Frequency-dependent effects of subthalamic deep brain stimulation on motor symptoms in Parkinson’s disease: a meta-analysis of controlled trials

This study aims to investigate how the frequency settings of deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) influence the motor symptoms of Parkinson’s disease (PD). Stimulation with frequencies less than 100 Hz (mostly 60 or 80 Hz) is considered low-frequency stimulation (LFS) and with frequencies greater than 100 Hz (mostly 130 or 150 Hz) is considered high-frequency stimulation (HFS). We conducted a comprehensive literature review and meta-analysis with a random-effect model. Ten studies with 132 patients were included in our analysis. The pooled results showed no significant difference in the total Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores (mean effect, −1.50; p = 0.19) or the rigidity subscore between HFS and LFS. Compared to LFS, HFS induced greater reduction in the tremor subscore within the medication-off condition (mean effect, 1.01; p = 0.002), while no significance was shown within the medication-on condition (mean effect, 0.01; p = 0.92). LFS induced greater reduction in akinesia subscore (mean effect, −1.68, p = 0.003), the time to complete the stand-walk-sit (SWS) test (mean effect, −4.84; p < 0.00001), and the number of freezing of gait (FOG) (mean effect, −1.71; p = 0.03). These results suggest that two types of frequency settings may have different effects, that is, HFS induces better responses for tremor and LFS induces greater response for akinesia, gait, and FOG, respectively, which are worthwhile to be confirmed in future study, and will ultimately inform the clinical practice in the management of PD using STN-DBS.

The effectiveness of STN-DBS on PD depends mainly upon the parameters used in the intervention, including the intensity, frequency, pulse width (PW) and contact configuration 7 . No guidelines are currently available to determine the optimal parameters of the DBS intervention. Only the impact of the intensity (i.e., amplitude of the applied current) and pulse width on the intervention effects are fairly well-understood. For example, the high voltage and/or narrow PW (e.g., 30 µs) of stimulation can induce greater effects (e.g., longer therapeutic window) compared to low voltage and/or wide PW 8,9 . However, the influence of the frequency settings on the therapeutic effects of STN-DBS on motor symptoms are still not fully understood.
The frequency of DBS is often categorized as high frequency (i.e., HFS, >100 Hz, mostly 130 or 150 Hz) or low frequency (i.e., LFS, <100 Hz, mostly 60 or 80 Hz) 1 . These two categories have varied therapeutic effects on motor function in those with PD. For example, Khoo et al. reported that LFS induced greater improvements in motor control performance (i.e., lower UPDRS scores, particularly in akinesia and axial subscores) compared to HFS. Xie et al. showed using LFS significantly improved aspiration, swallowing, FOG and axial symptoms 10,11 . However, Vallabhajosula et al. observed no significant improvements in total UPDRS-III scores, step length and velocity during gait initiation, and gait speed after LFS 12 . As such, no consensus on the effects of STN-DBS frequency settings has been reached, and the potential roles of frequency in ameliorating motor symptoms in PD may be underestimated. Therefore, we here completed a meta-analysis to quantitatively analyze the acute effects (i.e., several minutes to hours) of LFS and HFS of STN-DBS on motor symptoms in PD patients based upon previously published studies. This work may provide us a better understanding on the influences of the frequency settings on motor symptoms in PD, which will ultimately optimize the frequency-programming protocols of STN-DBS for different motor symptoms in clinical practice.

Methods
Search criteria. We conducted a comprehensive review of the published literature reporting the acute effects of LFS and HFS in STN-DBS on motor symptoms in PD. The Pubmed, Embase, the Cochrane Library and the Web of Science were used for the literature research. We reviewed publications up to February 2018 by searching citing and cited articles. We also checked cross-references for certain crucial articles. We used a combination of MeSH and text word searching for the following terms: "(deep brain stimulation OR electrical stimulation OR neuromodulation or DBS) AND frequency AND (subthalamic nucleus OR STN) AND (Parkinson's disease OR PD)".
Eligibility criteria. The inclusion criteria for the searched studies were: written in English; focusing on human participants; participants with PD; unilateral or bilateral procedures; STN-DBS; prospective studies; comparison between LFS (<100 Hz, mostly 60 or 80 Hz) and HFS (>100 Hz, mostly 130 or 150 Hz); UPDRS-III, stand-walk-sit (SWS) test and FOG questionnaire as measurements. The exclusion criteria were: DBS procedure as a treatment for diseases other than PD; targeting other than STN or combined targets; less than 5 participants; retrospective analyses; case reports; review articles; editorials; letters; conference articles. The Prospero registration number of this study is 42017060545.

Quality evaluation and data collection. Quality evaluation was conducted according to the Cochrane
Collaboration's tool for assessing the risk of bias by two physicians separately. Subsequently, study details were extracted from the retrieved studies, including the number of patients, mean age, duration of disease, study designs, post-surgery duration, medication status (on and off), time for adapting to the changed stimulation conditions. The means and standard deviations (SDs) of UPDRS-III scores and subscores, as well as the time to complete SWS tests were collected. The means and SDs were calculated for those data presented as medians and range values as previously described 13 . These procedures were also conducted by two physicians independently to ensure accuracy of analyses.
Statistical analysis. The acute effects of LFS and HFS on motor performance, tremors, rigidity, gait and akinesia were assessed by the changes in the corresponding subscores in the UPDRS III. The results of the SWS test were also summarized. Using Review Manager Version 5.3, a random-effect meta-analysis of continuous variables was performed to pool the mean effect and 95% confidence intervals (CI) for a more conservative estimate of pooled effects. The Cochran's Q-test and I2-values were adapted for assessment of statistical heterogeneity between studies. Heterogeneity was regarded as mild, moderate and high separately when the I2 was above 25%, 50% and 75%, respectively 14 . The extent of DBS-induced improvement in motor symptoms may possibly influenced by the medication states (i.e., on and off) 15,16 . But due to the limited number of studies within the medication-on state, we only summarized and analyzed the data within the medication-off condition. No publication bias analysis was performed due to the low number of included studies.

Study identification and characteristics of included studies.
We identified a total of 876 records from databases following our search strategy. After reviewing titles and abstracts, we excluded 241 unqualified records. We then retrieved full-text articles and found 24 studies that compared the acute effects of low-and high-frequency STN-DBS on motor symptoms in PD. Ten of them met the inclusion criteria (Fig. 1). We then evaluated the allocation, blinding, incomplete outcome data, selective reporting, and other potential sources of bias of the 10 eligible studies (Fig. 2). Four out of the ten studies were completed under the medication-on condition 10,11,17 , five were completed under the medication-off condition 12,[18][19][20] , and the other one did not separate different medication conditions. The age of participants ranged from 31 to 76 years old, and their history of PD ranged from 8 to 29 years. Time intervals between DBS parameter adjustment and motor performance evaluation ranged from 10 to 180 minutes. Among these studies, UPDRS-III scores were reported in 9 studies, and the results of SWS tests were reported in 4 studies. Characteristics of the included studies are presented in Table 1.

Rigidity.
Four studies including 49 patients measured the UPDRS-III Item 22 rigidity subscore. No significant difference between the HFS and LFS was observed regardless of the medication condition (p > 0.05) (Fig. 5d-f). High inconsistency was found between the studies.

Discussion
In this meta-analysis, we provide first-of-its kind evidence of frequency-dependent effects of STN-DBS on different motor symptoms. By analyzing the acute effects of LFS and HFS in STN-DBS on the motor symptoms of patients with PD, our results demonstrated that HFS alleviates tremors better than LFS in the medication-off state, but not in the medication-on state, which is probably due to ceiling-effects on the improvement of tremor in the medication-on state. LFS had greater alleviating effects on akinesia and FOG, and improvement in gait speed compared to HFS. These findings indicates that frequency is an essential parameter for the therapeutic effects of STN-DBS on motor symptoms in PD, and the determination of the frequency setting is critical for the use of DBS in clinical practice.
Similarly, greater reduction in tremors induced by HFS in the medication-off state may arise from the frequency-specific interference effect of STN-DBS on pathological oscillations, that is, HFS attenuates low-beta power, while LFS cannot. Blumenfeld et al. proposed that the superior effect of HFS on tremors might be due to reduced coupling in the cortico-striato-STN circuitry with low-beta bands 2 . In addition, other pathological oscillations may be involved in the regulation of tremors. Anzak et al. found that low gamma oscillations in the STN are associated with tremor severity in PD. In another study, Beudel et al. reported that suppression of the gamma-band in the STN by STN-DBS is inversely related to tremor amplitude. However, as the influence of LFS on gamma-band oscillation is unclear, the frequency-specific effects within gamma power band requires further exploration.
The underlying mechanism through which LFS and HFS influence gait and FOG events may both relate to the pedunculopontine nucleus (PPN), which is located in the caudal pontomesencephalic tegmentum and five mm away from the STN 21,22 , projecting to the cortex and the spinal cord 23 . LFS in the STN may thus affect neural activity in the PPN 24 with diffused current delivered by the implanted electrode or reciprocal connections between the STN and the PPN. In animal studies, Sitti et al. explored the effects of STN-DBS on PPN neural activity and observed that compared to stimulation with 10 Hz or 130 Hz, only 60 Hz STN-DBS produced entrainment of the neural firing pattern in the PPN 25 . Moreover, several studies have comfimed that stimulation of PPN with lower frequency such as 10-25 Hz, sometimes even 60 Hz, had better efficacy of improving gait and locomotion [26][27][28][29][30] . Therefore, LFS targeting the STN may yield a potential propagation to the PPN and induces the changes in the neural activities in PPN, which is needed to be confirmed in future studies by comparing the effects of stimulation targeting STN and PPN.

Limitations
Two out of four studies on the effects on FOG were excluded. Specifically, in study reported by Xie et al. 11 , after the LFS, people perform no any FOG symptom, and thus the scores of FOG were zero, which cannot be used in the meta-analysis 11 . But the findings of Xie et al. 11 was consistent with the results of our analysis, that is, LFS had better efficacy on reducing numbers of FOG 11 . In the other study, no participants presented FOG though the FOG score was measured 17 . The number and the sample sizes of the literatures are thus relatively small and the study designs are of high heterogeneity. Future randomized and double-blinded studies with larger sample sizes are needed to explore explicitly the effects of different frequency bands of on the pathological motor symptoms in population with PD.

Conclusion
In conclusion, our meta-analysis reveal that HFS of STN-DBS is an effective strategy to alleviate tremors within medication-off condition, and LFS is helpful for severe akinesia and gait disturbances in patients with PD. Although these results are needed to be further confirmed in future, the observed frequency-specific effects can ultimately inform the frequency programming of STN-DBS in the clinic use.