Cerebral Blood Flow and tDCS
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional

Summary: 
      With this study, the investigators will substantiate if regional cerebral blood flow (CBF) is
      affected by tDCS, assess the amount of CBF change in relation to different currents, and
      measure differences in regional CBF under stimulation reactivity between healthy subjects and
      people with Multiple Sclerosis (PwMS)using Water O-15 PET (Water Oxygen-15 Positron
      EmissionTomography) imaging. The objective is to investigate the changes in regional CBF
      after transcranial direct current stimulation (tDCS) at different intensities (1 mA, 2 mA, 3
      mA, 4 mA) in healthy subjects and PwMS. The design is a cross-sectional proof of principle
      study in 10 healthy subjects and 10 PwMS.

      Relative regional brain CBF (rCBF) will be analyzed semi-quantitatively using voxel-wise and
      region of interest-based approaches. Changes in CBF associated with tDCS-application will be
      calculated with a general linear model in a ramp function of the task-specific rCBF,
      according to previous work in our group using a glucose analogue. Exploratory statistical
      testing will be done using a paired samples t-test between task and rest conditions and
      unpaired t-tests between PwMS and healthy controls at the same intensities.

      With this study the investigators will be able to dose-dependently measure real-time rCBF
      changes after non-invasively stimulating the superficial parts of the dorsolateral prefrontal
      cortex (DLPFC), a commonly used target in therapeutic tDCS applications. This will provide
      further insight into whether tDCS is capable of inducing changes in rCBF.
    

Detailed description: 
      Aim 1: To determine the effects of different stimulation intensities on relative cerebral
      blood flow (rCBF).

      Currently, researchers use tDCS as an interventional modality to modulate the excitability of
      the brain, with measureable changes in both motor evoked potentials and physical
      performances. However, because of the relatively large size of most electrodes, and the
      electrodynamics of the brain, it still remains unclear what specific brain structures are
      being stimulated and how the mechanics of stimulation (e.g., stimulation penetration and
      areas affected outside of target area) change with different intensities. The investigators
      hypothesize that regional CBF at the DLPFC (target area) will increase in a dose-dependent
      way with greater stimulation intensity. Furthermore, it is hypothesized that the areas
      surrounding the DLPFC will be increasingly affected by higher stimulation intensities.

      Aim 2: To contrast the effects of transcranial direct current stimulation on relative
      cerebral blood flow between healthy subjects and people with Multiple Sclerosis.

      PwMS typically present with glucose hypometabolism compared to their healthy peers and
      because CBF and glucose metabolism are highly coupled, a similar trend in CBF may be
      expected. Additionally, tDCS has been shown to be effective at increasing cortical
      excitability and glucose metabolism in both populations. However, what still remains
      uncertain is if PwMS and healthy subjects experience the same amount of increased activity
      for the same stimulation intensity. The investigators hypothesize that PwMS will experience a
      greater increase in rCBF at the DLPFC and surrounding areas than healthy controls for the
      same stimulation intensity.

      Aim 3: To extend our understanding of the safety and efficacy of transcranial direct current
      stimulation at higher current intensities for healthy subjects and people with Multiple
      Sclerosis.

      Despite some work on the feasibility and safety of performing tDCS at intensities > 2 mA
      (i.e., up to 4 mA), the convention for most tDCS studies is to use intensities less than or
      equal to 2 mA. This has been sufficient to illicit measurable effects in both excitability
      and performance outcomes. However, the potential benefits of increasing intensity to either
      enhance the effects of a given stimulation protocol (e.g., time or magnitude) or to
      potentially access deeper brain areas justifies further exploration of current intensities >
      2 mA. It is also important to add to the safety protocol of higher intensities in healthy and
      clinical (e.g., PwMS) subjects. The investigators hypothesize that higher intensities (i.e.,
      > 2 mA) will be well tolerated by both healthy subjects and PwMS. Additionally, the
      investigators hypothesize no serious adverse effects from higher stimulation intensities. The
      existing side-effects of tDCS at intensities less than or equal to 2 mA include low-grade
      occurrences of tingling, itching, and burning sensation at the electrode sites; a few
      subjects have reported short-lived (< 5 min) headaches. In a study testing the safety of
      higher intensities similar to those proposed here, these same side-effects were observed in
      50% of the subjects. This rate of occurrence is slightly higher than studies using less than
      or equal to 2 mA, but the magnitudes of the negative effects were still well within safely
      tolerable limits and were all transient in nature.

      I.6 Background and significance and/or Preliminary studies related to this project.

      (do not indicate "see protocol") Transcranial direct current stimulation (tDCS) is a
      non-invasive and well-tolerated brain stimulation technique (1-4) that can modulate the
      cortical excitability of targeted brain regions (5) as well as cerebral blood flow (6) in a
      polarity-dependent manner.

      Models of tDCS current flow (7,8) and findings from studies in which human functional
      magnetic resonance Imaging (fMRI) has been used to measure brain activity (9-11) suggest that
      tDCS can alter processing across large areas of the cortex. In this sense, the effects of
      tDCS are likely to be relatively broad. Thus, while the neural changes induced by tDCS are
      concentrated around regions of cortex closest to the electrodes (12), broader networks of
      functionally-connected regions may also be recruited (9,10,13,14). Furthermore, no systematic
      investigation has been done to determine the most efficacious current intensity for PwMS.

      There is empirical evidence that tDCS with current intensity between 1 and 2 mA for 20-40
      minutes for either single or multiple sessions can safely and effectively be administered to
      PwMS (15-20). Although tDCS with current intensities > 2 mA are considered safe 21, no
      studies have investigated how brain activity is affected during tDCS at intensities > 2 mA.
      Although the safety of higher intensity tDCS in PwMS may be initially assumed from previous
      work using subjects who have experienced a stroke (21), it has also been suggested that more
      studies on the safety of higher intensity stimulation in other populations are needed in
      order to exercise due diligence before widely prescribing intensities greater than the
      present convention (22).

      The cerebral activation in PwMS has been investigated with [15O] water and with [15O] O2 PET
      (indexes oxygen metabolism)(23). Widespread reductions in cerebral blood flow and oxygen
      metabolism in both gray and white mater have been reported in PwMS (24). Furthermore, these
      studies indicate that the degree of oxygen metabolism reduction correlated with worse
      cognitive performance and expanded disability status scale (EDSS), and that the degree of
      cerebral oxygen hypometabolism was associated with the number of relapses (25).

      A close coupling of perfusion and metabolism is assumed, reflecting oxidative phosphorylation
      of glucose as the predominant source of energy production. Consequently, CBF is often
      considered as an indirect measure of neuronal function and integrity (26). This is supported
      by the significant association of metabolism with regional CBF (rCBF) across different brain
      regions (27,28), and with global CBF (gCBF) across varying states of consciousness (29).

      With this study, the investigators will be able to substantiate if rCBF is affected by tDCS,
      assess the amount of signal change in relation to different currents, and measure differences
      in CBF distribution under stimulation reactivity between healthy subjects and PwMS. The
      objective is to investigate the changes in rCBF after transcranial direct current stimulation
      at different intensities (1 mA, 2 mA, 3 mA, 4 mA) in healthy subjects and PwMS. The design is
      a cross-sectional proof of principle study in 10 healthy subjects and 10 PwMS.
    

Intervention name(s): tDCS
Intervention type(s): Device
Intervention description(s): Subjects will get tDCS at intensities of 0, 1, 2, 3, and 4 mA.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: People with Multiple Sclerosis and healthy controls will receive tDCS at different intensities while in the PET scanner.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Multiple Sclerosis; tDCS; Cerebral Blood Flow