Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder
Introduction
Gambling disorder (GD) has been included in the category substance-related and addictive disorders in the DSM-5 (American Psychiatric Association, 2013). It is characterized by a loss of control over gambling craving and behaviors despite negative consequences. Long-term remission is often difficult to achieve despite intensive cognitive-behavioral therapy and there are still no approved medications for the treatment of GD (Cowlishaw et al., 2012). However, recent work indicates that medications targeting the Glutamatergic/GABAergic system have some efficacy in substance use disorders (Addolorato et al., 2012, Douaihy et al., 2013). In GD, agents increasing GABA levels have also shown promising results in reducing abnormally elevated impulsivity (Berlin et al., 2013), as well as diminishing craving (Pettorruso et al., 2014). These therapeutic advances are based in part on observations using magnetic resonance spectroscopy (MRS) in patients with substance use disorders. This non-invasive neuroimaging technique enables the quantification of neural metabolites such as GABA and Glx, a combination of the major excitatory neurotransmitter glutamate and the neurotransmitter precursor glutamine (Urenjak et al., 1993). Patients with substance use disorders, as compared to healthy subjects, displayed reduced prefrontal GABA (Chang et al., 2003, Moeller et al., 2016) and glutamate levels (Moeller et al., 2016, Thoma et al., 2011, Murray et al., 2016). Altered GABA and glutamate levels have also been associated with behaviors relevant to substance use disorders, such as impulsivity, reward seeking, craving (Koob and Volkow, 2010, Kalivas, 2009). Further, lower prefrontal GABA has been linked to higher levels of impulsivity even among healthy adults (Boy et al., 2011, Silveri et al., 2013). MRS also allows measuring, N-acetyl aspartate (NAA), a metabolite implicated in neuronal regulatory processes such as protein synthesis and lipid production as well as an indicator of neuronal viability and metabolism activity (Urenjak et al., 1993). Altered NAA levels have been observed in psychiatric disorders (Maddock and Buonocore, 2012). Specifically, prefrontal NAA seems to be important in substance-related and addictive disorders as patients with substance use disorders (Murray et al., 2016, Yucel et al., 2007, Verdejo-Garcia et al., 2013) and patients with on-line game addiction displayed lower prefrontal NAA levels. Importantly, level of prefrontal NAA negatively correlated with on-line game addiction severity (Han et al., 2014).
Another approach that holds therapeutic promises for substance use disorders is the use of transcranial direct current stimulation (tDCS). tDCS is a noninvasive tool delivering a constant, low-intensity current through electrodes that can modulate neural activity and behaviors. Several studies have reported that tDCS applied over the dorsolateral prefrontal cortex (DLPFC) reduced craving levels in patients with substance use disorders (Feil and Zangen, 2010, Jansen et al., 2013, Wing et al., 2012). We proposed that stimulation of the DLPFC may act upon glutamate and GABA levels in the targeted DLPFC and its connected circuit (e.g., ventral striatum), indirectly facilitating dopamine release in the mesocortical pathway, and thus transiently reducing craving, reward seeking, and impulsivity (Fecteau et al., 2010, Hone-Blanchet and Fecteau, 2014). In the present work, we address this hypothesis in GD with a straightforward question: what are the effects of tDCS on brain metabolites during stimulation in patients with GD? In this sham-controlled, crossover study, we tested whether a single 30-min session of tDCS over the DLPFC modulates GABA, Glx and NAA levels in the DLPFC and striatum with magnetic resonance spectroscopy (MRS).
Section snippets
Patients
Eighteen patients who met DSM-5 criteria for GD and were eligible to receive tDCS and MRI were recruited through electronic mail distribution service at Université Laval and at Centre de Réadaptation et Dépendance de Québec. The study received ethical approval from the institutional review board of the Institut de réadaptation en déficience physique de Québec. Patients gave written informed consent prior to their participation. One patient dropped out after the first session because of
Results
In the right DLPFC, active as compared to sham tDCS elevated GABA levels (mean active = 1.98 (SD = 0.46), mean sham = 1.66 (0.35), t (15) = 2.264, p = 0.039, Glass' Δ = 0.92) (Fig. 1B), but no significant differences in Glx levels (mean active = 3.38 (1.17), mean sham = 3.59 (1.93), t (15) = −0.347, p = 0.733, Glass' Δ = −0.11) and NAA levels (mean active = 6.11 (1.82), mean sham = 5.95 (1.41), t (15) = 0.286, p = 0.779, Glass’ Δ = 0.11).
In the right striatum, differences between active and
Discussion
In this work, we investigated whether tDCS can modulate metabolite levels in patients with GD using a tDCS/MRS concurrent approach. Active tDCS with the anode over the right DLPFC and the cathode over the left DLPFC significantly elevated GABA levels in the right DLPFC as compared to sham tDCS. This is of significant interest as medications targeting the GABAergic system have reported to be relatively effective in reducing craving in various addictive behaviors (Addolorato et al., 2012),
Funding and disclosures
The authors declare no competing interests. This work was supported by Parkinson Society Canada grant (Université Laval: FO103232) and Natural Sciences and Engineering Research Council of Canada Grant (402629-2011) to S. Fecteau. M. Dickler is supported the by Fonds de Recherche en Santé du Québec scholarship program. S. Fecteau is supported by the Canada Research Chair in Cognitive Neuroplasticity.
Acknowledgements
We thank Antoine Hone-Blanchet for his advice on MRS analysis. This project applies tools developed under NIH grants P41 EB 015909 and R01 016089 (to R.A. Edden also received salary support from these grants) and the Consortium d'imagerie en neuroscience et santé mentale de Québec via a Platform Support Grant from the Brain Canada Foundation (to S. Fecteau).
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