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Abstract Background Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington’s disease (HD). Objectives To identify stimulation-dependent effects on motor symptoms and to determine if these alterations are associated with the local impact of DBS on different pallidal parcellations. Methods We prospectively evaluated the effects of bilateral GPi-DBS within one year in 5 HD patients. We evaluated the effects of GPi-DBS on choreatic symptoms and UHDRS. Electrode placement in the pallidum was localized, and the local impact of DBS was estimated. Results The chorea subscore (p

Abstract Body weight gain in combination with metabolic alterations has been observed after deep brain stimulation (DBS) of subthalamic nucleus (STN) in patients with Parkinson’s disease (PD), which potentially counteracts the positive effects of motor improvement. We aimed to identify stimulation-dependent effects on motor activities, body weight, body composition, energy metabolism, and metabolic blood parameters and to determine if these alterations are associated with the local impact of DBS on different STN parcellations. We assessed 14 PD patients who underwent STN DBS (PD-DBS) before as well as 6- and 12-months post-surgery. For control purposes, 18 PD patients under best medical treatment (PD-CON) and 25 healthy controls (H-CON) were also enrolled. Wrist actigraphy, body composition, hormones, and energy expenditure measurements were applied. Electrode placement in the STN was localized, and the local impact of STN DBS was estimated. We found that STN DBS improved motor function by ~ 40% (DBS ON, Med ON). Weight and fat mass increased by ~ 3 kg and ~ 3% in PD-DBS (all P ≤ 0.005). fT3 (P = 0.001) and insulin levels (P = 0.048) increased solely in PD-DBS, whereas growth hormone levels (P = 0.001), daily physical activity, and VO2 during walking were decreased in PD-DBS (all P ≤ 0.002). DBS of the limbic part of the STN was associated with changes in weight and body composition, sedentary activity, insulin levels (all P ≤ 0.040; all r ≥ 0.56), and inversely related to HOMA-IR (P = 0.033; r = − 0.62). Daily physical activity is decreased after STN DBS, which can contribute to weight gain and an unfavorable metabolic profile. We recommend actigraphy devices to provide feedback on daily activities to achieve pre-defined activity goals.

Glioblastoma multiforme (GBM) and the GBM variant gliosarcoma (GS) are among the tumors with the highest morbidity and mortality, providing only palliation. Stem-like glioma cells (SLGCs) are involved in tumor initiation, progression, therapy resistance, and relapse. The identification of general features of SLGCs could contribute to the development of more efficient therapies. Commercially available protein arrays were used to determine the cell surface signature of eight SLGC lines from GBMs, one SLGC line obtained from a xenotransplanted GBM-derived SLGC line, and three SLGC lines from GSs. By means of non-negative matrix factorization expression metaprofiles were calculated. Using the cophenetic correlation coefficient (CCC) five metaprofiles (MPs) were identified, which are characterized by specific combinations of 7-12 factors. Furthermore, the expression of several factors, that are associated with GBM prognosis, GBM subtypes, SLGC differentiation stages, or neural identity was evaluated. The investigation encompassed 24 distinct SLGC lines, four of which were derived from xenotransplanted SLGCs, and included the SLGC lines characterized by the metaprofiles. It turned out that all SLGC lines expressed the epidermal growth factor EGFR and EGFR ligands, often in the presence of additional receptor tyrosine kinases. Moreover, all SLGC lines displayed a neural signature and the IDH1 wildtype, but differed in their p53 and PTEN status. Pearson Correlation analysis identified a positive association between the pluripotency factor Sox2 and the expression of FABP7, Musashi, CD133, GFAP, but not with MGMT or Hif1α. Spherical growth, however, was positively correlated with high levels of Hif1α, CDK4, PTEN, and PDGFRβ, whereas correlations with stemness factors or MGMT (MGMT expression and promoter methylation) were low or missing. Factors highly expressed by all SLGC lines, irrespective of their degree of stemness and growth behavior, are Cathepsin-D, CD99, EMMPRIN/CD147, Intβ1, the Galectins 3 and 3b, and N-Cadherin.

Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs.

PurposeIn brain tumor surgery, it is crucial to achieve complete tumor resection while conserving adjacent noncancerous brain tissue. Several groups have demonstrated that optical coherence tomography (OCT) has the potential of identifying tumorous brain tissue. However, there is little evidence on human in vivo application of this technology, especially regarding applicability and accuracy of residual tumor detection (RTD). In this study, we execute a systematic analysis of a microscope integrated OCT-system for this purpose.Experimental designMultiple 3-dimensional in vivo OCT-scans were taken at protocol-defined sites at the resection edge in 21 brain tumor patients. The system was evaluated for its intraoperative applicability. Tissue biopsies were obtained at these locations, labeled by a neuropathologist and used as ground truth for further analysis. OCT-scans were visually assessed with a qualitative classifier, optical OCT-properties were obtained and two artificial intelligence (AI)-assisted methods were used for automated scan classification. All approaches were investigated for accuracy of RTD and compared to common techniques.ResultsVisual OCT-scan classification correlated well with histopathological findings. Classification with measured OCT image-properties achieved a balanced accuracy of 85%. A neuronal network approach for scan feature recognition achieved 82% and an auto-encoder approach 85% balanced accuracy. Overall applicability showed need for improvement.ConclusionContactless in vivo OCT scanning has shown to achieve high values of accuracy for RTD, supporting what has well been described for ex vivo OCT brain tumor scanning, complementing current intraoperative techniques and even exceeding them in accuracy, while not yet in applicability.

Abstract Background Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates. Methods The PARS-trial is designed as a double-blinded, randomized, and placebo-controlled multi-center crossover study. It will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. The trial will recruit 60 patients suffering from intractable neuropathic pain of the lower extremities, who have been considered for SCS therapy and were already implanted with a wireless SCS device prior to study participation. Over a time period of 35 days, patients will be treated consecutively with three different SCS paradigms (“burst,” “1 kHz,” and “1.499 kHz”) and placebo stimulation. Each SCS paradigm will be applied for 5 days with a washout period of 70 h between stimulation cycles. The primary endpoint of the study is the level of pain self-assessment on the visual analogue scale after 5 days of SCS. Secondary, exploratory endpoints include self-assessment of pain quality (as determined by painDETECT questionnaire), quality of life (as determined by Quality of Life EQ-5D-5L questionnaire), anxiety perception (as determined by the Hospital Anxiety and Depression Scale), and physical restriction (as determined by the Oswestry Disability Index). Discussion Combining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients. This trial will advance our understanding of the clinical effectiveness of the most relevant SCS paradigms. Trial registration German Clinical Trials Register, DRKS00018929 . Registered on 14 January 2020.

Abstract Background Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. Methods A standardized monopolar review to identify the contact with the best acute antidystonic effect was applied in 40 patients, who were then programmed 0.5 V below the adverse effect threshold and maintained on these settings for at least 3 months, if tolerated. If no acute effects were observed, contact selection was based on adverse effects or anatomical criteria. Three-year follow-up data was available for 31 patients, and five-year data for 32 patients. The efficacy of the algorithm was based on changes in motor scores, adverse events, and the need for reprogramming. Results The mean (±standard deviation) dystonia motor score decreased by 73 ± 24% at 3 years and 63 ± 38% at 5 years for contacts that exhibited acute improvement of dystonia (n = 17) during the monopolar review. Contacts without acute benefit improved by 58 ± 30% at 3 years (n = 63) and 53 ± 31% at 5 years (n = 59). Interestingly, acute worsening or induction of dystonia/dyskinesia (n = 9) correlated significantly with improvement after 3 years, but not 5 years. Conclusions Monopolar review helped to detect the best therapeutic contact in approximately 30% of patients exhibiting acute modulation of dystonic symptoms. Acute improvement, as well as worsening of dystonia, predicted a good long-term outcome, while induction of phosphenes did not correlate with outcome. Trial registration ClinicalTrials.gov NCT00142259.

Abstract Case report  The reported female patient underwent sub-total resection of an intra-medullary cervicothoracic astrocytoma classified as WHO grade II in 1984 at the age of 18 months and received local irradiation. In 1989, a local recurrence was diagnosed and a partial resection was performed. Sixteen years later, a small recurrent cervicothoracic tumour was found and spinal seeding to the equine nerve roots and the left cerebellar cortex was apparent on MRI. The patient was implanted with a ventriculoperitoneal shunt for a pseudo-tumour cerebri producing papilloedema, which eventually lead to amaurosis. After an extended biopsy, the invasive lumbosacral tumour was classified as glioblastoma multiforme. Two months later, the patient died after rapid progression of the caudal cranial nerve dysfunction. Discussion and conclusion  Anaplastic progression and dissemination of spinal astrocytomas even two decades after initial diagnosis and treatment are rare. Therapies and diagnostic follow-up strategies are discussed. [ABSTRACT FROM AUTHOR]