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Neurophysiological effects of prefrontal tDCS in patients with disorders of consciousness

Manon Carrière1, 2*, Alice Barra1, 2, Sepehr Mortaheb1, 2, Mariachiara Binda Fossati1, 2, Géraldine Martens1, 2, Steven Laureys1, 2, Camille Chatelle1, 2 and Aurore Thibaut1, 2
  • 1 Coma Science Group, University of Liège, Belgium
  • 2 GIGA Consciousness, University of Liège, Belgium

Introduction Currently, therapeutic options for severely brain-injured patients with disorders of consciousness (DOC), including patients in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), are limited and still need to be improved to influence long-term outcomes. Non-invasive brain stimulations (NIBS) techniques have recently shown promising results in DOC (1). Notably, transcranial direct current stimulation (tDCS) applied over the left dorsolateral prefrontal cortex has proved to be effective in improving signs of consciousness in 43% of patients in MCS either after a single stimulation (2) or after repeated sessions (3,4). However, brain mechanisms underlying tDCS effects remain poorly understood. In the present protocol, we aimed to assess the effects of prefrontal tDCS on neurophysiological (i.e., electroencephalography – EEG – primary outcome) and behavioral (secondary outcome) measures in severely brain-injured patients with DOC. Methods In a double-blind sham-controlled design, one anodal and one sham tDCS were delivered in a randomized order in 3 chronic (>28 days post-onset) severely brain-damaged patients (1 UWS, 1 MCS and 1 Locked-in-syndrome). The stimulation had an intensity of 2 mA and lasted 20 minutes. The anode was placed on the left dorsolateral prefrontal cortex and the cathode on the right supraorbital region. Patients were eligible for the study if they suffered from a traumatic or non-traumatic accident that occurred between 3 months and 1 year before the inclusion; and if they had been assessed with the CRS-R at least twice in the 2 weeks preceding the first session and diagnosed as UWS, MCS, emergence from MCS or LIS, with at least 1 subscale on which there was no sign of consciousness. Patients were excluded if there was any evidence of uncontrolled seizure, implanted electronic brain medical device or pacemaker, or history of recent craniotomy or cranioplasty in the frontal region. Ten minutes of high-density EEG (hd-EEG) were recorded using a 256-channel saline electrode net (Electrical Geodesics) directly before and after each tDCS session. Behavioral assessments were performed using the Coma Recovery Scale-Revised (CRS-R – 5) before and after each session by an investigator blinded to the treatment allocation. EEG data were first filtered from 1 Hz to 30 Hz and were further divided into 2-sec epochs. Eye blinks and muscle artifacts were removed using visual inspection and independent component analysis. Then, bad channels were interpolated by spherical interpolation and signals were re-referenced to the common average of all electrodes. Z-score normalization was further applied on each electrode. Multitapers method (6) was used to calculate power spectral density of each electrode and power analysis was performed for standard frequency bands of delta (0-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-25 Hz). Non-parametric corrected two-tailed cluster permutation test (7) was performed to compare the significant difference of the power topographic maps before and after tDCS as compared to the sham ((post_tdcs – pre_tdcs) – (post_sham - pre_sham)). Electrode clusters with p-value less than 0.01 were considered as significant power changes. Given the small number of patients included so far, descriptive analyses were used for the behavioural data. Results and discussion The UWS patient showed significant power decrease in theta, alpha and beta bands and no significant change in the delta band after the active tDCS as compared to sham. For the MCS patient, a significant increase of power in the theta band and decrease of power in delta band were found after the active stimulation compared to sham. Finally, we found a significant global increase of power in alpha and beta bands for the LIS patient after tDCS as compared to the sham. This power increase was more dominant in frontal and parietal electrodes (see Figure 1). On the other hand, no global effect was observed in the theta and delta bands. Behaviorally, none of the 3 patients presented improvement of signs of consciousness as measured with the CRS-R after the active session, nor after the sham session. CRS-R sub-scores for each patient are shown in Table 1. The fact that the UWS patient did not show any new sign of consciousness after the tDCS is consistent with previous studies in which no treatment effect was observed in UWS patients (1). This absence of behavioral changes was supported by an absence of increase in any of the bandwidths as shown by the EEG results. The absence of behavioral improvement for the MCS patient is concordant with the EEG results which do not show significant power increase after tDCS in alpha and beta bands, as what is usually observed in healthy subjects following tDCS (8, 9, 10). However, an increase in theta power was found. Therefore, it could be speculated that an increase in theta is not sufficient to induce behavioral improvements and an effect on alpha and/or beta could be necessary to induce such clinical changes. On the other hand, it could also be hypothesized that one session, for this patient, was not sufficient to induce clinical enhancement and more sessions are required as it has been previously shown in DOC but also in other pathologies (4, 11, 12, 13). If this is confirmed, the change in theta could be a marker of further EEG and behavioral improvement after repetitive tDCS. For the LIS patient, the lack of behavioral improvement, together with an increase in alpha and beta power, could be explained by a ceiling effect on the CRS-R (except for the motor and oro-motor subscales that remained very low due to paralysis), therefore limiting the possibility to observe an improvement after treatment. However, tDCS might have led to attentional or arousal changes that could not be detected with the CRS-R. Henceforth, more sensitive scales should be employed with LIS or patients who have emerged from the MCS (EMCS) to allow identification of cognitive changes (e.g., use of visual analog scale to score their level of alertness and attention). Conclusion As shown by previous studies, an improvement of the level of consciousness is usually associated with an increase of alpha and beta power as well as a decrease of theta and delta power (15, 16). Given that none of the DOC patients showed this pattern after the active session, the present EEG results seem to be consistent with the absence of behavioral changes. For the LIS patient, given the increase in alpha and beta power, the absence of behavioral improvement can be explained by the lack of sensitivity of the scale we used. By enrolling more patients, we will be able to determine if an increase in alpha power is necessary to induce behavioral changes in MCS patients and if a certain ratio of this power band is required for a patient to clinically respond to tDCS. Table 1. Demographical and behavioral data (CRS-R subscores and total scores) for each patient and each session (A= auditory subscale; V = visual subscale; M = motor subscale ; O/V = oro-motor/verbal subscale; C = communication subscale; A = arousal subscale). Patients Etiology Time since injury (days) Baseline diagnosis tDCS allocation CRS-R subscores Before active After active Before sham After sham P1 TBI 90 UWS sham/active A0 V1 M1 O/V1 C0 A1 Total: 4 A0 V1 M1 O/V0 C0 A1 Total: 3 A0 V1 M2 O/V1 C0 A1 Total: 5 A1 V1 M2 O/V1 C0 A2 Total: 7 P2 Meningitis 90 MCS sham/active A0 V3 M5 O/V2 C0 A1 Total: 11 A0 V3 M5 O/V1 C0 A1 Total: 10 A0 V3 M5 O/V2 C0 A1 Total: 11 A0 V1 M5 O/V1 C0 A1 Total: 8 P3 Vertebro-basilar stroke 3130 LIS active/sham A4 V5 M0 O/V0 C2 A3 Total: 14 A4 V5 M0 O/V0 C2 A3 Total: 14 A4 V5 M0 O/V0 C2 A3 Total: 14 A4 V5 M0 O/V0 C2 A3 Total: 14 Figure 1. Topographic maps for each patients showing either increase (red) or decrease (blue) of power after tDCS as compared to the sham for each frequency band.

Figure 1
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Acknowledgements

The study was further supported by the University Hospital of Liege,the Belgian National Funds for Scientific Research (FRS-FNRS),the Human Brain Project (EU-H2020-fetflagshiphbpsga1-ga720270),the Luminous project (EU-H2020-fetopenga686764),the Center-TBI project (FP7-HEALTH- 602150),the Public Utility Foundation ‘Université Européenne du Travail’,“Fondazione Europea di Ricerca Biomedica”,the Bial Foundation, the European Space Agency,the Mind Science Foundation and the European Commission.

References

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Keywords: transcranial direct current stimulation (tDCS), disorders of consciousness, Electroencephalography (EEG), Minimally Conscious State, Non-invasive brain stimulation (NIBS)

Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.

Presentation Type: e-posters

Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE

Citation: Carrière M, Barra A, Mortaheb S, Binda Fossati M, Martens G, Laureys S, Chatelle C and Thibaut A (2019). Neurophysiological effects of prefrontal tDCS in patients with disorders of consciousness. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00063

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Received: 29 Aug 2018; Published Online: 17 Jan 2019.

* Correspondence: Miss. Manon Carrière, Coma Science Group, University of Liège, Liège, Liège, 4000, Belgium, manon.carriere@uliege.be