Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

A phase 1 open-label trial evaluating focused ultrasound unilateral anterior thalamotomy for focal onset epilepsy.

OBJECTIVE: Focused ultrasound ablation (FUSA) is an emerging treatment for neurological and psychiatric diseases. We describe the initial experience from a pilot, open-label, single-center clinical trial of unilateral anterior nucleus of the thalamus (ANT) FUSA in patients with treatment-refractory epilepsy. METHODS: Two adult subjects with treatment-refractory, focal onset epilepsy were recruited. The subjects received ANT FUSA using the Exablate Neuro (Insightec) system. We determined the safety and feasibility (primary outcomes), and changes in seizure frequency (secondary outcome) at 3, 6, and 12 months. Safety was assessed by the absence of side effects, that is, new onset neurological deficits or performance deterioration on neuropsychological testing. Feasibility was defined as the ability to create a lesion within the anterior nucleus. The monthly seizure frequency was compared between baseline and postthalamotomy. RESULTS: The patients tolerated the procedure well, without neurological deficits or serious adverse events. One patient experienced a decline in verbal fluency, attention/working memory, and immediate verbal memory. Seizure frequency reduced significantly in both patients; one patient was seizure-free at 12 months, and in the second patient, the frequency reduced from 90-100 seizures per month to 3-6 seizures per month. SIGNIFICANCE: This is the first known clinical trial to assess the safety, feasibility, and preliminary efficacy of ANT FUSA in adult patients with treatment-refractory focal onset epilepsy.

Reliability of Intraoperative Testing During Deep Brain Stimulation Surgery.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for medically refractory Parkinson's disease (PD). During DBS surgery, intraoperative testing is performed to confirm optimal lead placement by determining the stimulation thresholds for symptom improvement and side effects. However, the reliability of intraoperative testing in predicting distant postoperative thresholds is unknown. In this study, we hypothesized that intraoperative testing reliably estimates postoperative thresholds for both symptom improvement and side effects. METHODS: We retrospectively analyzed a prospective database with intraoperative and postoperative thresholds for symptom improvement and side effects from a cohort of 66 PD patients who underwent STN DBS. We recorded the stimulation locations relative to the mid-commissural point. Within-patient stimulation pairs were generated by clustering the intraoperative stimulation locations closest to the DBS contacts. We computed the distance between stimulation locations and atlas-based pyramidal tract (PT) and medial lemniscus (ML) masks. A leave-one-out cross-validation analysis was performed to determine the reliability of intraoperative testing in predicting postoperative thresholds while controlling for the distance from the relevant tracks. RESULTS: Intraoperative testing reliably predicted (area under ROC >0.8) postoperative thresholds for tremor and rigidity improvements, as well as stimulation-induced motor contractions and paresthesias. The reliability was poor for improvement in bradykinesia. CONCLUSION: Intraoperative testing reliably predicts postoperative thresholds. These results are relevant during the informed consent process and patient counseling for DBS surgery. These will also guide the development of future methods for intraoperative feedback, especially during asleep DBS.

The Utility of Diffusion Tensor Imaging in Neuromodulation: Moving Beyond Conventional Magnetic Resonance Imaging.

OBJECTIVES: Conventional targeting methods for neuromodulation therapies are insufficient for visualizing targets along white matter pathways and localizing targets in patient-specific space. Diffusion tensor imaging (DTI) holds promise for enhancing neuromodulation targeting by allowing detailed visualization of white matter tracts and their connections on an individual level. MATERIAL AND METHODS: We review the literature on DTI and neuromodulation, focusing on clinical studies that have utilized DTI tractography for surgical neuromodulation planning. This primarily includes the growing number of studies on tractography-guided targeting in deep brain stimulation as well as magnetic resonance-guided focused ultrasound. RESULTS: In this review, we discuss three main topics: 1) an overview of the basic principles of DTI, its metrics, and tractography, 2) the evolution and utility of DTI to better guide neuromodulation targets, and 3) the ability of DTI to investigate structural connectivity and brain networks, and how such a network perspective may be an integral part of identifying new or optimal neuromodulation targets. CONCLUSION: There is increasing evidence that DTI is superior to conventional targeting methods with respect to improving brain stimulation therapies. DTI has the ability to better define anatomical targets by allowing detailed visualization of white matter tracts and localizing targets based on individual anatomy. Network analyses can lead to the identification of new or optimal stimulation targets based on understanding how target regions are connected. The integration of DTI as part of routine MRI and surgical planning offers a more personalized approach to therapy and may be an important path for the future of neuromodulation.

Phase-amplitude coupling within the anterior thalamic nuclei during seizures.

Cross-frequency phase-amplitude coupling (cfPAC) subserves an integral role in the hierarchical organization of interregional neuronal communication and is also expressed by epileptogenic cortex during seizures. Here, we sought to characterize patterns of cfPAC expression in the anterior thalamic nuclei during seizures by studying extra-operative recordings in patients implanted with deep brain stimulation electrodes for intractable epilepsy. Nine seizures from two patients were analyzed in the peri-ictal period. CfPAC was calculated using the modulation index and interregional functional connectivity was indexed using the phase-locking value. Statistical analysis was performed within subjects on the basis of nonparametric permutation and corrected with Gaussian field theory. Five of the nine analyzed seizures demonstrated significant cfPAC. Significant cfPAC occurred during the pre-ictal and ictal periods in three seizures, as well as the postictal windows in four seizures. The preferred phase at which cfPAC occurred differed 1) in space, between the thalami of the epileptogenic and nonepileptogenic hemispheres; and 2) in time, at seizure termination. The anterior thalamic nucleus of the epileptogenic hemisphere also exhibited altered interregional phase-locking synchrony concurrent with the expression of cfPAC. By analyzing extraoperative recordings from the anterior thalamic nuclei, we show that cfPAC associated with altered interregional phase synchrony is lateralized to the thalamus of the epileptogenic hemisphere during seizures. Electrophysiological differences in cfPAC, including preferred phase of oscillatory interactions may be further investigated as putative targets for individualized neuromodulation paradigms in patients with drug-resistant epilepsy. NEW & NOTEWORTHY The association between fast brain activity and slower oscillations is an integral mechanism for hierarchical neuronal communication, which is also manifested in epileptogenic cortex. Our data suggest that the same phenomenon occurs in the anterior thalamic nuclei during seizures. Further, the preferred phase of modulation shows differences in space, between the epileptogenic and nonepileptogenic hemispheres and time, as seizures terminate. Our data encourage the study of cross-frequency coupling for targeted, individualized closed-loop stimulation paradigms.

Neurological adverse event profile of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor.

BACKGROUND: Magnetic resonance imaging-guided focused ultrasound thalamotomy is approved by the U.S. Food and Drug Administration for treatment of essential tremor. Although this incisionless technology creates an ablative lesion, it potentially avoids serious complications of open stereotactic surgery. OBJECTIVE: To determine the safety profile of magnetic resonance imaging-guided focused ultrasound unilateral thalamotomy for essential tremor, including frequency, and severity of adverse events, including serious adverse events. METHODS: Analysis of safety data for magnetic resonance imaging-guided focused ultrasound thalamotomy (186 patients, five studies). RESULTS: Procedure-related serious adverse events were very infrequent (1.6%), without intracerebral hemorrhages or infections. Adverse events were usually transient and were commonly rated as mild (79%) and rarely severe (1%). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related adverse events. CONCLUSION: The overall safety profile of magnetic resonance imaging-guided focused ultrasound thalamotomy supports its role as a new option for patients with medically refractory essential tremor. © 2018 International Parkinson and Movement Disorder Society.

Neuronal activity organization features in human consciousness: summary of introductory remarks in a dialogue with neurological surgery residents.

Agreeing with Damasio's statement defining the "process" of consciousness, we propose the self as created by mind-based knowledge and a combination of images of an organism's intentional motor responses interacting with its environment. The lemniscal system, with plastic capabilities, manages gravity in voluntary movement. The spinal segment motor reflex represents the schema of gravity-managing neuronal activity, and it can become "nested" in cortical areas participating in consciousness-building, allowing consideration of the brain as a hyper-evolved nervous system segment harboring atavic spinal organization. Consciousness' capability to change itself makes humans co-participants in their own mental and consciousness evolution.

Physiology of freezing of gait.

Freezing of gait (FOG) is a common and debilitating, but largely mysterious, symptom of Parkinson disease. In this review, we will discuss the cerebral substrate of FOG focusing on brain physiology and animal models. Walking is a combination of automatic movement processes, afferent information processing, and intentional adjustments. Thus, normal gait requires a delicate balance between various interacting neuronal systems. To further understand gait control and specifically FOG, we will discuss the basic physiology of gait, animal models of gait disturbance including FOG, alternative etiologies of FOG, and functional magnetic resonance studies investigating FOG. The outcomes of these studies point to a dynamic network of cortical areas such as the supplementary motor area, as well as subcortical areas such as the striatum and the mesencephalic locomotor region including the pedunculopontine nucleus (PPN). Additionally, we will review PPN (area) stimulation as a possible treatment for FOG, and ponder whether PPN stimulation truly is the right step forward. Ann Neurol 2016;80:644-659.

Sequence of electrode implantation and outcome of deep brain stimulation for Parkinson's disease.

INTRODUCTION: The effect of the variability of electrode placement on outcomes after bilateral deep brain stimulation of subthalamic nucleus has not been sufficiently studied, especially with respect to the sequence of hemisphere implantation. METHODOLOGY: We retrospectively analysed the clinical and radiographic data of all the consecutive patients with Parkinson's disease who underwent surgery at our centre and completed at least 1 year follow-up. The dispersion in electrode location was calculated by the square of deviation from population mean, and the direction of deviation was analysed by comparing the intended and final implantation coordinates. Linear regression analysis was performed to analyse the predictors of postoperative improvement of the motor condition, also controlling for the sequence of implanted hemisphere. RESULTS: 76 patients (mean age 58±7.2 years) were studied. Compared with the first side, the second side electrode tip had significantly higher dispersion as an overall effect (5.6±21.6 vs 2.2±4.9 mm(2), p=0.04), or along the X-axis (4.1±15.6 vs 1.4±2.4 mm(2), p=0.03) and Z-axis (4.9±11.5 vs 2.9±3.6 mm(2), p=0.02); the second side stimulation was also associated with a lower threshold for side effects (contact 0, p<0.001 and contact 3, p=0.004). In the linear regression analysis, the significant predictors of outcome were baseline activities of daily living (p=0.010) and dispersion of electrode on the second side (p=0.005). CONCLUSIONS: We observed a higher dispersion for the electrode on the second implanted side, which also resulted to be a significant predictor of motor outcome at 1 year.

Tractography-Based Ventral Intermediate Nucleus Targeting: Novel Methodology and Intraoperative Validation.

BACKGROUND: The ventral intermediate nucleus of the thalamus is not readily visible on structural magnetic resonance imaging. Therefore, a method for its visualization for stereotactic targeting is desirable. OBJECTIVE: The objective of this study was to define a tractography-based methodology for the stereotactic targeting of the ventral intermediate nucleus. METHODS: The lateral and posterior borders of the ventral intermediate nucleus were defined by tracking the pyramidal tract and medial lemniscus, respectively. A thalamic seed was then created 3 mm medial and anterior to these borders, and its structural connections were analyzed. The application of this method was assessed in an imaging cohort of 14 tremor patients and 15 healthy controls, in which we compared the tractography-based targeting to conventional targeting. In a separate surgical cohort (3 tremor and 3 tremor-dominant Parkinson's disease patients), we analyzed the accuracy of this method by correlating it with intraoperative neurophysiology. RESULTS: Tractography of the thalamic seed revealed the tracts corresponding to cerebellar input and motor cortical output fibers. The tractography-based target was more lateral (12.5 [1.2] mm vs 11.5 mm for conventional targeting) and anterior (8.5 [1.1] mm vs 6.7 [0.3] mm, anterior to the posterior commissure). In the surgical cohort, the Euclidian distance between the ventral intermediate nucleus identified by tractography and the surgical target was 1.6 [1.1] mm. The locations of the sensory thalamus, lemniscus, and pyramidal tracts were concordant within <1 mm between tractography and neurophysiology. INTERPRETATION: The tractography-based methodology for identification of the ventral intermediate nucleus is accurate and useful. This method may be used to improve stereotactic targeting in functional neurosurgery procedures. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Younger age predicts greater effectiveness of spinal cord stimulation for chronic pain.

BACKGROUND: Spinal cord stimulation (SCS) is an accepted surgical treatment for neuropathic pain in failed back syndrome or complex regional pain syndrome. However, even in the best selected surgical cases the predictors of adequate pain control are not well defined. The aim of this study was to identify predictors of outcome in patients who underwent SCS in our center. METHODS: We performed a retrospective analysis of our neurosurgical database for patients who underwent SCS over the last 8 years in an attempt to identify factors predictive of outcome. RESULTS: Forty-one patients underwent implantation of epidural electrodes, 34 patients had a successful stimulation trial and received permanent devices. Nine patients experienced a late failure at a median time of 7.8 months (range, 4.5-19 months) after implantation. Age was significantly associated with outcome. Younger patients had a significantly lower rate of treatment failure, and none of the patients above 65 years had a successful long-term outcome. CONCLUSIONS: Our results suggest that younger age is associated with greater long-term effectiveness of spinal cord stimulation and therefore age may influence the success of SCS therapy with older patients having a greater tendency to failure. Earlier intervention may be beneficial in these chronic pain patients.

The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease.

Dexmedetomidine (an alpha-2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep-brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording (MER) data from patients with Parkinson's disease who underwent STN DBS. A 'Dex bolus' group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a 'no sedation' group (29 cells from 11 patients). We also performed within-patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke-Vitek methodology and local field potential (LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 ± 9.9 vs. 34.5 ± 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike-oscillations analysis(beta peak, P = 0.4; signal-to-noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high-dose dexmedetomidine should be avoided during DBS surgery.

Disease applications of spinal cord stimulation: Chronic nonmalignant pain.

Neuropathic pain is a chronic condition representing a significant burden for society. It is estimated 1 out of 10 people over the age of 30 that in the US have been diagnosed with neuropathic pain. Most of the available treatments for neuropathic pain have moderate efficacy over time which limit their use; therefore, other therapeutic approaches are needed for patients. Spinal cord stimulation is an established and cost-effective modality for treating severe chronic pain. In this article we will review the current approved indications for the use of spinal cord stimulation in the US and the novel therapeutic options which are now available using this therapy.

Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review.

The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.

Diffusion and functional MRI in surgical neuromodulation.

Surgical neuromodulation has witnessed significant progress in recent decades. Notably, deep brain stimulation (DBS), delivered precisely within therapeutic targets, has revolutionized the treatment of medication-refractory movement disorders and is now expanding for refractory psychiatric disorders, refractory epilepsy, and post-stroke motor recovery. In parallel, the advent of incisionless treatment with focused ultrasound ablation (FUSA) can offer patients life-changing symptomatic relief. Recent research has underscored the potential to further optimize DBS and FUSA outcomes by conceptualizing the therapeutic targets as critical nodes embedded within specific brain networks instead of strictly anatomical structures. This paradigm shift was facilitated by integrating two imaging modalities used regularly in brain connectomics research: diffusion MRI (dMRI) and functional MRI (fMRI). These advanced imaging techniques have helped optimize the targeting and programming techniques of surgical neuromodulation, all while holding immense promise for investigations into treating other neurological and psychiatric conditions. This review aims to provide a fundamental background of advanced imaging for clinicians and scientists, exploring the synergy between current and future approaches to neuromodulation as they relate to dMRI and fMRI capabilities. Focused research in this area is required to optimize existing, functional neurosurgical treatments while serving to build an investigative infrastructure to unlock novel targets to alleviate the burden of other neurological and psychiatric disorders.

Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: a systematic review.

CONTEXT: There is considerable interest in translating laboratory advances in neuronal regeneration following spinal cord injury (SCI). A multimodality approach has been advocated for successful functional neuronal regeneration. With this goal in mind several biomaterials have been employed as neuronal bridges either to support cellular transplants, to release neurotrophic factors, or to do both. A systematic review of this literature is lacking. Such a review may provide insight to strategies with a high potential for further investigation and potential clinical application. OBJECTIVE: To systematically review the design strategies and outcomes after biomaterial-based multimodal interventions for neuronal regeneration in rodent SCI model. To analyse functional outcomes after implantation of biomaterial-based multimodal interventions and to identify predictors of functional outcomes. METHODS: A broad PubMed, CINHAL, and a manual search of relevant literature databases yielded data from 24 publications; 14 of these articles included functional outcome information. Studies reporting behavioral data in rat model of SCI and employing biodegradable polymer-based multimodal intervention were included. For behavioral recovery, studies using severe injury models (transection or severe clip compression (>16.9 g) or contusion (50 g/cm)) were categorized separately from those investigating partial injury models (hemisection or moderate-to-severe clip compression or contusion). RESULTS: The cumulative mean improvements in Basso, Beattie, and Bresnahan scores after biomaterial-based interventions are 5.93 (95% CI = 2.41 - 9.45) and 4.44 (95% CI = 2.65 - 6.24) for transection and hemisection models, respectively. Factors associated with improved outcomes include the type of polymer used and a follow-up period greater than 6 weeks. CONCLUSION: The functional improvement after implantation of biopolymer-based multimodal implants is modest. The relationship with neuronal regeneration and functional outcome, the effects of inflammation at the site of injury, the prolonged survival of supporting cells, the differentiation of stem cells, the effective delivery of neurotrophic factors, and longer follow-up periods are all topics for future elucidation. Future investigations should strive to further define specific factors associated with improved functional outcomes in clinically relevant models.