Genomic evidence for inbreeding depression and purging of deleterious genetic variation in Indian tigers.

Increasing habitat fragmentation leads to wild populations becoming small, isolated, and threatened by inbreeding depression. However, small populations may be able to purge recessive deleterious alleles as they become expressed in homozygotes, thus reducing inbreeding depression and increasing population viability. We used whole-genome sequences from 57 tigers to estimate individual inbreeding and mutation load in a small-isolated and two large-connected populations in India. As expected, the small-isolated population had substantially higher average genomic inbreeding (FROH = 0.57) than the large-connected (FROH = 0.35 and FROH = 0.46) populations. The small-isolated population had the lowest loss-of-function mutation load, likely due to purging of highly deleterious recessive mutations. The large populations had lower missense mutation loads than the small-isolated population, but were not identical, possibly due to different demographic histories. While the number of the loss-of-function alleles in the small-isolated population was lower, these alleles were at higher frequencies and homozygosity than in the large populations. Together, our data and analyses provide evidence of 1) high mutation load, 2) purging, and 3) the highest predicted inbreeding depression, despite purging, in the small-isolated population. Frequency distributions of damaging and neutral alleles uncover genomic evidence that purifying selection has removed part of the mutation load across Indian tiger populations. These results provide genomic evidence for purifying selection in both small and large populations, but also suggest that the remaining deleterious alleles may have inbreeding-associated fitness costs. We suggest that genetic rescue from sources selected based on genome-wide differentiation could offset any possible impacts of inbreeding depression.

Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson's disease.

Although motor subtypes of Parkinson's disease (PD), such as tremor dominant (TD) and postural instability and gait difficulty (PIGD), have been defined based on symptoms since the mid-1990s, no underlying neural correlates of these clinical subtypes have yet been identified. Very limited data exist regarding the electrophysiological abnormalities within the subthalamic nucleus (STN) that likely accompany the symptom severity or the phenotype of PD. Here, we show that activity in subbands of local field potentials (LFPs) recorded with multiple microelectrodes from subterritories of STN provide distinguishing neurophysiological information about the motor subtypes of PD. We studied 24 patients with PD and found distinct patterns between TD (n = 13) and PIGD (n = 11) groups in high-frequency oscillations (HFOs) and their nonlinear interactions with beta band in the superior and inferior regions of the STN. Particularly, in the superior region of STN, the power of the slow HFO (sHFO) (200-260 Hz) and the coupling of its amplitude with beta-band phase were significantly stronger in the TD group. The inferior region of STN exhibited fast HFOs (fHFOs) (260-450 Hz), which have a significantly higher center frequency in the PIGD group. The cross-frequency coupling between fHFOs and beta band in the inferior region of STN was significantly stronger in the PIGD group. Our results indicate that the spatiospectral dynamics of STN-LFPs can be used as an objective method to distinguish these two motor subtypes of PD. These observations might lead to the development of sensing and stimulation strategies targeting the subterritories of STN for the personalization of deep-brain stimulation (DBS).

Ambulatory neurosurgery in the COVID-19 era: patient and provider satisfaction with telemedicine.

OBJECTIVE: Telemedicine has rapidly expanded in the recent years as technologies have afforded healthcare practitioners the ability to diagnose and treat patients remotely. Due to the COVID-19 pandemic, nonessential clinical visits were greatly limited, and much of the outpatient neurosurgical practice at the authors' institution was shifted quickly to telehealth. Although there are prior data suggesting that the use of telemedicine is satisfactory in other surgical fields, data in neurosurgery are limited. This study aimed to investigate both patient and provider satisfaction with telemedicine and its strengths and limitations in outpatient neurosurgery visits. METHODS: This quality improvement study was designed to analyze provider and patient satisfaction with telemedicine consultations in an outpatient neurosurgery clinic setting at a tertiary care, large-volume, academic center. The authors designed an 11-question survey for neurosurgical providers and a 13-question survey for patients using both closed 5-point Likert scale responses and multiple choice responses. The questionnaires were administered to patients and providers during the period when the clinic restricted in-person visits. At the conclusion of the study, the overall data were analyzed qualitatively and quantitatively. RESULTS: During the study period, 607 surveys were sent out to patients seen by telehealth at the authors' academic center, and 122 responses were received. For the provider survey, 85 surveys were sent out to providers at the authors' center and other academic centers, and 40 surveys were received. Ninety-two percent of patients agreed or strongly agreed that they were satisfied with that particular telehealth visit. Eighty-eight percent of patients agreed that their telehealth visit was more convenient for them than an in-person visit, but only 36% of patients stated they would like their future visits to be telehealth. Sixty-three percent of providers agreed that telehealth visits were more convenient for them than in-person visits, and 85% of responding providers stated that they wished to incorporate telehealth into their future practice. CONCLUSIONS: Although the authors' transition to telehealth was both rapid and unexpected, most providers and patients reported positive experiences with their telemedicine visits and found telemedicine to be an effective form of ambulatory neurosurgical care. Not all patients preferred telemedicine visits over in-person visits, but the high satisfaction with telemedicine by both providers and patients is promising to the future expansion of telehealth in ambulatory neurosurgery.

Minimally Invasive Cordotomy for Refractory Cancer Pain: A Randomized Controlled Trial.

BACKGROUND: Up to 30% of patients with cancer continue to suffer from pain despite aggressive supportive care. The present study aimed to determine whether cordotomy can improve cancer pain refractory to interdisciplinary palliative care. MATERIALS AND METHODS: In this randomized controlled trial, we recruited patients with refractory unilateral somatic pain, defined as a pain intensity (PI) ≥4, after more than three palliative care evaluations. Patients were randomized to percutaneous computed tomography-guided cordotomy or continued interdisciplinary palliative care. The primary outcome was 33% improvement in PI at 1 week after cordotomy or study enrollment as measured by the Edmonton Symptom Assessment Scale. RESULTS: Sixteen patients were enrolled (nine female, median age 58 years). Six of seven patients (85.7%) randomized to cordotomy experienced >33% reduction in PI (median preprocedure PI = 7, range 6-10; 1 week after cordotomy median PI = 1, range 0-6; p = .022). Zero of nine patients randomized to palliative care achieved a 33% reduction in PI. Seven patients (77.8%) randomized to palliative care elected to undergo cordotomy after 1 week. All of these patients experienced >33% reduction in PI (median preprocedure PI = 8, range 4-10; 1 week after cordotomy median PI = 0, range 0-1; p = .022). No patients were withdrawn from the study because of adverse effects of the intervention. CONCLUSION: These data support the use of cordotomy for pain refractory to optimal palliative care. The findings of this study justify a large-scale randomized controlled trial of percutaneous cordotomy. IMPLICATIONS FOR PRACTICE: This prospective clinical trial was designed to determine the improvement in pain intensity in patients randomized to either undergo cordotomy or comprehensive palliative care for medically refractory cancer pain. This study shows that cordotomy is effective in reducing pain for medically refractory cancer pain, and these results can be used to design a large-scale comparative randomized controlled trial that could provide the evidence needed to include cordotomy as a treatment modality in the guidelines for cancer pain management.

Gastrointestinal stromal tumor with intracranial metastasis: case presentation and systematic review of literature.

BACKGROUND: Intracranial metastasis of Gastrointestinal Stromal Tumors (GISTs) is rare but presents unique treatment challenges. We present a case of intracranial metastasis of GIST with a systematic review of the literature. A literature search using key terms "'gastrointestinal stromal tumor' AND brain AND metastasis"" was conducted through May 2019 via Embase and Pubmed according to PRISMA guidelines. Only cases describing intradural metastases rather than calvarial or intraorbital metastases were included. CASE PRESENTATION: A 57-year-old woman with history of GIST metastatic to the liver presented with a six-week history of left facial weakness, left hearing loss, and left facial numbness, and a one-week history of headaches, gait disturbance, and dizziness. MRI revealed a contrast-enhancing dural-based left middle cranial fossa mass measuring 2.9 cm × 3.1 cm × 3.4 cm with extension into the internal auditory canal and cerebral edema. A left temporal craniotomy was performed to excise the lesion, and the patient was discharged to a rehabilitation facility at her preoperative baseline. Intraoperative pathology revealed a spindle cell neoplasm, postoperative MRI demonstrated gross total resection of the lesion, and microscopic analysis demonstrated sheets of spindled tumor cells with short ovoid, irregular, hyperchromatic nuclei and scattered large atypical nuclei without extensive necrosis. Immunohistochemical staining was positive for KIT proto-oncogene (CD117, c-KIT), and the patient was put on imatinib (400 mg/day). CONCLUSIONS: Of the 18 cases analyzed and our present case, metastasis typically involved the cerebrum with only one in infratentorial elements. The tumors in seven of the cases involved the dura, and one case metastasized to the pituitary. Eight patients died following treatment. Surgery remains the mainstay of intracranial metastatic GIST, however there are many reports of good responses to radiation or chemotherapy alone. More investigation is required to determine the best treatment course for these patients.

The effects of rainforest fragment area on the strength of plant-pathogen interactions.

Pathogenic interactions between fungi and plants facilitate plant species coexistence and tropical rainforest diversity. Such interactions, however, may be affected by forest fragmentation as fungi are susceptible to anthropogenic disturbance. To examine how fragmentation affects fungus-induced seed and seedling mortality, we sowed seeds of six plant species in soils collected from 21 forest fragments. We compared seedling establishment in unmanipulated soils to soils treated with fungicides. Fungicides increased germination of Toona ciliata seeds and decreased mortality of Syzygium rubicundum and Olea dioica seedlings. The fungus-induced mortality of one of these species, S. rubicundum, decreased with decreasing fragment size, indicating that its interactions with pathogenic fungi may weaken as fragments become smaller. We provide evidence that a potential diversity-maintaining plant-fungus interaction weakens in small forest fragments and suggest that such disruptions may have important long-term consequences for plant diversity. However, we emphasize the need for further research across rainforest plant communities to better understand the future of diversity in fragmented rainforest landscapes.

Deep brain stimulation of the anterior limb of the internal capsule for treatment of therapy-refractory obsessive compulsive disorder (OCD): a case study highlighting neurocognitive and psychiatric changes.

Obsessive compulsive disorder (OCD) is an anxiety disorder characterized by repeated, unwanted thoughts and behaviors. Individuals with this condition often experience significant emotional distress secondary to their symptoms. Additionally, impairments in attention/concentration, processing speed, and executive functions are typically observed. The exact pathology of OCD remains unknown; consequently, it can be difficult to treat patients with severe symptomatology. Deep brain stimulation (DBS) may be a viable treatment option for individuals who do not respond to medication and/or cognitive behavioral therapy. The following case discusses DBS of the anterior limb of the internal capsule for a patient with severe, therapy-refractory OCD, including pre- to postoperative neurocognitive and psychiatric changes.

Use of Spinal Cord Diffusion Tensor Imaging to Quantify Neural Ablation and Evaluate Outcome after Percutaneous Cordotomy for Intractable Cancer Pain.

BACKGROUND: Up to 20% of patients experience only partial pain relief after percutaneous cordotomy for cancer pain. OBJECTIVE: To determine whether diffusion tensor imaging (DTI) can quantify neural ablation and help evaluate early postoperative outcomes after cordotomy. METHODS: Patients undergoing percutaneous CT-guided cordotomy for intractable cancer pain were prospectively studied. Pre- and postoperative assessment was made using the visual analog scale (VAS) on pain and the pain severity scores of the Brief Pain Inventory Short Form. On postoperative day 1, DTI images of the high cervical spinal cord were obtained. DTI metrics were correlated with the number of ablations as well as early postoperative pain outcomes. RESULTS: Seven patients (4 male, mean age 53.8 ± 4.6 years) were studied. Fractional anisotropy of the hemicord was significantly lower on the side of the lesion as compared to the contralateral side (0.54 ± 0.03 vs. 0.63 ± 0.03, p < 0.001). Mean diffusivity correlated with the improvement in the VAS score at 1 week (r = 0.88, 95% CI = 0.34-1.00, p = 0.008), as well as the change in pain severity scores at 1 week (r = 0.99, 95% CI = 0.82-1.00, p < 0.001). CONCLUSION: DTI metrics are sensitive to the number of ablations as well as early improvement in pain scores after cordotomy. DTI of the cervical spinal cord is a potential biomarker of neural ablation after percutaneous cordotomy for intractable cancer pain.

Headache and arachnoid cysts.

Arachnoid cysts are commonly encountered when neuroimaging is obtained for headaches. Their clinical relevance is not always immediately clear and they may confound medical management.

Treatment of medically refractory cancer pain with a combination of intrathecal neuromodulation and neurosurgical ablation: case series and literature review.

OBJECTIVE: Up to 90% of patients with advanced cancer experience intractable pain. For these patients, oral analgesics are the mainstay of therapy, often augmented with intrathecal drug delivery. Neurosurgical ablative procedures have become less commonly used, though their efficacy has been well-established. Unfortunately, little is known about the safety of ablation in the context of previous neuromodulation. Therefore, the aim of this study is to present the results from a case series in which patients were treated successfully with a combination of intrathecal neuromodulation and neurosurgical ablation. DESIGN: Retrospective case series and literature review. SETTING: Three institutions with active cancer pain management programs in the United States. METHODS: All patients who underwent both neuroablative and neuromodulatory procedures for cancer pain were surveyed using the visual analog scale prior to the first procedure, before and after a second procedure, and at long-term follow-up. Based on initial and subsequent presentation, patients underwent intrathecal morphine pump placement, cordotomy, or midline myelotomy. RESULTS: Five patients (2 male, 3 female) with medically intractable pain (initial VAS = 10) were included in the series. Four subjects were initially treated with intrathecal analgesic neuromodulation, and 1 with midline myelotomy. Each patient experienced recurrence of pain (VAS ≥ 9) following the initial procedure, and was therefore treated with another modality (intrathecal, N = 1; midline myelotomy, N = 1; percutaneous radiofrequency cordotomy, N = 3), with significant long-term benefit (VAS 1-7). CONCLUSION: In cancer patients with medically intractable pain, intrathecal neuromodulation and neurosurgical ablation together may allow for more effective control of cancer pain.

Trigeminal and Glossopharyngeal Neuralgia.

Trigeminal neuralgia and glossopharyngeal neuralgia are craniofacial pain syndromes characterized by recurrent brief shock-like pains in the distributions of their respective cranial nerves. In this article, the authors aim to summarize each condition's characteristics, pathophysiology, and current pharmacotherapeutic and surgical interventions available for managing and treating these conditions.

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition.

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via 'RiboTag,' morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

Deep brain stimulation entrains local neuronal firing in human globus pallidus internus.

Deep brain stimulation (DBS) in the internal segment of the globus pallidus (GPi) relieves the motor symptoms of Parkinson's disease, yet the mechanism of action remains uncertain. To address the question of how therapeutic stimulation changes neuronal firing in the human brain, we studied the effects of GPi stimulation on local neurons in unanesthetized patients. Eleven patients with idiopathic Parkinson's disease consented to participate in neuronal recordings during stimulator implantation surgery. A recording microelectrode and a DBS macroelectrode were advanced through the GPi in parallel until a single neuron was isolated. After a baseline period, stimulation was initiated with varying voltages and different stimulation sites. The intra-operative stimulation parameters (1-8 V, 88-180 Hz, 0.1-ms pulses) were comparable with the postoperative DBS settings. Stimulation in the GPi did not silence local neuronal activity uniformly, but instead loosely entrained firing and decreased net activity in a voltage-dependent fashion. Most neurons had decreased activity during stimulation, although some increased or did not change firing rate. Thirty-three of 45 neurons displayed complex patterns of entrainment during stimulation, and burst-firing was decreased consistently after stimulation. Recorded spike trains from patients were used as input into a model of a thalamocortical relay neuron. Only spike trains that occurred during therapeutically relevant voltages significantly reduced transmission error, an effect attributable to changes in firing patterns. These data indicate that DBS in the human GPi does not silence neuronal activity, but instead disrupts the pathological firing patterns through loose entrainment of neuronal activity.

Surgical/radiological interventions for cancer pain.

Pain is a major morbidity associated with cancer and up to 20% patients require invasive procedures for pain relief. Ablative techniques can be directed towards the spinal cord and brain to palliate pain or modify its perception. Anterolateral cordotomy, myelotomy, DREZotomy and cingulotomy are useful interventions for the management of refractory cancer pain. Advanced imaging modalities, including intraoperative computed tomography (CT) guidance, have increased safety and efficacy of these interventions. In this paper, authors review the recent literature regarding surgical interventions for the management of cancer pain.

Effect of subthalamic nucleus or globus pallidus interna stimulation on oculomotor function in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) of either the globus pallidus interna (GPi) or subthalamic nucleus (STN) is similarly effective for treating somatomotor manifestations of Parkinson's disease (PD), but differences in how stimulation of each target affects oculomotor function are poorly understood. OBJECTIVE: We sought to determine if stimulation of the STN, but not the GPi, affects oculomotor function in PD patients. METHODS: Nineteen PD patients with DBS implants (8 bilateral GPi, 9 bilateral STN and 2 unilateral STN) were studied. Testing was performed with stimulation on, then off. Somatomotor function was tested using the Unified Parkinson's Disease Rating Scale (UPDRS) motor exam. For oculomotor testing, patients performed pro- and antisaccade tasks while monitored with an infrared eye tracker. Saccadic latency, saccadic intrusions, and square-wave jerks (SWJs) were measured for each trial. RESULTS: As expected, UPDRS motor scores improved with both GPi and STN stimulation. With GPi stimulation, there was no significant difference in oculomotor function with stimulation on or off. However, with STN stimulation on, there was a significant increase in the mean number of SWJs/s, as well as a significant decrease in latency for both pro- and antisaccade tasks. CONCLUSION: Stimulation of either GPi or STN had similar effects on somatomotor function, but only STN stimulation significantly altered oculomotor function.

Cordotomy for treatment of cancer-related pain: patient selection and intervention timing.

Many neurosurgical interventions for the management of cancer-related pain have been tried, but their role in today's advanced supportive and palliative care is not well described. The authors discuss the current knowledge gaps that prevent successful integration of neurosurgical interventions and patients with cancer-related pain. Two patients underwent percutaneous CT-guided cordotomy for refractory cancer-related pain: one patient had melanoma and the other had ovarian carcinoma. Both patients seemed to have unilateral, somatic, nociceptive cancer-related pain. Cordotomy was effective for only 1 patient. Percutaneous CT-guided cordotomy is a low-risk intervention that can benefit carefully selected patients with cancer-related pain. There is a clear need for prospective controlled studies to evaluate the effectiveness of cordotomy for patients receiving optimal medical treatment. A multidisciplinary study design could help to identify factors correlated with a positive outcome.

Cingulotomy for medically refractory cancer pain.

OBJECT: Cingulotomy has been reported in the literature as a potential treatment option for refractory cancer-related pain. However, the optimal candidates for this intervention and the outcomes are not well characterized. The goal of this study was to review the available literature on cingulotomy, specifically for cancer-related pain. METHODS: A search of PubMed, PubMed Central, the Cochrane Library, and MEDLINE was performed to identify all articles discussing cingulotomy for cancer pain. The text strings "cingul*" and "pain" were separated by the Boolean AND operator, and used to perform the query on PubMed. Only studies in which a stereotactic technique was used, as opposed to an open technique, and specifically detailing outcomes for cancer pain were included. For centers with multiple publications, care was taken not to double-count individual patients. RESULTS: The literature review revealed only 8 unique studies describing outcomes of stereotactic cingulotomy for cancer pain. Between 32% and 83% of patients had meaningful pain relief. The location of the lesion was variable, ranging between 1 cm and 4 cm posterior to the tip of the anterior horn. Although serious adverse events are rare, a decline in focused attention can been seen in the early postoperative period, along with apathy and decreased activity. CONCLUSIONS: For patients with cancer pain with diffuse pain syndromes, head and neck malignancies, and significant emotional distress, cingulotomy may be a safe treatment option with minimal cognitive changes.

Treatment of contact dermatitis associated with spinal cord stimulator pulse generator--technical note.

BACKGROUND: Expanded polytetrafluoroethylene sheets have been successfully used as a biologic barrier in the treatment of pacemaker contact dermatitis. TECHNIQUE: In this report, we describe two patients with contact dermatitis related to the implantable pulse generator of a spinal cord stimulator who were treated with expanded polytetrafluoroethylene as a barrier. RESULTS: Resolution of the dermatitis was achieved in both cases. CONCLUSIONS: This technique is an effective way of treating contact dermatitis related to implantable pulse generators, without the need for explantation of the neuromodulation system.

Construction of semi-supervised spatial projections to identify the source of beta- and high frequency oscillations in Parkinson's disease.

Traditional deep brain stimulation (DBS) treatment for Parkinson's disease (PD) targets the placement of DBS leads into subthalamic nucleus (STN). Extraction of neurobiomarkers from STN local field potential activity can be used for the optimization of DBS. Beta (12-30 Hz) and high frequency oscillations (200-450 Hz, HFO) of STN and their phase-amplitude coupling have been previously correlated with symptom severity in PD. The typical approach is to take bipolar derivations of electrode contacts in order to enhance recordings of local brain activity and suppress noise levels. This approach can often cancel the signals in correlated neighboring contacts and create ambiguity in which monopolar contact to select for the identification of the main source of the oscillatory signal. To improve local specificity and help identify the source of beta and HFO in terms of electrode contact, we propose a semi supervised blind-source separation method. This approach presents a novel perspective to investigate electrophysiology by projecting the recorded channels into a subspace of virtual channels. We show the contribution of each channel to the identified source and correlate the spatial information with imaging and postoperative programming parameters. We anticipate such a source identification strategy can be used in the future to investigate the distribution of beta and HFO on individual contacts of the DBS lead and can improve the interpretation of these signals.

Trigeminal Neuralgia: Diagnosis and Treatment.

Trigeminal neuralgia is characterized classically by recurrent, evocable, unilateral brief, electric, shocklike pains with an abrupt onset and cessation that affects one or more divisions of the trigeminal nerve. In recent years, the classification of trigeminal neuralgia has been updated based on further understanding. In this manuscript, the authors aim to explain the current understanding of the pathophysiology of trigeminal neuralgia, current diagnosis criteria, and the pharmacologic management and surgical treatments of options currently available.