Anesthesia and Functional Connectivity: An Analysis of fMRI Changes

March 21, 2017 updated by: Scott Peltier, University of Michigan

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Background:

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.

Objective:

To examine functional connectivity in the human brain both at rest and after anesthetic sedation using functional magnetic resonance imaging (fMRI).

Specific Aims/Hypotheses:

  1. Measure the degree of functional connectivity in three study groups (healthy volunteers, chronic back pain, and refractory depression).
  2. Analyze for differences in baseline functional connectivity.
  3. Measure changes in functional connectivity after IV low-dose anesthetic sedation.
  4. Document study group differences in anesthetic response.
  5. Measure for any correlation between fMRI changes and therapeutic effects.

Study Protocol:

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

Interventional

Enrollment (Actual)

16

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan - fMRI Laboratory

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Control Group:

Inclusion Criteria:

(4) Ability to tolerate small, enclosed spaces without anxiety; (6) English fluency.

Exclusion Criteria:

  • Pregnant or trying to become pregnant.
  • history of serious head injury;
  • possibility of ferrous metals within the body, e. g. aneurysm clips, retained particles; or metal that would impair the magnetic resonance (MR) signal, e.g., some dental hardware;
  • Smoking usage > 10 cigarettes per day
  • Daily intake of caffeine exceeds 2 cups of coffee per day
  • Unstable cardiac problems (e.g. severe or poorly treated hypertension, unstable arrhythmia, etc.) or concurrent medications for which anesthesia would be contraindicated
  • Patients with a current general medical illness that is life threatening or inadequately treated will be excluded: moderate-to-severe chronic pain, evidence of fracture or malignancy, inflammatory joint disease, severe physical impairment (e.g., bilateral amputation, blindness), morbid obesity, autoimmune/inflammatory diseases, cardiopulmonary disorders (i.e., angina, congestive heart failure, COPD), chronic renal insufficiency, uncontrolled endocrine or allergic disorders (i.e., hyper-/hypothyroidism, diabetes, allergic rhinitis), malignancy.
  • Taking any medication, prescription or non-prescription, with psychotropic effects.
  • History of psychiatric or neurological illness; History of substance abuse or dependence Positive urine toxicology screen.

Refractory Depression Group:

  • Meets all above control group screening criteria except history of psychiatric illness and prescription medication usage
  • Included subjects will have a Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) diagnosis of major depressive disorder, recurrent or chronic, moderate-to-severe, without psychotic features, with medication resistance, accepted with agreement by two different psychiatrists. For this study, treatment resistance is defined as ≥2 failed adequate antidepressant trials.
  • Patients with a DSM-IV diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorder will be excluded. Any history of antidepressant- or substance- induced hypomania or mania will be excluded.
  • Subjects will be free of comorbid substance abuse or dependence for at least 3 months, with a negative urine toxicology screen.
  • No current suicide plan or intent.
  • Comorbid Axis I anxiety disorder diagnoses will be permitted if they do not require current treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Initial MRI
The subject will receive intravenous ketamine 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)
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 Names:
  • Ketamine
Experimental: Initial hospital
The subject will receive intravenous ketamine 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)
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 Names:
  • Ketamine
Experimental: Depression MRI
The subject will receive intravenous ketamine 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)
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 Names:
  • Ketamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
8 minutes scans, acquired between 1 day and 3 days (see above)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Michigan

Investigators

  • Principal Investigator: Scott Peltier, PhD, University of Michigan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2008

Primary Completion (Actual)

May 1, 2015

Study Completion (Actual)

May 1, 2015

Study Registration Dates

First Submitted

July 17, 2014

First Submitted That Met QC Criteria

July 17, 2014

First Posted (Estimate)

July 22, 2014

Study Record Updates

Last Update Posted (Actual)

May 2, 2017

Last Update Submitted That Met QC Criteria

March 21, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • U028860-MICHR-Pilot

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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