Deep Brain Stimulation (DBS) is a well-established surgical therapy used to treat medication refractory disorders such as Parkinson's disease (PD), essential tremor (ET), and dystonia. While DBS can deliver promising clinical benefits, its therapeutic window can be reduced due to stimulation induced side effects. Consequently, patients may experience suboptimal DBS responses as well as persistent stimulation induced side effects ranging across motor and cognitive domains (Okun, 2000; Parsons et al., 2006; Follett et al., 2010).

To further optimize patient outcomes after DBS and minimize its side effects, a variety of stimulation delivery strategies such as novel stimulation waveform shapes (Foutz and McIntyre, 2010; Hofmann et al., 2011), different pulse-width (Daniel et al., 2019; Dayal et al., 2020), frequency (Khoo et al., 2014; Su et al., 2018), and charge balancing systems have been used (De Jesus et al., 2018; Boogers et al., 2022). In particular, charge balancing is crucial to prevent net charge accumulation in the tissues and subsequent neural damage (Lilly et al., 1955), especially when delivering high-frequency stimulation as DBS (Piallat et al., 2009). Currently, DBS therapy from the implantable pulse generator (IPG) is delivered as a monophasic, square wave that relies on passive charge dissipation to neutral prior to the next pulse. This is known as passive recharge stimulation. An alternative charge balancing mechanism, active recharge, uses an active charge redistribution which requires additional battery power to deliver symmetric anodic and cathodic stimulation pulses to balance the net charge at the electrode-tissue interface (Figure 1). Compared to the monophasic passive recharge scheme of conventional DBS, biphasic active recharge can have differential clinical benefits by interfering in the depolarization-repolarization cycle of neurons (Almeida et al., 2017).

Several human studies have assessed the feasibility and clinical efficacy of active recharge, biphasic DBS in PD (Akbar et al., 2016; Okun, 2000; De Jesus et al., 2019), ET (Akbar et al., 2016; De Jesus et al., 2018; Boogers et al., 2022), and dystonia (Almeida et al., 2017; Wong et al., 2023). Compared to conventional passive recharge DBS systems, it has been shown that biphasic stimulation can deliver comparable clinical improvement. In some patients, biphasic stimulation may deliver similar or greater motor symptom improvement than traditional DBS therapy (Okun, 2000; De Jesus et al., 2019).

While passive recharge is the conventional stimulation paradigm in IPGs, intraoperative microelectrode recording platforms for awake DBS can deliver stimulation under a variety of paradigms. In this study, we sought to characterize differences between intraoperative active vs. passive recharge during the monopolar review with respect to stimulation induced side effects. Understanding the full extent of the therapeutic window of different stimulation paradigms is crucial to guide intraoperative decision making. Additionally, understanding the relationship between passive and active recharge can help optimize our intraoperative electrophysiologic testing to best represent anticipated therapeutic effects in the outpatient setting. In this retrospective study, we compared the side-effect stimulation thresholds between active and passive recharge strategies during DBS surgery through monopolar review and compared it to outpatient side effect thresholds.

The University of Florida Institutional Review Board (IRB) approved this study (IRB201901807).

There were 65 consecutive patients who underwent DBS with a single attending neurologist (JW) from July 2021 through September 2022. Patients were excluded if only active recharge was performed (N = 41), lead trajectory was changed after monopolar review (n = 4), or if there was no follow-up testing at time of review (n = 4). The resulting 16 patients with 64 total DBS contacts were included for further analysis (Figure 2). Contacts where no side effects were experienced at maximum stimulation amplitude were excluded for analysis.

In this study, we found that side effect thresholds obtained by intraoperative passive recharge had a stronger correlation to chronic outpatient follow-up thresholds compared to intraoperative active recharge. While both stimulation paradigms correlated well with chronic postoperative side effect thresholds, the correlation was stronger for the passive recharge setting. When comparing the correlations for each intraoperative stimulation paradigm, the difference was not statistically significant, however our study was likely underpowered to find a statistical difference.

Our observations suggest that intraoperative passive recharge could potentially be used in place of the conventional Neuro Omega active recharge setting intraoperatively. By using intraoperative passive recharge, we may be able to better represent the anticipated clinical effects that patients experience in the postoperative setting. This knowledge on the reliability of our intraoperative patient assessments can help guide treatment decisions such as predictive value of procedure efficacy and informing potential trajectory changes. This is the first study to compare how different intraoperative stimulation paradigms correlate with chronic stimulation settings.

In this study, we also found that active recharge tended to produce side effect thresholds at greater amplitudes compared to passive recharge, as only seven of the 64 contacts had passive recharge thresholds that were higher than active recharge. This difference is likely due to the wider distribution of charge in the neural tissue. This difference was observed at each contact, however with a limited sample size, statistical significance was lacking. Additionally, intraoperative side effect thresholds tend to be higher than postoperative side effect thresholds, regardless of whether they are obtained by passive or active recharge. This is likely due to the effects of acute cerebral edema and inflammation at the electrode-tissue interface during lead placement which increases impedance, as well as the controlled outpatient setting which may allow for increased time and sensitivity of side effect testing (Wong et al., 2018).

Overall, active recharge produces higher side effect thresholds, suggesting that the utility of chronic active recharge paradigms (available on rechargeable implantable pulse generators) could provide an enhanced stimulation paradigm in patients with narrow therapeutic windows. Similarly, Boogers et al. recently evaluated side effect thresholds between different stimulation paradigms and found that biphasic stimulation pulses had a wider therapeutic window and higher side effect threshold compared to traditional stimulation, and that that these differences were most pronounced for anodic-first biphasic pulses (Boogers et al., 2022). Our findings are consistent with the findings from Boogers et al. Future studies with larger cohorts involving different stimulation patterns are needed to further assess optimal stimulation patterns and outcomes.

Both intraoperative active recharge and passive recharge stimulation were well-correlated with the monopolar review at the first programming visit. No statistically significant differences were observed suggesting that either passive or active recharge may be utilized intraoperatively.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by University of Florida Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The Ethics Committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants' legal guardians/next of kin because the study was a retrospective chart review without risk to participants.

DM: Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing. MK: Writing—original draft, Writing—review & editing. TO: Writing—original draft, Writing—review & editing. ZS: Investigation, Writing—original draft, Writing—review & editing. VC: Investigation, Writing—original draft, Writing—review & editing. CC: Investigation, Writing—original draft, Writing—review & editing. RZ-F: Investigation, Writing—original draft, Writing—review & editing. JH: Formal analysis, Investigation, Methodology, Software, Supervision, Writing—original draft, Writing—review & editing. JW: Conceptualization, Formal analysis, Investigation, Methodology, Software, Supervision, Writing—original draft, Writing—review & editing.