Interleaved Propofol-Ketamine Maintains DBS Physiology and Hemodynamic Stability: A Double-Blind Randomized Controlled Trial.

BACKGROUND: The gold standard anesthesia for deep brain stimulation (DBS) surgery is the "awake" approach, using local anesthesia alone. Although it offers high-quality microelectrode recordings and therapeutic-window assessment, it potentially causes patients extreme stress and might result in suboptimal surgical outcomes. General anesthesia or deep sedation is an alternative, but may reduce physiological testing reliability and lead localization accuracy. OBJECTIVES: The aim is to investigate a novel anesthesia regimen of ketamine-induced conscious sedation for the physiological testing phase of DBS surgery. METHODS: Parkinson's patients undergoing subthalamic DBS surgery were randomly divided into experimental and control groups. During physiological testing, the groups received 0.25 mg/kg/h ketamine infusion and normal saline, respectively. Both groups had moderate propofol sedation before and after physiological testing. The primary outcome was recording quality. Secondary outcomes included hemodynamic stability, lead accuracy, motor and cognitive outcome, patient satisfaction, and adverse events. RESULTS: Thirty patients, 15 from each group, were included. Intraoperatively, the electrophysiological signature and lead localization were similar under ketamine and saline. Tremor amplitude was slightly lower under ketamine. Postoperatively, patients in the ketamine group reported significantly higher satisfaction with anesthesia. The improvement in Unified Parkinson's disease rating scale part-III was similar between the groups. No negative effects of ketamine on hemodynamic stability or cognition were reported perioperatively. CONCLUSIONS: Ketamine-induced conscious sedation provided high quality microelectrode recordings comparable with awake conditions. Additionally, it seems to allow superior patient satisfaction and hemodynamic stability, while maintaining similar post-operative outcomes. Therefore, it holds promise as a novel alternative anesthetic regimen for DBS. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

[CHANGING CONCEPTS IN THE CLINICAL APPROACH FOR EPILEPSY SURGERY].

INTRODUCTION: Epilepsy is a common disease state, occurring in approximately 1% of the population worldwide, including both pediatric and adult populations. It is characterized by recurrent episodes of unpredictable pathologic cortical brain activity. One-third of patients develop drug intractability and experience recurrent seizures, despite optimal treatment. These result in cognitive decline, behavioral changes, decreased quality of life, and increased risk for trauma and death (SUDEP- sudden unprovoked death from epilepsy). Therefore, the international league against epilepsy (ILAE) recommends referral of intractable patients to highly specialized epilepsy centers, for further evaluation for epilepsy surgery.

Asleep DBS under ketamine sedation: Proof of concept.

BACKGROUND: Deep brain stimulation (DBS) is commonly and safely performed for selective Parkinson's disease patients. Many centers perform DBS lead positioning exclusively under local anesthesia, to optimize brain microelectrode recordings (MER) and testing of stimulation-related therapeutic and side effects. These measures enable physiological identification of the DBS borders and subdomains based on electrophysiological properties like firing rates and patterns, intra-operative evaluation of therapeutic window, and improvement of lead placement accuracy. Nevertheless, due to the challenges of awake surgery, some centers use sedation or general anesthesia, despite the distortion of discharge properties and interference with clinical testing, resulting in potential impact on surgical outcomes. Thus, there is a need for a novel anesthesia regimen that enables sedation without compromising intra-operative monitoring. OBJECTIVE: This open-label study investigates the use of low-dose ketamine for conscious sedation during microelectrode recordings and lead positioning in subthalamic nucleus (STN) DBS for Parkinson's disease patients. METHODS: Three anesthetic regimens were retrospectively compared in 38 surgeries (74 MER trajectories, 5962 recording sites) across three DBS centers: 1) Interleaved propofol-ketamine (PK), 2) Interleaved propofol-awake (PA), and 3) Fully awake (AA). RESULTS: All anesthesia regimens achieved satisfactory MER. Detection of STN borders and subdomains by expert electrophysiologist was similar between the groups. Electrophysiological signature of the STN under ketamine was not inferior to either control group. All patients completed stimulation testing. CONCLUSIONS: This study supports a low-dose ketamine anesthesia regimen for DBS which allows microelectrode recordings and stimulation testing that are not inferior to those conducted under awake and propofol-awake regimens and may optimize patient experience. A prospective double-blind study that would also compare patients' satisfaction level and clinical outcome should be performed to confirm these findings.

Eight cylindrical contact lead recordings in the subthalamic region localize beta oscillations source to the dorsal STN.

BACKGROUND: In Parkinson's disease (PD) patients, the subthalamic nucleus (STN) has prominent oscillatory activity in the beta band, which may be related to the motor symptoms severity. Local field potential (LFP) studies using standard four-contact deep brain stimulation (DBS) leads indicate that the source of beta activity in the STN region is the dorsolateral segment of the nucleus. However, these leads have few contacts outside of the STN, making the source localization of beta activity around the STN region uncertain. OBJECTIVE: This study aimed to investigate the electrophysiological characteristics of the STN and the surrounding area in PD to better locate the source of these oscillations and their clinical relevance. METHODS: Eight PD patients were bilaterally implanted in the STN with the eight ring-contact DBS lead (Boston Scientific Corporation). LFPs were recorded intra-operatively from each DBS contact in the off medication state at rest. Each contact location was normalized relative to the STN borders based on microelectrode recordings. For each recording, power spectral density was computed, averaged over multiple frequency bands and phase reversal analysis was used to localize the source of oscillatory activity. Beta burst, high-frequency activity (HFA), and phase-amplitude coupling (PAC) were also computed. Neurophysiological signatures were correlated with hemibody symptoms severity and clinical outcomes. RESULTS: Beta band power and phase reversal localized the beta oscillator to the dorsal STN and correlated with pre-operative off medication hemibody bradykinesia and rigidity score. The contact along the electrode with the largest beta oscillatory power co-localized with the independently chosen optimized contact used for long-term chronic DBS. Lastly, beta bursting, HFA, and Beta-HFA PAC co-localized with the beta oscillator at the dorsal STN, and Beta-HFA PAC correlated with DBS effect. CONCLUSIONS: Our findings support the hypothesis that the primary source of beta oscillations is located in dorsal STN, and argue against the alternative hypothesis that beta activity in the STN region arises from volume conduction from other sources. We demonstrate intrinsic STN beta-HFA PAC as an independent marker of DBS effect.

Movement context modulates neuronal activity in motor and limbic-associative domains of the human parkinsonian subthalamic nucleus.

The subthalamic nucleus (STN), a preferred target for treating movement disorders, has a crucial role in inhibition and execution of movement. To better understand the mechanism of movement regulation in the STN of Parkinson's disease patients, we compared the same movement with different context, facilitation vs. inhibition context. We recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (off medications, n = 43 patients, 173 recording sites) performed increasingly complex oddball paradigms with frequent and deviant tones: first, passive listening to tone series with no movement ('None-Go' task, n = 7, 28 recording sites); second, pressing a button after every tone ('All-Go' task, n = 7, 26 recording sites); and third, pressing a button only for frequent tones, thus adding inhibition of movement following deviant tones ('Go-NoGo' task, n = 29, 119 recording sites). The STN responded mainly to movement-involving tasks. In the limbic-associative STN, evoked response to the deviant tone (inhibitory cue) was not significantly different between the Go-NoGo and the All-Go task. However, the evoked response to the frequent tone (go cue) in the Go-NoGo task was significantly reduced. The reduction was mainly prominent in the negative component of the evoked response amplitude aligned to the press. Successful movement inhibition was correlated with higher baseline activity. We suggest that the STN in Parkinson's disease patients adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the limbic- associative STN domains in movement planning and in global movement regulation.

Theta-alpha oscillations characterize emotional subregion in the human ventral subthalamic nucleus.

BACKGROUND: Therapeutic outcomes of STN-DBS for movement and psychiatric disorders depend on electrode location within the STN. Electrophysiological and functional mapping of the STN has progressed considerably in the past years, identifying beta-band oscillatory activity in the dorsal STN as a motor biomarker. It also has been suggested that STN theta-alpha oscillations, involved in impulse control and action inhibition, have a ventral source. However, STN local field potential mapping of motor, associative, and limbic areas is often limited by poor spatial resolution. OBJECTIVES: Providing a high-resolution electrophysiological map of the motor, associative and limbic anatomical sub-areas of the subthalamic nucleus. METHODS: We have analyzed high-spatial-resolution STN microelectrode electrophysiology recordings of PD patients (n = 303) that underwent DBS surgery. The patients' STN intraoperative recordings of spiking activity (933 electrode trajectories) were combined with their imaging data (n = 83 patients, 151 trajectories). RESULTS: We found a high theta-alpha (7-10 Hz) oscillatory area, located near the STN ventromedial border in 29% of the PD patients. Theta-alpha activity in this area has higher power and lower central frequency in comparison to theta-alpha activity in more dorsal subthalamic areas. When projected on the DISTAL functional atlas, the theta-alpha oscillatory area overlaps with the STN limbic subarea. CONCLUSIONS: We suggest that theta-alpha oscillations can serve as an electrophysiological marker for the ventral subthalamic nucleus limbic subarea. Therefore, theta-alpha oscillations can guide optimal electrode placement in neuropsychiatric STN-DBS procedures and provide a reliable biomarker input for future closed-loop DBS device. © 2019 International Parkinson and Movement Disorder Society.

Local vs. volume conductance activity of field potentials in the human subthalamic nucleus.

Subthalamic nucleus field potentials have attracted growing research and clinical interest over the last few decades. However, it is unclear whether subthalamic field potentials represent locally generated neuronal subthreshold activity or volume conductance of the organized neuronal activity generated in the cortex. This study aimed at understanding of the physiological origin of subthalamic field potentials and determining the most accurate method for recording them. We compared different methods of recordings in the human subthalamic nucleus: spikes (300-9,000 Hz) and field potentials (3-100 Hz) recorded by monopolar micro- and macroelectrodes, as well as by differential-bipolar macroelectrodes. The recordings were done outside and inside the subthalamic nucleus during electrophysiological navigation for deep brain stimulation procedures (150 electrode trajectories) in 41 Parkinson's disease patients. We modeled the signal and estimated the contribution of nearby/independent vs. remote/common activity in each recording configuration and area. Monopolar micro- and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity. However, bipolar macroelectrode recordings inside the subthalamic nucleus can detect locally generated potentials. These results are confirmed by high correspondence between the model predictions and actual correlation of neuronal activity recorded by electrode pairs. Differential bipolar macroelectrode subthalamic field potentials can overcome volume conductance effects and reflect locally generated neuronal activity. Bipolar macroelectrode local field potential recordings might be used as a biological marker of normal and pathological brain functions for future electrophysiological studies and navigation systems as well as for closed-loop deep brain stimulation paradigms.NEW & NOTEWORTHY Our results integrate a new method for human subthalamic recordings with a development of an advanced mathematical model. We found that while monopolar microelectrode and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity, bipolar macroelectrode recordings inside the subthalamic nucleus (STN) detect locally generated potentials that are significantly different than those recorded outside the STN. Differential bipolar subthalamic field potentials can be used in navigation and closed-loop deep brain stimulation paradigms.

Electrophysiology-aided DBS targeting the ventral intermediate nucleus in an essential tremor patient with MRI-incompatible lead: A case report.

Essential tremor (ET) is a common disease in the elderly population. Severe, medication-refractory ET may require surgical intervention via ablation or deep brain stimulation (DBS). Thalamic Vim (Ventral intermediate nucleus), targeted indirectly using atlas-based coordinates, is the classical target in these procedures. We present a case of an ET patient with a non-MR-compatible cardiac orphaned leads who was a candidate for DBS surgery. Due to the lead constraints of MR use, we used a head computed tomography (CT) with contrast media as the reference exam to define the AC, PC, and midline, and to register and indirectly target the Vim. For target validation, we used intraoperative electrophysiological recordings and intraoperative CT. We implanted bilateral directional leads at the target location. We used the-essential-tremor-rating-assessment-scale (TETRAS) pre and postoperatively to clinically evaluate tremor. Intraoperative micro-electrode recordings (MERs) showed individual tremor cells and a robust increase in normalized root mean square (NRMS) indicating entry to the Vim. Postoperative visualization using lead-DBS along with dramatic clinical improvements show that we were able to accurately target the Vim. Our results show that CT-only registration and planning for thalamic Vim DBS is feasible, and that MERs and intraoperative CT are useful adjuncts for Vim target validation.

Reduced risk trajectory planning in image-guided keyhole neurosurgery.

PURPOSE: The authors present and evaluate a new preoperative planning method and computer software designed to reduce the risk of candidate trajectories for straight rigid tool insertion in image-guided keyhole neurosurgery. METHODS: Trajectories are computed based on the surgeon-defined target and a candidate entry point area on the outer head surface on preoperative CT/MRI scans. A multiparameter risk card provides an estimate of the risk of each trajectory according to its proximity to critical brain structures. Candidate entry points in the outer head surface areas are then color-coded and displayed in 3D to facilitate selection of the most adequate point. The surgeon then defines and/or revised the insertion trajectory using an interactive 3D visualization of surrounding structures. A safety zone around the selected trajectory is also computed to visualize the expected worst-case deviation from the planned insertion trajectory based on tool placement errors in previous surgeries. RESULTS: A retrospective comparative study for ten selected targets on MRI head scans for eight patients showed a significant reduction in insertion trajectory risk. Using the authors' method, trajectories longer than 30 mm were an average of 2.6 mm further from blood vessels compared to the conventional manual method. Average planning times were 8.4 and 5.9 min for the conventional technique and the authors' method, respectively. Neurosurgeons reported improved understanding of possible risks and spatial relations for the trajectory and patient anatomy. CONCLUSIONS: The suggested method may result in safer trajectories, shorter preoperative planning time, and improved understanding of risks and possible complications in keyhole neurosurgery.

Real-time machine learning classification of pallidal borders during deep brain stimulation surgery.

OBJECTIVE: Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) in patients with Parkinson's disease and dystonia improves motor symptoms and quality of life. Traditionally, pallidal borders have been demarcated by electrophysiological microelectrode recordings (MERs) during DBS surgery. However, detection of pallidal borders can be challenging due to the variability of the firing characteristics of neurons encountered along the trajectory. MER can also be time-consuming and therefore costly. Here we show the feasibility of real-time machine learning classification of striato-pallidal borders to assist neurosurgeons during DBS surgery. APPROACH: An electrophysiological dataset from 116 trajectories of 42 patients consisting of 11 774 MER segments of background spiking activity in five classes of disease was used to train the classification algorithm. The five classes included awake Parkinson's disease patients, as well as awake and lightly anesthetized genetic and non-genetic dystonia patients. A machine learning algorithm was designed to provide prediction of the striato-pallidal borders, based on hidden Markov models (HMMs) and the L1-distance measure in normalized root mean square (NRMS) and power spectra of the MER. We tested its performance prospectively against the judgment of three electrophysiologists in the operating rooms of three hospitals using newly collected data. MAIN RESULTS: The awake and the light anesthesia dystonia classes could be merged. Using MER NRMS and spectra, the machine learning algorithm was on par with the performance of the three electrophysiologists across the striatum-GPe, GPe-GPi, and GPi-exit transitions for all disease classes. SIGNIFICANCE: Machine learning algorithms enable real-time GPi navigation systems to potentially shorten the duration of electrophysiological mapping of pallidal borders, while ensuring correct pallidal border detection.

A swine model of intracellular cerebral edema - Cerebral physiology and intracranial compliance.

Cerebral edema leading to elevated intracranial pressure (ICP) is a fundamental concern after severe traumatic brain injury (TBI), stroke, and severe acute hyponatremia. We describe a swine model of water intoxication and its cerebral histological and physiological sequela. We studied female swine weighing 35-45 kg. Four serum sodium intervals were designated: baseline, mild, moderate, and severe hyponatremia attained by infusing hypotonic saline. Intracranial fluid injections were performed to assess intracranial compliance. At baseline and following water intoxication wedge biopsy was obtained for pathological examination and electron microscopy. We studied 8 swine and found an increase in ICP that was strongly related to the decrease in serum sodium level. Mean ICP rose from a baseline of 6 ±â€¯2 to 28 ±â€¯6 mm Hg during severe hyponatremia, while cerebral perfusion pressure (CPP) decreased from 72 ±â€¯10 to 46 ±â€¯11 mm Hg. Brain tissue oxygen tension (PbtO2) decreased from 18.4 ±â€¯8.9 to 5.3 ±â€¯3.0 mm Hg. Electron microscopy demonstrated intracellular edema and astrocytic foot process swelling following water intoxication. With severe hyponatremia, 2 cc intracranial fluid injection resulted in progressively greater ICP dose, indicating a worsening intracranial compliance. Our model leads to graded and sustained elevation of ICP, lower CPP, and decreased PbtO2, all of which cross clinically relevant thresholds. Intracranial compliance worsens with increased cerebral swelling. This model may serve as a platform to study which therapeutic interventions best improve the cerebral physiological profile in the face of severe brain edema.

Subthalamic theta activity: a novel human subcortical biomarker for obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common and serious psychiatric disorder. Although subthalamic nucleus deep brain stimulation (DBS) has been studied as a treatment for OCD patients the underlying mechanism of this treatment and the optimal method of stimulation are unknown. To study the neural basis of subthalamic nucleus DBS in OCD patients we used a novel, implantable DBS system with long-term local field potential sensing capability. We focus our analysis on two patients with OCD who experienced severe treatment-resistant symptoms and were implanted with subthalamic nucleus DBS systems. We studied them for a year at rest and during provocation of OCD symptoms (46 recording sessions) and compared them to four Parkinson's disease (PD) patients implanted with subthalamic nucleus DBS systems (69 recording sessions). We show that the dorsal (motor) area of the subthalamic nucleus in OCD patients displays a beta (25-35 Hz) oscillatory activity similar to PD patients whereas the ventral (limbic-cognitive) area of the subthalamic nucleus displays distinct theta (6.5-8 Hz) oscillatory activity only in OCD patients. The subthalamic nucleus theta oscillatory activity decreases with provocation of OCD symptoms and is inversely correlated with symptoms severity over time. We conclude that beta oscillations at the dorsal subthalamic nucleus in OCD patients challenge their pathophysiologic association with movement disorders. Furthermore, theta oscillations at the ventral subthalamic nucleus in OCD patients suggest a new physiological target for OCD therapy as well as a promising input signal for future emotional-cognitive closed-loop DBS.

Plasticity of intrinsic firing response gain in principal hippocampal neurons following pilocarpine-induced status epilepticus.

OBJECTIVE: In experimental models of temporal lobe epilepsy (TLE), brain neurons manifest multiple changes in intrinsic excitability that contribute to neuronal network hyperexcitability. We have investigated whether the intrinsic firing response gain, quantified by the slope of the function relating the number of evoked spikes (Ns) to input excitatory current intensity (I), is modified in principal rat hippocampal neurons in the pilocarpine-status epilepticus (SE) model of TLE. METHODS: Intracellular recordings were made in CA3 and CA1 pyramidal cells (PCs) and dentate granule cells (GCs) in acute hippocampal slices obtained 7-36days after pilocarpine-SE. Firing response gains were determined empirically from Ns/I relationships and compared to other measured neuronal properties. RESULTS: The firing response gain in all three types of principal neurons, particularly in CA3 PCs, was markedly multiplied following pilocarpine-SE. Analyses of persistent changes in active and passive properties of CA3 PCs suggested that this increase is multifactorial in origin, the major factors being a reduction in amplitude of the slow afterhyperpolarization and an increase in the fraction of bursting neurons. SIGNIFICANCE: Here we show that pilocarpine-SE causes multiplication of the firing response gain in the three principal neurons in the hippocampal trisynaptic pathway. This alteration undoubtedly would contribute to hippocampal hyperexcitability in SE-induced TLE.

Posterolateral Trajectories Favor a Longer Motor Domain in Subthalamic Nucleus Deep Brain Stimulation for Parkinson Disease.

OBJECTIVE: The clinical outcome of patients with Parkinson disease (PD) who undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is, in part, determined by the length of the electrode trajectory through the motor STN domain, the dorsolateral oscillatory region (DLOR). Trajectory length has been found to correlate with the stimulation-related improvement in patients' motor function (estimated by part III of the United Parkinson's Disease Rating Scale [UPDRS]). Therefore, it seems that ideally trajectories should have maximal DLOR length. METHODS: We retrospectively studied the influence of various anatomic aspects of the brains of patients with PD and the geometry of trajectories planned on the length of the DLOR and STN recorded during DBS surgery. We examined 212 trajectories and 424 microelectrode recording tracks in 115 patients operated on in our center between 2010 and 2015. RESULTS: We found a strong correlation between the length of the recorded DLOR and STN. Trajectories that were more lateral and/or posterior in orientation had a longer STN and DLOR pass, although the DLOR/STN fraction length remained constant. The STN target was more lateral when the third ventricle was wider, and the latter correlated with older age and male gender. CONCLUSIONS: Trajectory angles correlate with the recorded STN and DLOR lengths, and should be altered toward a more posterolateral angle in older patients and atrophied brains to compensate for the changes in STN location and geometry. These fine adjustments should yield a longer motor domain pass, thereby improving the patient's predicted outcome.

Intractable Blepharospasm Treated with Bilateral Pallidal Deep Brain Stimulation.

BACKGROUND: Blepharospasm can be present as an isolated dystonia or in conjunction with other forms of cranial dystonia, causing significant disability. CASE REPORT: We report a case of a 69-year-old male with craniocervical dystonia, manifesting primarily as incapacitating blepharospasm refractory to medical treatments. He underwent bilateral globus pallidus (GP) deep brain stimulation (DBS) with complete resolution of his blepharospasm and sustained benefit at 12 months postoperatively. DISCUSSION: This case illustrates successful treatment of blepharospasm with pallidal stimulation. GP-DBS should be considered a reasonable therapeutic option for intractable blepharospasm.

Solitary juvenile xanthogranuloma mimicking intracranial tumor in children.

Juvenile xanthogranuloma (JXG) is primarily a benign cutaneous disorder of non-Langerhans hystiocytic proliferation. Systemic involvement occurs in 4% of patients; isolated central nervous system (CNS) lesions are rare. We report solitary CNS-JXG lesions in two patients. A 3.5-year-old boy with a parietal-occipital lesion underwent total resection with no surgical morbidity and no recurrence at 16-month follow-up. A 3.5-year-old girl underwent subtotal resection of a tumor extending from the left Meckel's cave and invading the cavernous sinus and left orbit with extensive cranial nerve involvement. Tumor regrowth with leptomeningeal spread at 9-month and 12-month follow-up was managed with steroids and chemotherapy (vinblastine and later cladribine). We present our experience and review the literature pertaining to rare reports of solitary CNS-JXG.

A method for planning safe trajectories in image-guided keyhole neurosurgery.

We present a new preoperative planning method for reducing the risk associated with insertion of straight tools in image-guided keyhole neurosurgery. The method quantifies the risks of multiple candidate trajectories and presents them on the outer head surface to assist the neurosurgeon in selecting the safest path. The surgeon can then define and/or revise the trajectory, add a new one using interactive 3D visualization, and obtain a quantitative risk measures. The trajectory risk is evaluated based on the tool placement uncertainty, on the proximity of critical brain structures, and on a predefined table of quantitative geometric risk measures. Our results on five targets show a significant reduction in trajectory risk and a shortening of the preoperative planning time as compared to the current routine method.