Malignant transformation of adult-onset pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor within the thoracic spine: a case report and review of the literature.

We describe a 31-year-old male who presented with progressive myelopathy from a thoracic pilocytic astrocytoma (PA). Following multiple recurrences and resections, 10 years after his index surgery, pathology revealed diffuse leptomeningeal glioneuronal tumor (DLGNT) with high-grade features. We discuss his clinical course, management, histopathological findings, and present a comprehensive review of spinal PA undergoing malignant transformation in adults and adult-onset spinal DLGNT. To our knowledge, we present the first reported case of adult-onset spinal PA malignant transformation to DLGNT. Our case adds to the paucity of clinical data characterizing such transformations and highlights the importance of developing novel management paradigms.

Freezing of Gait in Parkinson's Disease: Invasive and Noninvasive Neuromodulation.

INTRODUCTION: Freezing of gait (FoG) is one of the most disabling yet poorly understood symptoms of Parkinson's disease (PD). FoG is an episodic gait pattern characterized by the inability to step that occurs on initiation or turning while walking, particularly with perception of tight surroundings. This phenomenon impairs balance, increases falls, and reduces the quality of life. MATERIALS AND METHODS: Clinical-anatomical correlations, electrophysiology, and functional imaging have generated several mechanistic hypotheses, ranging from the most distal (abnormal central pattern generators of the spinal cord) to the most proximal (frontal executive dysfunction). Here, we review the neuroanatomy and pathophysiology of gait initiation in the context of FoG, and we discuss targets of central nervous system neuromodulation and their outcomes so far. The PubMed database was searched using these key words: neuromodulation, freezing of gait, Parkinson's disease, and gait disorders. CONCLUSION: Despite these investigations, the pathogenesis of this process remains poorly understood. The evidence presented in this review suggests FoG to be a heterogenous phenomenon without a single unifying pathologic target. Future studies rigorously assessing targets as well as multimodal approaches will be essential to define the next generation of therapeutic treatments.

Cell-based high-throughput screen for small molecule inhibitors of Bax translocation.

Aberrant regulation of programmed cell death (PCD) has been tied to an array of human pathologies ranging from cancers to autoimmune disorders to diverse forms of neurodegeneration. Pharmacologic modulation of PCD signalling is therefore of central interest to a number of clinical and biomedical applications. A key component of PCD signalling involves the modulation of pro- and anti-apoptotic Bcl-2 family members. Among these, Bax translocation represents a critical regulatory phase in PCD. In the present study, we have employed a high-content high-throughput screen to identify small molecules which inhibit the cellular process of Bax re-distribution to the mitochondria following commitment of the cell to die. Screening of 6246 Generally Recognized As Safe compounds from four chemical libraries post-induction of cisplatin-mediated PCD resulted in the identification of 18 compounds which significantly reduced levels of Bax translocation. Further examination revealed protective effects via reduction of executioner caspase activity and enhanced mitochondrial function. Consistent with their effects on Bax translocation, these compounds exhibited significant rescue against in vitro and in vivo cisplatin-induced apoptosis. Altogether, our findings identify a new set of clinically useful small molecules PCD inhibitors and highlight the role which cAMP plays in regulating Bax-mediated PCD.

Stereotactic mesencephalotomy for palliative care pain control: A case report, literature review and plea to rediscover this operation.

Introduction Stereotactic mesencephalotomy is an ablative procedure which lesions the pain pathways (spinothalamic and trigeminothalamic tracts) at the midbrain level to treat medically refractory, nociceptive, contralateral pain. Sparsely reported in contemporary English language literature, this operation is at risk of being lost from the modern-day neurosurgical practice. Methods We present a case report and brief review of the literature on stereotactic mesencephalotomy. A 17-year-old girl with cervical cord glioblastoma and medically refractory unilateral head and neck pain was treated with contralateral stereotactic mesencephalotomy. The lesion was placed at the level of the inferior colliculus, half way between the lateral edge of the aqueduct and lateral border of the midbrain. Results The patient had no head and neck pain immediately after the procedure and remained pain-free for the remainder of her life (five months). She was weaned off her pre-operative narcotics and was able to leave hospital, meeting her palliative care goals. Conclusions Cancer-related unilateral head and neck nociceptive pain in the palliative care setting can be successfully treated with stereotactic mesencephalotomy. We believe that stereotactic mesencephalotomy is the treatment of choice for a small number of patients typified by our case. The authors make a plea to the palliative care and neurosurgical communities to rediscover this operation.

The Influence of Positioning and Muscle Activity on Motor Threshold during Motor Cortex Stimulation Programming.

Background: Stimulation parameters are crucial for the efficacy and safety of motor cortex stimulation (MCS). Motor threshold (MT) can be defined as the lowest voltage that produces motor contraction. The final stimulation parameters are always a smaller percentage of MT in order to avoid seizures. We determined how patient position and activity affect MT. Methods: Prospective MT measurements were made while patients were either lying down or sitting up, and in a resting state or while actively contracting the target muscle. Paired 1-tailed t tests were performed to assess for statistically significant differences between MT measurements made under the 4 different combinations of position and activity. Results: The MT was lower when the target muscle was being actively contracted compared to resting in both supine and upright positions (both p < 0.001). The MT was also lower when upright compared to supine in both resting and active states of muscle contraction (both p < 0.001). The mean difference between supine resting and upright active states is 0.79 V. Conclusion: When selecting final stimulation parameters for MCS, clinicians should be aware that the lowest MT is elicited while patients are seated upright and actively contracting the target muscle. Using this method of determining the MT when calculating the final stimulation parameters could reduce the chance of MCS-induced seizures. © 2015 S. Karger AG, Basel.

Motor Threshold: A Possible Guide to Optimizing Stimulation Parameters for Motor Cortex Stimulation.

OBJECTIVES: No widely accepted programming guidelines for motor cortex stimulation (MCS) exist. We propose that an individual's effective stimulation voltage can be predicted as their percentage of motor threshold (PMT). MATERIALS AND METHODS: Seven patients already successfully treated with MCS for neuropathic pain were included. Patients received stimulation that was the same as their baseline PMT ("medium"), 10% higher ("high") or 10% lower ("low") in a blinded, randomized study. Outcome was assessed after 14 days with the visual analogue scale for pain, the McGill pain questionnaire, and the SF-36 questionnaire. RESULTS: The best treatment response (mean VAS 3.4) was seen with the medium setting which was at a mean of 62% PMT. High and low settings both resulted in a significant increase in pain compared with the medium setting (mean VAS 6.0 and 6.3, respectively) and a significant decrease in SF-36 scores. No significant difference in pain control was observed between the high and low settings. The mean time from changes in treatment settings to reported change in pain level was 2.9 days (±1.0 day). CONCLUSIONS: We propose that the PMT represents an important parameter that measures the degree to which MCS may be affecting the motor cortex. A mean PMT of 62% was required for effective pain relief. Higher settings did not result in increased therapeutic efficacy but rather in a significant increase in pain. Targeting therapy to a PMT level may speed initial programming, allow more consistent longitudinal follow-up, and be a basis for a standardized programming paradigm.

Treatment-responsive Holmes tremor in a child with low-pressure hydrocephalus: video case report and systematic review of the literature.

OBJECTIVE: Holmes tremor (HT) is a rare and debilitating movement disorder comprising both rest and action tremor, and it is known for its resistance to treatment. Its most common causes include ischemic or hemorrhagic insults and trauma. Mechanistically, the combined rest and action tremor is thought to require a double lesion of both the dopaminergic nigrostriatal system and the dentatorubrothalamic pathways, often near the midbrain where both pathways converge. The aim of this study was to characterize HT as a presenting sign in cases of hydrocephalus and to discuss potential pathomechanisms, clinical presentations, and treatment options. METHODS: MEDLINE and Web of Science were searched for cases of HT with hydrocephalus from database inception to August 2021, and these were compiled along with the authors' own unique case of treatment-responsive HT in a child with low-pressure obstructive hydrocephalus secondary to a tectal tumor. Patient characteristics, presenting signs/symptoms, potential precipitating factors, interventions, and patient outcomes were recorded. RESULTS: Nine patients were identified including the authors' video case report. All patients had a triventriculomegaly pattern with at least a component of obstructive hydrocephalus, and 4 patients were identified as having low-pressure hydrocephalus. Parinaud's syndrome and bradykinesia were the most commonly associated signs. Levodopa and CSF diversion were the most commonly used and effective treatments for HT in this population. This review was not registered and did not receive any funding. CONCLUSIONS: HT is a poorly understood and probably underrecognized presentation of hydrocephalus that is difficult to treat, limiting the strength of the evidence in this review. Treatment options include CSF diversion, antiparkinsonian agents, antiepileptic agents, deep brain stimulation, and MR-guided focused ultrasound, and aim toward the nigrostriatal and dentatorubrothalamic pathways hypothesized to be involved in its pathophysiology.

Non-contrast-enhancing subdural empyema: illustrative case.

BACKGROUND: Subdural empyema (SDE) is a life-threatening intracranial infection that, without timely surgical intervention and appropriate antibiotic treatment, is inevitably fatal. SDE is classically recognized on brain imaging as a subdural collection surrounded by a contrast-enhancing ring. OBSERVATIONS: The authors describe the case of a 41-year-old male with clinical features consistent with SDE but without any contrast enhancement on multiple computed tomography scans obtained more than 48 hours apart. Given the high clinical suspicion for SDE, a craniotomy was performed that demonstrated frank pus that eventually grew Streptococcus pyogenes. LESSONS: This case demonstrates that SDE may present without ring enhancement on contrast-enhanced imaging. In critically ill patients with a high clinical suspicion for SDE despite lack of contrast enhancement, we demonstrate that exploratory burr holes or craniotomy can provide diagnostic confirmation and source control.

Deep brain stimulation of midbrain locomotor circuits in the freely moving pig.

BACKGROUND: Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been studied as a therapeutic target in rodent models of stroke, parkinsonism, and spinal cord injury. Clinical DBS trials have targeted the closely related pedunculopontine nucleus in patients with Parkinson's disease as a therapy for gait dysfunction, with mixed reported outcomes. Recent studies suggest that optimizing the MLR target could improve its effectiveness. OBJECTIVE: We sought to determine if stereotaxic targeting and DBS in the midbrain of the pig, in a region anatomically similar to that previously identified as the MLR in other species, could initiate and modulate ongoing locomotion, as a step towards generating a large animal neuromodulation model of gait. METHODS: We implanted Medtronic 3389 electrodes into putative MLR structures in Yucatan micropigs to characterize the locomotor effects of acute DBS in this region, using EMG recordings, joint kinematics, and speed measurements on a manual treadmill. RESULTS: MLR DBS initiated and augmented locomotion in freely moving micropigs. Effective locomotor sites centered around the cuneiform nucleus and stimulation frequency controlled locomotor speed and stepping frequency. Off-target stimulation evoked defensive and aversive behaviors that precluded locomotion in the animals. CONCLUSION: Pigs appear to have an MLR and can be used to model neuromodulation of this gait-promoting center. These results indicate that the pig is a useful model to guide future clinical studies for optimizing MLR DBS in cases of gait deficiencies associated with such conditions as Parkinson's disease, spinal cord injury, or stroke.

Deep brain stimulation of the Cuneiform nucleus for levodopa-resistant freezing of gait in Parkinson's disease: study protocol for a prospective, pilot trial.

BACKGROUND: Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson's disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG, was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive mesencephalic locomotor region (MLR) preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation. METHODS: We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up. DISCUSSION: This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020).

MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson's Disease Patient With Levodopa-Resistant Freezing of Gait.

BACKGROUND: Freezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson's Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted. METHODS: As part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise CartesiaTM) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject. RESULTS: Post-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia. CONCLUSION: DTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04218526.

Differential Recovery in Early- and Late-Onset Delayed Facial Palsy Following Vestibular Schwannoma Resection.

BACKGROUND: Delayed facial palsy (DFP) after resection of vestibular schwannomas (VS) is worsening of facial nerve function after an initially normal postoperative result. OBJECTIVE: To characterize different types of DFP, compare recovery rates, and review of series of outcomes in patients following resection of VS. METHODS: Between 2001 and 2017, 434 patients (51% female) with VS underwent resection. We categorized the patients who developed facial palsy into groups based on timing of onset after surgery, immediate facial palsy (IFP), early-onset DFP (within 48 h), and late-onset DFP (after 48 h). Introduction of facial nerve motor-evoked potentials (fMEP) in 2002 and a change of practice utilizing perioperative minocycline in 2005 allowed for historical analysis of these interventions. RESULTS: Mean age of study cohort was 49.1 yr (range 13-81 yr), with 19.8% developing facial palsy. The late-onset DFP group demonstrated a significantly faster recovery than the early-onset DFP group (2.8 ± 0.5 vs 47 ± 8 wk, P < .0001), had prolonged latency to palsy onset after initiating perioperative minocycline (7.3 vs 12.5 d, P = .001), and had a nonsignificant trend towards faster recovery from facial palsy with use of minocycline (2.6 vs 3.4 wk, P = .11). CONCLUSION: Given the timings, it is likely axonal degeneration is responsible for early-onset DFP, while demyelination and remyelination lead to faster facial nerve recovery in late-onset DFP. Reported anti-apoptotic properties of minocycline could account for the further delay in onset of DFP, and possibly reduce the rate and duration of DFP in the surgical cohort.

Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation.

There are a pressing and unmet need for effective therapies for freezing of gait (FOG) and other neurological gait disorders. Deep brain stimulation (DBS) of a midbrain target known as the pedunculopontine nucleus (PPN) was proposed as a potential treatment based on its postulated involvement in locomotor control as part of the mesencephalic locomotor region (MLR). However, DBS trials fell short of expectations, leading many clinicians to abandon this strategy. Here, we discuss the potential reasons for this failure and review recent clinical data along with preclinical optogenetics evidence to argue that another nearby nucleus, the cuneiform nucleus (CnF), may be a superior target.

In vivo Population Averaged Stereotaxic T2w MRI Brain Template for the Adult Yucatan Micropig.

Population averaged brain templates are an essential tool for imaging-based neuroscience research, providing investigators with information about the expected size and morphology of brain structures and the spatial relationships between them, within a demographic cross-section. This allows for a standardized comparison of neuroimaging data between subjects and provides neuroimaging software with a probabilistic framework upon which further processing and analysis can be based. Many different templates have been created to represent specific study populations and made publicly available for human and animal research. An increasingly studied animal model in the neurosciences that still lacks appropriate brain templates is the adult Yucatan micropig. In particular, T2-weighted templates are absent in this species as a whole. To address this need and provide a tool for neuroscientists wishing to pursue neuroimaging research in the adult micropig, we present the construction of population averaged (n = 16) T2-weighted MRI brain template for the adult Yucatan micropig. Additionally, we present initial analysis of T1-weighted (n = 3), and diffusion-weighted (n = 3) images through multimodal registration of these contrasts to our T2 template. The strategies used here may also be generalized to create similar templates for other study populations or species in need of template construction.

Activation of Brainstem Neurons During Mesencephalic Locomotor Region-Evoked Locomotion in the Cat.

The distribution of locomotor-activated neurons in the brainstem of the cat was studied by c-Fos immunohistochemistry in combination with antibody-based cellular phenotyping following electrical stimulation of the mesencephalic locomotor region (MLR) - the anatomical constituents of which remain debated today, primarily between the cuneiform (CnF) and the pedunculopontine tegmental nuclei (PPT). Effective MLR sites were co-extensive with the CnF nucleus. Animals subject to the locomotor task showed abundant Fos labeling in the CnF, parabrachial nuclei of the subcuneiform region, periaqueductal gray, locus ceruleus (LC)/subceruleus (SubC), Kölliker-Fuse, magnocellular and lateral tegmental fields, raphe, and the parapyramidal region. Labeled neurons were more abundant on the side of stimulation. In some animals, Fos-labeled cells were also observed in the ventral tegmental area, medial and intermediate vestibular nuclei, dorsal motor nucleus of the vagus, n. tractus solitarii, and retrofacial nucleus in the ventrolateral medulla. Many neurons in the reticular formation were innervated by serotonergic fibers. Numerous locomotor-activated neurons in the parabrachial nuclei and LC/SubC/Kölliker-Fuse were noradrenergic. Few cholinergic neurons within the PPT stained for Fos. In the medulla, serotonergic neurons within the parapyramidal region and the nucleus raphe magnus were positive for Fos. Control animals, not subject to locomotion, showed few Fos-labeled neurons in these areas. The current study provides positive evidence for a role for the CnF in the initiation of locomotion while providing little evidence for the participation of the PPT. The results also show that MLR-evoked locomotion involves the parallel activation of reticular and monoaminergic neurons in the pons/medulla, and provides the anatomical and functional basis for spinal monoamine release during evoked locomotion. Lastly, the results indicate that vestibular, cardiovascular, and respiratory centers are centrally activated during MLR-evoked locomotion. Altogether, the results show a complex pattern of neuromodulatory influences of brainstem neurons by electrical activation of the MLR.

What Is the Evidence for Inter-laminar Integration in a Prefrontal Cortical Minicolumn?

The objective of this perspective article is to examine columnar inter-laminar integration during the executive control of behavior. The integration hypothesis posits that perceptual and behavioral signals are integrated within the prefrontal cortical inter-laminar microcircuits. Inter-laminar minicolumnar activity previously recorded from the dorsolateral prefrontal cortex (dlPFC) of nonhuman primates, trained in a visual delay match-to-sample (DMS) task, was re-assessed from an integrative perspective. Biomorphic multielectrode arrays (MEAs) played a unique role in the in vivo recording of columnar cell firing in the dlPFC layers 2/3 and 5/6. Several integrative aspects stem from these experiments: 1. Functional integration of perceptual and behavioral signals across cortical layers during executive control. The integrative effect of dlPFC minicolumns was shown by: (i) increased correlated firing on correct vs. error trials; (ii) decreased correlated firing when the number of non-matching images increased; and (iii) similar spatial firing preference across cortical-striatal cells during spatial-trials, and less on object-trials. 2. Causal relations to integration of cognitive signals by the minicolumnar turbo-engines. The inter-laminar integration between the perceptual and executive circuits was facilitated by stimulating the infra-granular layers with firing patterns obtained from supra-granular layers that enhanced spatial preference of percent correct performance on spatial trials. 3. Integration across hierarchical levels of the brain. The integration of intention signals (visual spatial, direction) with movement preparation (timing, velocity) in striatum and with the motor command and posture in midbrain is also discussed. These findings provide evidence for inter-laminar integration of executive control signals within brain's prefrontal cortical microcircuits.

Nicotine replacement therapy in patients with aneurysmal subarachnoid hemorrhage: Systematic review of the literature, and survey of Canadian practice.

Tobacco smoke increases the risk of aneurysmal subarachnoid hemorrhage (SAH), as well as complications such as vasospasm. Most patients presenting with aneurysmal SAH smoke, and many survivors continue to smoke after discharge. Neurosurgeons often hesitate to use nicotine replacement therapy (NRT) during hospitalization of patients with SAH due to concerns of inducing vasospasm. We aimed to evaluate the safety and efficacy, and patterns of use of NRT in smokers hospitalized for SAH. We performed a systematic review of MEDLINE, CENTRAL, Embase, and unpublished sources of literature to October 2016 for randomized and observational studies comparing exposure to non-exposure of smoking cessation products in the acute phase of aneurysmal SAH. Additionally, we surveyed 50 Canadian vascular neurosurgeons to evaluate patterns of NRT use in SAH. Four cohort studies (n=1210) met our eligibility criteria. Three studies enrolled patients with aneurysmal SAH, and one study enrolled all neurocritically ill patients. We rated the quality of evidence as very low using the GRADE approach. We could not meta-analyze studies due to methodological heterogeneity. Individual studies reported beneficial or neutral effects of NRT on functional outcome, death, and clinical or radiographic vasospasm. None of the studies assessed long-term abstinence from tobacco. Of the 14 vascular neurosurgeons responding to our survey, most never used NRT in patients hospitalized with SAH, often citing training or standard of practice as the reason. Current evidence suggests that NRT does not induce vasospasm, and is associated with improved outcomes in smokers hospitalized for SAH. Protocol registered in PROSPERO, available at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016037200.