Epithelioid glioblastoma diagnosed 70 years after craniofacial radiotherapy.

The authors report a rare case of most likely radiation-induced glioma (RIG) with epithelioid features and the presence of molecular features consistent with RIG. This occurred 70 years after craniofacial brachytherapy. Such a late development of radiation-induced glioblastoma (RIGBM) and the advanced age of presentation for an epithelioid glioblastoma are both unique in the literature. Despite not receiving the full course of adjuvant chemotherapy after surgery and radiotherapy, the patient displayed no signs of recurrence during a 5-year follow-up. RIGBM should be further studied to reveal potential unique clinical and molecular characteristics, as well as to better predict survival and treatment response.

Closed-loop firing rate regulation of two interacting excitatory and inhibitory neural populations of the basal ganglia.

This paper develops a new closed-loop firing rate regulation strategy for a population of neurons in the subthalamic nucleus, derived using a model-based analysis of the basal ganglia. The system is described using a firing rate model, in order to analyse the generation of beta-band oscillations. On this system, a proportional regulation of the firing rate reduces the gain of the subthalamo-pallidal loop in the parkinsonian case, thus impeding pathological oscillation generation. A filter with a well-chosen frequency is added to this proportional scheme, in order to avoid a potential instability of the feedback loop due to actuation and measurement delays. Our main result is a set of conditions on the parameters of the stimulation strategy that guarantee both its stability and a prescribed delay margin. A discussion on the applicability of the proposed method and a complete set of mathematical proofs is included.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.

BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica.

Using the Accelerometers Integrated in Smartphones to Evaluate Essential Tremor.

Background/Aims: Evaluation of tremor constitutes a crucial step from the diagnosis to the initial treatment and follow-up of patients with essential tremor. The severity of tremor can be evaluated using clinical rating scales, accelerometry, or electrophysiology. Clinical scores are subjectively given, may be affected by intra- and interevaluator variations due to different experience, delays between consultations, and subtle changes in tremor severity. Existing medical devices are not routinely used: they are expensive, time-consuming, not easily accessible. We aimed at showing that a smartphone application using the accelerometers embedded in smartphones is effective for quantifying the tremor of patients presenting with essential tremor. Methods: We developed a free iPhone/iPod application, Itremor, and evaluated different parameters on 8 patients receiving deep brain stimulation of the ventral intermediate nucleus of the thalamus: average and maximum accelerations, time above 1 g of acceleration, peak frequency, typical magnitude of tremor, for postural and action tremors, on and off stimulation. Results: We demonstrated good correlations between the parameters measured with Itremor and clinical score in all conditions. Itremor evaluation enabled higher discriminatory power and degree of reproducibility than clinical scores. Conclusion: Itremor can be used for routine objective evaluation of essential tremor, and may facilitate adjustment of the treatment. © 2015 S. Karger AG, Basel.

[Therapeutic potential of optogenetic neuromodulation]. / Potentiel thérapeutique de la neuromodulation optogénétique.

Optogenetic neuromodulation techniques, which have emerged during the last 15 years, have considerably enhanced our ability to probe the functioning of neural circuits by allowing the excitation and inhibition of genetically-defined neuronal populations using light. Having gained tremendous popularity in the field of fundamental neuroscience, these techniques are now opening new therapeutic avenues. Optogenetic neuromodulation is a method of choice for studying the physiopathology of neurological and neuropsychiatric disorders in a range of animal models, and could accelerate the discovery of new therapeutic strategies. New therapeutic protocols employing optogenetic neuromodulation may also emerge in the near future, offering promising alternative approaches for disorders which lack appropriate treatments, such as pharmacoresistant epilepsy and inherited retinal degeneration.

Achieving Gross Total Resection in Neurosurgery: A Review of Intraoperative Techniques and Their Influence on Surgical Goals.

The definition of complete resection in neurosurgery depends on tumor type, surgical aims, and postoperative investigations, directly guiding the choice of intraoperative tools. Most common tumor types present challenges in achieving complete resection due to their infiltrative nature and anatomical constraints. The development of adjuvant treatments has altered the balance between oncological aims and surgical risks. We review local recurrence associated with incomplete resection based on different definitions and emphasize the importance of achieving maximal safe resection in all tumor types. Intraoperative techniques that aid surgeons in identifying tumor boundaries are used in practice and in preclinical or clinical research settings. They encompass both conservative and invasive techniques. Among them, morphological tools include imaging modalities such as intraoperative magnetic resonance imaging, ultrasound, and optical coherence tomography. Fluorescence-guided surgery, mainly using 5-aminolevulinic acid, enhances gross total resection in glioblastomas. Nuclear methods, including positron emission tomography probes, provide tumor detection based on beta or gamma emission after a radiotracer injection. Mass spectrometry- and spectroscopy-based methods offer molecular insights. The adoption of these techniques depends on their relevance, effectiveness, and feasibility. With the emergence of positron emission tomography imaging for use in recurrence benchmarking, positron emission tomography probes raise particular interest among those tools. While all such tools provide valuable insights, their clinical benefits need further evaluation.

Deep brain stimulation in multiple sclerosis-associated tremor. A large, retrospective, longitudinal open label study, with long-term follow-up.

BACKGROUND: Tremor affects up to 25%-58% in multiple sclerosis (MS) population. Deep-brain stimulation (DBS) of the ventral-intermediate nucleus (VIM) of the thalamus is considered as a potential option following medical treatments. Long term DBS efficacy is not well known in these patients with a poor outcome mostly related to disease progression. OBJECTIVE: To report a large and retrospective study of thalamic DBS in MS tremor. METHODS: We conducted a large and retrospective study of patients with MS disabling and pharmacologically resistant upper limb tremor, who underwent thalamic DBS procedure from January 1992 to January 2015 in University Hospital of Henri Mondor, France. Demographic data, clinical assessment and activity daily living were collected. A three-month and twelve-month post-operative assessment with clinical and functional rating scales have been achieved, as well as long term follow-up for most patients. RESULTS: One hundred and four patients underwent DBS procedure. There were 71 female (68%) and 33 male (32%). At three-month post-operative assessment, 64% patients were improved clinically and functionally. Among these, 93% of patients kept a good efficacy at one-year post-operative assessment. Mean duration of follow-up for these patients was 6 years. CONCLUSION: We described a long-term sustained clinical and functional improvement in this large and retrospective report of thalamic DBS. This neuromodulation approach could be a therapeutic option for all severe upper extremity refractory tremor in MS patients.

Motor cortex stimulation in the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Despite the rapid development of neuropharmacotherapy, medical treatment of neuropathic pain (NP) still constitutes a significant socioeconomic problem. The authors herein present a group of patients treated with motor cortex stimulation (MCS) for NP of various types and aetiologies. MATERIAL AND METHODS: Our cohort included 12 female and 11 male NP patients aged 53 ± 16 treated with MCS. Eleven patients were diagnosed with neuropathic facial pain (NFP), 8 with hemi-body neuropathic pain (HNP), and 4 with deafferentation pain (DP). Prior to surgery, 16 out of 23 patients were treated with repetitive transcranial magnetic stimulation (rTMS), with a positive response in 10 cases. Pain intensity in our group was evaluated with the visual analogue scale (VAS) one month before and three months after MCS implantation. RESULTS: Improvement on the VAS was reported in the whole group of patients (p < 0.001). The best results were reported in the NFP group (p < 0.001) while the worst ones were noted in the DP group (p = 0.04). Anamnesis duration positively correlated with outcome. Infection forced the authors to permanently remove the system in one case. There were no other complications in the group. CONCLUSIONS: Minimally invasive, safe neuromodulative treatment with MCS permits neuropathic pain control with good efficacy. The type of neuropathic pain might be a prognostic factor.

Direct visualization of non-human primate subcortical nuclei with contrast-enhanced high field MRI.

Subcortical nuclei are increasingly targeted for deep brain stimulation (DBS) and for gene transfer to treat neurological and psychiatric disorders. For a successful outcome in patients, it is critical to place DBS electrodes or infuse viral vectors accurately within targeted nuclei. However current MRI approaches are still limited to localize brainstem and basal ganglia nuclei accurately. By combining ultra-high resolution structural MRI and contrast-enhanced MRI using iron oxide nanoparticles at high field (3T and 7T), we could precisely locate the subcortical nuclei, in particular the subthalamic nucleus in macaques, and validate this location by intracranial electrophysiological mapping. The present data pave the way to a clinical application.

Rodent models used in preclinical studies of deep brain stimulation to rescue memory deficits.

Deep brain stimulation paradigms might be used to treat memory disorders in patients with stroke or traumatic brain injury. However, proof of concept studies in animal models are needed before clinical translation. We propose here a comprehensive review of rodent models for Traumatic Brain Injury and Stroke. We systematically review the histological, behavioral and electrophysiological features of each model and identify those that are the most relevant for translational research.

Identification of biomarkers that predict response to subthalamic nucleus deep brain stimulation in resistant obsessive-compulsive disorder: protocol for an open-label follow-up study.

INTRODUCTION: Deep brain stimulation (DBS) of bilateral anteromedial subthalamic nucleus (amSTN) has been found to be helpful in a subset of patients with severe, chronic and treatment-refractory obsessive-compulsive disorder (OCD). Biomarkers may aid in patient selection and optimisation of this invasive treatment. In this trial, we intend to evaluate neurocognitive function related to STN and related biosignatures as potential biomarkers for STN DBS in OCD. METHODS AND ANALYSIS: Twenty-four subjects with treatment-refractory OCD will undergo open-label STN DBS. Structural/functional imaging, electrophysiological recording and neurocognitive assessment would be performed at baseline. The subjects would undergo a structured clinical assessment for 12 months postsurgery. A group of 24 healthy volunteers and 24 subjects with treatment-refractory OCD who receive treatment as usual would be recruited for comparison of biomarkers and treatment response, respectively. Baseline biomarkers would be evaluated as predictors of clinical response. Neuroadaptive changes would be studied through a reassessment of neurocognitive functioning, imaging and electrophysiological activity post DBS. ETHICS AND DISSEMINATION: The protocol has been approved by the National Institute of Mental Health and Neurosciences Ethics Committee. The study findings will be disseminated through peer-reviewed scientific journals and scientific meetings.

Case Report: Multimodal Functional and Structural Evaluation Combining Pre-operative nTMS Mapping and Neuroimaging With Intraoperative CT-Scan and Brain Shift Correction for Brain Tumor Surgical Resection.

Background: Maximum safe resection of infiltrative brain tumors in eloquent area is the primary objective in surgical neuro-oncology. This goal can be achieved with direct electrical stimulation (DES) to perform a functional mapping of the brain in patients awake intraoperatively. When awake surgery is not possible, we propose a pipeline procedure that combines advanced techniques aiming at performing a dissection that respects the anatomo-functional connectivity of the peritumoral region. This procedure can benefit from intraoperative monitoring with computerized tomography scan (iCT-scan) and brain shift correction. Associated with this intraoperative monitoring, the additional value of preoperative investigation combining brain mapping by navigated transcranial magnetic stimulation (nTMS) with various neuroimaging modalities (tractography and resting state functional MRI) has not yet been reported. Case Report: A 42-year-old left-handed man had increased intracranial pressure (IICP), left hand muscle deficit, and dysarthria, related to an infiltrative tumor of the right frontal lobe with large mass effect and circumscribed contrast enhancement in motor and premotor cortical areas. Spectroscopy profile and intratumoral calcifications on CT-scan suggested an WHO grade III glioma, later confirmed by histology. The aforementioned surgical procedure was considered, since standard awake surgery was not appropriate for this patient. In preoperative time, nTMS mapping of motor function (deltoid, first interosseous, and tibialis anterior muscles) was performed, combined with magnetic resonance imaging (MRI)-based tractography reconstruction of 6 neural tracts (arcuate, corticospinal, inferior fronto-occipital, uncinate and superior and inferior longitudinal fasciculi) and resting-state functional MRI connectivity (rs-fMRI) of sensorimotor and language networks. In intraoperative time, DES mapping was performed with motor evoked response recording and tumor resection was optimized using non-rigid image transformation of the preoperative data (nTMS, tractography, and rs-fMRI) to iCT data. Image guidance was updated with correction for brain shift and tissue deformation using biomechanical modeling taking into account brain elastic properties. This correction was done at crucial surgical steps, i.e., when tumor bulged through the craniotomy after dura mater opening and when approaching the presumed eloquent brain regions. This procedure allowed a total resection of the tumor region with contrast enhancement as well as a complete regression of IICP and dysarthria. Hand paresis remained stable with no additional deficit. Postoperative nTMS mapping confirmed the good functional outcome. Conclusion: This case report and technical note highlights the value of preoperative functional evaluation by nTMS updated intraoperatively with correction of brain deformation by iCT. This multimodal approach may become the optimized technique of reference for patients with brain tumors in eloquent areas that are unsuitable for awake brain surgery.

[Vagus nerve stimulation and depression]. / Stimulation du nerf vague dans le traitement de la dépression.

Vagus nerve stimulation (VNS) is an old, yet new, option for treatment-resistant depression. Despite several clinical trials over the last 15 years showing a consistent benefit-risk balance of the technic, VNS still struggles to find its place in our therapeutic algorithms. This is especially true in France, where only a few surgeries have been performed nationwide, all in the last year. The reasons behind this lag are manifolds; (1) psychiatrists usually do not consider surgical treatments, even when they are minimally invasive and reversible, (2) early VNS trials stumbled on methodological difficulties that are common to all invasive neurostimulation technics, and initially failed to provide strong evidence for its efficacy, and (3) VNS requires multidisciplinary teams involving psychiatrists and neurosurgeons that did not exist then. Nevertheless, studies of the past twenty years support VNS as a treatment of depression endowed with a unique efficacy profile: a long runner best at maintaining remission in hard-to-stabilize depression, even in the context of ECT withdrawal, and irrespective of whether it is unipolar or bipolar. Thus, VNS potentially addresses the unmet medical needs of some of the most severe and chronic patients with depression. This review aims at introducing VNS as a treatment option for depression, summarizing available evidence for its efficacy and tolerance, and delineating patient profiles that might benefit the most of such treatment.

Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder: Towards an Individualized Approach.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder featuring repetitive intrusive thoughts and behaviors associated with a significant handicap. Of patients, 20% are refractory to medication and cognitive behavioral therapy. Refractory OCD is associated with suicidal behavior and significant degradation of social and professional functioning, with high health costs. Deep brain stimulation (DBS) has been proposed as a reversible and controllable method to treat refractory patients, with meta-analyses showing 60% response rate following DBS, whatever the target: anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAcc), anteromedial subthalamic nucleus (amSTN), or inferior thalamic peduncle (ITP). But how do we choose the "best" target? Functional neuroimaging studies have shown that ALIC-DBS requires the modulation of the fiber tract within the ventral ALIC via the ventral striatum, bordering the bed nucleus of the stria terminalis and connecting the medial prefrontal cortex with the thalamus to be successful. VC/VS effective sites of stimulation were found within the VC and primarily connected to the medial orbitofrontal cortex (OFC) dorsomedial thalamus, amygdala, and the habenula. NAcc-DBS has been found to reduce OCD symptoms by decreasing excessive fronto-striatal connectivity between NAcc and the lateral and medial prefrontal cortex. The amSTN effective stimulation sites are located at the inferior medial border of the STN, primarily connected to lateral OFC, dorsal anterior cingulate, and dorsolateral prefrontal cortex. Finally, ITP-DBS recruits a bidirectional fiber pathway between the OFC and the thalamus. Thus, these functional connectivity studies show that the various DBS targets lie within the same diseased neural network. They share similar efficacy profiles on OCD symptoms as estimated on the Y-BOCS, the amSTN being the target supported by the strongest evidence in the literature. VC/VS-DBS, amSTN-DBS, and ALIC-DBS were also found to improve mood, behavioral adaptability and potentially both, respectively. Because OCD is such a heterogeneous disease with many different symptom dimensions, the ultimate aim should be to find the most appropriate DBS target for a given refractory patient. This quest will benefit from further investigation and understanding of the individual functional connectivity of OCD patients.

Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.

A recent phase I-II, open-label trial of ProSavin, a lentiviral vector delivering the key enzymes in the dopamine biosynthetic pathway to non-dopaminergic striatal neurons, demonstrated safety and improved motor function in parkinsonian patients. However, the magnitude of the effect suggested that optimal levels of dopamine replacement may not have been achieved. OXB-102, a lentiviral vector with an optimized expression cassette for dopamine biosynthesis, has been shown to achieve a significantly higher dopamine yield than ProSavin. We assessed the efficacy of OXB-102 in the MPTP macaque model of Parkinson's disease (PD). At 6 months post-vector administration, all treated animals showed significant improvements in clinical scores and spontaneous locomotor activity compared to controls, with the highest recovery observed in the OXB-102 high-dose (HD) group. Positron emission tomography quantification of 6-[18F]-fluoro-L-m-tyrosine uptake showed a significant increase in amino acid decarboxylase activity for all treated animals, compared with controls, where the OXB-102 HD group showed the highest level of dopaminergic activity. A toxicology study in macaques demonstrated that the vector was safe and well tolerated, with no associated clinical or behavioral abnormalities and no immune response mounted against any transgene products. Overall, these data support the further clinical development of OXB-102 for the treatment of PD.

Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation.

A concept in Parkinson's disease postulates that motor cortex may pattern abnormal rhythmic activities in the basal ganglia, underlying the genesis of observed motor symptoms. We conducted a preclinical study of electrical interference in the primary motor cortex using a chronic MPTP primate model in which dopamine depletion was progressive and regularly documented using 18F-DOPA positron tomography. High-frequency motor cortex stimulation significantly reduced akinesia and bradykinesia. This behavioral benefit was associated with an increased metabolic activity in the supplementary motor area as assessed with 18-F-deoxyglucose PET, a normalization of mean firing rate in the internal globus pallidus (GPi) and the subthalamic nucleus (STN), and a reduction of synchronized oscillatory neuronal activities in these two structures. Motor cortex stimulation is a simple and safe procedure to modulate subthalamo-pallido-cortical loop and alleviate parkinsonian symptoms without requiring deep brain stereotactic surgery.

Adverse Event with the Use of Carmustine Wafers and Postoperative Radiochemotherapy for the Treatment of High-grade Glioma.

Randomized, controlled trials have shown significant improvement of survival after implantation of 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) wafers for patients suffering from high-grade glioma. A combination of local chemotherapy with BCNU and concomitant radiochemotherapy with temozolomide (TMZ) appears to be attractive to enhance the overall survival, even though these treatments may potentially cumulate their toxicity. We report a clinical case of a patient submitted to this combined treatment protocol. Severe brain edema and a cystic formation in the surgical cavity rapidly developed. Data supporting the use of Gliadel® combined with TMZ comes from small retrospective studies, and some series have shown a very high rate of adverse events (AEs) when this multimodality treatment is applied. Combined protocols of local and systemic chemotherapy might provide survival benefits, although AEs seem currently underestimated.

Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease.

Parkinson's disease is typically treated with oral dopamine replacement therapies. However, long-term use is complicated by motor fluctuations from intermittent stimulation of dopamine receptors and off-target effects. ProSavin, a lentiviral vector based gene therapy that delivers local and continuous dopamine, was previously shown to be well tolerated in a Phase I/II first-in-human study, with significant improvements in motor behavior from baseline at 1 year. Here, patients with Parkinson's disease from the open-label trial were followed up in the long term to assess the safety and efficacy of ProSavin after bilateral injection into the putamen. Fifteen patients who were previously treated with ProSavin have been followed for up to 5 years, with some having been seen for 8 years. Eight patients received deep brain stimulation at different time points, and their subsequent assessments continued to assess safety. Ninety-six drug-related adverse events were reported (87 mild, 6 moderate, 3 severe) of which more than half occurred in the first year. The most common drug-related events were dyskinesias (33 events, 11 patients) and on-off phenomena (22 events, 11 patients). A significant improvement in the defined "off" Unified Parkinson's Disease Rating Scale part III motor scores, compared to baseline, was seen at 2 years (mean score 29 · 2 vs. 38 · 4, n = 14, p < 0.05) and at 4 years in 8/15 patients. ProSavin continued to be safe and well tolerated in patients with Parkinson's disease. Moderate improvements in motor behavior over baseline continued to be reported in the majority of patients who could still be evaluated up to 5 years of follow-up.