Tremor Severity and Operative Parameters Predict Imbalance in Patients Undergoing Focused Ultrasound Thalamotomy.

BACKGROUND: Imbalance is the most commonly reported side effect following focused ultrasound (FUS) thalamotomy for essential tremor (ET). It remains unknown which patients are more likely to develop imbalance following FUS treatment. OBJECTIVE: To identify preoperative and treatment-related sonication parameters that are predictive of imbalance following FUS treatment. METHODS: We retrospectively collected demographic data, preoperative Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) scores and FUS treatment parameters in patients undergoing FUS thalamotomy for treatment of ET. The presence of imbalance was evaluated at several discrete time-points with up to 4 years of follow-up. Multiple machine learning classifiers were built and evaluated, aiming to maximize accuracy while minimizing feature set. RESULTS: Of the 297 patients identified, the presence of imbalance peaked at 1 week following operation at 79%. This declined rapidly with 29% reporting imbalance at 3 months, and only 15% at 4 years. At 1 week, total preoperative FTM scores and Maximum Energy delivered in FUS could predict the presence of imbalance at 92.8% accuracy. At 3 months, the total preoperative FTM scores and maximum power delivered could predict the presence of imbalance with 90.6% accuracy. Post-operative lesion size and extent into thalamic nuclei, internal capsule, and subthalamic regions were identified as likely key underlying drivers of these predictors. CONCLUSIONS: A machine learning model based on preoperative tremor scores and maximum energy/power delivered predicted the development of short-term imbalance and long-term imbalance following FUS thalamotomy.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor in Fahr's Disease: Case Report.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy effectively treats medication-resistant essential tremor (ET). Usually, intracranial calcifications are excluded as no-pass zones because of their low penetrability which may limit the effectiveness of treatment and lead to unintended side effects. This case report illustrates the efficacy of unilateral MRgFUS for tremor control in a patient with extensive basal ganglia calcifications due to Fahr's disease. CASE PRESENTATION: A 69-year-old right-handed male with debilitating Fahn-Tolosa-Marin grade 3-4 bilateral hand tremor underwent unilateral left MRgFUS thalamotomy. The treatment involved careful preoperative planning to accommodate his extensive basal ganglia calcifications, element path consideration, and skull density ratio to ensure accurate and effective lesioning. Posttreatment, the patient exhibited complete abolition of tremor on the treated side with minor transient dysarthria and imbalance. Follow-up at 12 weeks posttreatment showed sustained tremor relief and an absence of any adverse effects, validating the procedural adjustments made to accommodate the unique challenges posed by his intracranial calcifications. CONCLUSION: MRgFUS can be safely and effectively applied in certain patients with extensive basal ganglia calcifications - in this case, due to Fahr's disease. This case report suggests expanding the application of MRgFUS to patients with extensive intracranial calcifications who previously might not have been considered suitable candidates for MRgFUS.

Magnetic resonance-guided focused ultrasound thalamotomy for tremor.

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has emerged as an effective treatment for tremor, particularly in those patients who are excluded from deep brain stimulation. The authors illustrate an example of MRgFUS thalamotomy, targeting the ventralis intermedius nucleus, in a 78-year-old patient with tremor who had features of essential tremor and tremor-predominant Parkinson's disease. Significant tremor improvement was seen during the procedure. The authors review step-by-step the preoperative considerations, Vim targeting, treatment, and outcomes for this evolving treatment modality. The video can be found here: https://stream.cadmore.media/r10.3171/2024.7.FOCVID249.

Brain targeting for focused ultrasound essential tremor ablation: proceedings from the 2023 Focused Ultrasound Foundation workshop.

Essential tremor (ET) is the most common movement disorder globally and has negative impacts on quality of life. While medical treatments exist, approximately 50% of patients have tremor that is refractory to medication or experience intolerable medication side effects. Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an option for these patients and while incisionless, it is still invasive, although less so than other surgical treatments such as deep brain stimulation and radiofrequency thalamotomy. Despite MRgFUS being FDA-approved since 2016, there is still no current consensus on the best approaches for targeting, imaging, and outcome measurement. A 2-day workshop held by the Focused Ultrasound Foundation in September of 2023 convened experts and critical stakeholders in the field to share their knowledge and experiences. The goals of the workshop were to determine the optimal target location within the thalamus and compare best practices for localizing the target and tracking patient outcomes. This paper summarizes the current landscape, important questions, and discussions that will help direct future treatments to improve patient care and outcomes.

Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor patients with low skull density ratio: a case-matched analysis.

Introduction: Skull density ratio (SDR) is the ratio between the mean Hounsfield units of marrow and cortical bone, impacting energy transmission through the skull. Low SDR has been used as an exclusion criterion in major trials of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor (ET). However, some studies have suggested that patients with low SDR can safely undergo MRgFUS with favorable outcomes. In this case-matched study, we aim to compare the characteristics, sonication parameters, lesion sizes, and clinical outcomes of patients with low SDR vs. patients with high SDR who underwent unilateral MRgFUS thalamotomy for medication-refractory ET. Methods: Between March 2016 and April 2023, all patients (n = 270) who underwent unilateral MRgFUS thalamotomy for medication-refractory ET at a single institution were classified as low SDR (<0.40) and high SDR (≥0.40). All clinical and radiological data was prospectively collected and retrospectively analyzed using non-case-matched and 1:1 case-matched methodology. Results: Thirty-one patients had low SDR, and 239 patients had high SDR. Fifty-six patients (28 in each cohort) were included in 1:1 case-matched analysis. There were no significant differences in baseline characteristics between the two groups in both non-case-matched and 1:1 case-matched analyses. In both analyses, compared to patients with high SDR, patients with low SDR required a significantly higher maximum sonication power, energy, and duration, and reached a lower maximum temperature with smaller lesion volumes. In the non-case-matched and case-matched analyses, low SDR patients did not have significantly less tremor control at any postoperative timepoints. However, there was a higher chance of procedure failure in the low SDR group with three patients not obtaining an appropriately sized lesion. In both analyses, imbalance was observed more often in high SDR patients on postoperative day 1 and month 3. Discussion: ET patients with SDR <0.40 can be safely and effectively treated with MRgFUS, though there may be higher rates of treatment failure and intraoperative discomfort.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

The role of the motor thalamus in deep brain stimulation for essential tremor.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

Strategies to improve surgical technical competency: a systematic review.

BACKGROUND: A cornerstone of surgical residency training is an educational program that produces highly skilled and effective surgeons. Training structures are constantly being revised due to evolving program structures, shifting workforces, and variability in the clinical environment. This has resulted in significant heterogeneity in all surgical resident education, training tools utilized, and measures of training efficacy. METHODS: We systematically reviewed educational interventions for technical skills in neurosurgery published across PubMed, Embase, and Web of Science over four decades. We extracted general characteristics of each surgical training tool while categorizing educational interventions by modality and neurosurgical application. RESULTS: We identified 626 studies which developed surgical training tools across eight different training modalities: textbooks and literature (11), online resources (53), didactic teaching and one-on-one instruction (7), laboratory courses (50), cadaveric models (63), animal models (47), mixed reality (166), and physical models (229). While publication volume has grown exponentially, a majority of studies were cited with relatively low frequency. Most training programs were published in the development and validation phase with only 2.1% of tools implemented long-term. Each training modality expressed unique strengths and limitations, with limited data reported on the educational impact connected to each training tool. CONCLUSIONS: Numerous surgical training tools have been developed and implemented across residency training programs. Though many creative and cutting-edge tools have been devised, evidence supporting educational efficacy and long-term application is lacking. Increased utilization of novel surgical training tools will require validation of metrics used to assess the training outcomes and optimized integration with clinical practice.

Longitudinal MR imaging after unilateral MR-guided focused ultrasound thalamotomy: clinical and radiological correlation.

Introduction: Magnetic-resonance-guided focused ultrasound (MRgFUS) thalamotomy uses multiple converging high-energy ultrasonic beams to produce thermal lesions in the thalamus. Early postoperative MR imaging demonstrates the location and extent of the lesion, but there is no consensus on the utility or frequency of postoperative imaging. We aimed to evaluate the evolution of MRgFUS lesions and describe the incidence, predictors, and clinical effects of lesion persistence in a large patient cohort. Methods: A total of 215 unilateral MRgFUS thalamotomy procedures for essential tremor (ET) by a single surgeon were retrospectively analyzed. All patients had MR imaging 1 day postoperatively; 106 had imaging at 3 months and 32 had imaging at 1 year. Thin cut (2 mm) axial and coronal T2-weighted MRIs at these timepoints were analyzed visually on a binary scale for lesion presence and when visible, lesion volumes were measured. SWI and DWI sequences were also analyzed when available. Clinical outcomes including tremor scores and side effects were recorded at these same time points. We analyzed if patient characteristics (age, skull density ratio), preoperative tremor score, and sonication parameters influenced lesion evolution and if imaging characteristics correlated with clinical outcomes. Results: Visible lesions were present in all patients 1 day post- MRgFUS and measured 307.4 ± 128.7 mm3. At 3 months, residual lesions (excluding patients where lesions were not visible) were 83.6% smaller and detectable in only 54.7% of patients (n = 58). At 1 year, residual lesions were detected in 50.0% of patients (n = 16) and were 90.7% smaller than 24 h and 46.5% smaller than 3 months. Lesions were more frequently visible on SWI (100%, n = 17), DWI (n = 38, 97.4%) and ADC (n = 36, 92.3%). At 3 months, fewer treatment sonications, higher maximum power, and greater distance between individual sonications led to larger lesion volumes. Volume at 24 h did not predict if a lesion was visible later. Lesion visibility at 3 months predicted sensory side effects but was not correlated with tremor outcomes. Discussion: Overall, lesions are visible on T2-weighted MRI in about half of patients at both 3 months and 1 year post-MRgFUS thalamotomy. Certain sonication parameters significantly predicted persistent volume, but residual lesions did not correlate with tremor outcomes.

Differential cortical network engagement during states of un/consciousness in humans.

What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing we`re reduced, while variability increased in any type of unconscious state. These changes were more pronounced during anesthesia than sleep and involved different cortical engagement. During sleep, changes were mostly uniformly distributed across the brain, whereas during anesthesia, the prefrontal cortex was the most disrupted, suggesting that the lack of arousability during anesthesia results not from just altered overall physiology but from a disconnection between the prefrontal and other brain areas. These findings provide direct evidence for different neural dynamics during loss of consciousness compared with loss of arousability.

Deep Brain Stimulation Lead Localization Variability Comparing Intraoperative MRI Versus Postoperative Computed Tomography.

BACKGROUND AND OBJECTIVES: Commercially available lead localization software for deep brain stimulation (DBS) often relies on postoperative computed tomography (CT) scans to define electrode positions. When cases are performed with intraoperative MRI, another imaging set exists with which to perform these localizations. To compare DBS localization error between postoperative CT scans and intraoperative MRI. METHODS: A retrospective cohort of patients who underwent MRI-guided placement of DBS electrodes using the ClearPoint platform was identified. Using Brainlab Elements, postoperative CT scans were coregistered to intraoperative magnetic resonance images visualizing the ClearPoint guidance sheaths and ceramic stylets. DBS electrodes were identified in CT scans using Brainlab's lead localization tool. Trajectory and vector errors were quantified between scans for each lead in each patient. RESULTS: Eighty patients with a total of 157 implanted DBS electrodes were included. We observed mean trajectory and vector errors of 0.78 ± 0.44 mm (range 0.1-2.0 mm) and 1.57 ± 0.79 mm (range 0.2-4.2 mm), respectively, between postoperative CT and intraoperative MRI. There were 7 patients with CT scans collected at multiple time points. Trajectory error increased by 0.15 ± 0.42 mm ( P = .31), and vector error increased by 0.22 ± 0.53 mm ( P = .13) in the later scans. Across all scans, there was no significant association between trajectory ( P = .053) or vector ( P = .98) error and the date of CT acquisition. DBS electrodes targeting the subthalamic nucleus had significantly greater trajectory errors ( P = .02) than those targeting the globus pallidus pars internus nucleus. CONCLUSION: Commercially available software produced largely concordant lead localizations when comparing intraoperative MRIs with postoperative CT scans, with trajectory errors on average <1 mm. CT scans tend to be more comparable with intraoperative MRI in the immediate postoperative period, with increased time intervals associated with a greater magnitude of error between modalities.

Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

BACKGROUND: Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. OBJECTIVES: To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. METHODS: Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. RESULTS: Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. CONCLUSIONS: MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

Publication Rates and Characteristics of Clinical Trials in Deep Brain and Responsive Neurostimulation.

INTRODUCTION: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting. METHODS: Trials were identified using ClinicalTrials.gov. Associated publications were identified using ClinicalTrials.gov and PubMed.gov. Pearson's χ2 tests were used to assess differences in trial characteristics between published and unpublished trials. RESULTS: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson's disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on ClinicalTrials.gov, and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics. CONCLUSION: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished >1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications.

A Transcriptomic Comparative Study of Cranial Vasculature.

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls.

Initial case series of a novel sensing deep brain stimulation device in drug-resistant epilepsy and consistent identification of alpha/beta oscillatory activity: A feasibility study.

OBJECTIVE: Here, we report a retrospective, single-center experience with a novel deep brain stimulation (DBS) device capable of chronic local field potential (LFP) recording in drug-resistant epilepsy (DRE) and explore potential electrophysiological biomarkers that may aid DBS programming and outcome tracking. METHODS: Five patients with DRE underwent thalamic DBS, targeting either the bilateral anterior (n = 3) or centromedian (n = 2) nuclei. Postoperative electrode lead localizations were visualized in Lead-DBS software. Local field potentials recorded over 12-18 months were tracked, and changes in power were associated with patient events, medication changes, and stimulation. We utilized a combination of lead localization, in-clinic broadband LFP recordings, real-time LFP response to stimulation, and chronic recordings to guide DBS programming. RESULTS: Four patients (80%) experienced a >50% reduction in seizure frequency, whereas one patient had no significant reduction. Peaks in the alpha and/or beta frequency range were observed in the thalamic LFPs of each patient. Stimulation suppressed these LFP peaks in a dose-dependent manner. Chronic timeline data identified changes in LFP amplitude associated with stimulation, seizure occurrences, and medication changes. We also noticed a circadian pattern of LFP amplitudes in all patients. Button-presses during seizure events via a mobile application served as a digital seizure diary and were associated with elevations in LFP power. SIGNIFICANCE: We describe an initial cohort of patients with DRE utilizing a novel sensing DBS device to characterize potential LFP biomarkers of epilepsy that may be associated with seizure control after DBS in DRE. We also present a new workflow utilizing the Percept device that may optimize DBS programming using real-time and chronic LFP recording.

Neuroethical implications of focused ultrasound for neuropsychiatric illness.

BACKGROUND: MR-guided focused ultrasound is a promising intervention for treatment-resistant mental illness, and merits contextualized ethical exploration in relation to more extensive ethical literature regarding other psychosurgical and neuromodulation treatment options for this patient population. To our knowledge, this topic has not yet been explored in the published literature. OBJECTIVE: The purpose of this paper is to review and discuss in detail the neuroethical implications of MR-guided focused ultrasound for neuropsychiatric illness as an emerging treatment modality. METHODS: Due to the lack of published literature on the topic, the approach involved a detailed survey and review of technical and medical literature relevant to focused ultrasound and established ethical issues related to alternative treatment options for patients with treatment-resistant, severe and persistent mental illness. The manuscript is structured according to thematic and topical findings. RESULTS: This technology has potential benefits for patients suffering with severe mental illness, compared with established alternatives. The balance of technical, neuroscientific and clinical considerations should inform ethical deliberations. The nascent literature base, nuances in legal classification and permissibility depending upon jurisdiction, influences of past ethical issues associated with alternative treatments, tone and framing in media articles, and complexity of clinical trials all influence ethical assessment and evaluations of multiple stakeholders. Recommendations for future research are provided based on these factors. CONCLUSION: Salient ethical inquiry should be further explored by researchers, clinicians, and ethicists in a nuanced manner methodologically, one which is informed by past and present ethical issues related to alternative treatment options, broader psychiatric treatment frameworks, pragmatic implementation challenges, intercultural considerations, and patients' ethical concerns.

The return of the lesion for localization and therapy.

Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation have led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations, and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion.

Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology.

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine's antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine's NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.