Structural hyperconnectivity of the subthalamic area with limbic cortices underpins anxiety and impulsivity in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, which is often associated with psychiatric comorbidities. Dysfunction of basal ganglia pathways might account for the wide spectrum of symptoms in TS patients. Although psychiatric symptoms may be related to limbic networks, the specific contribution of different limbic structures remains unclear. We used tractography to investigate cortical connectivity with the striatal area (caudate, putamen, core and shell of the nucleus accumbens), the subthalamic nucleus (STN), and the adjacent medial subthalamic region (MSR) in 58 TS patients and 35 healthy volunteers. 82% of TS patients showed psychiatric comorbidities, with significantly higher levels of anxiety and impulsivity compared to controls. Tractography analysis revealed significantly increased limbic cortical connectivity of the left MSR with the entorhinal (BA34), insular (BA48), and temporal (BA38) cortices in TS patients compared to controls. Furthermore, we found that left insular-STN connectivity was positively correlated with impulsivity scores for all subjects and with anxiety scores for all subjects, particularly for TS. Our study highlights a heterogenous modification of limbic structure connectivity in TS, with specific abnormalities found for the subthalamic area. Abnormal connectivity with the insular cortex might underpin the higher level of impulsivity and anxiety observed in TS.

Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

A threshold for mitotic activity and post-surgical residual volume defines distinct prognostic groups for astrocytoma IDH-mutant.

AIMS: The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era. METHODS: Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm2 was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation. RESULTS: Seventy-one per cent of the samples had <6 mitoses per 3 mm2 . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm2 identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm3 also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm2 and a residual volume <1 cm3 had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours. CONCLUSIONS: Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm2 and a residual volume <1 cm3 were the best candidates for observational follow-up.

European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part IV: deep brain stimulation.

In 2011 the European Society for the Study of Tourette Syndrome (ESSTS) published its first European clinical guidelines for the treatment of Tourette Syndrome (TS) with part IV on deep brain stimulation (DBS). Here, we present a revised version of these guidelines with updated recommendations based on the current literature covering the last decade as well as a survey among ESSTS experts. Currently, data from the International Tourette DBS Registry and Database, two meta-analyses, and eight randomized controlled trials (RCTs) are available. Interpretation of outcomes is limited by small sample sizes and short follow-up periods. Compared to open uncontrolled case studies, RCTs report less favorable outcomes with conflicting results. This could be related to several different aspects including methodological issues, but also substantial placebo effects. These guidelines, therefore, not only present currently available data from open and controlled studies, but also include expert knowledge. Although the overall database has increased in size since 2011, definite conclusions regarding the efficacy and tolerability of DBS in TS are still open to debate. Therefore, we continue to consider DBS for TS as an experimental treatment that should be used only in carefully selected, severely affected and otherwise treatment-resistant patients.

Whispering dysphonia in TUBB4A-related disorders responsive to bipallidal deep brain stimulation.

BACKGROUND: Mutations in TUBB4A are associated with a wide phenotypic spectrum including generalized dystonia with whispering dysphonia (DYT-TUBB4A). METHODS: We report the case of a 44-year-old patient with DYT-TUBB4A with a clinical presentation of disabling progressive dystonia, with a prominent laryngeal, cervical and facial involvement. RESULTS: Bipallidal deep brain stimulation (DBS) resulted in a 55% reduction of dystonia severity assessed by the Burke-Fahn-Marsden scale score 6 months after surgery. The effect was obvious on the cervical and facial components of dystonia. CONCLUSION: We suggest that bipallidal DBS should be considered in patients with disabling dystonia related to TUBB4A variants.

Anatomo-Functional Mapping of the Primate Mesencephalic Locomotor Region Using Stereotactic Lesions.

BACKGROUND: Dysfunction of the mesencephalic locomotor region has been implicated in gait disorders. However, the role of its 2 components, the pedunculopontine and the cuneiform nuclei, in locomotion is poorly understood in primates. OBJECTIVES: To analyze the effect of cuneiform lesions on gait and balance in 2 monkeys and to compare them with those obtained after cholinergic pedunculopontine lesions in 4 monkeys and after lesions in both the cuneiform and pedunculopontine nuclei in 1 monkey. METHODS: After each stereotactic lesion, we performed a neurological examination and gait and balance assessments with kinematic measures during a locomotor task. The 3-dimensional location of each lesion was analyzed on a common brainstem space. RESULTS: After each cuneiform lesion, we observed a contralateral cervical dystonia including an increased tone in the proximal forelimb and an increase in knee angle, back curvature and walking speed. Conversely, cholinergic pedunculopontine lesions increased tail rigidity and back curvature and an imbalance of the muscle tone between the ipsi- and contralateral hindlimb with decreased knee angles. The walking speed was decreased. Moreover, pedunculopontine lesions often resulted in a longer time to waking postsurgery. CONCLUSIONS: The location of the lesions and their behavioral effects revealed a somatotopic organization of muscle tone control, with the neck and forelimb represented within the cuneiform nucleus and hindlimb and tail represented within the pedunculopontine nucleus. Cuneiform lesions increased speed, whereas pedunculopontine lesions decreased it. These findings confirm the complex and specific role of the cuneiform and pedunculopontine nuclei in locomotion and suggest the role of the pedunculopontine in sleep control. © 2020 International Parkinson and Movement Disorder Society.

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations.

BACKGROUND: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined. MATERIALS AND METHODS: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM. RESULTS: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma. CONCLUSION: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway. IMPLICATIONS FOR PRACTICE: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.

Normal and pathological neuronal distribution of the human mesencephalic locomotor region.

BACKGROUND: Deep brain stimulation of the pedunculopontine nucleus has been performed to treat dopamine-resistant gait and balance disorders in patients with degenerative diseases. The outcomes, however, are variable, which may be the result of the lack of a well-defined anatomical target. OBJECTIVES: The objectives of this study were to identify the main neuronal populations of the pedunculopontine and the cuneiform nuclei that compose the human mesencephalic locomotor region and to compare their 3-dimensional distribution with those found in patients with Parkinson's disease and progressive supranuclear palsy. METHODS: We used high-field MRI, immunohistochemistry, and in situ hybridization to characterize the distribution of the different cell types, and we developed software to merge all data within a common 3-dimensional space. RESULTS: We found that cholinergic, GABAergic, and glutamatergic neurons comprised the main cell types of the mesencephalic locomotor region, with the peak densities of cholinergic and GABAergic neurons similarly located within the rostral pedunculopontine nucleus. Cholinergic and noncholinergic neuronal losses were homogeneous in the mesencephalic locomotor region of patients, with the peak density of remaining neurons at the same location as in controls. The degree of denervation of the pedunculopontine nucleus was highest in patients with progressive supranuclear palsy, followed by Parkinson's disease patients with falls. CONCLUSIONS: The peak density of cholinergic and GABAergic neurons was located similarly within the rostral pedunculopontine nucleus not only in controls but also in pathological cases. The neuronal loss was homogeneously distributed and highest in the pedunculopontine nucleus of patients with falls, which suggests a potential pathophysiological link. © 2018 International Parkinson and Movement Disorder Society.

Long-term GPi-DBS improves motor features in myoclonus-dystonia and enhances social adjustment.

BACKGROUND: Good short-term results of pallidal deep brain stimulation have been reported in myoclonus-dystonia. Efficacy and safety in the long term remain to be established. In addition, the actual impact of DBS treatment on social inclusion is unknown. The objective of this study was to assess the long-term clinical outcome, quality of life, and social adjustment of GPi-DBS in patients with ε-sarcoglycan (DYT11)-positive myoclonus-dystonia. METHODS: Consecutive myoclonus-dystonia patients with ε-sarcoglycan mutations who underwent GPi-DBS were evaluated at least 5 years postoperatively. Motor symptoms were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale including the Disability Scale, a composite score combining the rest and action parts of the Unified Myoclonus Rating Scale and modified Abnormal Involuntary Movement Scale. Standardized video-protocols were assessed by a blinded and external movement disorder specialist. Social adjustment, cognition, and mood were evaluated. RESULTS: Nine patients (5 women) with long-term GPi-DBS (8.7 ± 3.1 years) were included. There was significant improvement in the composite myoclonus score (94.1% ± 4% improvement; P = 0.008). Dystonia severity was also markedly improved (71.4% ± 28.33% improvement; P = 0.008) as well as motor disability (88.3% ± 20% improvement; P = 0.008) and abnormal involuntary movement score (71.1% ± 15.0% improvement; P = 0.008). No patients experienced postoperative speech or gait problems or any permanent adverse effects. Eight of the 9 patients had fully enhanced social adjustment and personal achievement, with little or no mood or behavioral disorders. CONCLUSIONS: GPi-DBS seems to be a safe and efficacious treatment for medically refractory ɛ-sarcoglycan myoclonus-dystonia, with sustained motor benefit, good quality of life, and social adjustment in long-term follow-up. © 2018 International Parkinson and Movement Disorder Society.

Beta burst coupling across the motor circuit in Parkinson's disease.

Exaggerated activity in the beta band (13-35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.

The feasibility and positive effects of a customised videogame rehabilitation programme for freezing of gait and falls in Parkinson's disease patients: a pilot study.

BACKGROUND: Freezing of gait and falls represent a major burden in patients with advanced forms of Parkinson's disease (PD). These axial motor signs are not fully alleviated by drug treatment or deep-brain stimulation. Recently, virtual reality has emerged as a rehabilitation option for these patients. In this pilot study, we aim to determine the feasibility and acceptability of rehabilitation with a customised videogame to treat gait and balance disorders in PD patients, and assess its effects on these disabling motor signs. METHODS: We developed a customised videogame displayed on a screen using the Kinect system. To play, the patient had to perform large amplitude and fast movements of all four limbs, pelvis and trunk, in response to visual and auditory cueing, to displace an avatar to collect coins and avoid obstacles to gain points. We tested ten patients with advanced forms of PD (median disease duration = 16.5 years) suffering from freezing of gait and/or falls (Hoehn&Yahr score ≥ 3) resistant to antiparkinsonian treatment and deep brain stimulation. Patients performed 18 training sessions during a 6-9 week period. We measured the feasibility and acceptability of our rehabilitation programme and its effects on parkinsonian disability, gait and balance disorders (with clinical scales and kinematics recordings), positive and negative affects, and quality of life, after the 9th and 18th training sessions and 3 months later. RESULTS: All patients completed the 18 training sessions with high feasibility, acceptability and satisfaction scores. After training, the freezing-of-gait questionnaire, gait-and-balance scale and axial score significantly decreased by 39, 38 and 41%, respectively, and the activity-balance confidence scale increased by 35%. Kinematic gait parameters also significantly improved with increased step length and gait velocity and decreased double-stance time. Three months after the final session, no significant change persisted except decreased axial score and increased step length and velocity. CONCLUSIONS: This study suggests that rehabilitation with a customised videogame to treat gait and balance disorders is feasible, well accepted, and effective in parkinsonian patients. These data serve as preliminary evidence for further larger and controlled studies to propose this customised videogame rehabilitation programme at home. TRIAL REGISTRATION: ClinicalTrials.gov NCT02469350 .

Anatomical evidence for functional diversity in the mesencephalic locomotor region of primates.

The mesencephalic locomotor region (MLR) is a highly preserved brainstem structure in vertebrates. The MLR performs a crucial role in locomotion but also controls various other functions such as sleep, attention, and even emotion. The MLR comprises the pedunculopontine (PPN) and cuneiform nuclei (CuN) but their specific roles are still unknown in primates. Here, we sought to characterise the inputs and outputs of the PPN and CuN to and from the basal ganglia, thalamus, amygdala and cortex, with a specific interest in identifying functional anatomical territories. For this purpose, we used tract-tracing techniques in monkeys and diffusion weighted imaging-based tractography in humans to understand structural connectivity. We found that MLR connections are broadly similar between monkeys and humans. The PPN projects to the sensorimotor, associative and limbic territories of the basal ganglia nuclei, the centre median-parafascicular thalamic nuclei and the central nucleus of the amygdala. The PPN receives motor cortical inputs and less abundant connections from the associative and limbic cortices. In monkeys, we found a stronger connection between the anterior PPN and motor cortex suggesting a topographical organisation of this specific projection. The CuN projected to similar cerebral structures to the PPN in both species. However, these projections were much stronger towards the limbic territories of the basal ganglia and thalamus, to the basal forebrain (extended amygdala) and the central nucleus of the amygdala, suggesting that the CuN is not primarily a motor structure. Our findings highlight the fact that the PPN integrates sensorimotor, cognitive and emotional information whereas the CuN participates in a more restricted network integrating predominantly emotional information.

The integrative role of the pedunculopontine nucleus in human gait.

The brainstem pedunculopontine nucleus has a likely, although unclear, role in gait control, and is a potential deep brain stimulation target for treating resistant gait disorders. These disorders are a major therapeutic challenge for the ageing population, especially in Parkinson's disease where gait and balance disorders can become resistant to both dopaminergic medication and subthalamic nucleus stimulation. Here, we present electrophysiological evidence that the pedunculopontine and subthalamic nuclei are involved in distinct aspects of gait using a locomotor imagery task in 14 patients with Parkinson's disease undergoing surgery for the implantation of pedunculopontine or subthalamic nuclei deep brain stimulation electrodes. We performed electrophysiological recordings in two phases, once during surgery, and again several days after surgery in a subset of patients. The majority of pedunculopontine nucleus neurons (57%) recorded intrasurgically exhibited changes in activity related to different task components, with 29% modulated during visual stimulation, 41% modulated during voluntary hand movement, and 49% modulated during imaginary gait. Pedunculopontine nucleus local field potentials recorded post-surgically were modulated in the beta and gamma bands during visual and motor events, and we observed alpha and beta band synchronization that was sustained for the duration of imaginary gait and spatially localized within the pedunculopontine nucleus. In contrast, significantly fewer subthalamic nucleus neurons (27%) recorded intrasurgically were modulated during the locomotor imagery, with most increasing or decreasing activity phasically during the hand movement that initiated or terminated imaginary gait. Our data support the hypothesis that the pedunculopontine nucleus influences gait control in manners extending beyond simply driving pattern generation. In contrast, the subthalamic nucleus seems to control movement execution that is not likely to be gait-specific. These data highlight the crucial role of these two nuclei in motor control and shed light on the complex functions of the lateral mesencephalus in humans.

Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion.

Patients with Parkinson's disease (PD) display significant sleep disturbances and daytime sleepiness. Dopaminergic treatment dramatically improves PD motor symptoms, but its action on sleep remains controversial, suggesting a causal role of nondopaminergic lesions in these symptoms. Because the pedunculopontine nucleus (PPN) regulates sleep and arousal, and in view of the loss of its cholinergic neurons in PD, the PPN could be involved in these sleep disorders. The aims of this study were as follows: (1) to characterize sleep disorders in a monkey model of PD; (2) to investigate whether l-dopa treatment alleviates sleep disorders; and (3) to determine whether a cholinergic PPN lesion would add specific sleep alterations. To this end, long-term continuous electroencephalographic monitoring of vigilance states was performed in macaques, using an implanted miniaturized telemetry device. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment induced sleep disorders that comprised sleep episodes during daytime and sleep fragmentation and a reduction of sleep efficiency at nighttime. It also induced a reduction in time spent in rapid eye movement (REM) sleep and slow-wave sleep and an increase in muscle tone during REM and non-REM sleep episodes and in the number of awakenings and movements. l-Dopa treatment resulted in a partial but significant improvement of almost all sleep parameters. PPN lesion induced a transient decrease in REM sleep and in slow-wave sleep followed by a slight improvement of sleep quality. Our data demonstrate the efficacy of l-dopa treatment in improving sleep disorders in parkinsonian monkeys, and that adding a cholinergic PPN lesion improves sleep quality after transient sleep impairment.

Pallidal activity in myoclonus dystonia correlates with motor signs.

BACKGROUND: Myoclonus-dystonia related to epsilon-sarcoglycan gene mutations is characterized by myoclonic jerks and mild to moderate dystonia. The role of basal ganglia dysfunction in the pathogenesis is unknown. METHODS: Pallidal neuronal activity was recorded in six myoclonus-dystonia and six primary generalized dystonia patients operated on for internal globus pallidus deep brain stimulation. RESULTS: In myoclonus-dystonia patients compared with primary-dystonia patients, internal pallidum neurons showed higher burst frequency, lower mean burst, and pause durations. External pallidum neurons showed higher mean pause frequency. Oscillatory activity was present in 33% and 35% of internal pallidum neurons in myoclonus-dystonia and primary-dystonia patients, respectively, predominantly in the theta frequency band (3-8 Hz). In myoclonus-dystonia patients with more severe myoclonus, internal pallidum neurons exhibited a higher bursting activity with high intraburst frequency and lower oscillatory activity frequency. CONCLUSIONS: Myoclonus-dystonia appears to be related to specific changes in internal pallidum activity, leading to disruption in striato-pallido-thalamo-cortical circuits. © 2015 International Parkinson and Movement Disorder Society.

Patterns of relapse and growth kinetics of surgery- and radiation-refractory meningiomas.

Patients with surgery- and radiation-refractory meningiomas have a poor outcome. Due to our lack of knowledge concerning multi-recurrent meningioma natural history, their clinical course is poorly defined. This retrospective study aims at defining patterns of relapse in order to help in the definition of response criteria in future clinical trials. We performed a retrospective review of surgery- and radiotherapy-refractory meningioma cases with interpretable radiological follow-up treated in our department. Tumor volumes were measured on 3D T1 Gadolinium volumetric sequences using a semi-automated algorithm for tumor segmentation. Twenty nine patients with multi-treated meningioma (11 WHO Grade II, 5 de novo WHO Grade III and 13 transformed WHO Grade III), were evaluated. Median PFS was 16 months for patients with Grade II meningiomas. In patients with Grade III meningiomas, the de novo subgroup had a median PFS of 4 months compared with 7 months in patients with malignant transformation. Volumetric analysis of tumor growth concerned 95 tumor nodules in 50 relapses. The mean growth rate of tumor nodules was 10.4 cm(3)/year (95% CI 7.3-14.8 cm(3)/year). Three patterns of tumor growth were described: "classical" for 9 (31%) patients, "local multi-nodular" for 6 (21%) patients and "multi-nodular metastatic" for the last 14 (48%) patients. Considering all tumor nodules, median time to tumor progression (TTP) was 3.7 months. Progressing tumors represent the most frequent histological subgroup of surgery and radiation-refractory meningiomas while tumors with multi-nodular metastatic dissemination are the prominent radiological pattern of progression.

Gait disorders in parkinsonian monkeys with pedunculopontine nucleus lesions: a tale of two systems.

Gait and balance disorders unresponsive to dopaminergic drugs in Parkinson's disease (PD) are secondary to lesions located outside the dopaminergic system. However, available animal models of PD fail to display l-3,4-dihydroxyphenylalanine (DOPA)-responsive parkinsonism and drug-resistant gait and balance disorders, and this lack of appropriate model could account for the deficit of efficient treatments. Because the pedunculopontine nucleus (PPN) plays an important role in locomotion control, we conducted the present study to investigate the consequences of combined dopaminergic and PPN lesions in a same animal. We used macaques that received first 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to render them parkinsonian and then local stereotaxic lesion of the PPN. Adding bilateral PPN lesions in MPTP-lesioned macaques induced dopamine-resistant gait and balance disorders but unexpectedly improved hypokinesia. Additional MPTP injections resulted in the association of a severe DOPA-responsive parkinsonism together with DOPA-unresponsive gait disorders. Histological examination assessed a severe dopaminergic degeneration and a significant loss of PPN cholinergic neurons. We observed similar results in aged monkeys intoxicated with MPTP: they developed severe DOPA-responsive hypokinesia and tremor together with unresponsive gait and balance disorders and displayed dopaminergic lesion and a weak but significant cholinergic PPN lesion. Our results highlight the complex role of the cholinergic PPN neurons in the pathophysiology of PD because its lesion induces a dual effect with an improvement of hypokinesia contrasting with a worsening of DOPA-unresponsive gait and balance disorders. Thus, we obtained a primate model of PD that could be useful to test symptomatic treatments for these heavily disabling symptoms.

Sustained reduction of essential tremor with low-power non-thermal transcranial focused ultrasound stimulations in humans.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. OBJECTIVE: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. METHODS: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. RESULTS: VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. CONCLUSIONS: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.