Current-dependent ocular tilt reaction in deep brain stimulation of the subthalamic nucleus: Evidence for an incerto-interstitial pathway?

BACKGROUND AND PURPOSE: The aim was to characterize a combined vestibular, ocular motor and postural syndrome induced by deep brain stimulation (DBS) of the subthalamic nucleus in a patient with Parkinson's disease. METHODS: In a systematic DBS programming session, eye, head and trunk position in roll and pitch plane were documented as a function of stimulation amplitude and field direction. Repeat ocular coherence tomography was used to estimate ocular torsion. The interstitial nucleus of Cajal (INC), zona incerta (ZI) and ascending vestibular fibre tracts were segmented on magnetic resonance imaging using both individual and normative structural connectomic data. Thresholded symptom-associated volumes of tissue activated (VTA) were calculated based on documented stimulation parameters. RESULTS: Ipsilateral ocular tilt reaction and body lateropulsion as well as contralateral torsional nystagmus were elicited by the right electrode in a current-dependent manner and subsided after DBS deactivation. With increasing currents, binocular tonic upgaze and body retropulsion were observed. Symptoms were consistent with an irritative effect on the INC. Symptom-associated VTA was found to overlap with the dorsal ZI and the ipsilateral vestibulothalamic tract, while lying rather distant to the INC proper. A ZI-to-INC 'incerto-interstitial' tract with contact to the medial-uppermost portion of the VTA could be traced. CONCLUSION: Unilateral stimulation of INC-related circuitry induces an ipsilateral vestibular, ocular motor and postural roll-plane syndrome, which converts into a pitch-plane syndrome when functional activation expands bilaterally. In this case, tractography points to an incerto-interstitial pathway, a tract previously only characterized in non-human primates. Directional current steering proved useful in managing this rare side effect.

German S3 Guideline: Oxygen Therapy in the Acute Care of Adult Patients.

BACKGROUND: Oxygen (O2) is a drug with specific biochemical and physiological properties, a range of effective doses and may have side effects. In 2015, 14% of over 55,000 hospital patients in the UK were using oxygen. 42% of patients received this supplemental oxygen without a valid prescription. Health care professionals are frequently uncertain about the relevance of hypoxemia and have low awareness about the risks of hyperoxemia. Numerous randomized controlled trials about targets of oxygen therapy have been published in recent years. A national guideline is urgently needed. METHODS: A national S3 guideline was developed and published within the Program for National Disease Management Guidelines (AWMF) with participation of 10 medical associations. A literature search was performed until February 1, 2021, to answer 10 key questions. The Oxford Centre for Evidence-Based Medicine (CEBM) System ("The Oxford 2011 Levels of Evidence") was used to classify types of studies in terms of validity. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for assessing the quality of evidence and for grading guideline recommendation, and a formal consensus-building process was performed. RESULTS: The guideline includes 34 evidence-based recommendations about indications, prescription, monitoring and discontinuation of oxygen therapy in acute care. The main indication for O2 therapy is hypoxemia. In acute care both hypoxemia and hyperoxemia should be avoided. Hyperoxemia also seems to be associated with increased mortality, especially in patients with hypercapnia. The guideline provides recommended target oxygen saturation for acute medicine without differentiating between diagnoses. Target ranges for oxygen saturation are based depending on ventilation status risk for hypercapnia. The guideline provides an overview of available oxygen delivery systems and includes recommendations for their selection based on patient safety and comfort. CONCLUSION: This is the first national guideline on the use of oxygen in acute care. It addresses health care professionals using oxygen in acute out-of-hospital and in-hospital settings.

[German S3 Guideline - Oxygen Therapy in the Acute Care of Adult Patients]. / S3-Leitlinie Sauerstoff in der Akuttherapie beim Erwachsenen.

BACKGROUND: Oxygen (O2) is a drug with specific biochemical and physiologic properties, a range of effective doses and may have side effects. In 2015, 14 % of over 55 000 hospital patients in the UK were using oxygen. 42 % of patients received this supplemental oxygen without a valid prescription. Healthcare professionals are frequently uncertain about the relevance of hypoxemia and have low awareness about the risks of hyperoxemia. Numerous randomized controlled trials about targets of oxygen therapy have been published in recent years. A national guideline is urgently needed. METHODS: A S3-guideline was developed and published within the Program for National Disease Management Guidelines (AWMF) with participation of 10 medical associations. Literature search was performed until Feb 1st 2021 to answer 10 key questions. The Oxford Centre for Evidence-Based Medicine (CEBM) System ("The Oxford 2011 Levels of Evidence") was used to classify types of studies in terms of validity. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used and for assessing the quality of evidence and for grading guideline recommendation and a formal consensus-building process was performed. RESULTS: The guideline includes 34 evidence-based recommendations about indications, prescription, monitoring and discontinuation of oxygen therapy in acute care. The main indication for O2 therapy is hypoxemia. In acute care both hypoxemia and hyperoxemia should be avoided. Hyperoxemia also seems to be associated with increased mortality, especially in patients with hypercapnia. The guideline provides recommended target oxygen saturation for acute medicine without differentiating between diagnoses. Target ranges for oxygen saturation are depending on ventilation status risk for hypercapnia. The guideline provides an overview of available oxygen delivery systems and includes recommendations for their selection based on patient safety and comfort. CONCLUSION: This is the first national guideline on the use of oxygen in acute care. It addresses healthcare professionals using oxygen in acute out-of-hospital and in-hospital settings. The guideline will be valid for 3 years until June 30, 2024.

Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?

Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.

Longitudinal Assessment of Rotation Angles after Implantation of Directional Deep Brain Stimulation Leads.

PURPOSE: The risk/benefit-ratio of deep brain stimulation (DBS) depends on focusing the electrical field onto the target volume, excluding side-effect eliciting structures. Directional leads limiting radial current diffusion can target stimulation but add a spatial degree of freedom that requires control to align multimodal imaging datasets and for anatomical interpretation of stimulation. Unpredictable postoperative lead rotations have been reported. The extent and timing of rotation from the surgically intended alignment remain uncertain, as does the time point at which directional stimulation can be safely initiated without risking unexpected shifts in stimulation volume. We present a retrospective analysis of clinically indicated, repeated neuroimaging controls postimplantation in patients with directional DBS systems, which allow estimation of the amount and timing of postoperative lead rotation. METHODS: Data from 67 patients with directional leads and multiple cranial computer tomographies (CCT) and/or rotation fluoroscopies at different postoperative time points were included. Rotation angles were detected based on CCT artifacts (n = 56) or direct visualization of lead segments on rotation fluoroscopies (n = 52). Cross-validation of both methods was conducted in patients who received both imaging modalities (n = 51). RESULTS: Rotation angles deviated significantly (∼30°) from their intended 0° anterior/posterior orientation. Rotation was firmly established within the first postoperative day, with no additional torque in subsequent scans. The two methods highly correlated (right hemisphere: R2 = 0.94, left hemisphere: R2 = 0.91). CONCLUSION: Both methods for measuring rotation angles led to comparable results and can be used interchangeably. Directional stimulation settings can safely be initiated after the first postoperative day, without risking subsequent lead rotation-related anatomical shifts.

Impaired differentiation of human induced neural stem cells by TOR1A overexpression.

DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.

Visualizing the Synaptic and Cellular Ultrastructure in Neurons Differentiated from Human Induced Neural Stem Cells-An Optimized Protocol.

The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures.

Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism.

BACKGROUND: The most likely genetic cause of X-linked dystonia-parkinsonism, a neurodegenerative movement disorder endemic to the Philippines, is a 2672-bp-long retrotransposon insertion in intron 32 of the TAF1 gene. The objectives of this study were to investigate whether (1) TAF1 expression is altered in induced pluripotent stem cells and differentiated neuronal models and (2) excision of the retrotransposon insertion restores normal TAF1 expression. METHODS: Expression of TAF1 and its neuronal isoform were determined in induced pluripotent stem cells and in induced pluripotent stem cell-derived cortical neurons and spiny projection neurons using quantitative PCR. Genome editing-based excision of the retrotransposon insertion was performed on induced pluripotent stem cells from 3 X-linked dystonia-parkinsonism patients. Edited and unedited induced pluripotent stem cells from X-linked dystonia-parkinsonism patients and controls were differentiated into cortical neurons and spiny projection neurons, and TAF1 expression was compared across groups. RESULTS: TAF1 was reduced in patient-derived induced pluripotent stem cells (P < 0.05) and spiny projection neurons (P < 0.01). After genome editing, we observed higher TAF1 expression in edited compared with unedited induced pluripotent stem cells (P < 0.0001). In edited spiny projection neurons, TAF1 expression was also increased, but did not reach statistical significance. No expression differences were observed in cortical neurons. CONCLUSIONS: (1) TAF1 reduction in X-linked dystonia-parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X-linked dystonia-parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome-edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases. © 2018 International Parkinson and Movement Disorder Society.

EIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts.

BACKGROUND: Missense mutations in the eukaryotic translation initiation factor 4-γ 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings. METHODS: We assessed the relevance of EIF4G1 mutations in a European cohort of 2146 PD patients. Of these, 2051 sporadic PD patients were screened for the reported p.Ala502Val and p.Arg1205His mutations. In addition, the complete coding region of EIF4G1 was directly sequenced in 95 familial PD patients with autosomal-dominant inheritance. Moreover, we imputed the p.Arg1205His substitution and tested for association with PD in the Icelandic population (93 698 samples). RESULTS: We did not observe the presence of the p.Ala502Val substitution in our cohort; however, the p.Arg1205His mutation was identified in one sporadic PD patient. The same mutation was also found in 76 Icelandic subjects older than 65 years using haplotype imputing. Only five of these subjects reported PD symptoms (OR 1.3, p=0.50). Thus, if causal, the p.Arg1205His EIF4G1 mutation has a low penetrance or a late onset manifestation. A novel variant p.Arg566Cys found in a patient with familial PD did not cosegregate with PD in all three affected siblings. All further recently published EIF4G1 mutations found in our cohort are likely to be benign polymorphisms. CONCLUSIONS: This is the largest genetic study of EIF4G1 mutations in PD. Our data do not support the EIF4G1 gene as a high-risk PD locus, neither for the familial nor the sporadic condition. Furthermore, the p.Arg1205His mutation is not significantly associated with increased risk of PD in the Icelandic population. Therefore, caution should be exercised when interpreting EIF4G1 genotyping results in isolated patients and PD families. In summary, diagnostic testing of EIF4G1 should not be recommended in clinical settings.

Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations.

A three-nucleotide (GAG) deletion (ΔE) in TorsinA (TOR1A) has been identified as the most common cause of dominantly inherited early-onset torsion dystonia (DYT1). TOR1A encodes a chaperone-like AAA+-protein localized in the endoplasmic reticulum. Currently, only three additional, likely mutations have been reported in single dystonia patients. Here, we report two new, putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wild-type (WT) protein and two known mutations (ΔE and p.R288Q). While inclusion formation is a characteristic feature for ΔE TOR1A, elevated levels of aggregates for other mutations were not observed when compared with WT TOR1A. WT and mutant TOR1A showed preferred degradation through the autophagy-lysosome pathway, which is most pronounced for p.A14_P15del, p.R288Q, and ΔE TOR1A. Notably, blocking of the autophagy pathway with bafilomycin resulted in a significant increase in inclusion formation in p.E121K TOR1A. In addition, all variants had an influence on protein stability. Although the p.A14_P15del mutation affects the proposed oligomerization domain of TOR1A, this mutation did not disturb the ability to dimerize. Our findings demonstrate functional changes for all four mutations on different levels. Thus, both diagnostic and research genetic screening of dystonia patients should not be limited to testing for the ∆E mutation.

Pallidal Recordings in Chronically Implanted Dystonic Patients: Mitigation of Tremor-Related Artifacts.

Low-frequency oscillatory patterns of pallidal local field potentials (LFPs) have been proposed as a physiomarker for dystonia and hold the promise for personalized adaptive deep brain stimulation. Head tremor, a low-frequency involuntary rhythmic movement typical of cervical dystonia, may cause movement artifacts in LFP signals, compromising the reliability of low-frequency oscillations as biomarkers for adaptive neurostimulation. We investigated chronic pallidal LFPs with the PerceptTM PC (Medtronic PLC) device in eight subjects with dystonia (five with head tremors). We applied a multiple regression approach to pallidal LFPs in patients with head tremors using kinematic information measured with an inertial measurement unit (IMU) and an electromyographic signal (EMG). With IMU regression, we found tremor contamination in all subjects, whereas EMG regression identified it in only three out of five. IMU regression was also superior to EMG regression in removing tremor-related artifacts and resulted in a significant power reduction, especially in the theta-alpha band. Pallido-muscular coherence was affected by a head tremor and disappeared after IMU regression. Our results show that the Percept PC can record low-frequency oscillations but also reveal spectral contamination due to movement artifacts. IMU regression can identify such artifact contamination and be a suitable tool for its removal.

Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson's disease: A comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. OBJECTIVE: To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. METHODS: We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). RESULTS: All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). CONCLUSION: Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.

Extrahepatic portosystemic shunts as an unusual but treatable cause of hyperammonemic encephalopathy in a noncirrhotic patient - a case report.

We report a case of hyperammonemic encephalopathy due to extrahepatic portosystemic shunts in a noncirrhotic patient. A 79-year-old woman suffered from episodic confusion, disorientation, dysphasia and fluctuating level of consciousness. Electroencephalography (EEG) showed encephalopathic changes and serum levels of ammonia were elevated. Further investigation revealed mesenterorenal and mesenterocaval shunts, which had possibly evolved after pancreatic surgery 5 years ago. After shunt obliteration, the symptoms completely resolved, ammonia levels dropped to the normal range and EEG findings normalized. Clinicians should be aware of this rare but treatable cause of encephalopathy in noncirrhotic patients.

[Oxygen in the acute care of adults : Short version of the German S3 guideline]. / Sauerstoff in der Akuttherapie beim Erwachsenen : Kurzversion der S3-Leitlinie.

BACKGROUND: Oxygen is a drug with specific properties, a defined dose-effect range and side effects. In 2015, in a sample of UK hospital patients, 14% were treated with oxygen, of which only 42% had a prescription. Health care workers are often uncertain about the relevance of hypoxemia, and there is limited awareness of the risks of hyperoxemia. Numerous randomized controlled trials on oxygen therapy have recently been published. METHODS: As part of the guideline program of the Working Group of Scientific Medical Societies e. V. (AWMF), this S3 guideline was developed with the participation of 10 medical societies on the basis of a literature search up to 02/01/2021. The system of the Oxford Centre for Evidence-Based Medicine (CEBM) (The Oxford 2011 Levels of Evidence) was used to evaluate the literature. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE), and a formal consensus process of recommendations was performed. RESULTS: The guideline contains 34 evidence-based recommendations on the indication, prescription, monitoring, and discontinuation of oxygen therapy in acute care. The indication for oxygen is mainly hypoxemia. Hypoxemia and hyperoxemia should be avoided, since both increase mortality. The guideline recommends target ranges of oxygen saturation for acute oxygen therapy without differentiating between different diagnoses. Target areas depend on the risk for hypercapnia and ventilation status. The guideline provides an overview of available oxygen delivery systems and contains recommendations for their selection based on patient safety and comfort. CONCLUSION: This is the first German guideline on the use of oxygen in acute care. It is aimed at medical professionals who use oxygen in and outside hospitals and is valid until June 30th, 2024.

Ventral Telencephalic Patterning Protocols for Induced Pluripotent Stem Cells.

The differentiation of human induced pluripotent stem cells (hiPSCs) into specific cell types for disease modeling and restorative therapies is a key research agenda and offers the possibility to obtain patient-specific cells of interest for a wide range of diseases. Basal forebrain cholinergic neurons (BFCNs) play a particular role in the pathophysiology of Alzheimer's dementia and isolated dystonias. In this work, various directed differentiation protocols based on monolayer neural induction were tested for their effectiveness in promoting a ventral telencephalic phenotype and generating BFCN. Ventralizing factors [i.e., purmorphamine and Sonic hedgehog (SHH)] were applied at different time points, time intervals, and concentrations. In addition, caudal identity was prevented by the use of a small molecule XAV-939 that inhibits the Wnt-pathway. After patterning, gene expression profiles were analyzed by quantitative PCR (qPCR). Rostro-ventral patterning is most effective when initiated simultaneously with neural induction. The most promising combination of patterning factors was 0.5 µM of purmorphamine and 1 µM of XAV-939, which induces the highest expression of transcription factors specific for the medial ganglionic eminence, the source of GABAergic inter- and cholinergic neurons in the telencephalon. Upon maturation of cells, the immune phenotype, as well as electrophysiological properties were investigated showing the presence of marker proteins specific for BFCN (choline acetyltransferase, ISL1, p75, and NKX2.1) and GABAergic neurons. Moreover, a considerable fraction of measured cells displayed mature electrophysiological properties. Synaptic boutons containing the vesicular acetylcholine transporter (VACHT) could be observed in the vicinity of the cells. This work will help to generate basal forebrain interneurons from hiPSCs, providing a promising platform for modeling neurological diseases, such as Alzheimer's disease or Dystonia.

Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming.

Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model. Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated. Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82%, ABP: 88.6 ± 29.0%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32). Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.

Towards adaptive deep brain stimulation: clinical and technical notes on a novel commercial device for chronic brain sensing.

Objective. Technical advances in deep brain stimulation (DBS) are crucial to improve therapeutic efficacy and battery life. We report the potentialities and pitfalls of one of the first commercially available devices capable of recording brain local field potentials (LFPs) from the implanted DBS leads, chronically and during stimulation. The aim was to provide clinicians with well-grounded tips on how to maximize the capabilities of this novel device, both in everyday practice and for research purposes.Approach. We collected clinical and neurophysiological data of the first 20 patients (14 with Parkinson's disease (PD), five with dystonia, one with chronic pain) that received the Percept™ PC in our centres. We also performed tests in a saline bath to validate the recordings quality.Main results. The Percept PC reliably recorded the LFP of the implanted site, wirelessly and in real time. We recorded the most promising clinically useful biomarkers for PD and dystonia (beta and theta oscillations) with and without stimulation. Furthermore, we provide an open-source code to facilitate export and analysis of data. Critical aspects of the system are presently related to contact selection, artefact detection, data loss, and synchronization with other devices.Significance. New technologies will soon allow closed-loop neuromodulation therapies, capable of adapting stimulation based on real-time symptom-specific and task-dependent input signals. However, technical aspects need to be considered to ensure reliable recordings. The critical use by a growing number of DBS experts will alert new users about the currently observed shortcomings and inform on how to overcome them.

Combined subthalamic and nucleus basalis of Meynert deep brain stimulation for Parkinson's disease with dementia (DEMPARK-DBS): protocol of a randomized, sham-controlled trial.

INTRODUCTION: Dementia in Parkinson's disease (PDD) is a common non-motor symptom of advanced disease, associated with pronounced neocortical cholinergic deficits due to neurodegeneration of the nucleus basalis of Meynert (NBM) and its cholinergic terminals. In advanced PD, patients often require advanced therapies such as infusion therapy or deep brain stimulation (DBS) to improve motor control. However, patients with associated dementia are commonly excluded from DBS because of potential deterioration of cognitive functions. Yet marked reductions in dopaminergic medication and the subsequent risk of side effects (e.g., cognitive decline, psychosis, delirium) suggest that critical re-consideration of DBS of the subthalamic nucleus (STN-DBS) for advanced stages of PD and PDD is worthwhile. In this Phase 1b study, we will provide STN-DBS to a cohort of PDD patients with severe motor fluctuations and combine two additional electrodes for augmentative neurostimulation of the NBM. METHODS: We aim to include 12 patients with mild-to-moderately severe PDD who fulfill indication criteria regarding motor symptoms for STN-DBS. Eligible patients will undergo implantation of a neurostimulation system with bilateral electrodes in both the STN and NBM. After 12 weeks of STN-DBS (visit 1/V1), participants will be randomized to receive either effective neurostimulation of the NBM (group 1) or sham stimulation of the NBM (group 2). NBM-DBS will be activated in all participants after 24 weeks of blinded treatment (visit 2/V2). The primary outcome will be the safety of combined bilateral STN- and NBM-DBS, determined by spontaneously-reported adverse events. Other outcome measures will comprise changes on scales evaluating cognition, activities of daily living functioning and clinical global impression, as well as motor functions, mood, behavior, caregiver burden and health economic aspects, and several domain-specific cognitive tests. Changes in scores (V1 - V2) for both treatment arms will undergo analysis of covariances, with baseline scores as covariates. PERSPECTIVE: The feasibility and safety of combined STN-NBM-DBS in patients with PDD will be assessed to determine whether additional NBM-DBS improves or slows the progression of cognitive decline. Positive results would provide a basic concept for future studies evaluating the efficacy of NBM-DBS in larger PDD cohorts. Indirectly, proof-of-safety of STN-DBS in PDD might influence patient selection for this standard treatment option in advanced PD. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT number): NCT02589925.

Modulation of androgen and estrogen receptor expression by antiepileptic drugs and steroids in hippocampus of patients with temporal lobe epilepsy.

PURPOSE: Many of the antiepileptic drugs (AED) used in therapy of temporal lobe epilepsy (TLE) are known as cytochrome P450 (CYP, P450) inducers. These AEDs are thought to modulate androgen and estrogen pathways in hippocampus, and therefore cause mental and reproductive disorders found in TLE patients. In the present study, we analyzed expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), and CYP3A in the hippocampus of TLE patients and in murine hippocampal cell line HN25.1. METHODS: Patients and cell lines had been treated with P450-inducing or noninducing AEDs, or with prednisolone, applied to prevent oedema formation prior to neurosurgical resection of the epileptic hippocampus. Human patient samples were analyzed by immunohistochemical approach, the HN25.1 cell line by quantitative RT-PCR, CAT reporter gene assay, and immunoblot. RESULTS: In both, humans and cell lines, the expression of testosterone metabolising CYP3A4 (human) or CYP3A11 (mouse) and AR was up-regulated when P450-inducing AEDs and/or prednisolone had been applied. AR responsive CAT reporter gene assay indicated an increase of AR-signalling after treatment of the HN25.1 cells with the P450-inducers phenytoin and carbamazepine. ERalpha expression was increased only by the P450-inducing AEDs, but not by prednisolone, which indicates that pathways different from CYP3A4/11 led to ERalpha enhancement. DISCUSSION: We conclude that P450-inducing AEDs influence AR expression and signalling in hippocampus most likely via CYP3A4/11-induction. The HN25.1 cell line holds promise to investigate the correlation between drug application and AR regulation, and to specifically address issues that are relevant to human TLE patients.

Single-Step Plasmid Based Reprogramming of Human Dermal Fibroblasts to Induced Neural Stem Cells.

Reprogramming of somatic cells to induced pluripotent stem cells (iPSC) and subsequent differentiation opened up the opportunity of deriving cell types in vitro which (like neurons) had a very restricted accessibility in the past. However, cell culture protocols for iPSC reprogramming, neural induction and differentiation tend to be labor and time intensive, costly and commonly depend on viral vector delivery. Single-step reprogramming to induced neural stem cells (iNSC) avoids many of the necessary intermediate steps of the aforementioned method but yields a cell type that proliferates over longer time spans and readily differentiates to mature neurons when required. Here we describe a plasmid based reprogramming protocol employing defined, commercially available components for induction and proliferation of iNSC, followed by a defined, small molecule based differentiation step toward mature neurons. The described method might be of particular interest for groups with limited resources and/or restricted access to higher biosafety level facilities required for viral transduction, but also for groups requiring a high throughput for dealing with large numbers of cell lines.