Identifying and Treating Arousal Related Deficits in Neglect and Dysphagia

The purpose of this study is to examine how stroke can alter arousal, alertness, neglect and dysphagia, and whether a medication, modafinil, can improve arousal.

Study Overview

• Status: Completed
• Conditions: Dysphagia; Spatial Neglect
• Intervention / Treatment: Behavioral: Baseline; Behavioral: CPS; Behavioral: Post CPS; Behavioral: Follow up; Drug: Modafinil; Drug: Placebo

Detailed Description

Neglect and dysphagia are two of the most problematic behavioral disorders encountered in stroke rehabilitation with 300,000 patients affected annually in the US. Both disorders impede progress in therapy and both lead to costly medical complications, like falls which are associated with neglect and aspiration pneumonia and malnutrition which are associated with dysphagia. No widely accepted pharmacological treatment exists for either disorder.

A new direction of this application is to view neglect and dysphagia as different disorders that share a common deficit in magnitude estimation (ME). ME refers to one's ability to perceive the intensity of sensory stimulation. Deficits in ME explain how much of a stimulus is neglected by stroke patients. Sensory deficits are also known to produce dysphagia. Perceptual deficits influence how patients response to stimuli like failing to act on all stimuli present (neglect) and failing to generate swallowing reflexes sufficient for normal bolus flow (dysphagia).

We know from previous work that ME is altered by change in cortical arousal following stroke (decreased or hypoarousal). Hypoarousal is evidenced by objective and subjective post-stroke fatigue and daytime sleepiness which occurs in 50% of stroke patients and can persist chronically. Increasing arousal could potentially reverse the perceptual deficits associated with hypoarousal and improve neglect and dysphagia. This proposal manipulates arousal in two ways. Cold pressor stimulation (CPS), immersing the foot in cold water for 50 seconds, is used to increase arousal and reverse neglect and dysphagia temporarily. A brief, 3-day trial of modafinil (Provigil) versus placebo is then used in stroke patients to learn if a positive response to cold-pressor stimulation can predicts patients who respond positively to modafinil.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Conway, Arkansas, United States, 72035
      • Conway Regional Rehabilitation Hospital
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent
• Willingness to complete study procedures
• Ability to comprehend and sign informed consent

• Evidence of unilateral, ischemic stroke based on:

  • Neuroimaging (clinically obtained imaging studies showing evidence of stroke)

    • Acceptable categories of stroke include:
    • Unilateral ischemic stroke
    • Atherothrombotic stroke
    • Cardioembolic stroke
    • Lacunar stroke >1.5 cm
    • Chronic stable, unilateral hemorrhagic stroke

• Or Behavioral evidence of stroke including:

  • Hemiplegia
  • Unilateral sensory impairment
  • Localized higher cortical dysfunction (e.g. neglect,dysphagia, apraxia)

Exclusion Criteria:

• Cardiac valvular disease
• Left heart hypertrophy
• Poorly controlled hypertension
• Active variant angina
• Pre-menopausal women capable of having children, including those using active contraception (precaution for study medication and not applicable to normal subjects)
• Severe renal or hepatic disease
• History of psychosis or substance abuse
• Patients on other Central Nervous System (CNS) stimulants, dopamine agonists or antagonists (antipsychotics)
• Severe speech comprehension deficit and/or inability to communicate responses
• Allergies that could put the research subject at risk during the course of the study
• Cannot speak English
• Active cerebral neurologic disease other than stroke such as multiple sclerosis or Alzheimer's Disease
• Active psychiatric illness except past history of treated depression or anxiety disorders
• For persons needing an MRI - standard MRI exclusion criteria (cardiac pacemaker or defibrillator, artificial heart valves, metallic aneurysm clips eye or ear implants, implanted insulin or infusion pumps, battery activated stimulators, and history of claustrophobia)
• Concomitant medications excluded: Based on recommendations of manufacturer, the following concomitant medications are excluded: Tricyclic antidepressants and Monoamine oxidase (MAO) inhibitors. Any other CNS stimulation producing medications. Antifungal agents Itraconazole or Ketoconazole as plasma concentrations of modafinil may be increased.
• Stroke patients will be excluded from the modafinil trial if they cannot swallow a capsule.
• Stroke patients are excluded if they are able to become pregnant
• Any other criteria that the PI or study physicians feel would put the volunteer's health at risk during the course of the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: normal subjects; Normal subjects are persons without stroke who receive baseline, CPS, Post CPS and Follow up interventions.	Behavioral: Baseline; Observations made at baseline before any intervention; Other Names: baseline observation; Behavioral: CPS; Submerging each participant's foot into ice water (36-44 F) for 50 seconds.; Other Names: cold pressor stimulation; Behavioral: Post CPS; 20 minutes following the CPS condition.; Other Names: post cold pressor stimulation; Behavioral: Follow up; Follow up testing occurred at 3 months; Other Names: three month follow up
Active Comparator: stroke subjects; Stroke subjects are persons who have had a stroke affecting the right hemisphere and are subject to neglect or dysphagia who receive modafinil, placebo, baseline, CPS, Post CPS and Follow up interventions.	Behavioral: Baseline; Observations made at baseline before any intervention; Other Names: baseline observation; Behavioral: CPS; Submerging each participant's foot into ice water (36-44 F) for 50 seconds.; Other Names: cold pressor stimulation; Behavioral: Post CPS; 20 minutes following the CPS condition.; Other Names: post cold pressor stimulation; Behavioral: Follow up; Follow up testing occurred at 3 months; Other Names: three month follow up; Drug: Modafinil; 200 mg once daily with morning meal for three days administered only to stroke patients; Other Names: Provigil; Drug: Placebo; Subjects will receive a placebo designed to look like 200 mg dose of modafinil. The dose will be taken once daily with the morning meal for three days and will only be administered to stroke patients; Other Names: inert

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P50 Percent Habituation Score	This is an electrophysiological measure of arousal - a percent change in the P50 evoked response potential amplitudes with a 250 ms inter stimulus interval. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).	baseline and after three days of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PVT Fastest 10 Percent of Reaction Times	This is a behavioral measure of arousal - the fastest 10 percent of all cued reaction time trials. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).	baseline and after three days of intervention
Power Function Exponent for Oral Bolus Estimation	This is a behavioral measure of sensation in the oral cavity. The power function exponent is equal to the slope of a regression equation relating bolus size to a person's estimate of that size. An exponent below one implies an underestimate of bolus size. The difference score is calculated as CPS - baseline and as modafinil - placebo (stroke subjects only).	baseline and after three days of intervention
Time to Swallow Puree Food	This is a behavioral measure of swallowing - the time it takes for pureed food to transition across a part of the throat. The difference score is calculated as CPS - placebo and as modafinil - placebo (for stroke subjects only).	baseline and after three days of intervention

Collaborators and Investigators

• Sponsor: University of Arkansas
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Mark S Mennemeier, PhD, University of Arkansas; Principal Investigator: Gary McCullough, PhD, University of Central Arkansas

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: March 9, 2010
• First Submitted That Met QC Criteria: March 11, 2010
• First Posted (Estimate): March 12, 2010

Study Record Updates

• Last Update Posted (Estimate): October 18, 2016
• Last Update Submitted That Met QC Criteria: October 17, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Stroke; Dysphagia; Spatial Neglect; Arousal; Modafinil
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Pharyngeal Diseases; Otorhinolaryngologic Diseases; Esophageal Diseases; Deglutition Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Central Nervous System Stimulants; Wakefulness-Promoting Agents; Modafinil; Vasoconstrictor Agents
• Other Study ID Numbers: 110644; R21HD055677 (U.S. NIH Grant/Contract)