Mechanism and Dosimetry Exploration in TES Magnetic Resonance Current Mapping Methods
Condition: Transcranial Direct Current Stimulation
Study type: Interventional

Summary: 
      In this study the investigators will explore dosimetry in transcranial electrical stimulation
      using a novel magnetic resonance imaging technique that can determine how electrical
      stimulation distributes within the brain. The investigators will then combine this imaging
      technique with functional MR imaging to attempt mechanistic associations. If successful, the
      study outcomes will be an improved understanding of the interactions between electric current
      distributions and structures presumed to be targeted by stimulation.
    

Detailed description: 
      Transcranial electrical stimulation (tES) techniques such as transcranial DC stimulation
      (tDCS) and transcranial AC stimulation (tACS) have been indicated for conditions as diverse
      as stroke rehabilitation, epilepsy and for improvements in memory tasks. Thousands of tES
      studies have been published since 20001. In typical tDCS procedures a pair of large
      electrodes (e.g., 25cm2) is attached to the scalp and a constant current of 1-2 mA passed
      between them for periods of 10-30 min. In tACS, the constant current intensity is similar,
      but an alternating sinusoidal waveform is usually employed. Variations on these techniques
      exist. For example, in oscillatory tDCS, a temporally oscillating current is combined with a
      DC offset current. In transcranial random noise stimulation (tRNS) temporally random currents
      with a fixed maximum intensity are applied. These transcranial electrical neuromodulation
      strategies have been indicated for a wide range of conditions, including stroke
      rehabilitation, treatment of epilepsy and for improving cognitive, motor and language and
      memory performance in healthy subjects. Details of the underlying mechanisms of both tDCS and
      tACS remain unclear. It has been assumed that the effects of tDCS are greatest in brain
      structures nearest to stimulating electrodes and that these structures experience the largest
      electric fields or current flow. In tDCS applied at 1 mA current intensities, it has been
      found that excitatory effects broadly correlate with placement of more positive electrodes
      over a targeted structure, and inhibitory effects are observed in structures under cathodes.
      It has been hypothesized that this is because externally applied field either depolarizes or
      hyperpolarizes resting membrane voltages in targeted tissue, leading to increased
      excitability or inhibition respectively. This suggests that increased excitability or
      inhibition would result when current intensity is increased. However, there is also evidence
      that at 2 mA intensity increased excitability is observed, regardless of polarity. The
      effects observed may also depend on the total stimulation time.

      In tACS, it has been found that at low frequencies (up to 80 Hz) tACS excitation frequencies
      may entrain neural networks with excitatory or inhibitory effects that depend on the
      frequency chosen, the current intensity and the phase of current application relative to
      underlying EEG rhythms.

      Intersubject variability has been reported in both tDCS and tACS, and study reproducibility
      has been problematic. Apart from factors relating to the subject initial state, individual
      neuroanatomy and differences in cerebrospinal fluid volume, it has also been suggested that
      major contributions to variability between individual sessions of a study or may be
      inconsistencies in electrode application protocol. In particular, overuse of saline contact
      medium can result in the effective electrode area increasing beyond the electrode face, and
      if fastening straps are thinner than electrodes, contact area may be reduced. Electrodes may
      also move during sessions, or be placed inconsistently on different subjects. Between sites,
      reproducibility may be degraded because electrode shapes, types and placements are not
      consistent.

      Knowledge of the exact distribution formed within the brain by the externally applied
      currents would clarify many study outcomes and most importantly allow more precise
      explorations of mechanism. Further, the effects of different current application protocols,
      electrode designs and study procedures could easily be resolved. Thus, a method for measuring
      current distributions formed by tDCS or tACS would answer many questions in this active
      field.

      In the absence of methods for easily measuring or imaging current flow distributions,
      computational models have been used extensively to predict flow patterns. A large literature
      exists using computational models to explore effects of different montages, electrode areas
      and geometries on voltage distributions, electric fields or current flow. Increasingly
      sophisticated approaches have been devised to model the head subject to tDCS stimulation. As
      the field has grown, head model complexity has increased from spherical uniform, spherical
      four-compartment, realistic geometry, to high-resolution anisotropic models of the human head
      subject to electrical stimulation. This last category has involved merging source images
      based on MR images with diffusion-weighted images of the subject to predict white matter
      conductivity tensors. One approach to this uses water translational diffusion tensor
      eigenvectors to determine the direction of the conductivity tensor (assuming they are
      co-aligned) in combination with literature values of white matter conductivities. Another
      approach involves direct scaling of the white matter diffusion tensor to conductivity values.
      Most other model tissue conductivities are chosen from values measured on bulk tissues in the
      literature. However, to date no validation of these models has been possible in human
      subjects.

      Some efforts have been made to measure current distributions resulting from tDCS. In a recent
      paper, Opitz et al. measured electric field distributions caused by transcranial stimulation
      via electrodes placed in a bilateral montage (left and right temples) using electrode arrays
      placed near the cortical surface of patients being monitored to identify epilepsy seizure
      foci. tACS was applied at 1-15 Hz with an intensity of 1 mA, and maximum electrical field
      strengths of 0.36 and 0.16 mV/mm were identified. A slight frequency dependent increase in
      conductivity (ca. 10%) was observed, and little capacitive effect. Again, these field
      strengths would not normally be sufficient to cause direct tissue stimulation, and support
      theories that slight depolarizations may be responsible for tDCS effects.

      Researchers seeking to understand tES mechanisms have initiated fMRI studies to investigate
      the correlation of therapeutic current administration and brain activity as evidenced by
      changes in the BOLD contrast18-20. In the course of this research it has been noted that
      current administration creates artifacts on MR images. In another paper, fMRI analysis
      methods were used to find voxel clusters correlating with current flow features22. However,
      to date, there have been no attempts to non-invasively image tDCS or tACS current density
      distributions in humans directly.

      The technique of Current Density Imaging (CDI) as suggested by Scott et al. (1991) is a
      method for translating the phase part of magnetic resonance images into individual magnetic
      flux density vector components caused by an externally applied current flow. These
      measurements can then be used to compute current density distributions using Ampere's law.
      The basic CDI technique requires the external current to be injected into subjects in concert
      with a sequence of RF pulses and gradient fields used to create MR images. The technique was
      demonstrated in phantoms and used to image current flow in a rabbit brain. Unfortunately, it
      is infeasible in humans because of the need to rotate the subject twice inside the scanner
      bore in order to obtain all three components of the magnetic flux density.

      MR Electrical Impedance Tomography (MREIT) has been developed over the last decade as a
      method for imaging current density and conductivity distributions in the human body. As in
      CDI, MREIT requires current to be applied to a subject in conjunction with a particular MR
      sequence. However, MREIT methods make it possible to reconstruct conductivity, electric field
      and current density distributions in subjects by using only one component (Bz) of magnetic
      flux density vectors. A recently developed MREIT method, DT-MREIT, can be used to reconstruct
      full anisotropic conductivities and current density distributions using MREIT and DTI data
      gathered from the same subject, and has recently been demonstrated in canines.

      In this work, the investigators will use MREIT methods to produce:

      A. Quantitative physical measures demonstrating tES reproducibility, exploring effects of
      current intensity, sex and neuroanatomic differences on measured current distributions.

      B. Comparisons of actual current density distributions developed in a target structure
      (DLPFC) with fMRI measures of activity.

      These studies will provide the first tests of the assumptions that

        -  effects of tDCS stimulation are largest in the targeted region

        -  that the largest field and current flow is found in the targeted region These studies
           therefore have the potential to revolutionize understanding of tES mechanisms and
           practice.

      This work has three aims, one focused on technical improvements in our present MREIT
      acquisition procedures, another targeted at quantifying replicability, measuring current flow
      distributions at different current intensities, and finally, in assessing correlations of
      electric field and current density distributions with brain activity measures using fMRI.

      Specific Aim 1 (SA1) MREIT Pulse Sequence Acceleration and Improvements.

      Specific Aim 2 (SA2) Replicability and Consistency in tDCS/tACS Protocols Current density
      distributions will be imaged in normal volunteers using an F3-F4 montage with three different
      current intensities, and repeat the measure at intervals of at least one week. Each time, the
      montage will be reapplied and subjects re-imaged. Both intra- and inter-subject variations in
      measured current and electric field distributions will be determined.

      Specific Aim 3 (SA3) Correlation of functional measures with measured electrical distribution
      measures Participants' performance on a 2-back/0-back memory task will be compared in both
      Sham and Active subjects, using either 1, 1.5 or 2 mA intensity stimulation.
    

Intervention name(s): tDCS; Sham
Intervention type(s): Device; Other
Intervention description(s): Current will be administered to subject groups as specified in arm descriptions.; Apparent Stimulation administered
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Structural (T1-weighted) and high angular resolution diffusion images of participant heads will be obtained. Current density distributions in normal participants will be imaged using an F3-F4 montage at three different current intensities. Measures will be repeated at intervals of at least one week. Each time, the montage will be reapplied and subjects re-imaged. Because the imaging method is quantitative, these measures will be used to provide an indication of baseline replicability. Both intra- and inter-subject variations in measured current and electric field distributions will be determined.
Participant performance on a 3-back/0-back memory task will be compared in both Sham and Active subjects, using either 1, 1.5 or 2 mA intensity stimulation.
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: fMRI; mechanism; tDCS; neuromodulation