Last updated on June 2018

Treatment of Memory Disorders in Gulf War Illness With High Definition Transcranial Direct Cortical Stimulation

Brief description of study

A debilitating and common symptom in Gulf War Illnesses (GWI) is the inability to retrieve words. This affects one's conversations, ability to fluidly exchange information verbally and retrieve information from memory. The investigators have discovered 3 brain regions - the PreSupplementary Motor Area (preSMA), caudate nucleus, and the thalamus - that are essential for word retrieval. They have also detected abnormal EEG signals related to these regions in GWI patients who have problems retrieving words.

The investigators have used their model of verbal retrieval to design a noninvasive, nonpharmacological treatment that uses High Definition transcranial Direct Current Stimulation (HD tDCS). Using HD tDCS, they deliver small amounts of electric current to areas of the head to stimulate specific brain regions. The objective is to determine if delivery of HD tDCS over the preSMA will improve performance in GWI veterans with a verbal retrieval deficit. The investigators will administer pre-treatment tests of verbal retrieval measures while recording brain electrical activity. They will then administer 10 sessions of HD tDCS over the preSMA (20 minutes a session) in half the veterans. The other half will go through the same procedures, except the current will not be turned on (called the sham condition). The investigators will then compare performance between the "active" and sham group and assess if the treatment had a significant effect on performing verbal retrieval tasks and if there is a change in the ERP markers to account for how the treatment worked. If the treatment is found to be effective it will be offered to those in the sham group at the study's end.

The investigators predict this treatment regimen will lead to positive effects on a person's daily functions, especially improved conversational abilities, with few, if any, side effects. They hope to outline the standard procedures for physicians to perform the treatment by creating a manual on how to apply the treatment in a clinical setting so that it will be quickly available to use in multiple sites if the proposed study demonstrates that it is efficacious. This treatment can be made widely available for Warrior Transition Units, military clinics, and VA medical centers. In addition, if successful, this could potentially lead to development of other targets of stimulation to improve other cognitive deficits in GWI, and help alleviate verbal fluency deficits associated with other disorders.

Detailed Study Description

The objective of this proposal is to identify patients with GWI who have a verbal retrieval deficit and determine if delivery of HD tDCS over the PreSupplementary Motor Area of the brain (preSMA) will improve performance in verbal retrieval-related tasks.

Key cognitive symptom described by patients with GWI extends from a disruption in the cognitive process of verbal retrieval. This is manifested in a variety of dysfunctions including word retrieval deficits, verbal fluency disruption and potentially verbal episodic memory. The investigators have delineated a circuit of verbal retrieval using functional neuroimaging and electrophysiology measures in normal controls and in patient populations showing that a circuit of the preSMA-caudate nucleus-thalamus is essential for effective retrieval of verbal information. This model has generated specific ERP neural markers of successful verbal retrieval and we have studied GWI patients with dysfunction in these ERP and functional MRI markers.

In addition, patients with MS and TBI have been treated by the investigators for similar verbal retrieval deficits as those with GWI by using the technique of High Definition transcranial Direct Current Stimulation (HD tDCS) over the preSMA region to strengthen the connections of this retrieval circuit.

The investigators hypothesize that application of 1 ma anodal HD tDCS over the preSMA for 20 minutes a session for 10 sessions over a two week period will lead to improvement in verbal retrieval that will be detectable in both performance measures of verbal retrieval tasks and in ERP markers of verbal retrieval processing. The objective is to determine if 10 sessions of 1 ma anodal HD tDCS to the preSMA for 20 minutes a session are an effective treatment for verbal retrieval deficits in GWI.

The goal of this proposal is to entrain the verbal retrieval circuit using HD tDCS to target the preSMA in order to improve retrieval in impaired GWI patients, using behavioral and electrophysiological markers to assess outcomes. After identifying GWI patients with retrieval deficits using standard neuropsychological measures, the following aims will be


Aim 1. Administer 10 20-minute sessions of either 1 mA high definition tDCS or sham to the preSMA region.

Subtypes of Gulf War Illness patients have been shown to have dysfunction that disrupts the above-described retrieval circuit. Transcranial DCS targeted to the preSMA has been shown in preliminary studies in other diseased populations to result in improved performance in tasks that engage this circuit by purportedly strengthening potentially weak connections within the preSMA-caudate-thalamus circuit for verbal retrieval.

Hypothesis #1:HD tDCS to the preSMA will produce long-term modulation of the basal state of the preSMA-caudate-thalamic-cortical retrieval circuit.

Aim 2. Assess neuropsychological and electrophysiological (ERP) markers of verbal retrieval following tDCS therapy. Long-term modulation of the preSMA-caudate-thalamic-cortical retrieval circuit, via tDCS to the preSMA region, will alter the neurophysiological properties of the circuit due to modulation of the readiness of the retrieval circuit. This will result in changes in neural markers as follows:

Hypothesis #2a: Neuropsychological measures of verbal retrieval that were impaired at baseline will be improved to expected premorbid levels of functioning for the treated individuals.

Hypothesis #2b: Patients with impairments in making a correct retrieval will exhibit both high false negative errors and false positive errors compared to norms and a decreased 750-ms ERP amplitude difference between retrievals and nonretrievals on the SORT task. The investigators hypothesize that after HD tDCS treatment, these patients will improve performance and/or have an increase in amplitude difference in the ERP between retrievals and nonretrievals.

Hypothesis #2c: An increase in false negative errors and a decreased "Go" P3 ERP response on the Semantic Selection Tasks is indicative of an impaired ability to select a correct memory for retrieval. Conversely, there will be increased false positive errors and a decreased "NoGo" P3 ERP on the Semantic Selection Tasks if a patient cannot inhibit an incorrect memory. The investigators hypothesize that following HD tDCS therapy, there will be a normalization of the patient's behavior (reduced errors, improved RTs) and/or ERP responses (increased P3 amplitudes for Go and/or NoGo trials) due to modulation of the retrieval circuit, with the changes based on the pre-treatment impaired retrieval function (selection and/or inhibition).

Clinical Study Identifier: NCT03542383

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