Anodal frontal tDCS for chronic cluster headache treatment: a proof-of-concept trial targeting the anterior cingulate cortex and searching for nociceptive correlates

Abstract

Background: Percutaneous occipital nerve stimulation (ONS) is effective in refractory chronic cluster headache (rCCH) patients. Responders to ONS differ from non-responders by greater glucose metabolism in subgenual anterior cingulate cortex (sgACC). We reasoned that transcranial direct current stimulation (tDCS), a non-invasive approach, might be able to activate this area and thus improve rCCH patients. Our objective was to explore in a pilot trial the therapeutic potential of tDCS (anode at Fz, cathode over C7) and its possible effects on pain perception, frontal executive functions and mood in rCCH patients.

Methods: Thirty-one patients were asked to apply daily 20-min sessions of 2 mA tDCS for 4 or 8 weeks after a 1-month baseline. CH attacks were monitored with paper diaries. The primary outcome measure was change in weekly attacks between baseline and the last week of tDCS. Twenty-three patients were available for a modified ITT analysis, 21 for per-protocol analysis. We also explored treatment-related changes in thermal pain thresholds and nociceptive blink reflexes (nBR), frontal lobe function and mood scales.

Results: In the per-protocol analysis there was a mean 35% decrease of attack frequency (p = 0.0001) with 41% of patients having a ≥ 50% decrease. Attack duration and intensity were also significantly reduced. After 8 weeks (n = 10), the 50% responder rate was 45%, but at follow-up 2 weeks after tDCS (n = 16) mean attack frequency had returned to baseline levels. The treatment effect was significant in patients with high baseline thermal pain thresholds in the forehead (n = 12), but not in those with low thresholds (n = 9). The Frontal Assessment Battery score increased after tDCS (p = 0.01), while there was no change in depression scores or nBR.

Conclusion: tDCS with a Fz-C7 montage may have a preventive effect in rCCH patients, especially those with low pain sensitivity, suggesting that a sham-controlled trial in cluster headache is worthwhile. Whether the therapeutic effect is due to activation of the sgACC that can in theory be reached by the electrical field, or of other prefrontal cortical areas remains to be determined.

Keywords: Chronic cluster headache; Subgenual anterior cingulate cortex; Transcranial direct current stimulation.

Fig. 1

Study flowchart

Fig. 2

Brain maps of absolute values of electric field intensity (E = V/m) and electric potential (V) in sagittal planes of right and left cerebral hemispheres simulated using COMETS [34] and taking into account tDCS electrode size and placement (insert on the left) as well as current intensity. Lower right: superimposed left sagittal section of a normalized MRI template displaying the subgenual area of the left anterior cingulate cortex (arrow) with increased glucose uptake on FDG-PET in rCCH patients responding to percutaneous ONS compared to non-responders [16]

Fig. 3

Attack frequency, attack duration and number of attack treatments during 4 weeks of daily tDCS (means ± sem). Significant changes (p < 0.05) from baseline are respectively indicated for each item (*), (†), (‡)

Fig. 4

Weekly CH attack frequency at baseline and after 4 weeks (left) and 8 weeks (right) of daily tDCS (means ± sem)

Fig. 5

Correlations between the percentage change in weekly CH attack frequency after daily tDCS (baseline vs. week 4) and the baseline standardized cold (CPT) and heat pain thresholds (HPT)