Dual-Target High Frequency Navigated Repetitive Transcranial Magnetic Stimulation in Parkinson’s Disease: A Randomized Placebo-Controlled Study
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1
Scientific Research Institute of Physiology & Basic Medicine, Department of Experimental and Clinical Neuroscience, Russia
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2
Novosibirsk State University, Department of Neurosciences, Russia
Repetitive transcranial magnetic stimulation (rTMS) became a noninvasive and nonpharmacological treatment option for several chronic disorders. Today rTMS seems to be a promising option as an add-on therapy to pharmacological treatment in Parkinson’s desease (PD) [Lefaucheur et al., 2014; Makkosh et al., 2016]. A recent meta-analysis showed that HF-rTMS (>5 Hz) of the motor cortex (M1) resulted in improvement of motor symptoms measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 (Motor Examination) score (level C evidence – possible efficacy), whereas HF-rTMS of the left dorsolateral prefrontal cortex (DLFPC) has the antidepressant effect (level A of evidence – definite efficacy) [Lefaucheur et al., 2014]. Depressive symptoms often occur in PD and the severity of motor symptoms and the severity of depression are positively correlated. Based on the above mentioned, we decided to evaluate the efficiency of dual-target navigated HF-rTMS, aiming at the M1 target for motor symptoms and at the left DLPC for depression in a randomized, single-blind, placebo-controlled, parallel-group study.
Twenty eight patients with PD, fulfilling the UK Brain Bank criteria for PD [Hughes et al, 1992], were initially enrolled.
Prior to the study all patients underwent mandatory for navigated rTMS MRI scanning. Individual DICOM data files were uploaded into the NEXSTIM Eximia NBS system for the 3D reconstruction of the brain model and alignment with the patient’s head.
The patients were randomly assigned to either an actively treated (real stimulation, n = 14) or a sham-stimulation (14) group using an automated stratified procedure on the severity of depression, age, type of PD (e.g. tremor-dominant or rigid-akinetic), and the applied dopamine agonist dosage [Tomlinson et al, 2010]).
The 10 Hz rTMS was performed sequentially over 2 targets: the primary motor cortex (M1, 5 s stimulation duration, separated by 10 s, with a total of 4000 pulses/sub-session, 100 % of the RMT) and the DLPFC (5 s stimulation duration, separated by 15 s, with a total of 3000 pulses per-sub session, 110% of the MRT) using the active or sham figure-of-eight stimulation coils. The M1 sub-session always came first. Sham rTMS was carried out over the same targets with the same stimulation parameters. Overall, patients received a total of 20 sessions on 20 consecutive days over 3 weeks.
Out of 28 intended-to-treat patients, only 26 completed the study. Two patients from the sham-treated group did not finish the study because of reasons unrelated to the study.
We performed three clinical examinations on each patient: at baseline (before stimulation), 1 day (short-term outcome) and 4 weeks (long-term outcome) after the last session. Outcome measures included the following: the total score of the validated Russian version of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS); the MDS-UPDRS Motor Examination part (Part 3) score; the Depression Anxiety Stress Scales (DASS); the 21-item Hamilton Depression Rating Scale (HDRS-21); the Beck Depression Inventory (BDI-II); the MMSE.
A two-way ANOVAs where the first factor had 2 levels and was independent (Simulation: real stimulation vs. sham stimulation) and the second factor had also levels and was repeated (Outcome: baseline, short-term outcome) were performed. The Greenhouse-Geisser correction was applied where appropriate. Bonferroni’s correction for multiple comparisons was used for analysis of changes in mean score at the two time points.
The total score of the MDS-UPDRS had an improvement in the actively treated group (from 67 to 41 points, median values), and a similar change could not be detected in the sham-treated group (from 69 to 62 points). As indexed by the Stimulation×Outcome interaction (F(1,24)= 19,32 p< ,001) the total score of the MDS-UPDRS significantly decreased only in the active stimulation group and at the between-group level the active stimulation group yielded significantly lower MDS-UPDRS values at the time point of short-term outcome (planned comparisons at p<0.05). Post hoc tests using separate ANOVAS revealed that sham stimulation produced a slight improvement in the total score of the MDS-UPDRS from baseline to short-term follow-up, which was not statistically significant (F(1,24)=3.30, p = ,082) whereas active stimulation reduced the short-term total score of the MDS-UPDRS, which was statistically significantly lower than at baseline (F(1,24)= 71,11 p< ,001) level.
Based on repeated measures ANOVA, not only the total score but also the Motor Examination Part (Part 3) of the MDS-UPDRS demonstrated a significant improvement in the active rTMS group: Stimulation×Outcome interaction - F(1,24)= 36,58 p< ,001; the short-term score lower than baseline values - F(1,24) = 83,59 p< ,001, post hoc ANOVA). The size of improvement (median of 6 points) clearly exceeded the minimal clinically important difference (MCID) threshold of 3.25 points [Horvath et al., 2015]. Therefore, it could be considered as clinically meaningful.
Depression significantly improved in the active stimulation group. This improvement was consistently identified for the HDRS-21 scale. The total depression score improved from a median of 11 points to 6 points in the actively treated group, while in the sham group it decreased from 11. 5 points to 8.5 points. A repeated measures ANOVA determined that the outcome scores differed significantly between the two time points (Outcome: F(1,24)= 12,08 p= 0,002). Post hoc ANOVAs revealed that sham stimulation produced a non-significant decrease (F(1,24)= 1,5 p - n.s.). However, active stimulation reduced the short-term score, yielding significant difference to baseline (F(1,24)= 14,35 p< ,001). Among the remaining affective measures, as evidenced by the only statistically significant effect of the factor of Outcome in the 2-way ANOVAs, the DASS depression (F(1,24)= 16,03 p< 0,001), anxiety (F(1,24)= 12,08 p= 0,02) and stress (F(1,24)= 7,66 p= 0,01) values decreased in both groups at the point of short-term outcome.
The findings demonstrate the beneficial effects of the dual-target HF-rTMS and should be confirmed in patients with more severe depression and at longer-term outcome by further clinical trials. It is suggested that the dual-target HF-rTMS triggered the large scale neuronal plasticity up-regulation thereby contributing to clinical improvements in motor and affective domains.
Acknowledgements
Research was supported by:
The Russian Science Foundation grant #16-15-00128 to Lyubomir Aftanas
The Russian Academy of Science Program 205-2017 "Affective neuroscience" to to Lyubomir Aftanas
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Keywords:
Parkinson’s disease,
Motor Cortex,
dorsolateral prefrontal cortex,
Transcranial Magnetic Stimulation,
Dual-target stimulation,
Depression,
negative affect
Conference:
SAN2016 Meeting, Corfu, Greece, 6 Oct - 9 Oct, 2016.
Presentation Type:
Oral Presentation in SAN 2016 Conference
Topic:
Oral Presentations
Citation:
Aftanas
LI,
Kulikova
KI,
Brack
IV,
Divert
VE,
Dzemidovich
SS and
Danilenko
KV
(2016). Dual-Target High Frequency Navigated Repetitive Transcranial Magnetic Stimulation in Parkinson’s Disease: A Randomized Placebo-Controlled Study
.
Conference Abstract:
SAN2016 Meeting.
doi: 10.3389/conf.fnhum.2016.220.00089
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Received:
01 Aug 2016;
Published Online:
01 Aug 2016.
*
Correspondence:
Prof. Lyubomir I Aftanas, Scientific Research Institute of Physiology & Basic Medicine, Department of Experimental and Clinical Neuroscience, Novosibirsk, 630117, Russia, liaftanas@gmail.com