Evidence for widespread changes in the structure, composition, and fire regimes of western North American forests.

Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.

Demographic trends in community functional tolerance reflect tree responses to climate and altered fire regimes.

Forests of the western United States are undergoing substantial stress from fire exclusion and increasing effects of climate change, altering ecosystem functions and processes. Changes in broad-scale drivers of forest community composition become apparent in their effect on survivorship and regeneration, driving demographic shifts. Here we take a community functional approach to forest demography, by investigating mean drought or shade functional tolerance in community assemblages. We created the Community Mean Tolerance Index (CMTI), a response metric utilizing drought/shade tolerance trade-offs to identify communities undergoing demographic change from a functional trait perspective. We applied the CMTI to Forest Inventory and Analysis data to investigate demographic trends in drought and shade tolerance across the southern Rocky Mountains. To find the major drivers of change in community tolerance within and across forest types, we compared index trends to climate and fire-exclusion-driven disturbance, and identified areas where demographic change was most pronounced. We predicted that greater shifts in drought tolerance would occur at lower forest type ecotones where climate stress is limiting and that shifts in shade tolerance would correspond to excursions from the historic fire regime leading to greater changes in forest types adapted to frequent, low-intensity fire. The CMTI was applied spatially to identify sites likely to transition to oak shrubfield, where disturbance history combined with a species-driven demographic shift toward drought tolerance. Within forest types, lower elevations are trending toward increased drought tolerance, while higher elevations are trending toward increased shade tolerance. Across forest types, CMTI difference peaked in mid-elevation ponderosa pine and mixed-conifer forests, where fire exclusion and autecology drive demographic changes. Peak CMTI difference was associated with fire exclusion in forest types adapted to frequent fire. At higher elevations, site-level stand dynamics appear to be influencing demographic tolerance trends more than broad climate drivers. Through a community demographic approach to functional traits, the CMTI highlights areas and forest types where ecosystem function is in the process of changing, before persistent vegetation type change occurs. Applied to regional plot networks, the CMTI provides an early warning of shifts in community functional processes as climate change pressures continue.

Life-threatening DBS withdrawal syndrome in Parkinson's disease can be treated with early reimplantation.

INTRODUCTION: The deep brain stimulation (DBS) withdrawal syndrome (DBS-WDS) is a rare, life-threatening complication in Parkinson's disease (PD) patients with long disease duration and stimulation when stimulation is terminated for extended periods mostly due to infection of the DBS-hardware. METHODS, RESULTS: In five patients explantation became necessary because of infection after a mean of 11.4 years (range 4-15 years) of DBS and a mean disease duration of 24.6 years (range 3-22 years). Mean UPDRS motor-score pre-explantation was 38 points (range 24-55 points) which increased to a mean of 78.4 points (range 58-90 points) after explantation, despite optimal Levodopa dosing. Reimplantation of the hardware after 23 days (range 3-45 days) under antibiotic treatment led to an improvement to a mean of 40 points (range 25-73 points) and a complication free survival. CONCLUSION: Early reimplantation of the DBS-hardware is a treatment option of the DBS-WDS when the life-threatening urgency overrides surgical standards. Observation of the syndrome indicates pharmacological unresponsiveness of the dopaminergic system in advanced PD and long-term DBS.

Produtividade de genótipos de trigo duplo propósito submetidos ao pastejo com vacas em lactação / Productivity of dual-purpose wheat genotypes under grazing with lactating cows

Esta pesquisa foi conduzida com o objetivo de avaliar a produtividade de dois genótipos de trigo de duplo propósito, BRS Tarumã e BRS Umbu, submetidos ao pastejo com vacas em lactação. O delineamento experimental foi o inteiramente ao acaso, com dois tratamentos (genótipos), três repetições (piquetes) e medidas repetidas no tempo (pastejos). Avaliaram-se a precocidade, a composição estrutural dos trigos, as produções de forragem e de biomassa de lâminas foliares, as taxas de acúmulo diário de forragem e de lâminas foliares, a taxa de lotação, as ofertas de forragem e de lâminas foliares, a eficiência de pastejo, o consumo aparente e a produção de grãos. O trigo mais precoce para produção de forragem foi o BRS Umbu. Houve diferença para a produção de forragem (3196 vs. 4143kg MS/ha) e de lâminas foliares (2281 vs. 3205kg MS/ha) para os genótipos BRS Umbu e BRS Tarumã, respectivamente. Valores similares foram encontrados para taxa de lotação (2,26UA/ha); eficiência de pastejo (52,26%), consumo aparente (2,91%) e produção de grãos (1716kg/ha). O genótipo BRS Tarumã é o mais indicado para o manejo de duplo propósito em condições de pastejo com vacas em lactação.(AU)

The objective of this research was to evaluate the productivity of two dual-purpose wheat genotypes BRS Tarumã and BRS Umbu under grazing with lactating cows. The experimental design was completely randomized, with two treatments, three replications (paddocks) and repeated measures (grazing cycles). Studied variables were early growth, the structural composition of wheat, forage production, leaf blade biomass, the stocking rate, the herbage and leaf blade allowance, the grazing efficiency, the herbage intake and grain yield. The earliest genotype for forage production was the BRS Umbu. Differences in herbage yield between BRS Umbu and BRS Tarumã genotypes (3196 vs. 4143kg DM/ha) and leaf blade production (2281 vs. 3205kg DM/ha), respectively, were detected. Similar values between cultivars were found in stocking rate (2,26AU/ha); grazing efficiency (52,26%), herbage intake (2,91 %) and grain yield (1716kg/ha). The BRS Tarumã genotype is the most suitable for dual-purpose under grazing with dairy cows.(AU)

Effect of high-frequency subthalamic neurostimulation on gait and freezing of gait in Parkinson's disease: a systematic review and meta-analysis.

The aim of this meta-analysis was to summarize the short- and long-term effects of bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) on gait and freezing of gait (FOG) in Parkinson's disease and to detect predictors of post-stimulation outcome. A comprehensive review of the literature was conducted up to October 2015 using Medline Ovid databases for studies analyzing the effect of bilateral STN-DBS on FOG and/or gait. Sixteen studies with available data for the gait item (no. 29) of the Unified Parkinson's Disease Rating Scale (UPDRS) and six studies with the FOG item (no. 14) were included. Data were summarized for the following follow-up periods: 6-15, 24-48 and >48 months. For the medication (Med)-Off/stimulation(Stim)-On condition compared with baseline Med-Off, STN-DBS significantly improved gait on average from 2.43 to 0.96, 2.53 to 1.31 and 2.56 to 1.40 points at 6-15, 24-48 and >48 months, respectively (P < 0.05). Pre-operative levodopa responsiveness of UPDRS-III and Med-Off severity of gait were the predictors of this beneficial effect. STN-DBS significantly improved FOG for the Med-Off/Stim-On condition compared with baseline on average from 2.26 to 0.82, 2.43 to 1.13 and 2.48 to 1.38 points at 6-15, 24-48 and >48 months, respectively (P < 0.05). There was no significant effect in the Med-On/Stim-On condition. This meta-analysis showed a robust improvement of gait and FOG by STN-DBS for more than 4 years in the Med-Off/Stim-On condition. No beneficial effect was found for the On state of medication. Pre-operative levodopa responsiveness of global motor performance (UPDRS-III) is the strongest predictor of the effect of deep brain stimulation on gait.

German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM).

BACKGROUND: Data on paediatric deep brain stimulation (DBS) is limited, especially for long-term outcomes, because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We seek to systematically evaluate the clinical outcome of paediatric patients undergoing DBS. METHODS: A German registry on paediatric DBS (GEPESTIM) was created to collect data of patients with dystonia undergoing DBS up to the age of 18 years. Patients were divided into three groups according to etiology (group 1 inherited, group 2 acquired, and group 3 idiopathic dystonia). RESULTS: Data of 44 patients with a mean age of 12.8 years at time of operation provided by 6 German centers could be documented in the registry so far (group 1 n = 18, group 2 n = 16, group 3 n = 10). Average absolute improvement after implantation was 15.5 ± 18.0 for 27 patients with pre- and postoperative Burke-Fahn-Marsden Dystonia Rating scale movement scores available (p < 0.001) (group 1: 19.6 ± 19.7, n = 12; group 2: 7.0 ± 8.9, n = 8; group 3: 19.2 ± 20.7, n = 7). Infection was the main reason for hardware removal (n = 6). 20 IPG replacements due to battery expiry were necessary in 15 patients at 3.7 ± 1.8 years after last implantation. DISCUSSION: Pre- and postoperative data on paediatric DBS are very heterogeneous and incomplete but corroborate the positive effects of DBS on inherited and acquired dystonia. Adverse events including relatively frequent IPG replacements due to battery expiry seem to be a prominent feature of children with dystonia undergoing DBS. The registry enables collaborative research on DBS treatment in the paediatric population and to create standardized management algorithms in the future.

Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology.

Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa-/-) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa-/- mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa-/- spinal cord. Third, many signal transduction pathways in the Gaa-/- cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were "synaptic plasticity pathways" including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system.

Osteoarthritis in temporomandibular joint of Col2a1 mutant mice.

OBJECTIVE: Col2a1 gene mutations cause premature degeneration of knee articular cartilage in disproportionate micromelia (Dmm) and spondyloepiphesial dysplasia congenita (sedc) mice. The present study analyses the temporomandibular joint (TMJ) in Col2a1 mutant mice in order to provide an animal model of TMJ osteoarthritis (OA) that may offer better understanding of the progression of this disease in humans. DESIGN: Dmm/+ mice and controls were compared at two, six, nine and 12 months. Craniums were fixed, processed to paraffin sections, stained with Safranin-O/Fast Green, and analysed with light microscopy. OA was quantified using a Mankin scoring procedure. Unfolded protein response (UPR) assay was performed and immunohistochemistry (IHC) was used to assay for known OA biomarkers. RESULTS: Dmm/+ TMJs showed fissuring of condylar cartilage as early as 6 months of age. Chondrocytes were clustered, leaving acellular regions in the matrix. Significant staining of HtrA1, Ddr2 and Mmp-13 was observed in Dmm/+ mice (p<0.01). We detected upregulation of the UPR in knee but not TMJ. CONCLUSIONS: Dmm/+ mice are subject to early-onset OA in the TMJ. We observed upregulation of biomarkers and condylar cartilage degradation concomitant with OA. An upregulated UPR may exacerbate the onset of OA. The Dmm/+ mouse TMJ is a viable model for the study of the progression of OA in humans.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

Kinematic effects of subthalamic stimulation on reach-to-grasp movements in Parkinson's disease.

BACKGROUND: Parkinsonian patients demonstrate particular difficulties when performing sequential motor tasks compared to simple movements indicating an important role of the basal ganglia in switching between different motor programs. OBJECTIVE: To investigate the impact of subthalamic stimulation on the kinematics of composed reach-to-grasp movements and on isolated movement segments. METHODS: 11 age matched controls and 16 PD patients with subthalamic stimulation were examined without medication with stimulation switched on and off. All subjects were instructed to perform three different externally cued hand movements: 1) The complete reach-to-grasp movement consisting of hand transport to and precision grip around a target. 2) The isolated reach movement to the grip device 3) The isolated precision grip and button press. Kinematic data were recorded with a 3D ultrasound movement analysis system (CMS 70 P4-V5, Zebris, Germany). RESULTS: The effect of subthalamic stimulation was accentuated during the reach phase compared to the grip formation during the composed movement. Stimulation induced kinematic changes of the composed movement were comparable to those of both isolated submovements. CONCLUSION: Subthalamic stimulation improved certain aspects of all three hand movement types but did not differentially impact the composed reach-to-grasp task compared to the simple submovements. We assume that the complete reach-to-grasp task is encoded in a single generalised motor program which is affected by stimulation.

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

BACKGROUND: SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. CASE: Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. CONCLUSION: This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

Effects of deep brain stimulation of the cerebellothalamic pathways on the sense of smell.

The cerebellum and the motor thalamus, connected by cerebellothalamic pathways, are traditionally considered part of the motor-control system. Yet, functional imaging studies and clinical studies including patients with cerebellar disease suggest an involvement of the cerebellum in olfaction. Additionally, there are anecdotal clinical reports of olfactory disturbances elicited by electrical stimulation of the motor thalamus and its neighbouring subthalamic region. Deep brain stimulation (DBS) targeting the cerebellothalamic pathways is an effective treatment for essential tremor (ET), which also offers the possibility to explore the involvement of cerebellothalamic pathways in the sense of smell. This may be important for patient care given the increased use of DBS for the treatment of tremor disorders. Therefore, 21 none-medicated patients with ET treated with DBS (13 bilateral, 8 unilateral) were examined with "Sniffin' Sticks," an established and reliable method for olfactory testing. Patients were studied either with DBS switched on and then off or in reversed order. DBS impaired odor threshold and, to a lesser extent, odor discrimination. These effects were sub-clinical as none of the patients reported changes in olfactory function. The findings, however, demonstrate that olfaction can be modulated in a circumscribed area of the posterior (sub-) thalamic region. We propose that the impairment of the odor threshold with DBS is related to effects on an olfacto-motor loop, while disturbed odor discrimination may be related to effects of DBS on short-term memory.

Deep brain stimulation of the internal globus pallidus in dystonia: target localisation under general anaesthesia.

UNLABELLED: Deep brain stimulation (DBS) of the internal globus pallidus (Gpi) is an effective therapy for various types of dystonia. The authors describe their technical approach for securing appropriate placement of the stimulating electrodes within the Gpi under general anaesthesia, including MRI based individualised anatomical targeting combined with electrophysiological mapping of the Gpi using micro-recording (MER) as well as macrostimulation and report the subsequent clinical outcome and complications using this method. METHOD: We studied 42 patients (male-female ratio 25:17; mean age 43.6 years, range 9 to 74 years) consecutively operated at the Department of Neurosurgery, University Hospital Schleswig-Holstein, Campus Kiel, between 2001 - 2006. One patient underwent unilateral implantation after a right-sided pallidotomy 30 years before and strictly unilateral symptoms; all other implantations were bilateral. Two patients had repeat surgery after temporary removal of uni- or bilateral implants secondary to infection. Overall, 86 DBS electrodes were implanted. In 97% of the implantations, at least three microelectrodes were inserted simultaneously for MER and test stimulation. Initial anatomical targeting was based on stereotactic atlas coordinates and individual adaptation by direct visualisation of the Gpi on the stereotactic T2 or inversion-recovery MR images. The permanent electrode was placed according to the results of MER and test stimulations for adverse effects. FINDINGS: The average improvement from baseline in clinical ratings using either the Burke-Fahn-Marsden-Dystonia (BFMDRS) or Toronto-Western-Spasmodic-Torticollis (TWSTR) rating scale at the last post-operative follow-up (mean 16.4 ; range 3-48 months) was 64.72% (range 20.39 to 98.52%). The post-operative MRI showed asymptomatic infarctions of the corpus caudatus in three patients and asymptomatic small haemorrhages in the lateral basal ganglia in two patients. One patient died due to a recurrent haemorrhage which occurred three months after the operation. The electrodes were implanted as follows: central trajectory in 64%, medial trajectory in 20%, anterior in 9% and lateral dorsal trajectories in 3.5% each. The reduction in BFMDRS or TWSTR motor score did not differ between the group implanted in the anatomically defined (central) trajectory bilateral (-64.15%, SD 23.8) and the physiologically adopted target (uni- or bilateral) (-63.39%, SD 23.1) indicating that in both groups equally effective positions were chosen within Gpi for chronic stimulation (t-test, p > 0.4). CONCLUSIONS: The described technique using stereotactic MRI for planning of the trajectory and direct visualisation of the target, intra-operative MER for delineating the boundaries of the target and macrostimulation for probing the distance to the internal capsule by identifying the threshold for stimulation induced tetanic contractions is effective in DBS electrode implantation in patients with dystonia operated under general anaesthesia. The central trajectory was chosen in only 64%, despite individual adaptation of the target due to direct visualisation of the Gpi in inversion recovery MRI in 43% of the patients, demonstrating the necessity of combining anatomical with neurophysiological information.

Accuracy and distortion of deep brain stimulation electrodes on postoperative MRI and CT.

OBJECTIVE: Postoperative monitoring of the electrode position is important to evaluate the best stimulation site in deep brain stimulation. MR imaging is excellent for ruling out postoperative complications e.g. haemorrhage, but its accuracy in electrode localisation is still controversial. The reasons for this are the size of the artefact around the electrode and its unclear relation to the electrode position (concentric or eccentric). The goal of this study was to determine the relation and size of these artefacts to the electrodes by comparing the position of the electrodes in postoperative MR and CT imaging. MATERIAL AND METHODS: Five patients underwent deep brain stimulation of the subthalamic nucleus due to levodopa-induced motor complications in Parkinson's disease. A stereotactic CT and a non-stereotactic MR were performed for postoperative localisation of the electrode position. The stereotactic MR for planning of the trajectories and targets was done under general anaesthesia. The latter two were fused to the stereotactic MR and the position of the DBS electrode contacts was determined on CT and MRI. The size of the artefact was measured at the level of each contact in two directions, anterior to posterior (AP) and lateral. Altogether 40 contacts were evaluated. RESULTS: Mean size of the CT-artefact was 2.6 mm AP (range, 2.0-3.2 mm) and 2.6 mm laterally (range, 2.0-3.8 mm). In comparison, mean size on the MRI was 3.5 mm AP (range, 2.9-5.3 mm) and 3.8 mm laterally (range, 2.9-4.8 mm). A trajectory with a 1.2 mm diameter (size of the DBS electrode) was centred on the electrodes' artefact of the CT and the MRI. The difference between the contact coordinates was calculated as deviation of the artefact around the electrode on the MR. Mean deviation was 0.2 mm on the x-axis (range, 0-0.5 mm), 0.5 mm on the y-axis (range, 0-1.1 mm) and 0.3 mm on the z-axis (range, 0-0.7 mm). There were no significant differences (t-test, p > 0.4). CONCLUSION: The size of the electrodes' artefact was smaller on CT compared to MR. Furthermore, the position was not precisely concentric around the electrode. Nevertheless, the mean deviation after measuring the contact position in both CT and MR was less than 1 mm in all three planes. Both techniques are eligible for postoperative localisation of DBS electrodes, with a small imprecision of the non-stereotactic MR compared to the stereotactic CT. This might be compensated by the fact that postoperative MR can rule out asymptomatic postoperative complications e.g. haemorrhages or infarctions, without radiation exposure of the patient.

Deep brain stimulation for movement disorders and its neuropsychological implications.

Deep brain stimulation (DBS) has gained increasing attention as a therapy for movement disorders. Neuropsychological alterations can accompany the disease evolution and medical therapy of PD. Also, interfering abruptly with the biological balance by means of a surgical intervention into complex circuits with motor but also cognitive and limbic functions, could potentially cause severe problems. Because cognitive or emotional impairments may have an even stronger impact on quality of life, than motor symptoms, care must be taken to perform surgery in the safest possible way to exclude adverse effects in these domains. Detailed neuropsychological evaluations may become helpful to further understand the mechanisms underlying some aspects of the clinical pictures both pre- and postoperatively and to define risk populations, that should be excluded from this intervention.

Electrode implantation for deep brain stimulation in dystonia: a fast spin-echo inversion-recovery sequence technique for direct stereotactic targeting of the GPI.

OBJECTIVE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment for medically refractory primary dystonia. We present our technique for direct preoperative visualization of the target using a fast spin-echo inversion-recovery (FSE-IR) sequence. METHODS: Twenty-three consecutive patients (mean age 41 years, range 9-68 years, male to female ratio 11:12) with severe dystonia were operated using a combination of FSE-IR imaging for direct visualization of the globus pallidus internus with stereotactic, gadolinium-enhanced T1-MPRage images. The complete procedure, including stereotactic MRI, was performed under general anesthesia with propofol and remifentanyl. We used multichannel microdrive systems (Medtronic; Alpha-Omega) to introduce up to five parallel microelectrodes for microelectrode recordings (MER) and test stimulation with the central trajectory directed at the anatomically predefined target. The initial standard coordinates in relation to the mid-commissural point (mid-AC-PC) were as follows: lateral 21 mm, anterior 3 mm, and inferior 2 mm, which were then adapted to the individual case based on direct visualization of the target area and further refined by the intraoperative neurophysiology. RESULTS: In ten patients (43%) atlas-based standard coordinates were modified based on the direct visualization of the GPi in the FSE-IR images (bilaterally in seven patients, unilaterally in three). The modified targets ranged from 18.5 to 23.5 mm (mean 20.76 mm) laterally, 1-7 mm (mean 2.75 mm) anteriorly and 1-2 mm (mean 1.95 mm) inferiorly to the mid-AC-PC. We implanted the permanent electrode based on the results of MER and intraoperative stimulation performed to determine the threshold for pyramidal tract responses on the central trajectory in 67%, medially in 16%, anteriorly in 11%, laterally in 4%, dorsally in 2%. The procedure resulted in excellent clinical benefits (average reduction of the Burke-Fahn-Marsden Dystonia Rating Score (BFMDRS) or the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) were respectively 65.9%, range 20.9-91.4%) within the first year after surgery. Safety was demonstrated by the absence of intracranial bleeding or other surgical complications causing neurological morbidity. CONCLUSION: Inversion recovery sequences are an excellent tool for direct visualization of the GPi. These images can be fused to stereotactic MRI or CCT and may help to improve anatomical targeting of the GPi for the implantation of DBS electrodes.

Failure of deep brain stimulation of the posterior inferior hypothalamus in chronic cluster headache - report of two cases and review of the literature.

OBJECTIVE: Deep brain stimulation (DBS) has become a standard procedure for movement disorders such as Parkinson's disease, essential tremor or dystonia. Recently, deep brain stimulation of the posterior hypothalamus has been shown to be effective in the treatment of drug-resistant chronic cluster headache. METHODS: DBS of the posterior inferior hypothalamus was performed on two patients with chronic cluster headaches, one 55-year-old man with medically intractable chronic cluster headache since 1996, and one 31-year-old woman with a chronic form since 2002. Both patients showed continuous worsening headaches in the last years despite high dose medical treatment. The patients fulfilled the published criteria for DBS in chronic cluster headaches. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to the published coordinates (2 mm lateral, 3 mm posterior, 5 mm inferior) referenced to the mid-AC-PC line. RESULTS: The intra- and postoperative course was uneventful and postoperative MRI control documented regular position of the DBS electrodes. The current stimulation parameters were at 12 months postoperatively 0 neg., G pos.; 5.5 V; 60 micros; 180 Hz (Case 1) and 0 neg., G pos.; 3.0 V; 60 micros; 185 Hz, at 3 months postoperatively (Case 2). Surgery- or stimulation-related side effects were not observed. Both patients showed initial pain reduction in the first days whereas 12 respectively 3 month follow-up did not show a significant reduction in attack frequency or intensity. CONCLUSION: Deep brain stimulation of the posterior inferior hypothalamus is an experimental procedure and should be restricted to selected therapy-refractory patients and should be performed in centers experienced in patient selection and performance of DBS as well as postoperative pain treatment. A prospective multi-centre study is necessary to evaluate its effectiveness.

Redox regulation of diaphragm proteolysis during mechanical ventilation.

Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox-sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control, 2) 6 h of MV, 3) 6 h of MV with infusion of the antioxidant Trolox, 4) 18 h of MV, and 5) 18 h of MV with Trolox. Trolox did not attenuate MV-induced increases in diaphragmatic levels of ubiquitin-protein conjugation, polyubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome alpha-subunit 7, 14-kDa E2, and proteasome-activating complex PA28). However, Trolox reduced both chymotrypsin-like and peptidylglutamyl peptide hydrolyzing (PGPH)-like 20S proteasome activities in the diaphragm after 18 h of MV. In addition, Trolox rescued diaphragm myofilament protein concentration (mug/mg muscle) and the percentage of easily releasable myofilament protein independent of alterations in ribosomal capacity for protein synthesis. In summary, these data are consistent with the notion that the protective effect of antioxidants on the diaphragm during MV is due, at least in part, to decreasing myofilament protein substrate availability to the proteasome.

Antioxidant administration attenuates mechanical ventilation-induced rat diaphragm muscle atrophy independent of protein kinase B (PKB Akt) signalling.

Oxidative stress promotes controlled mechanical ventilation (MV)-induced diaphragmatic atrophy. Nonetheless, the signalling pathways responsible for oxidative stress-induced muscle atrophy remain unknown. We tested the hypothesis that oxidative stress down-regulates insulin-like growth factor-1-phosphotidylinositol 3-kinase-protein kinase B serine threonine kinase (IGF-1-PI3K-Akt) signalling and activates the forkhead box O (FoxO) class of transcription factors in diaphragm fibres during MV-induced diaphragm inactivity. Sprague-Dawley rats were randomly assigned to one of five experimental groups: (1) control (Con), (2) 6 h of MV, (3) 6 h of MV with infusion of the antioxidant Trolox, (4) 18 h of MV, (5) 18 h of MV with Trolox. Following 6 h and 18 h of MV, diaphragmatic Akt activation decreased in parallel with increased nuclear localization and transcriptional activation of FoxO1 and decreased nuclear localization of FoxO3 and FoxO4, culminating in increased expression of the muscle-specific ubiquitin ligases, muscle atrophy factor (MAFbx) and muscle ring finger-1 (MuRF-1). Interestingly, following 18 h of MV, antioxidant administration was associated with attenuation of MV-induced atrophy in type I, type IIa and type IIb/IIx myofibres. Collectively, these data reveal that the antioxidant Trolox attenuates MV-induced diaphragmatic atrophy independent of alterations in Akt regulation of FoxO transcription factors and expression of MAFbx or MuRF-1. Further, these results also indicate that differential regulation of diaphragmatic IGF-1-PI3K-Akt signalling exists during the early and late stages of MV.

Mechanical ventilation promotes redox status alterations in the diaphragm.

Oxidative stress is an important mediator of diaphragm muscle atrophy and contractile dysfunction during prolonged periods of controlled mechanical ventilation (MV). To date, specific details related to the impact of MV on diaphragmatic redox status remain unknown. To fill this void, we tested the hypothesis that MV-induced diaphragmatic oxidative stress is the consequence of both an elevation in intracellular oxidant production in conjunction with a decrease in the antioxidant buffering capacity. Adult rats were assigned to one of two experimental groups: 1) control or 2) 12 h of MV. Compared with controls, diaphragms from MV animals demonstrated increased oxidant production, diminished total antioxidant capacity, and decreased glutathione levels. Heme oxygenase-1 (HO-1) mRNA and protein levels increased (23.0- and 5.1-fold, respectively) following MV. Thioredoxin reductase-1 and manganese superoxide dismutase mRNA levels were also increased in the diaphragm following MV (2.4- and 1.6-fold, respectively), although no change was detected in the levels of either protein. Furthermore, copper-zinc superoxide dismutase and glutathione peroxidase mRNA were not altered following MV, although protein content decreased -1.3- and -1.7-fold, respectively. We conclude that MV promotes increased oxidant production and impairment of key antioxidant defenses in the diaphragm; collectively, these changes contribute to the MV-induced oxidative stress in this key inspiratory muscle.