The impact of cathodal tDCS on the GABAergic system in the epileptogenic zone: A multimodal imaging study

Abstract

Objectives: We aimed to investigate the antiepileptic effects of cathodal transcranial direct current stimulation (c-tDCS) and mechanisms of action based on its effects on the neurotransmitters responsible for the abnormal synchrony patterns seen in pharmacoresistant epilepsy. This is the first study to test the impact of neurostimulation on epileptiform interictal discharges (IEDs) and to measure brain metabolites in the epileptogenic zone (EZ) and control regions simultaneously in patients with pharmacoresistant epilepsy.

Methods: This is a hypothesis-driven pilot prospective single-blinded repeated measure design study in patients diagnosed with pharmacoresistant epilepsy of temporal lobe onset. We included seven patients who underwent two sessions of c-tDCS (sham followed by real). The real tDCS session was 20 min in duration and had a current intensity of 1.5 mA delivered via two surface electrodes that had dimensions of 3 × 4 cm. The cathode electrode was placed at FT7 in the center whereas the anode at Oz in the center. After each session, we performed electroencephalographic recording to count epileptiform IEDs over 30 min. We also performed magnetic resonance spectroscopy (MRS) to measure brain metabolite concentrations in the two areas of interest (EZ and occipital region), namely, gamma-aminobutyric acid (GABA), glutamate (Glx), and glutathione. We focused on a homogenous sample where the EZ and antiepileptic medications are shared among patients.

Results: Real tDCS decreased the number of epileptiform IEDs per min (from 9.46 ± 2.68 after sham tDCS to 5.37 ± 3.38 after real tDCS), p = 0.018, as compared to sham tDCS. GABA was decreased in the EZ after real c-tDCS stimulation as compared to sham tDCS (from 0.129 ± 0.019 to 0.096 ± 0.018, p = 0.02). The reduction in EZ GABA correlated with the reduction in the frequency of epileptiform IED per min (rho: 0.9, p = 0.003).

Conclusion: These results provide a window into the antiepileptic mechanisms of action of tDCS, based on local and remote changes in GABA and neural oscillatory patterning responsible for the generation of interictal epileptiform discharges.

Keywords: GABA; MRS; epileptiform interictal discharges; pharmacoresistant epilepsy; tDCS.

Figure 1

Placement of the voxels for magnetic resonance spectroscopy (MRS) in patient no. 2, male, age 32 years. In red, we show the EZ voxel, which is positioned in the left anterior temporal lobe whereas in blue we show the reference voxel, which is positioned in the occipital zone medially. The EZ voxel was measured 25 × 25 × 25 mm whereas the occipital voxel was measured 30 × 30 × 30 mm.

Figure 2

Real transcranial direct current (tDCS) decreased the interictal discharges (IEDs) frequency per minute from (10.86 ± 3.74) prestimulation to (5.37 ± 3.38) post-stimulation [p = 0.045] and from (9.46 ± 2.74) after sham tDCS to (5.37 ± 3.38) after real tDCS [p = 0.018]. n.s.: not statistically significant, i.e., p > 0.05. * means statistically significant with a p < 0.05.