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Brain Stimulation 14 (2021) 154e160

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Brain Stimulation

journal homepage: http: / /www.journals .e lsevier .com/brain-st imulat ion

tDCS-induced modulation of GABA concentration and dopaminerelease in the human brain: A combination study of magneticresonance spectroscopy and positron emission tomography

Tomoyasu Bunai a, Tetsu Hirosawa b, Mitsuru Kikuchi b, Mina Fukai b,Masamichi Yokokura c, Shigeru Ito d, e, Yohei Takata e, Tatsuhiro Terada a,Yasuomi Ouchi a, d, *

a Department of Biofunctional Imaging, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine,Hamamatsu, Japanb Department of Psychiatry and Neurobiology, Kanazawa University, Kanazawa, Japanc Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japand Hamamatsu Medical Imaging Center, Hamamatsu Medical Photonics Foundation, Hamamatsu, Japane Global Strategic Challenge Center, Hamamatsu Photonics KK, Hamamatsu, Japan

a r t i c l e i n f o

Article history:Received 8 June 2020Received in revised form1 December 2020Accepted 21 December 2020Available online 28 December 2020

Keywords:Transcranial direct current stimulationg-aminobutyric acidMagnetic resonance spectroscopyDopaminePositron emission topography

* Corresponding author. Department of BiofuncMedical Photonics Education & Research Center, HamMedicine, Hamamatsu, Japan 1-20-1 Handayama, HShizuoka, 431-3192, Japan.

E-mail address: ouchi@hama-med.ac.jp (Y. Ouchi)

https://doi.org/10.1016/j.brs.2020.12.0101935-861X/© 2020 The Author(s). Published by Elsevie).

a b s t r a c t

Background: Transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC)hypothetically modulates cognitive functions by facilitating or inhibiting neuronal activities chiefly in thecerebral cortex. The effect of tDCS in the deeper brain region, the basal ganglia-cortical circuit, remainsunknown.Objective: To investigate the interaction between g-aminobutyric acid (GABA) concentrations anddopamine release following tDCS.Method: This study used a randomized, placebo-controlled, double-blind, crossover design. Seventeenhealthy male subjects underwent active and sham tDCS (13 min twice at an interval of 20 min) with theanode placed at the left DLPFC and the cathode at the right DLPFC, followed by examinations with [11C]-raclopride positron emission topography (PET) and GABA-magnetic resonance spectroscopy (MRS). MRSvoxels were set in the left DLPFC and bilateral striata. Paired t-tests and regression analyses were per-formed for PET and MRS parameters.Results: MRS data analyses showed elevations in GABA in the left striatum along with moderate re-ductions in the right striatum and the left DLPFC after active tDCS. PET data analyses showed that re-ductions in [11C]-raclopride binding potentials (increase in dopamine release) in the right striatum wereinversely correlated with those in the left striatum after active tDCS. GABA reductions in the left DLPFCpositively correlated with elevations in GABA in the left striatum and with increases in right striataldopamine release and negatively correlated with increases in left striatal dopamine release.Conclusion: The present results suggest that tDCS to the DLPFC modulates dopamine-GABA functions inthe basal ganglia-cortical circuit.© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

tional Imaging, Preeminentamatsu University School ofigashi-ku, Hamamatsu city,

.

r Inc. This is an open access article

Introduction

Transcranial direct current stimulation (tDCS) to the dorsolat-eral prefrontal cortex (DLPFC) has attracted attention as a newtreatment for neuropsychiatric disorders, and clinical improvementin Alzheimer’s disease [1] and depression [2] has been reported.The mechanism of tDCS is thought to be through electrophysio-logical modulation of neurotransmitters such as glutamate and g-

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

T. Bunai, T. Hirosawa, M. Kikuchi et al. Brain Stimulation 14 (2021) 154e160

aminobutyric acid (GABA) at the site of stimulation [3]. Recently,tDCS to the DLPFC has been shown to increases dopamine release inthe striatum [4], and we showed a clear correlation between im-provements in cognitive function and dopamine release in the rightstriatum [5]. Since the currently accepted mechanism of tDCS re-lates to the occurrence of polarity-specific changes in neuronalexcitability, i.e., increments or decrements [6], these findings helpunderstand a tDCS-related positive effect on cognitive functions ina variety of situations, i.e., a contribution of the dopaminergicsystem beyond the neuronal excitability theory itself. Although anonline effect of tDCS reportedly failed to alter brain GABA levels [7],there has been no study about its offline effect on GABA, which isthe most conventional application in a repeated/intermittentstimulation manner. Because tDCS was reported to alter dopaminein the striatum as mentioned, it can be speculated that tDCSmodulates neurotransmitters in the basal ganglia-cortical circuit.This speculation (stimulation-induced dopamine release) may befurther supported by a previous non-invasive brain stimulationstudy with transcranial magnetic stimulation (TMS) showing thatthe stimulation to the left DLPFC enhanced dopamine release in thestriatum [8]. However, it remains unclear how tDCS modulatesGABA within the basal ganglia-cortical circuit in relation to thedopaminergic response.

The basal ganglia-cortical circuit is not only an anatomical systembut also a functional system that is always working properly duringmotor, emotional and cognitive performances [9e11]. Glutamate,dopamine and GABA are key players as neurotransmitters engagingin basal ganglia-cortical circuit regulation, which has been closelylinked with various cognitive functions in humans [12e15]. Amongthese neurotransmitters, dopamine may have two functional roles:excitatory and inhibitory [16]. A previous functional connectivitystudy showed that L-DOPA administration to healthy subjectsincreased neuronal variability in various somatosensory and motorregions [17], suggesting that dopamine signaling increased intra-network functional connectivity and tissue activity within the so-matosensory region. In this respect, dopamineworks as an excitatorymolecule, unlike GABA, which functions in an inhibitory manner.Considering neuropsychiatric disorders such as Parkinson’s disease(PD) and schizophrenia, therapeutic targets are mostly dopamineand GABA systems within this circuit. In addition, recent reportsabout these neuropsychiatric disorders with tDCS amelioratingdopamine-related or GABA-involved symptoms [18] would suggestthat there is some interaction or modification in these two neuro-transmitter systems under tDCS. Indeed, most striatal medium spinyneurons contain GABA, and anodal stimulation that would theoret-ically depolarize neurons under glutamatergic activation may in-crease GABA concentrations in the striatum.

Many mechanistic studies of tDCS have likely focused on theneurons and glia residing in the cerebral cortical regions, not in adeeper brain region such as the basal ganglia. Here, we investigatedtDCS-induced changes in dopamine and GABA levels in the basalganglia-cortical circuit region using [11C]-raclopride positronemission topography (PET) and GABA-MRS to explore the rela-tionship between these two neurotransmitters following tDCS tothe DLPFC.

Material and methods

Subjects

We recruited 22 healthy 20e26-year-old men using poster ad-vertisements from a neighboring university. Five subjects wereexcluded for the following reasons: 2 experienced claustrophobiain the MRI scanner and 3 showed signal artifacts induced by mo-tion. Therefore, data from 17 subjects were analyzed in this study

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(Fig. 1A). All subjects were right-handed native Japanese with anintelligence quotient (IQ) higher than 80 (mean [SD] IQ, 109.2 [6.7];IQ range of 97e120) on the Japanese reading test (JART) [19].Subjects with a history of traumatic brain injury, organic braindiseases, psychiatric disorder, seizure, chronic headache, or anepisode of unconsciousness lasting more than 5 min and subjectswho could not undergo an MRI scan were excluded from the study.Written informed consent was obtained before enrollment. TheEthics Committees of Hamamatsu University School of Medicineand Hamamatsu Medical Photonics Foundation approved themethods and procedures used for this study, which were applied inaccordance with the Declaration of Helsinki. The study was regis-tered with the University Hospital Medical Information NetworkClinical Trials Registry (no. UMIN000020583).

Experimental design

This study used a randomized, sham-controlled, double-blind,crossover design. The participants completed two sessions at least1 month apart to control for carry-over effects. The participantsthen underwent 26 min of tDCS (either active or sham) to theDLPFC, after which PET, magnetic resonance imaging (MRI) andMRS were performed. PET was performed at 50 min after initiationof tDCS, followed by MRS measurement at 140 min post-stimulation (Supplementary Fig. 1).

Intervention: tDCS

Two soaked (NaCl 0.9%) anodal and cathodal electrodes (35 cm2)using DC-STIMULATOR PLUS (neuroCare Group GmbH, Ilmenau,Germany) were placed at the left frontal areas and right frontalareas, respectively. Thirteen minutes of tDCS with a current in-tensity of 2 mA was applied twice at an interval of 20 min. Aftermore than a month, sham stimulation was applied. With the sameelectrodes placed as in the true stimulation condition, the shamstimulation was switched off 30 s after the stimulation started. Thestimulation type (active or sham) was randomized across sessionsand crossovered across participants. The interventions with tDCSwere almost identical to those used in a recent study [5]. No sideeffects were found during and after active and sham tDCS in allparticipants.

MRI scanning and MRS measurements

Scanning was performed with a 3T MRI machine (Ingenia;Philips Healthcare, Best, The Netherlands). MRI was applied toascertain the areas of concern for establishing the volumes of in-terest (VOIs) with the following acquisition parameters: three-dimensional mode sampling, TR shortest (6 ms) and TE shortest(2.7 ms), 8� flip angle, 0.9 � 0.9 � 0.9 mm3 voxel size, 210 slices).

Spectroscopy measurements were acquired just after each PETscan. We obtained spectroscopy measurements using the MEGA-PRESS sequence for detecting GABA and other brain metabolites.VOIs for MRSwere established in the left DLPFC and bilateral striata(Fig. 1B). The MEGA-PRESS spectra were acquired from45� 30� 20mm3 voxels (left DLPFC) and 30� 30� 30mm3 voxels(bilateral striata). We used the following spectroscopy parameters:TR/TE ¼ 2000/68 ms, 320 averages, 10-min scan. We analyzedGABA and NAA concentrations using LCModel software (Version6.3-1L; Stephen Provencher Inc., Oakville, Ontario, Canada).

PET data acquisition and image data analyses

As recently described in detail [5], positron emission tomogra-phy was performed using a high-resolution brain PET scanner

Fig. 1. Experimental designConsolidated Standards of Reporting Trials (CONSORT) flow chart (A) and placement of volumes of interest (B).

T. Bunai, T. Hirosawa, M. Kikuchi et al. Brain Stimulation 14 (2021) 154e160

(SHR12000; Hamamatsu Photonics K.K., Hamamatsu, Japan), andthe [11C]-raclopride binding potential (BPND) in each region wasestimated based on a noninvasive Logan plot analysis using soft-ware (PMOD 3.5; PMOD Technologies LLC, Zurich, Switzerland).Regions of interest (ROIs) were located bilaterally in the striatum, inwhich tDCS has been shown to increase the level of endogenousdopamine release.

Statistical analyses

Datawere analyzed using software (Statistical Package for SocialSciences ver. 23; SPSS Inc., Chicago, IL, USA). Paired t tests wereapplied to compare the GABA:NAA ratios in the respective brainregions between active and sham stimulation conditions. Pearson

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correlations were used to assess the correlations between differ-ences ([active]-[sham]) in the GABA:NAA ratio in each region (leftDLPFC and bilateral striata) and %reduction ({[sham]-[active]}/[sham]) of [11C]-raclopride BPND in the bilateral striata after activeand sham stimulations. For all results, statistical significance wasinferred for p < 0.05 after correction for multiple comparisons.

Results

Post-tDCS changes in the GABA:NAA ratio and correlations

Paired t tests showed that the GABA:NAA ratio in the leftstriatum was higher after active stimulation than after shamstimulation, but correction for multiple comparisons prevented our

Table 1Levels of GABA/NAA after active and sham stimulation.

Stimulation Striatum DLPFC

Left Right Left

Active 0.38 ± 0.05* 0.31 ± 0.05 0.23 ± 0.06Sham 0.34 ± 0.06 0.33 ± 0.05 0.25 ± 0.05

Data are presented as mean ± SD. *p < 0.05 vs sham.DLPFC: dorsolateral prefrontal cortex.

T. Bunai, T. Hirosawa, M. Kikuchi et al. Brain Stimulation 14 (2021) 154e160

data from reaching significance (P ¼ 0.021). In contrast, the meanvalue of the difference in the GABA:NAA ratio in the right striatumand left DLPFC after active tDCS was below zero (Table 1, Fig. 2A). Asignificant negative correlation was found between changes in theGABA:NAA ratios in the left striatum and those in the left DLPFC(r ¼ �0.575, p ¼ 0.016) (Fig. 2B), indicating that the higher theGABA:NAA ratio in the left striatum became, the lower the value inthe left DLPFC. There was no correlation between the right striatumand the left DLPFC (Fig. 2C).

Correlations of [11C]-raclopride binding between the bilateral striata

The %reduction in [11C]-raclopride BPND (an index of dopaminerelease) was higher in the right striatum (Fig. 3A), as reportedpreviously [5]. There was a significantly negative correlation be-tween %reduction in [11C]-raclopride BPND in the right and leftstriata (r ¼ �0.542, p ¼ 0.025) (Fig. 3B). This [11C]-raclopride PETresult indicated that dopamine release in the bilateral striatal re-gions after prefrontal tDCS varied in opposite directions.

Fig. 2. Changes in GABA:NAA ratios in the cortico-striatal regionsThe GABA:NAA ratio was higher in the left striatum after active stimulation than sham stimuthe GABA:NAA ratio.

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Correlations between the cortical MRS and striatal PET data

Correlation analysis showed a significant positive correlationbetween %reduction of [11C]-raclopride BPND (dopamine releaseindex) in the left striatum and a difference in the GABA:NAA ratio inthe left DLPFC (r ¼ 0.564, p ¼ 0.018) (Fig. 4A) and a negative cor-relation between %reduction of [11C]-raclopride BPND in the rightstriatum and a difference in the GABA:NAA ratio in the left DLPFC(r ¼ �0.686, p ¼ 0.002) (Fig. 4B), indicating that as %reduction of[11C]-raclopride BPND (dopamine release index) in the left striatumdecreased and that in the right striatum increased, the GABA:NAAratio in the left DLPFC decreased.

Discussion

The present study showed that tDCS under this particularelectrode montage (an anode over the left DLPFC and a cathodeover the right DLPFC) caused significant increases in dopaminerelease in the right striatum and GABA concentrations in the leftstriatum. The GABA concentrations in the left DLPFC under theanode tended to be lower, in line with a previous report [3] thatstimulation of the anode suppressed GABA transmission. Positivecorrelations of cortical GABA change with ipsilateral striatal GABAchanges and with contralateral striatal dopamine release afterDLPFC anodal tDCS suggest that tDCS could modulate the mono-aminergic systems in the deep brain structures, which would gobeyond the theory of a tDCS mechanism based on glutamatergicand GABAergic activities changing within the cortical region.

In the present double-blind, crossover design study, the par-ticipants received 13 min of stimulation twice at an interval of

lation (*p < 0.05). The ordinate denotes %change. Fig. 2B and C shows correlations with

Fig. 3. Changes in [11C]-raclopride BPND in the striatumSignificant increases in [11C]-raclopride BPND in the right striatum (A). Correlation of changes in [11C]-raclopride BPND between the bilateral striata (B).

T. Bunai, T. Hirosawa, M. Kikuchi et al. Brain Stimulation 14 (2021) 154e160

20 min. It has been reported that tDCS induces after-effects lastingfor more than 24 h with a single stimulation [20,21] or repeatedstimulations within short intervals [22]; hence, our study wassufficient to evaluate after-effects using PET and MRS after thestimulations. Regarding the tDCS montage, stimulation of the mo-tor cortex is well known to induce changes in motor performanceand learning [23]. In contrast to motor cortex stimulation, stimu-lation of the DLPFC has been shown to strongly correlate withcognitive function and caused higher electric field peaks in thestriatum than stimulation with other montages [24]. Similarly, ourprevious study focused on attention enhancement and dopaminerelease in the striatum [5]. There has been only one study of thestriatal GABA system in which GABA concentrations did notsignificantly change under online stimulation: 1 mA of continuousstimulation for 30 min [7]. The discrepancy with our results couldbe explained by different protocols, such as the timing of thestimulation, the current intensity (1 mA vs. 2 mA) and interstim-ulation intervals.

In the present study, GABA in the left striatum and dopamine inthe right striatum were significantly increased after active tDCS.The left DLPFC and right striatal GABA levels tended to decrease.There was a positive correlation between reduced GABA in the leftDLPFC and increased GABA in the left striatum and dopamine in theright striatum and a negative correlation between reduced GABA inthe left DLPFC and increased dopamine in the left striatum. Fig. 5 isa schematic summary of the present study, illustrating that DLPFCanodal tDCS upregulates ipsilateral striatal GABA concentrationsand contralateral striatal dopamine release. Previous animal ex-periments with neurochemical substances have shown that pre-frontal cortical dopamine and GABA cooperate to modulate the

Fig. 4. Correlations between the cortical MRS and striatal PET data.A positive correlation is present between the left DLPFC MRS data and the left striatal PET dastriatal PET data (p < 0.05).

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release of dopamine in the striatum [25] and that stimulation ofGABA systems decreased dopamine release in the striatum [26,27].Consistently, we found in the present study that the GABA re-ductions in the left DLPFC were associated with striatal dopaminerelease, the GABA increases in the left striatum reduced dopaminerelease, and the GABA reductions in the right striatum coincidedwith dopamine release. A previous MRS study showed that thelower left DLPFC GABAwas associated with greater performance ofworking memory [28]. In line with this finding, we reported thatimprovement of attention correlates with striatal dopamine release[5] in the tDCS experiment, inwhich the GABA content in the DLPFCunder the anodal stimulation was lower as shown in the currentstudy. The functional connectivity study on the cortico-striatalcircuit showed that anodal tDCS on the motor cortex (albeit notDLPFC) augmented functional coupling between the striatum andparietal cortex on the same hemispheric side [29], suggesting thatthe striatum and cerebral cortex were functionally connectedpossibly using information of neurotransmitters such as GABA anddopamine as found in this study. Thus, anodal tDCS to the DLPFCmay exert a modulatory effect on behavior by regulating neuro-transmitters possibly to make functional connectivity optimallytuned within the cortico-striatal circuit.

The present study showing tDCS-induced dopamine and GABAchanges in the striatum may be a clinical proof of concept, whichallows us to apply this method to patients with monoaminergicdysfunction. Indeed, tDCS to the DLPFCmay be useful in Parkinson’sdisease (PD) because it has been reported that PD patients manifestdopamine deficiency and a decrease in GABA in the basal ganglia asassessed by MRS [30]. In many studies of tDCS applied to PD pa-tients, the motor cortex is a main target, and the effects have varied

ta, and a negative correlation is present between the left DLPFC MRS data and the right

Fig. 5. Illustration of the prefrontal tDCS effect on the GABA and dopamine systemsCortical tDCS differentially affects the monoaminergic systems in deep brain regions.

T. Bunai, T. Hirosawa, M. Kikuchi et al. Brain Stimulation 14 (2021) 154e160

depending on the study [31]. Considering the present result, i.e., thesignificant effect of tDCS to the DLPFC on dopamine and GABA inthe basal ganglia, tDCS to the DLPFC may be promising for treatingPD patients. Furthermore, as shown in patients with AD, whosecognitive functions were improved by stimulation of the temporalcortex [32], DLPFC stimulation may be effective in modulating af-fective changes in the course of the disease. The lack of studiesexamining the cholinergic system after tDCS may propel re-searchers to investigate whether tDCS to the DLPFC can exert aninfluence on the cholinergic system or accumulation of misfoldedproteins such as amyloid and tau not only in the cortex but also inthe deep brain regions in patients with AD.

There are some limitations to be noted in the present study.First, since PET and MRS were not simultaneously measured,interpretation of a direct relation between GABA and dopamineshould be cautiously made. However, consecutive examinationswithin a day may be sufficient for discussing effects across thedifferent modalities (PET and MRS). Simultaneous PET/MRI exper-iments may solve this problem. Second, a lack of MRS data from theright DLPFC due to time constraints did not allow us to furtherdiscuss the contribution of cathodal tDCS to changes in GABA. This

Fig. S1. Design and timeline of this study.The type of stimulation (active or sham) was randomized in a double-blind manner. Thirperformed at 50 min after initiation of tDCS, followed by MRS measurement at 140 min. Pa

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needs future study. Third, although the effects of tDCS may varybased on individual factors, e.g., brainmorphometry and BDNF genepolymorphisms [33,34], it is unlikely that the rather homogeneouspopulation, young Japanese male subjects, would show significantdifferences in parameters that confound the present results. Fourth,despite no emotional or behavioral changes apparent from self-reported data of spending one month between measurements(active and sham tDCS), an intra-individual fluctuation in the brainwas not measurable in this study. As such, we have to assumedifferent brain states because there are too many influencing fac-tors and our brain is an enormously complex system. Lastly,because of the limited number of regions selected, a strict correc-tion for multiple tests prevented our data (i.e., increase in GABA inthe left striatum) from reaching significance in this study. There-fore, further exploration of the cortico-striatal region with a largersample size is needed.

Conclusions

The tDCS montage including the left anodal DLPFC and rightcathodal DLPFC can generate GABAergic excitation in the ipsilateralstriatum concomitant with mild GABAergic reductions in the leftDLPFC. Although data were obtained from different modalities (PETand MRI), the 24-h lasting after-effects of tDCS [22] allows us tospeculate that dopamine release is responsive to the stimulation inan antagonistic manner to the GABA response. DLPFC-tDCS maymodulate dopamine-GABA systems in the basal ganglia-corticalcircuit at a molecular level.

CRediT authorship contribution statement

Tomoyasu Bunai: Methodology, Data curation, Formal analysis,Investigation, Writing - original draft. Tetsu Hirosawa: Investiga-tion.Mitsuru Kikuchi: Project administration, Funding acquisition.Mina Fukai: Investigation. Masamichi Yokokura: Investigation.Shigeru Ito: Investigation. Yohei Takata: Software. Tatsuhiro Ter-ada: Investigation. Yasuomi Ouchi: Conceptualization, Methodol-ogy, Writing - review & editing, Funding acquisition.

Declaration of competing interest

The authors have no competing financial interest related to thisstudy.

teen minutes duration tDCS was applied twice with an interval of 20 min. PET wasrticipants underwent twice experiments in a cross over fashion at least 1 month apart.

T. Bunai, T. Hirosawa, M. Kikuchi et al. Brain Stimulation 14 (2021) 154e160

Acknowledgments

This research is supported by the Center of Innovation Programfrom Japan Science and Technology Agency, JST, and partly by Sci-entific Research on Innovative Areas (JP16H06402). The authorswish to thank Professor Richard A. Edden at The Johns HopkinsUniversity (USA) for his great help with the GABA-MRS study andthe staff of Hamamatsu Medical Imaging Center for their valuablesupport. We also thank Philips for the MRS technical support.

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