Patients with long-standing Parkinson disease (PD) may need additional nonpharmacological therapeutic interventions to preserve independent mobility and function.1 Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique for brain stimulation,2 which is used to treat a variety of neuropsychiatric disorders.3 Several clinical studies of rTMS for the treatment of PD have been published, some of which reported moderate improvement of motor symptoms.4,5 In a meta-analysis,6 the authors concluded that rTMS can exert a significant, albeit modest, positive effect on the motor function of patients with PD, and a recent systematic literature review7 suggested that rTMS may be effective in improving motor symptoms in patients with PD in the short and long term, but definitive conclusions could not be drawn because of small sample sizes and other limiting factors.
Most rTMS studies have targeted the primary motor cortex (M1) and/or the prefrontal cortex (PFC). The specific effect of rTMS on cortical excitability depends on the frequency of stimulation, as well as its intensity and potentially other parameters such as duration and intertrain intervals. Broadly speaking, high-frequency (HF) stimulation (5–20 Hz) is considered to induce increased cortical excitability, whereas low-frequency (LF) rTMS (≤1 Hz) to decrease it.8 Regarding M1 stimulation, the efficacy is based on physiologic findings suggesting a role for increased excitability of corticostriatal pathways and decreased intracortical inhibition in the pathophysiology of motor deficit in PD9,10 and the assumption that rTMS can neutralize this hyperexcitability causing “pseudo-normalization” of the cortical activity. Potential effectiveness of PFC stimulation is based on its connectivity with basal ganglia circuitry11 and on indications that prefrontal projections modulate dopamine release in the striatum,12 possibly through activation of the substantia nigra,13 and that HF rTMS can cause a neurogenetic shift toward production of dopaminergic neurons.14
Previous studies using rTMS in PD have used standard TMS coils (round or figure-8) that target superficial brain areas (can reach, when using up to 120% of motor threshold [MT] to a depth of 1–2 cm).15 In this study, we choose to use the Hesed coil (H-coil), which is designed to maximize summation of induced fields around a target and to minimize nontangential coil elements close to that area.16,17 Based on mathematical modeling and on actual phantom brain measurements, it was shown that the H-coil allows safe (subconvulsive) of large brain tissue volumes and a penetration of the stimulation field to a depth of 3 to 4 cm.18–20 Because at least five frontal–subcortical circuits connecting the cortex with various structures of the basal ganglia have been identified,21 it is plausible that stimulation of larger volumes and deeper into the PFC will include large volumes of both dorsolateral and ventrolateral PFC areas, targeting the vast distribution of projections from these areas to the substantia nigra and striatum. In addition, the multiple stimulation sessions of these projections are aimed to facilitate plasticity in these networks.22 Therefore, the use of the H-coil can theoretically be more efficient than the regular coils and might induce more pronounceable therapeutic effects in patients with PD.
This H-coil was proved to be effective in the treatment of depression.23 In our previous exploratory studies with this coil in patients with PD, it was shown that using HF repetitive deep transcranial magnetic stimulation (rDTMS) over M1 did not provide beneficial effects on PD symptoms, whereas LF M1 stimulation was mildly beneficial.24 However, the effects seemed to be enhanced with dual stimulation, consisting of LF M1 stimulation that was followed by HF PFC stimulation, as shown in an open-label comparative study.25 The aim of this study was to further test the efficacy of this rDTMS protocol in a double-blind and sham-controlled manner and to test whether an extended treatment period of 3 months will enhance its beneficial effect.
Patients diagnosed with idiopathic PD according to the UK Brain Bank Criteria26 were included in this study, which was conducted between the years 2012 and 2014. The inclusion criteria were age 40 years or older, a Hoehn and Yahr stage of II to IV, and stable antiparkinsonian therapy for at least 1 month. Exclusion criteria were a history of seizures, frequent headaches, other neurologic disorders, head injury or any neurosurgical intervention, significant hearing loss, dementia (Mini-Mental State Examination27 score > 25), treatment with neuroleptics, the presence of metallic particles in the head, and implanted cardiac pacemaker or neurostimulators.
The study was approved by the institutional review board, and all participants signed an informed consent form before inclusion.
This study was a double-blind, randomized sham-controlled study, with a 1:1 allocation ratio. The power analysis was based on the results of our previous study25 and the study of Shulman et al.28 concerning clinically detectable differences. Patients were randomized using simple randomization to the active or sham treatment groups. The medication regimen remained unchanged throughout the study, and the levodopa-equivalent daily dose (milligram/day) was calculated for each patient. Both patients and raters were masked to the intervention. Stimulation was administered in the “on medication” state. The treatment schedule consisted of 24 rDTMS sessions during a 3-month period (3/week in the first month, 2/week in the second, and 1/week in the third).
Study Device and Procedure
Repetitive deep transcranial magnetic stimulation was performed with a high-speed magnetic stimulator (Magstim, United Kingdom) connected to the H5 version of the H-coil (rapid two model).20,29 To ascertain the accurate location and intensity of the stimulation, motor evoked potentials were recorded using surface electromyographic electrodes. The MT (defined as the lowest stimulation intensity able to produce motor evoked potentials of the right abductor pollicis brevis in 50% of the trials delivered) was initially determined in each treatment session. Spatial coordinates were recorded, using markings on a cloth cap placed on the subject's head, to ensure placement reproducibility in consequent sessions. M1 stimulation was performed at the location, which was found optimal for activation of the right hand. After M1 stimulation, the helmet was moved toward the midline and lowered 5.5 cm anterior to the motor spot (above the glabellar line) for PFC stimulation. At this location, the coil stimulates bilaterally the lateral and medial PFC. All patients received rDTMS over M1 and sequentially over the PFC; however, in the sham group, the coil produced only auditory artifact, but no magnetic field. Repetitive deep transcranial magnetic stimulation over M1 consisted of 900 pulses (1 Hz frequency, 110% intensity of MT) for 900 seconds (15 minutes), whereas rDTMS over the PFC consisted of 40 trains of 20 pulses (10 Hz frequency, 100% intensity of MT, 2 seconds duration and 20 seconds intertrain intervals) for additional 15 minutes.
Study participants were assessed before and after treatment in the on medication state. The primary outcome measures were the change in the total score of the Unified PD Rating Scale (t-UPDRS) and motor score (m-UPDRS)30 measured at the end of the study (day 90) versus baseline. Secondary outcome measures in these time points included the timed finger and foot tapping (both sides), the 3-m “Timed Up and Go” (TUG) test, the Beck Depression Inventory (BDI),31 the digit span test (forward and backward), and word fluency tests (both phonemic and semantic).32
Power analysis, based on the results of our preliminary study,25 yielded that a sample of 21 participants would achieve a minimal level of clinical important difference, as suggested by Shulman et al.,28 for the t-UPDRS scale, under α = 0.05 and β = 0.80. Summary statistics for continuous variables are presented as mean with SDs. Summary statistics for categorical variables are presented as counts and percentages. For continuous variables, baseline values and characteristics between treatment groups and subgroups were compared with t-tests or the Mann–Whitney test. For categorical variables, groups were compared with the Pearson χ2 test or Fisher exact test. The possible effect of treatment was tested using mixed models for repeated measures that included time (baseline and day 90), treatment (rDTMS and sham), and levodopa-equivalent daily dose units as independent variables, together with time by treatment as an interaction term. m-UPDRS or t-UPDRS served as the dependent variables (a separate model for each outcome measure). An unstructured variance–covariance matrix was used in all models. The main analysis was followed by post hoc simple effects analysis, applying the Bonferroni correction for multiple comparisons. Simple effects analysis was performed in case the main effects for time, treatment, or the interaction between them was significant. Effect sizes (referred as ES) for focused significant comparisons were calculated by converting F-values to Pearson r.33 All comparisons were two sided, and a P-value of 0.05 was considered statistically significant. All analyses were performed using IBM SPSS version 20, except the power analysis, which was performed using G*Power software version 220.127.116.11.
Fifty-two patients were screened for participation in the study. Four patients were excluded because they failed to meet inclusion/exclusion criteria or withdrew their consent. Thus, 48 patients were randomized to the active treatment group (n = 26) or sham group (n = 22). Forty-two patients completed all phases of the study (21 in the rDTMS group and 21 in the sham group) and were included in the analysis (Fig. 1).
Patients' group characteristics are presented in Table 1. There were no significant differences between the active rDTMS and sham treatment groups regarding age, sex, duration of illness, disease stage, or motor severity scores. However, there were more patients taking levodopa in the sham group, and as a consequence, the levodopa-equivalent daily dose was higher for this group.
Primary Outcome Measures
The model for t-UPDRS (Fig. 2A) revealed a significant main effect for time, indicating that the t-UPDRS score decreased over time in the whole sample (baseline estimate: M = 43.1, SE = 1.9; day 90 estimate: 39.6, SE = 1.4; F1,39 = 11.8; P = 0.001; ES = 0.48). In addition, a significant main effect for levodopa-equivalent daily dose units was found (F26,14.2 = 2.6; P < 0.05). No significant effects for treatment (P = 0.63) or for time-by-treatment interaction (P = 0.45) were observed. The simple effects analysis showed a significant decrement over time within the rDTMS group only (baseline estimate: M = 42.4, SE = 3.1; day 90 estimate: 38.1, SE = 2.5; F1,39 = 8.6; P = 0.006; ES = 0.43), whereas within the sham group, the equivalent decrement was insignificant (baseline estimate: M = 43.7, SE = 3.1; day 90 estimate: 41.1, SE = 2.5; F1,39 = 3.7; P = 0.06). The model for the m-UPDRS (Fig. 2B) revealed a significant main effect for time, indicating that the m-UPDRS values also decreased over time in the whole sample (baseline estimate: M = 28.8, SE = 1.4; day 90 estimate: 26.6, SE = 1.1; F1,39 = 7.6; P = 0.009; ES = 0.40). Main effects for treatment and LED units were insignificant (P = 0.93 and 0.20, respectively) as was the time-by-treatment interaction effect (P = 0.51). Here again, the simple effects analysis revealed that the decrement over time was significant only within the rDTMS group (baseline estimate: M = 29.3, SE = 2.3; day 90 estimate: 26.5, SE = 2.0; F1,39 = 5.7; P = 0.02; ES = 0.36), whereas within the sham group, the equivalent decrement was insignificant (baseline estimate: M = 28.4, SE = 2.3; day 90 estimate: 26.7, SE = 2.0; F1,39 = 2.2; P = 0.14).
Secondary Outcome Measures
The analysis of these measures did not reveal a significant main effect for treatment for all tasks. A significant main effect for time was found in most cognitive and motor tasks (digit span forward and backward; word fluency; Timed Up and Go; pegboard—more impaired side and foot tapping—more impaired side), indicating improvement over time in the whole sample on these tasks. The treatment-by-time interaction effect was insignificant in all tasks, except the pegboard less impaired side task (Table 2).
Analysis of Responders
Finally, an analysis of patients, who improved during the experiment, was performed to identify possible factors that may predict the response to the treatment. A “responder” was defined (in accordance with Shulman et al.28), as a patient whose m-UPDRS score decreased between baseline and day 90 by 4.5 points or more. According to this criterion, six patients in the active treatment group (30%) were classified as responders and 14 (70%) as nonresponders. A comparison between the responders and nonresponders revealed that the responders tended to be older (Md [median] = 66 years compared with Md = 64 years), used more levodopa (Md = 294 mg compared with Md = 194 mg), and had a lower MT (Md = 58% compared with Md = 61%). In addition, the responders were characterized by a higher baseline m-UPDRS score (Md = 38 points compared with Md = 29 points) and a longer disease duration (Md = 6 years compared with Md = 4 years). The difference between both subgroups was statistically significant for these two last variables (Mann–Whitney test: z = −2.1, P = 0.03 and z = −2.1, P < 0.04, respectively). Given the significant effect of disease severity on response, we examined the effect of treatment only in severe patients (m-UPDRS 25–50) from the current study. In this population, the response rate was found to be 40% (6/15) in the active rDTMS group but only 27% (4/15) in the sham group. In addition and in accordance with the findings above, there were no responders in the mild baseline symptoms group. Also, in patients with longer disease duration (≥5 years), the response rate was 50% (3/6) in the active rDTMS group but only 18% (2/11) in the sham group. No significant differences between the responders and the nonresponders were found for the secondary outcome measures.
Adverse events were more common in the real treatment group than those in the sham group (16 vs. 9, respectively, χ2 = 3.6, df = 1, P = 0.06); however, they were generally transient, and the interventions were well tolerated. The most common side effects were headache (five patients in the rDTMS group and one in the sham group), dizziness (four patients in the rDTMS group), pain in the head or neck during treatment (three patients in the rDTMS group and one in the sham group), nausea, general weakness, and transient aggravation of gait disturbance (two patients in each group).
The current sham-controlled study examined the efficacy of rDTMS treatment for patients with PD. A significant positive effect was found only within the rDTMS group at the end of the treatment period (day 90); however, no significant difference was found in the between-groups comparison.
The rational for the selection of the current stimulation parameters and sites lies on previous neuroimaging34 and electrophysiological studies35–37 that demonstrated an inhibitory effect of 1 Hz rDTMS on cortical excitability that has been previously documented in PD.10 A possible beneficial effect for LF stimulation of the motor cortex is also supported by our previous feasibility studies24,25 and by the results of a meta-analysis that concluded that LF rTMS had an effect on motor signs in PD38 and the review of eight randomized controlled studies of LF rTMS showing a pooled ES of −0.40 with a 5.05 point decrease in UPDRS part III compared with sham stimulation and concluding that LF rTMS had a significant effect on the motor signs in PD.39 Another recently published meta-analysis40 concluded that LF rTMS had a pooled mean difference of 3.3 points on UPDRS between treatment and control groups. The additional PFC stimulation is based on animal and human rTMS studies, indicating that prefrontal projections modulate dopamine release in the striatum12,41 possibly through activation of the substantia nigra and that HF rTMS can cause a neurogenetic shift toward production of dopaminergic neurons.13 In addition, in humans with PD, HF rTMS of prefrontal areas has been associated with improved motor and psychiatric symptoms and in healthy controls with increased striatal dopamine release.41,42 The reason for combined stimulation is the results of our feasibility study,25 indicating that stimulation of both sites was more beneficial than stimulation of the motor cortex alone. Our treatment protocol was therefore based on this rational and on our previous findings in an open comparative active study of 1 month duration that showed that LF rDTMS stimulation of M1 combined with HF stimulation of the PFC25 caused a significant improvement in the m-UPDRS and t-UPDRS, respectively. The decision to give the treatment 3 times a week was based on the results of our previous studies and on the feasibility and availability of the patients, and the decision to add a maintenance phase following the first month of a relatively intensive protocol was based on the on the results of our previous studies that showed wearing off of the effect after discontinuation of the treatment and on the reports that maintenance treatment is a common practice in electroconvulsive therapy protocols.43
A meta-analysis concluded that LF rTMS had a little effect on motor signs in PD,38 but this conclusion was obtained only by pooled analysis of two studies that were neither randomized nor controlled, and the statistical power was relatively low. Zhu et al.39 reviewed eight randomized controlled studies of LF rTMS, and after pooling the results, an ES of −0.40 with a 5.05 point decrease in UPDRS part III compared with sham stimulation was found, concluding that LF rTMS had a significant effect on the motor signs in PD.
The difference between our study and those positive studies may stem from several methodological factors, such as a heterogeneous sample (used by us and others) with a wide range of motor scores, disease duration, and medical treatment, which may cause type II error. It is also possible that the inclusion of patients with lower severity may have affected the results, which may become significant if patients with more severe symptoms would have been included.
Another possibility is that the LF rDTMS protocol used in this study is a suboptimal choice for the treatment of patients with PD. Indeed, Spagnolo et al.44 reported positive results of rDTMS using the H5 coil in patients with PD targeting the same brain sites; the disparity may stem from the fact that they used HF (10 Hz) and low-intensity (90% of MT) stimulation of M1. In another study, Brys et al.45 obtained superior results over sham with 10 Hz frequency stimulation of M1 and Dorsolateral PFC over 10 consecutive days. In addition, two other level 1 studies showed beneficial effects on PD for HF magnetic stimulation of the supplementary motor area46 and the motor and dorsolateral prefrontal areas.47
Alternatively, it is possible that the treatment schedule and/or frequency used in our study were inadequate. Torres et al.48 reported positive retrospective results when 1 Hz stimulation of M1 followed by 10 Hz stimulation of the PFC was performed with the H-coil in an intensive 3-week, five sessions per week protocol much more intensive than ours.
In addition, the subanalysis suggests that response rate may be higher in patients with more severe PD and in those with longer disease duration. We therefore propose that future studies testing rDTMS should be focused on these subgroups and should be conducted for a longer period of time.
Finally, if there is a slightly positive effect of rDTMS in our study, it is to note that it was observed 90 days after the initiation of the treatment, which may be attributed to the time required for the development of rDTMS-induced neuroplasticity caused by potential synaptic and nonsynaptic mechanisms.49
In conclusion, in this study, rDTMS exhibited some benefit on motor outcomes of patients with PD but failed to show a significant advantage over sham treatment. Nevertheless, the improvement that was obtained may suggest that greater effects of rDTMS may be achieved by selecting patients with more severe disease and following a longer treatment period (>3 months). It is also evident that there is a need for a systematic search of optimal stimulation parameters (e.g., HF stimulation) and sites (e.g., the cerebellum) an organized cooperation of several clinical sites to advance the development of TMS as a potential therapeutic tool for PD.
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