Feasibility of targeting the cingulate gyrus using high-intensity focused ultrasound on a cadaveric specimen: illustrative case.

BACKGROUND: Cancer is commonly associated with pain. For patients with advanced cancer and intractable pain, ablative neurosurgical procedures can significantly improve pain and transition patients out of inpatient settings. These procedures are normally invasive, and this poses an important risk in this population. Cingulotomy has been reported to improve pain perception and contribute substantially to the quality of life of cancer patients with refractory pain. OBSERVATIONS: One fresh human cadaver specimen was used for the setup. The cingulate gyrus was targeted using intraoperative magnetic resonance images, and osseous aberrations were corrected after coregistration with the preoperative head computed tomography. After accounting for sinuses, membrane folds, and calcifications, a total of 737 elements were available for thermal ultrasound ablation. On high-power sonications, the total energy delivered reached a peak temperature of 57°C (15,050 J, 350 W, 45 seconds) in the right cingulate and 52°C (13,000 J, 405 W, 46 seconds) in the left cingulate. LESSONS: Despite the limitations of using a cadaver model (temperature, vascularization), cingulotomy appears to be feasible using high-intensity focused ultrasound. https://thejns.org/doi/10.3171/CASE2459.

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.

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.

Superficial Vein Thrombosis After Intra-articular Particulate Steroid Injection for Knee Osteoarthritis.

ABSTRACT: Intra-articular steroid injections for knee osteoarthritis are a routine procedure in musculoskeletal clinics. While their role in osteoarthritis care is debatable, they serve as an important therapeutic option to relieve osteoarthritis-associated pain. Potential risks are self-limited (increased pain flare, local skin irritation, flushing, insomnia) or severe (septic arthritis, intravascular medication placement, and the deleterious effect on cartilage and bone). In our experience, more serious adverse events are rare. In this case, we present a complication secondary to intra-articular steroid administration that has not previously been reported in the literature: superficial vein thrombosis. This will raise awareness among clinicians, improve the informed consent process, and provide an approach for the management of subsequent injections.

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.

Polypoid arteriovenous malformation of the rectum: A case report.

Background: Intestinal arteriovenous malformation is an abnormal connection between arteries and veins that bypasses the capillary system and may be a cause of significant lower gastrointestinal bleeding. On endoscopy, arteriovenous malformations are usually flat or elevated, bright red lesions. Overall, rectal localization of arteriovenous malformations is rare. The same may be said about polypoid shape arteriovenous malformations. Herein, we present a case of a large rectal polypoid arteriovenous malformations. Methods: Clinical, diagnostic, and treatment modalities of the patient were reviewed. Pre- and post-operative parameters were collected and analyzed. The clinical English literature is also reviewed and discussed. Results: A 60-year-old female patient was admitted to our emergency department for rectorrhagia and anemia. Rectoscopy revealed a polypoid lesion in the rectum and the biopsy showed fibrosis, necrosis areas, and hyperplastic glands. A total body contrast-enhanced computed tomography (CT) was performed revealing a parietal pseudonodular thickening with concentric growth and contrast enhancement, extending for about 53 mm. The mass wasn't removed endoscopically due to concentric growth, sessile implant, and submucosal nature. The patient underwent an uneventful laparoscopic anterior rectal resection. The postoperative hospitalization was free of complications. Histology showed the presence of a polypoid AVM composed of dilated arteries, veins, capillaries, and lymphatics, engaging the submucosa, muscularis, and subserosa layer. Conclusion: After a review of the current English literature, we found only one case of rectal polypoid AVM. The scarcity of documented cases encumbers optimal diagnostic and treatment approaches.

Non-motor effects of subthalamic nucleus stimulation in Parkinson patients.

The current white matter connectivity analyses of the subthalamic region have focused on the motor effects of deep brain stimulation. We investigate white matter connectivity associated with the stimulation-induced non-motor acute clinical effects in three domains: mood changes, dizziness, and sweating. We performed whole-brain probabilistic tractography seeded from the domain-specific stimulation volumes. The resultant connectivity maps were statistically compared across patients. The cortical voxels associated with each non-motor domain were compared with stimulation-induced motor improvements in a multivariate model. The resulting voxel maps were thresholded for false discovery (FDR q < 0.05) and clustered using a multimodal atlas. We also performed a group-level parcellation of stimulation volumes to identify the local pathways associated with each non-motor domain. The non-motor effects were rarely observed during stimulation titration: from 1100 acute clinical effects, mood change was observed in 14, dizziness in 23, and sweating in 20. Distinct cortical clusters were associated with each domain; notably, mood change was associated with voxels in the salience network and dizziness with voxels in the visual association cortex. The subthalamic parcellation yielded a mediolateral gradient, with the motor parcel being lateral and the non-motor parcels medial. We also observed an anteroposterior organization in the medial non-motor clusters with mood changes being anterior, followed posteriorly by dizziness, and sweating. We interpret these findings based on the literature and foresee these to be useful in guiding DBS programming.

Lung Tumor Skin Metastasis: Case Report of a Solitary Cutaneous Ulcerated Lesion as Initial Manifestation of Lung Carcinoma.

Lung cancer has the highest cancer incidence, and it is the most common cause of cancer death worldwide. Cutaneous metastases are infrequent compared to hilar nodes, adrenal glands, liver, brain, and bones. However, unusual skin lesions in patients at high risk of lung cancer should be regarded carefully to rule out a metastatic manifestation of an occult primary site tumor. Surgical excision, or incisional biopsy when the former is deemed unfeasible, should be performed to allow histopathological examination in case of occult primary site. In patients affected by advanced lung tumors, surgical excision could be beneficial in terms of pain control and improvement of the quality of life. We report a case of a solitary large skin lesion as an early manifestation of a lung adenocarcinoma.

Hemorrhagic Cholecystitis. Report of a case with comprensive literature review and treatment algorithm.

Hemorrhagic Cholecystitis is a rare condition and usually represents a complication of acute cholecystitis. The clinical presentation is quite overlapping and usually involves abdominal pain that may be associated with fever, jaundice, nausea, vomiting, and finally haemobilia. It frequently involves patients with preexisting conditions such as chronic kidney disease undergoing hemodialysis or anticoagulation therapy. Due to the deadly potential of this condition attention must be high during diagnostics and treatment in order to avoid an ill-fated conclusion. To our knowledge, there is a lack of a comprehensive review on the subject as most of the literature consists of case reports or small case series. In order to give a contribution to improving the treatment strategy of this condition, we report a case successfully treated with cholecystectomy, and performed a literature review. Using the term "Hemorrhagic Cholecystitis", on PubMed database we found 67 cases reported in the English literature. The cases were analyzed by two researchers and clinical information was extrapolated and organized, aiming to create a comprehensive review on the subject, that may be clear and useful in clinical practice. KEY WORDS: Hemorrhagic cholecystitis, Surgical treatment.

Intraoperative lesion characterization after focused ultrasound thalamotomy.

OBJECTIVE: Outcomes after focused ultrasound ablation (FUSA) for essential tremor remain heterogeneous, despite therapeutic promise. Clinical outcomes are directly related to the volume and location of the therapeutic lesions, consistent with CNS ablative therapies. Recent data demonstrate that postoperative diffusion MRI, specifically the quantification of intracellular diffusion by restricted diffusion imaging (RDI), can accurately characterize focused ultrasound lesions. However, it is unclear whether RDI can reliably detect focused ultrasound lesions intraoperatively (i.e., within a few minutes of lesioning) and whether the intraoperative lesions predict delayed clinical outcomes. METHODS: An intraoperative imaging protocol was implemented that included RDI and T2-weighted imaging in addition to intraoperative MR thermography. Lesion characteristics were defined with each sequence and then compared. An imaging-outcomes analysis was performed to determine lesion characteristics associated with delayed clinical outcomes. RESULTS: Intraoperative RDI accurately identified the volume and location of focused ultrasound lesions. Intraoperative T2-weighted imaging underestimated the lesion volume but accurately identified the location. Intraoperative RDI revealed that lesions of the ventral border of the ventral intermediate nucleus were significantly associated with postoperative tremor improvement. In contrast, the lesions extending into the inferolateral white matter were associated with postoperative ataxia. CONCLUSIONS: These data support the acquisition of intraoperative RDI to characterize focused ultrasound lesions. Future research should test the histological correlates of intraoperative RDI and test whether it can be developed as feedback to optimize the current technique of FUSA.

Radiological identification of the globus pallidus motor subregion in Parkinson's disease.

OBJECTIVE: Globus pallidus (GP) lesioning improves motor symptoms of Parkinson's disease (PD) and is occasionally associated with nonmotor side effects. Although these variable clinical effects were shown to be site-specific within the GP, the motor and nonmotor subregions have not been distinguished radiologically in patients with PD. The GP was recently found to have a distinct radiological signature on diffusion MRI (dMRI), potentially related to its unique cellular content and organization (or tissue architecture). In this study, the authors hypothesize that the magnitude of water diffusivity, a surrogate for tissue architecture, will radiologically distinguish motor from nonmotor GP subregions in patients with PD. They also hypothesize that the therapeutic focused ultrasound pallidotomy lesions will preferentially overlap the motor subregion. METHODS: Diffusion MRI from healthy subjects (n = 45, test-retest S1200 cohort) and PD patients (n = 33) was parcellated based on the magnitude of water diffusivity in the GP, as measured orientation distribution function (ODF). A clustering algorithm was used to identify GP parcels with distinct ODF magnitude. The individual parcels were used as seeds for tractography to distinguish motor from nonmotor subregions. The locations of focused ultrasound lesions relative to the GP parcels were also analyzed in 11 patients with PD. RESULTS: Radiologically, three distinct parcels were identified within the GP in healthy controls and PD patients: posterior, central, and anterior. The posterior and central parcels comprised the motor subregion and the anterior parcel was classified as a nonmotor subregion based on their tractography connections. The focused ultrasound lesions preferentially overlapped with the motor subregion (posterior more than central). The hotspots for motor improvement were localized in the posterior GP parcel. CONCLUSIONS: Using a data-driven approach of ODF-based parcellation, the authors radiologically distinguished GP motor subregions in patients with PD. This method can aid stereotactic targeting in patients with PD undergoing surgical treatments, especially focused ultrasound ablation.

New Frontiers for Deep Brain Stimulation: Directionality, Sensing Technologies, Remote Programming, Robotic Stereotactic Assistance, Asleep Procedures, and Connectomics.

Over the last few years, while expanding its clinical indications from movement disorders to epilepsy and psychiatry, the field of deep brain stimulation (DBS) has seen significant innovations. Hardware developments have introduced directional leads to stimulate specific brain targets and sensing electrodes to determine optimal settings via feedback from local field potentials. In addition, variable-frequency stimulation and asynchronous high-frequency pulse trains have introduced new programming paradigms to efficiently desynchronize pathological neural circuitry and regulate dysfunctional brain networks not responsive to conventional settings. Overall, these innovations have provided clinicians with more anatomically accurate programming and closed-looped feedback to identify optimal strategies for neuromodulation. Simultaneously, software developments have simplified programming algorithms, introduced platforms for DBS remote management via telemedicine, and tools for estimating the volume of tissue activated within and outside the DBS targets. Finally, the surgical accuracy has improved thanks to intraoperative magnetic resonance or computerized tomography guidance, network-based imaging for DBS planning and targeting, and robotic-assisted surgery for ultra-accurate, millimetric lead placement. These technological and imaging advances have collectively optimized DBS outcomes and allowed "asleep" DBS procedures. Still, the short- and long-term outcomes of different implantable devices, surgical techniques, and asleep vs. awake procedures remain to be clarified. This expert review summarizes and critically discusses these recent innovations and their potential impact on the DBS field.

Functional Neuroimaging During Asleep DBS Surgery: A Proof of Concept Study.

Object: A real-time functional magnetic resonance imaging (fMRI) feedback during ventral intermediate nucleus (VIM) deep brain stimulation (DBS) under general anesthesia (or "asleep" DBS) does not exist. We hypothesized that it was feasible to acquire a reliable and responsive fMRI during asleep VIM DBS surgery. Methods: We prospectively enrolled 10 consecutive patients who underwent asleep DBS for the treatment of medication-refractory essential tremor. Under general anesthesia, we acquired resting-state functional MRI immediately before and after the cannula insertion. Reliability was determined by a temporal signal-to-noise-ratio >100. Responsiveness was determined based on the fMRI signal change upon insertion of the cannula to the VIM. Results: It was feasible to acquire reliable fMRI during asleep DBS surgery. The fMRI signal was responsive to the brain cannula insertion, revealing a reduction in the tremor network's functional connectivity, which did not reach statistical significance in the group analysis. Conclusions: It is feasible to acquire a reliable and responsive fMRI signal during asleep DBS. The acquisition steps and the preprocessing pipeline developed in these experiments will be useful for future investigations to develop fMRI-based feedback for asleep DBS surgery.

Thermal Neuromodulation With Focused Ultrasound: Implications for the Technique of Subthreshold Testing.

BACKGROUND: During focused ultrasound ablation (FUSA), the presumed stereotactic target is tested with subthreshold sonications before permanent ablation. This testing relies on ultrasound-induced reversible clinical effects (thermal neuromodulation, TN). However, the thermal dose and spot size thresholds to induce TN are not yet defined. OBJECTIVE: To define the thermal dose and spot size thresholds associated with TN. METHODS: We performed a retrospective analysis of intraoperative FUSA data of essential tremor patients. Sonications with a thermal dose of less than 25 cumulative equivalent minutes (CEM) were classified as subthreshold. The intraoperative writing samples were independently rated by 2 raters using the clinical rating scale for tremor. The association between thermal dose and tremor scores was statistically analyzed, and the thermal dose and spot size thresholds for TN were computed using leave-one-out cross-validation analysis. RESULTS: A total of 331 pairs of sonications and writing samples were analyzed; 97 were classified as subthreshold sonications. TN was observed in 23 (24%) subthreshold sonications. The median tremor improvement during TN was 20% (interquartile range = 41.6). The thermal dose threshold for TN was 0.67 CEM (equivalent to 30 s thermal exposure at 43°C). The spot size threshold for TN was 2.46 mm. Ventral intermediate medial nucleus was exposed to TN thermal dose during subablative and ablative sonications. CONCLUSION: The TN thermal dose and spot size thresholds are significantly higher than the current FUSA standard of care. We recommend long duration (>30 s), subthreshold sonications for intraoperative testing during FUSA. Future investigations should test whether the thermal dose threshold is tissue-specific and determine the mechanisms underlying focused ultrasound TN.

Acute Abdomen in a 91-Year-Old Male due to Perforated Jejunal Diverticulitis.

Non-Meckel small intestine diverticular disease is a rare and mostly asymptomatic condition. However, rare cases of acute and emergent complications bear a high mortality rate. We report a case of a 91-year-old male that presented with an acute abdomen due to perforated jejunal diverticulitis. A review of the literature and key points of the condition are depicted. Although jejunal diverticulosis is rare, it must be considered in the differential diagnosis, especially in the elderly with signs of ambiguous abdominal pain and peritonitis.

Cognitive Task Performance During Titration Predicts Deep Brain Stimulation Treatment Efficacy: Evidence From a Case Study.

Device titration is a major challenge when using deep brain stimulation (DBS) to treat behavioral disorders. Unlike in movement disorders, there is no reliable real-time clinical feedback for changes in complex behaviors resulting from DBS. Here, a female patient receiving DBS of the nucleus accumbens for the treatment of morbid obesity underwent cognitive testing via the flanker task alongside traditional methods of device titration. One set of stimulation parameters administered during titration resulted in acute cognitive improvement (p = 0.033) and increased frontal engagement as measured by electroencephalography (left anterior: p = 0.007, right anterior: p = 0.005) relative to DBS-OFF. The same parameters resulted in the most weight-loss during long-term continuous stimulation (47.8 lbs lost in 129 days) compared to the results of other stimulation settings. Diffusion tensor imaging analyses showed increased connectivity to dorsal attention networks and decreased connectivity to the default mode network for optimal parameters (p < 0.01). Our results provide evidence that targeted cognitive testing is a potentially useful tool for capturing acute effects of DBS stimulation during titration and predicting long-term treatment outcomes. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT01512134.

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.

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.

Predictors of Outcomes After Focused Ultrasound Thalamotomy.

BACKGROUND: Magnetic resonance-guided focused ultrasound thalamotomy (FUS-T) is an emerging treatment for essential tremor (ET). OBJECTIVE: To determine the predictors of outcomes after FUS-T. METHODS: Two treatment groups were analyzed: 75 ET patients enrolled in the pivotal trial, between 2013 and 2015; and 114 patients enrolled in the postpivotal trials, between 2015 and 2016. All patients had medication-refractory, disabling ET, and underwent unilateral FUS-T. The primary outcome (hand tremor score, 32-point scale with higher scores indicating worse tremor) and the secondary outcome variables (Clinical Rating Scale for Tremor Part C score: 32-point scale with higher scores indicating more disability) were assessed at baseline and 1, 3, 6, and 12 mo. The operative outcome variables (ie, peak temperature, number of sonications) were analyzed. The results between the 2 treatment groups, pivotal and postpivotal, were compared with repeated measures analysis of variance and adjusted for confounding variables. RESULTS: A total of 179 patients completed the 12-mo evaluation. The significant predictors of tremor outcomes were patient age, disease duration, peak temperature, and number of sonications. A greater improvement in hand tremor scores was observed in the postpivotal group at all time points, including 12 mo (61.9% ± 24.9% vs 52.1% ± 24.9%, P = .009). In the postpivotal group, higher energy was used, resulting in higher peak temperatures (56.7 ± 2.5 vs 55.6 ± 2.8°C, P = .004). After adjusting for age, years of disease, number of sonications, and maximum temperature, the treatment group was a significant predictor of outcomes (F = 7.9 [1,165], P = .005). CONCLUSION: We observed an improvement in outcomes in the postpivotal group compared to the pivotal group potentially reflecting a learning curve with FUS-T. The other associations of tremor outcomes included patient age, disease duration, peak temperature, and number of sonications.