Anesthesia and Functional Connectivity: An Analysis of fMRI Changes
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|ClinicalTrials.gov Identifier: NCT02196259|
Recruitment Status : Terminated (Funding cessation.)
First Posted : July 22, 2014
Results First Posted : May 2, 2017
Last Update Posted : May 2, 2017
|First Submitted Date ICMJE||July 17, 2014|
|First Posted Date ICMJE||July 22, 2014|
|Results First Submitted Date ICMJE||May 31, 2016|
|Results First Posted Date ICMJE||May 2, 2017|
|Last Update Posted Date||May 2, 2017|
|Study Start Date ICMJE||February 2008|
|Actual Primary Completion Date||May 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Functional Connectivity [ Time Frame: 8 minutes scans, acquired between 1 day and 3 days (see above) ]
The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps. The outcome of interest is whether ketamine reduces functional connectivity between the anterior (subgenual anterior cingulate corte, sgACC) and posterior regions (posterior cingulate cortex, PCC) of the default mode network. This is the z-score of the functional connectivity correlation. Timepoints for Initial fMRI were: Time 1:Immediately before Infusion, Time 2: After washout (Approx. 40 min after end of infusion). Timepoints for Depression were: Time 1: 1 Day before Infusion, Time 2: 1 Day after Infusion
|Original Primary Outcome Measures ICMJE
||Functional Connectivity of Brain Networks [ Time Frame: The day after the anesthesia infusion ]
The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps, and measures of cerebral blood flow (CBF).
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Anesthesia and Functional Connectivity: An Analysis of fMRI Changes|
|Official Title ICMJE||Anesthesia and Brain Functional Connectivity: An Analysis of fMRI Changes in Chronic Pain and Refractory Depression|
Functional connectivity is defined as a correlation in neural activity between distinct regions of the brain. Several recent studies have demonstrated areas of low-frequency functional connectivity inherent to brain tissue at rest. These oscillations can be measured using functional magnetic resonance imaging (fMRI) and appear to be synchronized between related areas of the brain.
To date, no investigators have examined the effects of low-dose anesthesia on functional connectivity. This study will image the human brain under conditions of rest, and low-dose anesthetic induced sedation. Quality of the acquired signals will be evaluated and functional networks in the brain will be examined. Of interest is whether administration of a low-dose anesthetic disrupts functional connectivity in the brain, and whether a disruption of functional connectivity is responsible for the reported analgesic and antidepressant effects of a anesthetic.
Participation in the study includes four visits: an in-person interview, an initial fMRI scan, the anesthesia infusion, and a second fMRI scan. There is an optional follow-up fMRI scan one week post infusion.
A phencyclidine derivative developed by Parke-Davis represented an attempt to mimic phencyclidine anesthesia without inducing the severe psychomimetic reactions of its parent compound. Initial reports were promising and received great enthusiasm. At high doses, the drug was found to provide profound analgesia whilst preserving airway reflexes. It induced reliable amnesia, yet could be delivered as a simple injection. It was claimed at the time that this anesthetic heralded a new phase in the history of anesthesia. Today, over 40 years since the anesthetic was introduced at Michigan, there has been a resurgence of interest in this old drug. A growing number of investigators are studying the effects of anesthesia on human subjects. There is currently tremendous interest in anesthesia as an opioid sparing agent, a model for schizophrenia, an antidepressant, and as an N-Methyl D-Aspartate (NMDA) antagonist in complex regional pain syndromes.
Functional connectivity is a measure of low-frequency oscillations (<0.08 Hz) that are inherent to brain tissue at rest. These oscillations are measured on fMRI, and appear to be synchronized between related areas of the brain. Although research in this area is still in its infancy, studies of the motor, auditory, visual, and sensorimotor systems, have shown that functionally related areas of the brain produce correlated low-frequency oscillations. This fascinating finding raises the possibility of a new approach to studying brain function as well as a potential tool for the diagnosis of disease. Recent fMRI studies of the precentral gyrus have demonstrated the ability of functional connectivity studies to differentiate healthy volunteers from patients with multiple sclerosis. Additional research is ongoing to determine whether functional connectivity will prove useful in the diagnosis of early Alzheimer's disease.
Recent research in functional connectivity has identified regions in the brain active at rest. These regions are often referred to at the "Default-mode network" (DMN). Activity in the DMN is increased in the brain at rest and decreased when a subject concentrates on a mental task. The first fMRI study examining functional connectivity in chronic pain patients was published in a recent issue of the Journal of Neuroscience. In this study abnormal patterns of functional connectivity were seen in chronic pain patients. Specifically, a dysfunction in down-regulating the DMN was seen. The chronic pain patients did not deactivate the medial prefrontal cortex, amygdala, or posterior cingulate cortex to the same degree as healthy controls.
The only fMRI study examining functional connectivity in major depression was published in September of 2007. This study also noted a dysfunction in the DMN. Depressed subjects were found to have increased network functional connectivity in the subgenual cingulate cortex, thalamus, orbitofrontal cortex, and the precuneus. Notably, the subgenual cingulate cortex is the location of a recent clinical trial suggesting that deep brain stimulation to this region may ameliorate symptoms of patients with severe refractory depression.
Interest in anesthesia for the treatment of chronic pain and depression has grown in recent years. Although there have been no randomized trials of low-dose anesthesia in chronic pain patients, the evidence currently available indicates it is most effective in the treatment of allodynia, hyperalgesia, and hyperpathia. For depression, there has been one randomized, placebo-controlled, double blinded crossover study. In the depression trial, robust and rapid antidepressant effects were found to result from a single intravenous dose of anesthesia and last for at least a week.
To examine functional connectivity in the human brain both at rest and after anesthetic sedation using functional magnetic resonance imaging (fMRI).
Participation in this study includes four main visits and an optional follow-up visit. The first visit is a baseline interview session to assess participant eligibility using a structured interview. The second visit is an initial fMRI scan at the fMRI center. The third visit is the anesthetic infusion at the hospital; management of any adverse events during the infusion will be monitored by the Post Anesthesia Care Unit ( PACU) personnel. The fourth visit is a follow-up fMRI scan at the fMRI center. There is an optional one week follow-up visit at the fMRI center for a final fMRI scan.
fMRI Statistical Analysis: The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps, and measures of cerebral blood flow (CBF). Final inferences will be made at the voxel level and for anatomically specific regions-of-interest (ROIs). The voxel-based analysis will be performed through the generation of summary images referred to as statistical parametric maps (SPMs) representing before-infusion vs. after-infusion, and, as data in the two patient groups become available, two-way ANOVA results of ketamine infusion state and patient diagnosis (chronic pain or refractory depression). The ROI-based analysis will be driven by the a priori selected fronto-limbic regions of interest generated in the self-reflection task, and by the anatomical nodes in the default mode network given in the literature.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
|Condition ICMJE||Changes in Brain Network Connectivity|
|Intervention ICMJE||Drug: Anesthetics, Dissociative
The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)
Other Name: Ketamine
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Terminated|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||May 2015|
|Actual Primary Completion Date||May 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
(4) Ability to tolerate small, enclosed spaces without anxiety; (6) English fluency.
Refractory Depression Group:
|Ages ICMJE||18 Years to 65 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02196259|
|Other Study ID Numbers ICMJE||U028860-MICHR-Pilot|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Current Responsible Party||Scott Peltier, University of Michigan|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||University of Michigan|
|Original Study Sponsor ICMJE||Same as current|
|Collaborators ICMJE||Not Provided|
|PRS Account||University of Michigan|
|Verification Date||March 2017|
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