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The impact of brain morphometry on tDCS effects on GABA levels

Open AccessPublished:October 18, 2019DOI:https://doi.org/10.1016/j.brs.2019.10.013

      Highlights

      • tDCS can change GABA levels during stimulation.
      • Brain morphometry of the area under the cathode electrode can impact tDCS changes on GABA levels.
      • Brain morphometry of the areas under the electrodes may be considered to optimize tDCS effects on neurotransmitter levels.

      Introduction

      Transcranial direct current stimulation (tDCS) applied over both dorsolateral prefrontal cortices (DLPFCs) can change neurotransmitter levels when measured with concurrent magnetic resonance spectroscopy (MRS) [
      • Dickler M.
      • Lenglos C.
      • Renauld E.
      • Ferland F.
      • Edden R.A.
      • Leblond J.
      • et al.
      Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder.
      ,
      • Hone-Blanchet A.
      • Edden R.A.
      • Fecteau S.
      Online effects of transcranial Direct Current Stimulation in real time on human prefrontal and striatal metabolites.
      ]. For instance, tDCS elevated prefrontal GABA levels in adults with gambling disorder (GD) [
      • Dickler M.
      • Lenglos C.
      • Renauld E.
      • Ferland F.
      • Edden R.A.
      • Leblond J.
      • et al.
      Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder.
      ]. Such effect may be clinically meaningful as medications targeting the GABAergic system can reduce craving [
      • Pettorruso M.
      • De Risio L.
      • Martinotti G.
      • Di Nicola M.
      • Ruggeri F.
      • Conte G.
      • Di Giannantonio M.
      • Janiri L.
      Targeting the glutamatergic system to treat pathological gambling: current evidence and future perspectives.
      ] and impulsivity in GD [
      • Berlin H.A.
      • Braun A.
      • Simeon D.
      • Koran L.M.
      • Potenza M.N.
      • McElroy S.L.
      • Fong T.
      • Pallanti S.
      • Hollander E.
      A double-blind, placebo-controlled trial of topiramate for pathological gambling.
      ]. However, there are still several unknowns on how tDCS influences brain activity. One factor that may influence tDCS effects is brain morphometry. This is of particular interest for populations known to display altered morphometry, such as GD [
      • Clark L.
      • Boileau I.
      • Zack M.
      Neuroimaging of reward mechanisms in Gambling disorder: an integrative review.
      ]. Further, animal studies showed that neuron morphology influences electric field stimulation in brain slices. Direct current is thought to favor depolarization of pyramidal neurons in layer V [
      • Radman T.
      • Ramos R.L.
      • Brumberg J.C.
      • Bikson M.
      Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro.
      ]. Considering that a greater number of neurons are found in areas of larger volume [
      • de Sousa A.A.
      • Proulx M.J.
      What can volumes reveal about human brain evolution? A framework for bridging behavioral, histometric, and volumetric perspectives.
      ], one could predict that brain areas with greater cortical volume have more pyramidal neurons that respond to tDCS. The goal of this exploratory study was to investigate the impact of brain morphometry on tDCS effects on GABA levels in adults with GD. We hypothesized that greater tDCS-induced elevation of GABA levels will correlate with greater volume and thickness of the DLPFCs.

      Methods

      We investigated the impact of brain morphometry on tDCS effects using data from a previous study [
      • Dickler M.
      • Lenglos C.
      • Renauld E.
      • Ferland F.
      • Edden R.A.
      • Leblond J.
      • et al.
      Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder.
      ]. This study was randomized, crossover, sham-controlled, and blinded at two levels (blinding assessed in patients and MRS experimenter). Each session, separated by 7 days, comprised an anatomical scan and a session of simultaneous tDCS delivery and MRS acquisition. Eighteen adults were recruited and two were not included in the analyses (one dropped out, one was rejected due to movement artifacts). Sixteen adults (seven women; mean age = 37.8 years, SD = 16.8) who met DSM 5 criteria for GD participated in this study. They provided their informed consent prior to their participation. tDCS was delivered with an MR-compatible DC-STIMULATOR (neuroConn GmbH, Germany). The 35-cm2 anode and cathode electrodes were placed over the right and left DLPFC, respectively, based on the 10–20 EEG system (F4, F3). Real tDCS was delivered for 30 min at 1 mA. Sham tDCS was delivered for 30 min with current applied during the first and last 30 sec of the session. Subjects were scanned with a Philips 3 Tesla Achieva scanner (Philips Healthcare, Netherlands). T1-weighted structural magnetic images were obtained with a magnetization prepared rapid acquisition gradient-echo sequence (repetition time = 8.2 ms; echo time = 3.7 ms; field of view = 250 mm; flip angle = 8°; 256 × 256 matrix; 180 slices/volume; slice thickness = 1 mm; no gap). We used CBrain to perform FreeSurfer 6.0.0 recon-all pipeline with default parameters [
      • Fischl B.
      • van der Kouwe A.
      • Destrieux C.
      • Halgren E.
      • Ségonne F.
      • Salat D.H.
      • Busa E.
      • Seidman L.J.
      • Goldstein J.
      • Kennedy D.
      • Caviness V.
      • Makris N.
      • Rosen B.
      • Dale A.M.
      Automatically parcellating the human cerebral cortex.
      ] and the Desikan-Killiany-Tourville protocol to label the cortices. Neurotransmitter levels were measured with the MEGA-PRESS acquisition sequence and a 3 × 3x3 cm3 voxel of interest in the right DLPFC. GABA levels were analyzed with GANNET 2.0 [
      • Edden R.A.
      • Puts N.A.
      • Harris A.D.
      • Barker P.B.
      • Evans C.J.
      Gannet: a batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra.
      ]. Pearson correlations were performed to test for correlations between neurotransmitter levels and morphometry measures, controlling for age. We used SPSS Statistics 26.0 (N.Y., U.S.). Effects were considered significant at p value ≤ .05. We applied Bonferroni correction for multiple comparisons within each tDCS site.

      Results

      For real tDCS, there were positive correlations between tDCS changes in GABA levels in the right DLPFC and morphometric measures of the left DLPFC (volume: r = 0.595, p = .019; thickness: r = 0.664, p = .007, after Bonferroni correction; Fig. 1a,b,c), but not of the right DLPFC (volume: r = 0.458, p = .086; thickness = r = 0.378, p = .165). There were no significant correlations for sham tDCS and morphometric measures of the left DLPFC (volume: r = 0.190, p = .498; thickness: r = 0.277, p = .317) or the right DLPFC (volume: r = 0.137; p = .626; thickness r = 0.076; p = .788). We then tested whether the left and right DLPFC differed in morphometric measures and found no differences for volume (t(30) = 1.792, p = .083; left DLPFC: mean = 10229.69, SD = 1543.66; right DLPFC: mean = 11311.88, SD = 1857.79) or thickness (t(30) = 1.736, p = .093; left DLPFC: mean = 2.24, SD = 0.154; right DLPFC: mean = 2.35, SD = 0.203).
      Fig. 1
      Fig. 1a) confidence intervals of correlations between changes in GABA levels in the right DLPFC during tDCS with morphometry of the right and left DLPFC, b) correlations between changes in GABA levels in the right DLPFC during tDCS with volume and c) thickness of the left DLPFC, and d) correlation between volume of the left DLPFC and scores at the non-planning subscale of the Barratt Impulsiveness Scale.
      We also explored for correlations between morphometric measures of the left and right DLPFC and behaviours related to gambling (i.e., South Oaks Gambling Screen, Barratt Impulsiveness Scale (BIS), and duration of GD) and found no correlations. There was one correlation, although not significant, that indicated a fair relationship between the volume of the left DLPFC and scores at the non-planning subscale of the BIS (r = −.462, p = .083; Fig. 1d).

      Discussion

      Results from this work revealed that brain morphometry influenced tDCS changes in prefrontal GABA levels. Elevation of GABA levels in the right DLPFC induced by tDCS delivered over both DLPFC was higher for greater volume and thickness of the left DLPFC, the area under the cathode. This may reflect that greater cortical areas comprise more pyramidal neurons that respond to tDCS. This is in line with studies showing that areas containing large pyramidal neurons are more prone to respond to direct current [
      • Radman T.
      • Ramos R.L.
      • Brumberg J.C.
      • Bikson M.
      Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro.
      ]. Results of this study also indicate that smaller volume of the left DLPFC was related with greater impulsivity at the non-planning subscale of the BIS, which evaluates “careful thinking and planning and enjoyment of challenging mental tasks” [
      • Patton J.H.
      • Stanford M.S.
      • Barratt E.S.
      Factor structure of the Barratt impulsiveness scale.
      ]. In bilateral tDCS montages, it is expected that the current flows from the area under the anode to that under the cathode, here across cortices, from the right to the left DLPFC. Thus, it would be interesting to test for potential changes in GABA levels in the area under the cathode, which we did not due to time constraint (MRS acquisition sequence of 12 min/voxel of interest during the 30-min tDCS delivery). Overall, it seems that patients with smaller volume of the left DLPFC are more impulsive and respond less to tDCS in regards to GABA levels. This may be peculiarly relevant for tDCS studies aiming at modulating GABA levels that consequently may reduce impulsivity in clinical populations that are known to display brain morphometry abnormalities, especially in tDCS targeted areas.

      Funding source

      This work was supported by a Parkinson Society Canada grant ( FO103232 ) and Natural Sciences and Engineering Research Council of Canada grant ( 402629-2011 ) to SF. AEB is supported by a Canadian Institutes of Health Research Frederick Banting and Charles Best Doctoral Award . SF is supported by the Canada Research Chair in Cognitive Neuroplasticity .

      Declaration of competing interest

      The authors declare no conflict of interest.

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