1. What is the nature of cerebellar input to the ventral tegmental area (VTA) in the brain reward system, and how is it perturbed in AUD? 2. What is the relationship between measures of cerebellar integrity and magnitude of reward activation to alcohol-related cues in cerebellar, VTA and other brain reward structures? 3. What is the therapeutic potential of cerebellar transcranial direct current stimulation (tDCS) for modulating alcohol cue reactivity, associated alcohol craving, and cerebellar - VTA functional connectivity in the brain reward system? Persons with AUD will be compared with healthy control participants.

Detailed description

Recent animal studies have provided new evidence that the cerebellum may have a stronger link to the reward system of the brain than was previously recognized. Direct projections from cerebellar deep nuclei (DN) to the ventral tegmental area (VTA) have been identified, and stimulation of these cerebellar afferents to the VTA was found to be rewarding. Such findings raise the possibility that cerebellar dysfunction could contribute substantially to addiction via a cerebellar influence over VTA. Consistent with animal findings, the investigators have found in human functional MRI (fMRI) preliminary data strong cerebellar and VTA activation in response to alcohol cues relative to non-alcohol stimuli in patients with alcohol use disorder (AUD) compared to controls, and close coupling observed between DN and VTA activation. Studying AUD and control participants, this project will address three important questions. The first is: What is the nature of cerebellar input to the VTA, and how is it perturbed in AUD? A number of investigations have suggested that when a stimulus is presented, the cerebellum generates a prediction of events that will follow based on prior associative learning, and then compares predicted and actual outcomes to generate a prediction error. The investigators hypothesize that these functions are disrupted in AUD. The investigators' preliminary data show that when an expected stimulus does not occur, a strong prediction error signal in the form of increased functional connectivity (FC) between cerebellum and its projection target is observed, and the investigators found an analogous increase in DN-VTA FC, that was abnormal in AUD patients, when alcohol pictures were presented. In Aim 1, using fMRI and a monetary incentive task, the investigators will investigate if DN-VTA FC reflects reward prediction and/or positive or negative reward prediction error. The second question is: Is the amount of activation in brain reward centers that is elicited by alcohol stimuli related to the amount of dysfunction in the cerebellum? In Aim 2 the investigators will investigate 2 measures of cerebellar integrity to determine the relationship with the magnitude of alcohol cue related activation in cerebellar, VTA, and other reward structures, and with DN-VTA FC: (1) The timing of the undershoot of the cerebellar hemodynamic response function (HRF), which has been found to be correlated with number of lifetime drinks; and (2) classical eyeblink conditioning, for which the cerebellum is necessary. The third question is: Can abnormal cerebellar activation and FC, as well as alcohol craving, be reduced by non-invasive cerebellar stimulation? In Aim 3, Using fMRI combined with cerebellar transcranial direct current stimulation (tDCS) during a cue reactivity task, the investigators hypothesize that in AUD participants cerebellar and VTA activation will be reduced, DN-VTA FC will be normalized, and alcohol craving will be reduced. The investigators will examine, using both resting state fMRI and psychophysiological interaction analysis, the effects of tDCS on FC among important structures of the reward system as well as on DN-VTA FC. These investigations will lead to a better understanding of the involvement of the cerebellum in AUD, as well as the therapeutic potential of cerebellar modulation.

Interventions

• Procedure cerebellar transcranial direct current stimulation
  TDCS is a safe and non-invasive technique for modulating cortical excitability and behavior. TDCS, delivered via surface electrodes, induces an intracerebral current flow sufficient to achieve changes in cortical excitability. Anodal stimulation up-regulates cortical excitability, while cathodal stimulation decreases excitability.

Primary outcome measures

• Craving for alcohol during the cue reactivity task as assessed by a rating scale [Time frame: 28 minutes]
• Resting state functional connectivity during tDCS [Time frame: 28 minutes]
• Brain activation to alcohol cues [Time frame: 28 minutes]
• Brain functional connectivity to alcohol vs non-alcohol cues [Time frame: 28 minutes]
• Brain activation related to reward prediction during the monetary incentive task [Time frame: 18 minutes]
• Brain functional connectivity related to reward prediction during the monetary incentive task [Time frame: 18 minutes]
• Brain activation to reward prediction error during the monetary incentive task [Time frame: 18 minutes]
• brain functional connectivity to reward prediction error during the monetary incentive task [Time frame: 18 minutes]
• Percentage of trials with a conditioned response during the classical eyeblink conditional task [Time frame: 21 minutes]
• Mean time (in milliseconds) at which peak of conditioned response occurs during the classical eyeblink conditional task [Time frame: 21 minutes]

Secondary outcome measures (2)

• Baseline cerebral blood flow (CBF) measured from a CBF MRI scan [Time frame: 4 minutes and 40 seconds]
• Behavioral accuracy during the monetary incentive task [Time frame: 18 minutes]

Eligibility criteria

Inclusion criteria

• completed at least 8 years of education

Exclusion criteria

• Estimated Intelligence Quotient (IQ) < 90
• less than 5th grade reading level
• Left handed
• Non-fluent in English
• current drug use disorder other than alcohol (except nicotine and caffeine) and or recent drug use in the last 90 days
• Positive breath alcohol level at time of MRI scan or discrepancies between alcohol biomarker and self-report that cannot be resolved
• Exhibiting symptoms of alcohol withdrawal on visit 1 assessment
• Significant current psychiatric distress and or treatment
• History of any central nervous system disorder, presence of a seizure disorder, or use of anticonvulsant medication in the past 3 months
• any serious medical condition detected on assessment or by medical record review; or have liver function tests more than three times normal at screening
• History of metal implantation that would preclude MRI scanning; or other implants, pumps, pacemakers that would be contraindications for MRI scanning
• Abnormal MRI scan or history of significant closed head trauma
• Evidence of dementia
• For women, pregnancy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Johns Hopkins University School of Medicine — Baltimore

Identifiers

NCT: NCT05732207 · IRB00337209 · R01AA030368

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗