Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has recently become the treatment of choice for advanced Parkinson disease (PD).1 – 4 To achieve optimal clinical results and avoid side effects, the DBS electrode has to be implanted precisely within the dorsolateral STN. In many centers, electrophysiological mapping of the nucleus is performed using microelectrode recording (MER) to achieve precise localization of the electrode.5,6 During this procedure, microelectrodes are passed through the STN, and the electrical neuronal activity is observed and recorded. The surgical team can identify the precise location of the STN and its borders according to the typical activity of its neurons.6
In most centers, during the MER mapping procedure, the patient's head is motionless, fixed inside a stereotaxic frame. The procedure may take several hours. It is therefore not unusual for patients to complain of anxiety or discomfort during the operation.7 Some centers use sedation or light general anesthesia during this surgery.7 – 10 However, most centers do not routinely use any kind of sedation because of concern that it might change the activity of STN neurons and interfere with the precise MER localization of the electrode.11 – 13
There are many reports of different drugs that have been used for sedation during electrophysiological mapping of the STN, including propofol,7,10,14 dexmedetomidine,8,14 remifentanil,7,9 midazolam,9,10 and even volatile anesthetics.15 We decided to assess propofol because it is frequently used for sedation during awake craniotomies.16 – 18 Propofol is a short-acting drug, allowing quick recovery and unbiased neurological examination during or at the end of the procedure.16 Propofol is also easily given IV as a continuous drip, and is easily titrated during different stages of surgery.16 However, reports comparing the clinical results of DBS electrode implantation in fully awake patients versus patients anesthetized with propofol have demonstrated conflicting results: some have shown inferior long-term outcome in the anesthetized patients19 whereas others have not shown a difference.7
We therefore compared the activity of STN neurons before, during, and after the administration of low-dose propofol while performing MER for DBS. Our goals were to examine whether propofol changes the activity of STN neurons, and to reveal the time constants of the propofol effects in the event that propofol did indeed change STN activity.
The study was approved by the IRB (ref. code 39-4.8.06; National Institutes of Health trial number NCT00355927) and the Israeli Ministry of Health (ref. code 3769). All patients signed an informed consent form.
All patients with advanced PD scheduled for STN electrode implantation for DBS treatment were considered candidates for this study. Exclusion criteria were obstructive sleep apnea, suspected difficult airway management, allergy to propofol, eggs, or soy, and patients in whom there was concern about the level of cooperation.
Surgery was performed using the CRW stereotactic frame (Radionics, Burlington, MA). STN target coordinates were chosen as a composite of direct 3T magnetic resonance imaging (T2-weighted axial sequences) and indirect atlas– based targeting using Framelink 5 software (Medtronic, Minneapolis, MN). Surgery was performed off dopaminergic medications (>12 hours after last medication).
During surgery, physiological mapping was performed, using 1 or 2 microelectrodes, starting 10 mm above the calculated target. When 2 microelectrodes were used, the second was advanced in parallel (2 mm anterior) to the central (aimed at the calculated target) electrode track. Further trajectories were only made if the results of microrecording or macrostimulation were suboptimal in the first trajectory; no such cases were included in this study.
No sedatives were used during surgery except during the experimental phase. The patient's level of awareness was continuously assessed clinically and with either entropy or a bispectral index (BIS) monitor (S/5 entropy module or S/5 BIS module, GE Healthcare AS/3 anesthesia monitor, Helsinki, Finland). Entropy and BIS values were collected every minute either manually from the monitor or using a computerized anesthesia record system (MetaVision; iMDsoft, Tel Aviv, Israel).
The experimental phase was performed at a constant electrode position after STN entry of either one or both electrodes, preferably in a position where the trace showed a favorable signal-to-noise ratio. During this phase, patients received an infusion of propofol (50 μg/kg/min) until light sedation was evident on clinical examination (patient was drowsy, but arousable by calling his or her name or a light tap on the shoulder). Once the patient's sedation level was found to be adequate by the anesthesiologist, propofol administration was stopped and the patient was allowed to regain consciousness (patient awake, follows orders, and answers questions). After the patient regained consciousness, electrode advancement was resumed to characterize the position within the STN and to localize the ventral border of the STN. Electrical activity recording continued on average every 100 μm. The experimental phase and clinical evaluation were conducted by a board certified anesthesiologist (either AR or DE).
Data Acquisition and Analysis
Our data acquisition methods have been reported elsewhere.20 Briefly, recording of the microelectrode electrical activity was performed throughout the mapping and the experimental phase. Data were recorded at every position in which the electrode stopped. Data acquisition started after a 2-second stabilization period after electrode movement cessation. Data acquisition was then performed continuously until the next movement (10–60 seconds during mapping and 15 to 25 minutes during the experimental phase).
Data acquisition was conducted with the MicroGuide system (AlphaOmega Engineering, Nazareth, Israel). Neuronal activity was recorded via polyamide-coated tungsten microelectrodes (AlphaOmega Engineering). The recorded signal was amplified either 10,000- or 25,000-fold and band-passed between 250 and 6000 Hz using a hardware 4-pole Butterworth filter. The signal was sampled at 48 kHz (in 1 case, 12-kHz sampling rate was used), by a 12-bit A/D converter, using a ±5-V input range.
The root mean square (RMS) estimate of the raw multiunit activity recorded by the microelectrode was used as a measure for evaluating STN activity.21 The RMS estimate is defined as the square root of the sum of the squares of differences of each data point from the mean, divided by the number of samples minus 1. Normalized RMS was calculated using the average RMS during the first 30 seconds of stable recording after mapping was initiated, before STN entry.
Calculations were performed for each electrode trajectory and averaged for every patient, and differences between the 2 approaches are reported in the text when encountered. A paired Student t test was used to identify differences between the awake and sedated states. The threshold for statistical significance was set at P < 0.05 (5%). When not specified otherwise, the statistics presented in this article are mean ± SD. Analysis was performed using custom-developed Matlab V6.5 (MathWorks, Natick, MA) routines.
Sixteen patients were enrolled in this study; the experiment was conducted once (during electrode implantation to 1 hemisphere) in each patient. All patients had severe PD and were not taking anti-Parkinsonian drugs for at least 12 hours before the procedure.
Propofol-Induced Changes of Level of Consciousness
The goal of this study was to achieve stable light sedation. We used clinical evaluation of the sedation level as the end point to achieve this goal. This was defined as a drowsy patient, arousable by calling his or her name or a light tap on the shoulder. This goal was achieved in all patients within 11.9 ± 3.0 minutes of starting the propofol infusion.
Sedation level was also monitored using either entropy (12 patients) or BIS (4 patients) monitors. However, in 1 case, a technical problem with the BIS monitor prevented BIS data from being obtained; therefore, the BIS data of only 3 patients are presented herein. The average values of these parameters at different times are presented in Table 1. It can be seen that response entropy, state entropy, and BIS all decreased during propofol administration. However, the reduced BIS value did not reach statistical significance because of the small sample size.
The Neuronal Database
During the experiment, we recorded 30 electrode tracks in 16 patients (in 2 cases only 1 electrode was used because of operation constraints). Of these electrode tracks, 6 did not pass via the STN and were excluded from further analysis. We analyzed data of STN activity recorded by 24 electrodes during propofol administration.
Effect of Propofol on STN Neuronal Spiking Activity
Examining the raw data demonstrated that both spiking activity and background electrical activity significantly decreased after administration of propofol and resumed prepropofol rates shortly after administration of propofol ceased (Fig. 1). This could be shown as a decrease of the RMS after propofol administration and return of the RMS to prepropofol values after propofol administration was stopped (Fig. 2).
The RMS of the electrical activity decreased significantly (>2 SDs from the value immediately before administration) in 18 of 24 trajectories. The average normalized RMS decreased by 23.2% ± 9.1% (n = 24): from normalized RMS of 2.18 ± 0.56 before propofol administration to 1.65 ± 0.38 after administration (Fig. 3A). After recovery, neuronal activity returned to baseline: normalized RMS of 2.17 ± 0.52 (n = 23; 1 electrode was advanced out of the STN before returning to baseline and was not included in this analysis). Timing of RMS recovery was defined as the initiation of an evident sustained increase in the RMS. In most cases, the recovery was an abrupt dramatic change unlike the decrease that was gradual in many cases. RMS recovered 9.3 ± 4.0 minutes after propofol administration was stopped (Fig. 3B). The longest recovery time we encountered was 17 minutes.
Administration of propofol for general anesthesia or sedation during DBS surgery has been reported and is frequently used in many centers performing this procedure.7,10,14 It is a short-acting, easily titratable and very predictable drug.16,17 Previous reports demonstrated that it can be used safely for this procedure to the satisfaction of both the surgeon and the patient.7,10 The only drawback of using propofol during DBS surgery is the debate regarding its effect on neuronal activity.7,12,19
Propofol has been shown to allow the recording of typical spiking STN neurons, but at the same time to change the typical background activity of the STN.7 Others have not demonstrated any change in the activity of well-isolated single neurons, but did not examine the population activity.a The background multiunit activity is an important component of the STN electrophysiological mapping, allowing precise identification of the STN borders.21,22 Thus, propofol sedation may affect this mapping and interfere with optimal location of the DBS electrode. An indication that this problem may have an effect on the outcome of the procedure has also been demonstrated.19 The researchers showed that the clinical outcomes of DBS implantation under general anesthesia with propofol were inferior to those achieved without anesthesia. However, even when performed under propofol anesthesia, the STN could still be identified, albeit less accurately.19
Our results indicate that STN neuronal population activity, as reflected by the RMS, decreased significantly after propofol administration. However, even during propofol administration, the RMS remained significantly higher than the baseline RMS outside the STN (normalized RMS 1.65 times the baseline level outside the STN), probably allowing for the identification of the STN borders but with a lower signal-to-noise ratio. Such a decrease of the signal-to-noise ratio may enable MER localization of the STN and electrode localization, but decrease the accuracy of this mapping and the precise localization of the STN borders.
These results do not exclude the possibility of using propofol for DBS surgery even when attempting maximal accuracy. A common approach in awake craniotomies is to use sedation or general anesthesia during part of the surgery, and to awaken the patient for the critical parts in which cooperation is necessary, an approach similar to the wake-up test used in spine surgery.16,18 This option minimizes the patient's discomfort, and allows the critical part of the surgery to be performed without sedation. We claim that this approach can be used in STN DBS surgery as well. Our results demonstrate that RMS activity returns to baseline within a maximum of 17 minutes after cessation of propofol continuous administration. Thus, it would be possible to use continuous propofol sedation during the application of the stereotactic frame, the skin incision, and craniotomy, and to stop the administration 17 minutes (which is also mean + 2 SDs of the time it took the RMS activity of our patients to return to baseline) before electrophysiological mapping begins. This option will enable patients to undergo the procedure with less stress and discomfort, but without affecting the MER.
We have demonstrated that propofol administration leads to a significant decrease of STN neuronal discharge rate. This change may interfere with MER-based DBS electrode localization. However, STN activity returns to baseline within 17 minutes after propofol administration is stopped. To ensure maximal information from MER, propofol administration should be stopped several minutes before the MER begins.
AR helped design and conduct the study, analyze the data, and write the manuscript. This author has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files. DE helped design and conduct the study and write the manuscript. This author has seen the original study data and approved the final manuscript. AZ helped conduct the study, analyze the data, and write the manuscript. This author has seen the original study data and approved the final manuscript. HB helped design and conduct the study, analyze the data, and write the manuscript. This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. ZI helped design and conduct the study and write the manuscript. This author has seen the original study data and approved the final manuscript.
ZI received honoraria from Medtronic. The other authors report no conflicts of interest.
We thank Anan Moran for his help with data collection.
a MacIver B, Brock-Utne J, Jaffe R. Subthalamic neurons recorded in humans are differentially altered by propofol and remifentanil. Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists, New Orleans, LA.
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© 2010 International Anesthesia Research Society
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