Modulation of Episodic Memory Using Theta Burst Stimulation (TBS)

September 4, 2018 updated by: Duke University

The goal of this study is to evaluate the effect of white matter guided theta burst stimulation on episodic memory task performance in healthy older adults. The investigators aim to propagate the effect of theta burst stimulation from a superficial locus of stimulation (angular gyrus) to hippocampus and parahippocampal regions using white matter tract connection between these regions. Study activities and population group - for the study plans to recruit 20 healthy older adults who already have white matter scans acquired as part of another study performed by the Cabeza Lab at Duke University.

Using tractography the exact site of stimulation on the cortical surface will be localized. An initial motor evoked potential (MEP) assessment will differentiate responders to theta burst stimulation from non responders. Responders will receive 1200 pulses of intermittent theta burst stimulation (iTBS) or sham stimulation to the angular gyrus while they perform the encoding portion of an episodic memory task. There after, they will perform retrieval piece of the task and data analysis will compare these performances.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Aims and Hypotheses The purpose of the study is to evaluate the effect of theta burst stimulation (TBS) which is a relatively new paradigm of transcranial magnetic stimulation (TMS) on episodic memory (EM) in healthy older adults (hOA).

Aim1: Evaluate the effect of theta burst stimulation (TBS) on episodic memory (EM) in healthy older adults. Hypothesis 1 - There will be significant improvement in EM compared to baseline with one session of TBS.

Aim 2: Correlate white matter integrity to improvement in task retrieval with TBS. Hypothesis 2- Stronger white matter (WM) tract connections correlate to greater improvement in retrieval performance.

BACKGROUND Alzheimer's disease (AD) affects 5 million Americans, at a cost of over 200 billion dollars. The first and most debilitating symptom of AD is a severe deficit in the ability to remembering personal past events, or episodic memory (EM), which eventually renders patients isolated from family and friends and unable to live independently. This EM deficit reflects primarily the deterioration of medial temporal lobe regions, particularly the hippocampus (HC). AD treatments must start very early in the disease progression, when brain damage is still small, and the earliest stage when AD can be diagnosed is known as mild cognitive impairment due to AD (MCI-AD).

Recently, different forms of noninvasive brain stimulation techniques have been applied to healthy older adults, AD and MCI-AD to improve memory impairment. Most of these trials used high-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC). Although a small number of these studies have shown beneficial effects, considerable questions remain as to whether TMS has clinically relevant effects in elderly populations, as well as to what neuroscience-based mechanisms account for these effects. An obstacle for using TMS to enhance EM is that the brain region most critical for EM and most affected by early AD, the hippocampus (HC), is situated deep inside the brain, beyond TMS direct effects (~1" below the skull). One study attempted to target hippocampus and peri-hippocampal regions for stimulation via TMS. They stimulated the lateral parietal cortex and utilized functional connectivity between this region and hippocampus/peri-hippocampal regions (mainly entorhinal cortex) to enhance performance on an associative memory task. The inferior longitudinal fasciculus connects angular gyrus to hippocampus and para-hippocampal regions, and could propagate stimulation effects from cortical to subcortical structures, although studies on effect on TMS on white matter neuronal populations are limited as detailed below. The effect of TMS on neuronal populations in the white matter tracts was recently modeled using tractography and e-field calculations, and increasingly, these approaches need to account for what percentage of variance in motor threshold (MT) would be accounted for by white matter tracts.

TBS is a potent paradigm of TMS. As detailed in a seminal paper by Huang et al, there are 2 patterns for the paradigm: - continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS). The former produces suppression of MEP and the latter produces increase in MEP. iTBS delivers 50 Hz stimuli in packets of 10 lasting 2 seconds. Each stimulus burst delivered at 50 Hz is given every 200 milliseconds making the overall frequency of stimulus delivery 5 Hz. Hence the stimulation encompasses nested 50 Hz bursts (gamma frequency) given at 5 Hz (theta frequency). Most investigational studies which did not have treatment outcome measures have used either 40 second of cTBS or 190 seconds of iTBS. Both these paradigms have been shown to cause changes in MEP for 60 minutes. Variations in pattern of stimulation have also been effective, although there are limited studies to warrant its use. The investigators therefore propose to use stimulate the function of the hippocampal formation in healthy older adults (hOA) by targeting a cortical region directly connected to the hippocampal formation: the angular gyrus. To increase indirect effects on hippocampal formation, the investigators will use the most powerful TMS technique available, intermittent Theta Burst Stimulation (iTBS).

METHODOLOGY The study is designed to be a pilot one evaluating the effect of TBS on EM in healthy older adults (hOA). The investigators plan to screen 30 participants to select 20 subjects.

Screening Potential participants will be in the age group of 60-80 years and encompasses subjects who have been recruited to previous studies at Cabeza Lab (Pro00005021), hence having brain imaging data already collected.

Study procedure On day 1 of the study, subjects will have the National Institute of Health (NIH) Toolbox administered to them. The NIH toolbox is a comprehensive set of neuro-behavioral measurements that quickly assesses cognitive functions from the convenience of an iPad. Total time allotted for NIH toolbox administration is 45 minutes. Following this, subjects will have motor evoked potential (MEP) performed after which they will be administered intermittent theta burst stimulation (iTBS) to motor cortex. This will be followed by measurement of motor evoked potential (MEP) again. Subjects who do not show a 10 % increase in motor evoked potential (MEP) with iTBS will be excluded from further parts of the study.

Our study uses a specific kind of TMS, known as intermittent theta burst stimulation (iTBS). On day 1 of the study, subjects will be administered either left-sided iTBS to the motor cortex. The subject will be seated in a chair. Electromyogram (EMG) electrodes will be applied to the right hand for motor evoked potential (MEP) recording. For iTBS the active motor threshold would be 80 % as used in most theta burst studies detailed in this review. Subjects would receive iTBS comprising 50 Hz bursts given at 3 to 5 Hz for close to 3 minutes which comprises 19 trains and 600 pulses. The subject will be monitored until MEPs return to baseline. A side effects checklist will be completed at the beginning and at the end of the experimental session. All sessions will be performed by one of the protocol investigators, or by a trained and accredited research assistant supervised by the protocol investigators.

If a 10 % increase is seen in the MEP, then subjects will receive a second session of iTBS or sham stimulation to the left angular gyrus one hour after the screening session. If they receive iTBS, this will comprise 6 minutes of stimulation equivalent to 1200 pulses and 38 trains of the stimulus. The subject will be monitored until MEPs return to baseline. A side effects checklist will be completed at the beginning and at the end of the experimental session. Sham stimulation will use superficial electrodes to mimic the experience of receiving actual stimulation. All sessions will be performed by one of the protocol investigators, or by a trained and accredited research assistant supervised by the protocol investigators. Subjects will perform encoding trials of episodic memory task with stimulation and retrieval piece of the task after the stimulation.

Study Type

Interventional

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
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center

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

60 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Healthy controls in the age group 60-80 years old
  • No other Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 axis 1 diagnoses
  • Willing to provide informed consent
  • Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) data available

Exclusion Criteria:

  • Subjects are unable or unwilling to give informed consent
  • Presence of any organic brain illness
  • Presence or history of stroke, traumatic brain injury or head injury with loss of consciousness, transient ischemic attack (TIA), any diagnosed neurological disorder including but not limited to multiple sclerosis, Huntington's disease, Parkinson's disease, dementia or major neurocognitive disorder.
  • Presence of cranial metal implants, structural brain lesion including but not limited to cerebral aneurysms.
  • Presence of devices that may be affected by repetitive transcranial magnetic stimulation (rTMS) (pacemaker, medication pump, cochlear implant, implanted brain stimulator)
  • Current or recent (within the past 6 months) substance abuse or dependence, excluding nicotine and caffeine.
  • Current serious medical illness
  • History of seizure except those therapeutically induced by electroconvulsive therapy (ECT) (childhood febrile seizures are acceptable and these subjects may be included in the study), history of epilepsy in self or first degree relatives
  • For subjects age > 59 years, a total scaled score < 8 on the Dementia Rating Scale-2.

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: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: healthy older adults
Healthy older adults who will receive TMS
Device: Transcranial magnetic stimulation (TMS)
TMS paradigm called theta burst stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Episodic memory retrieval task decision
Time Frame: 40 minutes
Four-choice decision (1- definitely there is a link, 2-probably there is a link, 3-probably there is no link, 4-definitely there is no link) in response to semantic link retrieval between 2 words
40 minutes

Collaborators and Investigators

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

Sponsor

Duke University

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 (ANTICIPATED)

December 15, 2018

Primary Completion (ANTICIPATED)

December 30, 2019

Study Completion (ANTICIPATED)

December 30, 2019

Study Registration Dates

First Submitted

January 16, 2018

First Submitted That Met QC Criteria

January 16, 2018

First Posted (ACTUAL)

January 23, 2018

Study Record Updates

Last Update Posted (ACTUAL)

September 6, 2018

Last Update Submitted That Met QC Criteria

September 4, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • Pro00086794

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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

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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