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IntroductionThe complexity of brain signals may hold clues to understand brain-based disorders. Sample entropy, an index that captures the predictability of a signal, is a promising tool to measure signal complexity. However, measurement of sample entropy from fMRI signals has its challenges, and numerous questions regarding preprocessing and parameter selection require research to advance the potential impact of this method. For one example, entropy may be highly sensitive to the effects of motion, yet standard approaches to addressing motion (e.g., scrubbing) may be unsuitable for entropy measurement. For another, the parameters used to calculate entropy need to be defined by the properties of data being analyzed, an issue that has frequently been ignored in fMRI research. The current work sought to rigorously address these issues and to create methods that could be used to advance this field.MethodsWe developed and tested a novel windowing approach to select and concatenate (ignoring connecting volumes) low-motion windows in fMRI data to reduce the impact of motion on sample entropy estimates. We created utilities (implementing autoregressive models and a grid search function) to facilitate selection of the matching length m parameter and the error tolerance r parameter. We developed an approach to apply these methods at every grayordinate of the brain, creating a whole-brain dense entropy map. These methods and tools have been integrated into a publicly available R package (“powseR”). We demonstrate these methods using data from the ABCD study. After applying the windowing procedure to allow sample entropy calculation on the lowest-motion windows from runs 1 and 2 (combined) and those from runs 3 and 4 (combined), we identified the optimal m and r parameters for these data. To confirm the impact of the windowing procedure, we compared entropy values and their relationship with motion when entropy was calculated using the full set of data vs. those calculated using the windowing procedure. We then assessed reproducibility of sample entropy calculations using the windowed procedure by calculating the intraclass correlation between the earlier and later entropy measurements at every grayordinate.ResultsWhen applying these optimized methods to the ABCD data (from the subset of individuals who had enough windows of continuous “usable” volumes), we found that the novel windowing procedure successfully mitigated the large inverse correlation between entropy values and head motion seen when using a standard approach. Furthermore, using the windowed approach, entropy values calculated early in the scan (runs 1 and 2) are largely reproducible when measured later in the scan (runs 3 and 4), although there is some regional variability in reproducibility.DiscussionWe developed an optimized approach to measuring sample entropy that addresses concerns about motion and that can be applied across datasets through user-identified adaptations that allow the method to be tailored to the dataset at hand. We offer preliminary results regarding reproducibility. We also include recommendations for fMRI data acquisition to optimize sample entropy measurement and considerations for the field.

Abstract Background Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. Methods The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5 to 5 year olds with FASD. Participants in this long-term follow-up study include 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11.0 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up included measures of executive functioning and an MRI scan. Results Children who received choline had better performance on several tasks of lower-order executive function (e.g., processing speed) and showed higher white matter microstructure organization (i.e., greater axon coherence) in the splenium of the corpus callosum compared to the placebo group. Conclusions These preliminary findings, although exploratory at this stage, highlight potential long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that choline may affect white matter development, representing a potential target of choline in this population. Trial registration Prior to enrollment, this trial was registered with clinicaltrials.gov ( NCT01149538 ) on June 23, 2010.

IntroductionFetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest trajectories of white matter microstructure maturation are atypical in PAE. We aimed to further characterize longitudinal trajectories of developmental white matter microstructure change in children and adolescents with PAE compared to typically-developing Controls using diffusion-weighted Neurite Orientation Dispersion and Density Imaging (NODDI).Materials and methodsParticipants: Youth with PAE (n = 34) and typically-developing Controls (n = 31) ages 8–17 years at enrollment. Participants underwent formal evaluation of growth and facial dysmorphology. Participants also completed two study visits (17 months apart on average), both of which involved cognitive testing and an MRI scan (data collected on a Siemens Prisma 3 T scanner). Age-related changes in the orientation dispersion index (ODI) and the neurite density index (NDI) were examined across five corpus callosum (CC) regions defined by tractography.ResultsWhile linear trajectories suggested similar overall microstructural integrity in PAE and Controls, analyses of symmetrized percent change (SPC) indicated group differences in the timing and magnitude of age-related increases in ODI (indexing the bending and fanning of axons) in the central region of the CC, with PAE participants demonstrating atypically steep increases in dispersion with age compared to Controls. Participants with PAE also demonstrated greater increases in ODI in the mid posterior CC (trend-level group difference). In addition, SPC in ODI and NDI was differentially correlated with executive function performance for PAE participants and Controls, suggesting an atypical relationship between white matter microstructure maturation and cognitive function in PAE.DiscussionPreliminary findings suggest subtle atypicality in the timing and magnitude of age-related white matter microstructure maturation in PAE compared to typically-developing Controls. These findings add to the existing literature on neurodevelopmental trajectories in PAE and suggest that advanced biophysical diffusion modeling (NODDI) may be sensitive to biologically-meaningful microstructural changes in the CC that are disrupted by PAE. Findings of atypical brain maturation-behavior relationships in PAE highlight the need for further study. Further longitudinal research aimed at characterizing white matter neurodevelopmental trajectories in PAE will be important.

Purpose: The childhood-to-adolescence transition is a notable period of change including pubertal development, neurodevelopment, and psychopathology onset, that occurs in divergent patterns between sexes. This study examined the effects of sex and puberty on cortical thickness (CT) in children and explored whether CT changes over time related to emergence of psychopathology in early adolescence. Methods: We used longitudinal data (baseline ages 9–10 and Year 2 [Y2] ages 11–12) from the ABCD Study (n = 9985). Linear and penalized function-on-function regressions modeled the impact of puberty, as it interacts with sex, on CT. Focusing on regions that showed sex differences, linear and logistic regressions modeled associations between change in CT and internalizing problems and suicide ideation. Results: We identified significant sex differences in the inverse relation between puberty and CT in fifteen primarily posterior brain regions. Nonlinear pubertal effects across age were identified in the fusiform, isthmus cingulate, paracentral, and precuneus. All effects were stronger for females relative to males during this developmental window. We did not identify associations between CT change and early adolescent clinical outcomes. Conclusion: During this age range, puberty is most strongly associated with regional changes in CT in females, which may have implications for the later emergence of psychopathology.

Background: Deep brain stimulation (DBS) is an invasive treatment option for patients with Parkinson's disease. Recently, adaptive DBS (aDBS) systems have been developed, which adjust stimulation timing and amplitude in real-time. However, it is unknown how changes in parameters, movement states and the controllability of subthalamic beta activity affect aDBS performance., Objective: To characterize how parameter choice, movement state and controllability interactively affect the electrophysiological and behavioral response to single threshold aDBS., Methods: We recorded subthalamic local field potentials in 12 patients with Parkinson's disease receiving single threshold aDBS in the acute post-operative state. We investigated changes in two aDBS parameters: the onset time and the smoothing of real-time beta power. Electrophysiological patterns and motor performance were assessed while patients were at rest and during a simple motor task. We further studied the impact of controllability on aDBS performance by comparing patients with and without beta power modulation during continuous stimulation., Results: Our findings reveal that changes in the onset time control the extent of beta power suppression achievable with single threshold adaptive stimulation during rest. Behavioral data indicate that only specific parameter combinations yield a beneficial effect of single threshold aDBS. During movement, action induced beta power suppression reduces the responsivity of the closed loop algorithm. We further demonstrate that controllability of beta power is a prerequisite for effective parameter dependent modulation of subthalamic beta activity., Conclusion: Our results highlight the interaction between single threshold aDBS parameter selection, movement state and controllability in driving subthalamic beta activity and motor performance. By this means, we identify directions for the further development of closed-loop DBS algorithms., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JR has received speaker honoraria from Medtronic outside of this work. GHS has received honoraria from Medtronic and Boston Scientific outside of this work. WJN has received speaker honoraria from Medtronic outside of this work. AAK has served on advisory boards of Medtronic and has received honoraria and travel support from Medtronic and Boston Scientific outside of this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) is an effective treatment option for patients with Parkinson's disease (PD). However, clinical programming remains challenging with segmented electrodes., Objective: Using novel sensing-enabled neurostimulators, we investigated local field potentials (LFPs) and their modulation by DBS to assess whether electrophysiological biomarkers may facilitate clinical programming in chronically implanted patients., Methods: Sixteen patients (31 hemispheres) with PD implanted with segmented electrodes in the subthalamic nucleus and a sensing-enabled neurostimulator were included in this study. Recordings were conducted 3 months after DBS surgery following overnight withdrawal of dopaminergic medication. LFPs were acquired while stimulation was turned OFF and during a monopolar review of both directional and ring contacts. Directional beta power and stimulation-induced beta power suppression were computed. Motor performance, as assessed by a pronation-supination task, clinical programming and electrode placement were correlated to directional beta power and stimulation-induced beta power suppression., Results: Better motor performance was associated with stronger beta power suppression at higher stimulation amplitudes. Across directional contacts, differences in directional beta power and the extent of stimulation-induced beta power suppression predicted motor performance. However, within individual hemispheres, beta power suppression was superior to directional beta power in selecting the contact with the best motor performance. Contacts clinically activated for chronic stimulation were associated with stronger beta power suppression than non-activated contacts., Conclusions: Our results suggest that stimulation-induced β power suppression is superior to directional β power in selecting the clinically most effective contact. In sum, electrophysiological biomarkers may guide programming of directional DBS systems in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Systematic studies 1-4 have revealed hundreds of ultra-compact dwarf galaxies (UCDs 5 ) in the nearby Universe. With half-light radii r h of approximately 10-100 parsecs and stellar masses M *  ≈ 10 6 -10 8  solar masses, UCDs are among the densest known stellar systems 6 . Although similar in appearance to massive globular clusters 7 , the detection of extended stellar envelopes 4,8,9 , complex star formation histories 10 , elevated mass-to-light ratio 11,12 and supermassive black holes 13-16 suggest that some UCDs are remnant nuclear star clusters 17 of tidally stripped dwarf galaxies 18,19 , or even ancient compact galaxies 20 . However, only a few objects have been found in the transient stage of tidal stripping 21,22 , and this assumed evolutionary path 19 has never been fully traced by observations. Here we show that 106 galaxies in the Virgo cluster have morphologies that are intermediate between normal, nucleated dwarf galaxies and single-component UCDs, revealing a continuum that fully maps this morphological transition and fills the 'size gap' between star clusters and galaxies. Their spatial distribution and redder colour are also consistent with stripped satellite galaxies on their first few pericentric passages around massive galaxies 23 . The 'ultra-diffuse' tidal features around several of these galaxies directly show how UCDs are forming through tidal stripping and that this evolutionary path can include an early phase as a nucleated ultra-diffuse galaxy 24,25 . These UCDs represent substantial visible fossil remnants of ancient dwarf galaxies in galaxy clusters, and more low-mass remnants probably remain to be found., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Bradykinesia is a cardinal hallmark of Parkinson's disease (PD). Improvement in bradykinesia is an important signature of effective treatment. Finger tapping is commonly used to index bradykinesia, albeit these approaches largely rely on subjective clinical evaluations. Moreover, recently developed automated bradykinesia scoring tools are proprietary and are not suitable for capturing intraday symptom fluctuation. We assessed finger tapping (i.e., Unified Parkinson's Disease Rating Scale (UPDRS) item 3.4) in 37 people with Parkinson's disease (PwP) during routine treatment follow ups and analyzed their 350 sessions of 10-s tapping using index finger accelerometry. Herein, we developed and validated ReTap, an open-source tool for the automated prediction of finger tapping scores. ReTap successfully detected tapping blocks in over 94% of cases and extracted clinically relevant kinematic features per tap. Importantly, based on the kinematic features, ReTap predicted expert-rated UPDRS scores significantly better than chance in a hold out validation sample (n = 102). Moreover, ReTap-predicted UPDRS scores correlated positively with expert ratings in over 70% of the individual subjects in the holdout dataset. ReTap has the potential to provide accessible and reliable finger tapping scores, either in the clinic or at home, and may contribute to open-source and detailed analyses of bradykinesia.

Background: Subthalamic nucleus (STN) beta (13 - 35 Hz) activity is a biomarker reflecting motor state in Parkinson's disease (PD). Adaptive deep brain stimulation (DBS) aims to use beta activity for therapeutic adjustments, but many aspects of beta activity in real-life situations are unknown., Objective: The aim was to investigate Christmas-related influences on beta activity in PD., Methods: Differences in Christmas Day to nonfestive daily averages in chronic biomarker recordings in 4 PD patients with a sensing-enabled STN DBS implant were retrospectively analyzed. Sweet-spot and whole-brain network connectomic analyses were performed., Results: Beta activity was significantly reduced on Christmas Eve in all patients (4.00-9.00 p.m.: -12.30 ± 10.78%, P = 0.015). A sweet spot in the dorsolateral STN connected recording sites to motor, premotor, and supplementary motor cortices., Conclusions: We demonstrate that festive events can reduce beta biomarker activity. We conclude that circadian and holiday-related changes should be considered when tailoring adaptive DBS algorithms to patient demands. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in controlling motor symptoms in patients with Parkinson's disease. However, correct selection of stimulation parameters is pivotal to treatment success and currently follows a time-consuming and demanding trial-and-error process. We aimed to assess treatment effects of stimulation parameters suggested by a recently published algorithm (StimFit) based on neuroimaging data., Methods: This double-blind, randomised, crossover, non-inferiority trial was carried out at Charité - Universitätsmedizin, Berlin, Germany, and enrolled patients with Parkinson's disease treated with directional octopolar electrodes targeted at the STN. All patients had undergone DBS programming according to our centre's standard of care (SoC) treatment before study recruitment. Based on perioperative imaging data, DBS electrodes were reconstructed and StimFit was applied to suggest optimal stimulation settings. Patients underwent motor assessments using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) during OFF-medication and in OFF-stimulation and ON-stimulation states under both conditions, StimFit and SoC parameter settings. Patients were randomly assigned (1:1) to receive either StimFit-programmed DBS first and SoC-programmed DBS second, or SoC-programmed DBS first and StimFit-programmed DBS second. The allocation schedule was generated using a computerised random number generator. Both the rater and patients were masked to the sequence of SoC and StimFit stimulation conditions. All patients who participated in the study were included in the analysis. The primary endpoint of this study was the absolute mean difference between MDS-UPDRS-III scores under StimFit and SoC stimulation, with a non-inferiority margin of 5 points. The study was registered at the German Register for Clinical Trials (DRKS00023115), and is complete., Findings: Between July 10, 2020, and Oct 28, 2021, 35 patients were enrolled in the study; 18 received StimFit followed by SoC stimulation, and 17 received SoC followed by StimFit stimulation. Mean MDS-UPDRS-III scores improved from 47·3 (SD 17·1) at OFF-stimulation baseline to 24·7 (SD 12·4) and 26·3 (SD 12·4) under SoC and StimFit stimulation, respectively. Mean difference between motor scores was -1·6 (SD 7·1; 95% CI -4·0 to 0·9; superiority test p superiority =0·20; n=35), establishing non-inferiority of StimFit stimulation at a margin of -5 points (non-inferiority test p non-inferiority =0·0038). In six patients (17%), initial programming of StimFit settings resulted in acute side-effects and amplitudes were reduced until side-effects disappeared., Interpretation: Automated data-driven algorithms can predict stimulation parameters that lead to motor symptom control comparable to SoC treatment. This approach could significantly decrease the time necessary to obtain optimal treatment parameters., Funding: Deutsche Forschungsgemeinschaft through NeuroCure Clinical Research Center and TRR 295., Competing Interests: Declaration of interests JR received speaker honoraria from Medtronic. TAD has received grants from the German Research Foundation (Cologne Clinician Scientist Program, FI 773/15-1) and received speaker honoraria from Medtronic and Boston Scientific. PK received speaker honoraria from Stadapharm. G-HS received Speaker honoraria from Medtronic, Boston Scientific, and Abbott. AH has received grants from the German Research Foundation (Emmy Noether Stipend 410169619 and Transregio CRC 424778381—TRR 295) as well as the German Aerospace Center, the National Institutes of Health (2R01 MH113929), and the Foundation for OCD Research (FFOR). AAK has received grants from the German Research Foundation (Transregio CRC 424778381—TRR 295) and the Lunbeck Foundation. AAK is on the advisory board of Boston Scientific and Medtronic and has received honoraria from Boston Scientific, Medtronic, Zambon, and Stadapharm. JA, JLB, A-PK, and KF declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The contribution of adaptive vs. innate lymphocytes to IL-17A and IL-22 secretion at the end stage of chronic lung diseases remains largely unexplored. In order to uncover tissue- and disease-specific secretion patterns, we compared production patterns of IL-17A and IL-22 in three different human end-stage lung disease entities., Methods: Production of IL-17A, IL-22 and associated cytokines was assessed in supernatants of re-stimulated lymphocytes by multiplex assays and multicolour flow cytometry of conventional T cells, iNKT cells, γδ T cells and innate lymphoid cells in bronchial lymph node and lung tissue from patients with emphysema ( n  = 19), idiopathic pulmonary fibrosis ( n  = 14) and cystic fibrosis ( n  = 23), as well as lung donors ( n  = 17)., Results: We detected secretion of IL-17A and IL-22 by CD4 + T cells, CD8 + T cells, innate lymphoid cells, γδ T cells and iNKT cells in all end-stage lung disease entities. Our analyses revealed disease-specific contributions of individual lymphocyte subpopulations to cytokine secretion patterns. We furthermore found the high levels of microbial detection in CF samples to associate with a more pronounced IL-17A signature upon antigen-specific and unspecific re-stimulation compared to other disease entities and lung donors., Conclusion: Our results show that both adaptive and innate lymphocyte populations contribute to IL-17A-dependent pathologies in different end-stage lung disease entities, where they establish an IL-17A-rich microenvironment. Microbial colonisation patterns and cytokine secretion upon microbial re-stimulation suggest that pathogens drive IL-17A secretion patterns in end-stage lung disease., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Deep brain stimulation (DBS) electrode implant trajectories are stereotactically defined using preoperative neuroimaging. To validate the correct trajectory, microelectrode recordings (MERs) or local field potential recordings can be used to extend neuroanatomical information (defined by MRI) with neurophysiological activity patterns recorded from micro- and macroelectrodes probing the surgical target site. Currently, these two sources of information (imaging vs. electrophysiology) are analyzed separately, while means to fuse both data streams have not been introduced., Methods: Here, we present a tool that integrates resources from stereotactic planning, neuroimaging, MER, and high-resolution atlas data to create a real-time visualization of the implant trajectory. We validate the tool based on a retrospective cohort of DBS patients (N = 52) offline and present single-use cases of the real-time platform., Results: We establish an open-source software tool for multimodal data visualization and analysis during DBS surgery. We show a general correspondence between features derived from neuroimaging and electrophysiological recordings and present examples that demonstrate the functionality of the tool., Conclusions: This novel software platform for multimodal data visualization and analysis bears translational potential to improve accuracy of DBS surgery. The toolbox is made openly available and is extendable to integrate with additional software packages., Funding: Deutsche Forschungsgesellschaft (410169619, 424778381), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti), National Institutes of Health (2R01 MH113929), and Foundation for OCD Research (FFOR)., Competing Interests: SO, JR, CN, LM, CG, PS, PV, WN No competing interests declared, AK Reports personal fees from Medtronic, Boston Scientific, Abbott, Teva, Ipsen and Stadapharm, all outside the submitted work, AH Reports lecture fee for Boston Scientific outside the submitted work, (© 2022, Oxenford et al.)

Adaptive deep brain stimulation (aDBS) is a promising concept for feedback-based neurostimulation, with the potential of clinical implementation with the sensing-enabled Percept neurostimulator. We aim to characterize chronic electrophysiological activity during stimulation and to validate beta-band activity as a biomarker for bradykinesia. Subthalamic activity was recorded during stepwise stimulation amplitude increase OFF medication in 10 Parkinson's patients during rest and finger tapping. Offline analysis of wavelet-transformed beta-band activity and assessment of inter-variable relationships in linear mixed effects models were implemented. There was a stepwise suppression of low-beta activity with increasing stimulation intensity (p = 0.002). Low-beta power was negatively correlated with movement speed and predictive for velocity improvements (p < 0.001), stimulation amplitude for beta suppression (p < 0.001). Here, we characterize beta-band modulation as a chronic biomarker for motor performance. Our investigations support the use of electrophysiology in therapy optimization, providing evidence for the use of biomarker analysis for clinical aDBS., (© 2022. The Author(s).)

Background: Finding the optimal deep brain stimulation (DBS) parameters from a multitude of possible combinations by trial and error is time consuming and requires highly trained medical personnel., Objective: We developed an automated algorithm to identify optimal stimulation settings in Parkinson's disease (PD) patients treated with subthalamic nucleus (STN) DBS based on imaging-derived metrics., Methods: Electrode locations and monopolar review data of 612 stimulation settings acquired from 31 PD patients were used to train a predictive model for therapeutic and adverse stimulation effects. Model performance was then evaluated within the training cohort using cross-validation and on an independent cohort of 19 patients. We inverted the model by applying a brute-force approach to determine the optimal stimulation sites in the target region. Finally, an optimization algorithm was established to identify optimal stimulation parameters. Suggested stimulation parameters were compared to the ones applied in clinical practice., Results: Predicted motor outcome correlated with observed outcome (R = 0.57, P < 10 -10 ) across patients within the training cohort. In the test cohort, the model explained 28% of the variance in motor outcome differences between settings. The stimulation site for maximum motor improvement was located at the dorsolateral border of the STN. When compared to two empirical settings, model-based suggestions more closely matched the setting with superior motor improvement., Conclusion: We developed and validated a data-driven model that can suggest stimulation parameters leading to optimal motor improvement while minimizing the risk of stimulation-induced side effects. This approach might provide guidance for DBS programming in the future. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Deep brain stimulation (DBS) is an established therapy for patients with Parkinson's disease. In silico computer models for DBS hold the potential to inform a selection of stimulation parameters. In recent years, the focus has shifted towards DBS-induced firing in myelinated axons, deemed particularly relevant for the external modulation of neural activity., Objective: The aim of this project was to investigate correlations between patient-specific pathway activation profiles and clinical motor improvement., Methods: We used the concept of pathway activation modeling, which incorporates advanced volume conductor models and anatomically authentic fiber trajectories to estimate DBS-induced action potential initiation in anatomically plausible pathways that traverse in close proximity to targeted nuclei. We applied the method on two retrospective datasets of DBS patients, whose clinical improvement had been evaluated according to the motor part of the Unified Parkinson's Disease Rating Scale. Based on differences in outcome and activation levels for intrapatient DBS protocols in a training cohort, we derived a pathway activation profile that theoretically induces a complete alleviation of symptoms described by UPDRS-III. The profile was further enhanced by analyzing the importance of matching activation levels for individual pathways., Results: The obtained profile emphasized the importance of activation in pathways descending from the motor-relevant cortical regions as well as the pallidothalamic pathways. The degree of similarity of patient-specific profiles to the optimal profile significantly correlated with clinical motor improvement in a test cohort., Conclusion: Pathway activation modeling has a translational utility in the context of motor symptom alleviation in Parkinson's patients treated with DBS., Competing Interests: Declaration of Competing Interest J.V. have business relationships with Medtronic, Abbott, and Boston Scientific, which are makers of DBS devices, outside the submitted work. A.A.K. reports personal fees and non-financial support from Medtronic, personal fees from Boston Scientific, grants and personal fees from Abbott, outside the submitted work. M.R. reports grant support and honoraria for speaking from Medtronic and Boston Scientific, outside the submitted work. A.H. reports lecture fees for Medtronic and Boston Scientific and is a consultant for AlphaOmega. G.R.W received travel expenses and attendance fees by Boston Scientific and Ipsen Pharma. K.B., N.L., C.N., J.R., H.E. and U.v.R. have nothing to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Adult stem cells play an essential role in adult organ physiology and tissue repair and regeneration. While much has been learnt about the property and function of various adult stem cells, the mechanisms of their development remain poorly understood in mammals. Earlier studies suggest that the formation of adult mouse intestinal stem cells takes place during the first few weeks after birth, the postembryonic period when plasma thyroid hormone (T3) levels are high. Furthermore, deficiency in T3 signaling leads to defects in adult mouse intestine, including reduced cell proliferation in the intestinal crypts, where stem cells reside. Our earlier studies have shown that protein arginine methyltransferase 1 (PRMT1), a T3 receptor coactivator, is highly expressed during intestinal maturation in mouse., Methods: We have analyzed the expression of PRMT1 by immunohistochemistry and studied the effect of tissue-specific knockout of PRMT1 in the intestinal epithelium., Results: We show that PRMT1 is expressed highly in the proliferating transit amplifying cells and crypt base stem cells. By using a conditional knockout mouse line, we have demonstrated that the expression of PRMT1 in the intestinal epithelium is critical for the development of the adult mouse intestine. Specific removal of PRMT1 in the intestinal epithelium results in, surprisingly, more elongated adult intestinal crypts with increased cell proliferation. In addition, epithelial cell migration along the crypt-villus axis and cell death on the villus are also increased. Furthermore, there are increased Goblet cells and reduced Paneth cells in the crypt while the number of crypt base stem cells remains unchanged., Conclusions: Our finding that PRMT1 knockout increases cell proliferation is surprising considering the role of PRMT1 in T3-signaling and the importance of T3 for intestinal development, and suggests that PRMT1 likely regulates pathways in addition to T3-signaling to affect intestinal development and/or homeostasis, thus affecting cell proliferating and epithelial turn over in the adult.

Background: Recent technological advances in deep brain stimulation (DBS) (e.g., directional leads, multiple independent current sources) lead to increasing DBS-optimization burden. Techniques to streamline and facilitate programming could leverage these innovations., Objective: We evaluated clinical effectiveness of algorithm-guided DBS-programming based on wearable-sensor-feedback compared to standard-of-care DBS-settings in a prospective, randomized, crossover, double-blind study in two German DBS centers., Methods: For 23 Parkinson's disease patients with clinically effective DBS, new algorithm-guided DBS-settings were determined and compared to previously established standard-of-care DBS-settings using UPDRS-III and motion-sensor-assessment. Clinical and imaging data with lead-localizations were analyzed to evaluate characteristics of algorithm-derived programming compared to standard-of-care. Six different versions of the algorithm were evaluated during the study and 10 subjects programmed with uniform algorithm-version were analyzed as a subgroup., Results: Algorithm-guided and standard-of-care DBS-settings effectively reduced motor symptoms compared to off-stimulation-state. UPDRS-III scores were reduced significantly more with standard-of-care settings as compared to algorithm-guided programming with heterogenous algorithm versions in the entire cohort. A subgroup with the latest algorithm version showed no significant differences in UPDRS-III achieved by the two programming-methods. Comparing active contacts in standard-of-care and algorithm-guided DBS-settings, contacts in the latter had larger location variability and were farther away from a literature-based optimal stimulation target., Conclusion: Algorithm-guided programming may be a reasonable approach to replace monopolar review, enable less trained health-professionals to achieve satisfactory DBS-programming results, or potentially reduce time needed for programming. Larger studies and further improvements of algorithm-guided programming are needed to confirm these results.

It is well known that endurance exercise modulates the cardiovascular, pulmonary, and musculoskeletal system. However, knowledge about its effects on brain function and structure is rather sparse. Hence, the present study aimed to investigate exercise-dependent adaptations in neurovascular coupling to different intensity levels in motor-related brain regions. Moreover, expertise effects between trained endurance athletes (EA) and active control participants (ACP) during a cycling test were investigated using multi-distance functional near-infrared spectroscopy (fNIRS). Initially, participants performed an incremental cycling test (ICT) to assess peak values of power output (PPO) and cardiorespiratory parameters such as oxygen consumption volume (VO 2 max) and heart rate (HRmax). In a second session, participants cycled individual intensity levels of 20, 40, and 60% of PPO while measuring cardiorespiratory responses and neurovascular coupling. Our results revealed exercise-induced decreases of deoxygenated hemoglobin (HHb), indicating an increased activation in motor-related brain areas such as primary motor cortex (M1) and premotor cortex (PMC). However, we could not find any differential effects in brain activation between EA and ACP. Future studies should extend this approach using whole-brain configurations and systemic physiological augmented fNIRS measurements, which seems to be of pivotal interest in studies aiming to assess neural activation in a sports-related context.

Objective: To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients., Methods: Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients)., Results: Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R 2  = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R 2  = 9%) and its sensorimotor subpart (R 2  = 10%). In the second independent cohort, sweet spot overlap explained R 2  = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R 2  = 21%) and sensorimotor STN (R 2  = 19%)., Interpretation: This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538., (© 2019 American Neurological Association.)

Introduction: We sought to assess the effect of subthalamic deep brain stimulation (STN DBS) on Parkinson's disease (PD)-associated postural abnormalities., Methods: A computerized analysis of posture was used to quantify the thoracolumbar, thoracic, and cervical-occipital ventral angles, as well as the thoracolumbar and cervical-occipital lateral angles from the video-repository of three specialized movement disorder centers (n = 158 patients). Data was extracted from frames from video-recordings in the pre-surgical medication-ON (dopaminergic therapy) and post-surgical stimulation-ON/medication-ON states (STN DBS plus dopaminergic therapy). The sum of the five postural angles (global postural angle) was used to compare pre-vs. post-surgical trunk posture alterations. A multivariate analysis was used to examine the association between changes in the postural angles and demographic or clinical variables., Results: There was a 6.7% amelioration in the global postural angle between the pre- and post-surgical assessments (p = 0.031). Motor response to and pre-surgical dosage of levodopa, male gender, and shorter PD duration were identified as predictors for posture improvement after STN DBS. Cases meeting criteria for lower (n = 2) or upper (n = 1) camptocormia respectively improved by 48.1% in the ventral thoracolumbar angle (from 36.4 ± 0.0° to 18.9 ± 4.2°) and 13.8% in the ventral thoracic angle (from 49.1° to 42.3°). Cases meeting criteria for Pisa syndrome (n = 2) improved by 67.5% in the lateral thoracolumbar angle (from 16.9 ± 2.0° to 5.5 ± 4.7°)., Conclusions: STN DBS has a relatively small but significant effect on PD-associated postural abnormalities, potentially enhancing the effect of dopaminergic medications alone., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The thyroid hormone triiodothyronine (T3) is critical for vertebrate development and affects the function of many adult tissues and organs. Its genomic effects are mediated by thyroid hormone nuclear receptors (TRs) present in all vertebrates. The discovery of patients with resistance to thyroid hormone (RTHβ) >50 years ago and subsequent identification of genetic mutations in only the THRB gene in these patients suggest that mutations in the THRA gene may have different pathological manifestations in humans. Indeed, the recent discovery of a number of human patients carrying heterozygous mutations in the THRA gene (RTHα) revealed a distinct phenotype that was not observed in RTH patients with THRB gene mutations (RTHβ). That is, RTHα patients have constipation, implicating intestinal defects caused by THRA gene mutations., Methods: To determine how TRα1 mutations affect the intestine, this study analyzed a mutant mouse expressing a strong dominantly negative TRα1 mutant (denoted TRα1PV; Thra1 PV mice). This mutant mouse faithfully reproduces RTHα phenotypes observed in patients., Results: In adult Thra1 PV/+ mice, constipation was observed just like in patients with TRα mutations. Importantly, significant intestinal defects were discovered, including shorter villi and increased differentiated cells in the crypt, accompanied by reduced stem-cell proliferation in the intestine., Conclusions: The findings suggest that further analysis of this mouse model should help to reveal the molecular and physiological defects in the intestine caused by TRα mutations and to determine the underlying mechanisms.

Objective: The objective of this study was to investigate whether directional deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) offers increased therapeutic windows, side-effect thresholds, and clinical benefit., Methods: In 10 patients, 20 monopolar reviews were conducted in a prospective, randomized, double-blind design to identify the best stimulation directions and compare them to conventional circular DBS regarding side-effect thresholds, motor improvement, and therapeutic window. In addition, circular and best-directional DBS were directly compared in a short-term crossover. Motor outcome was also assessed after an open-label follow-up of 3 to 6 months., Results: Stimulation in the individual best direction resulted in significantly larger therapeutic windows, higher side-effect thresholds, and more improvement in hand rotation than circular DBS. Rigidity and finger tapping did not respond differentially to the stimulation conditions. There was no difference in motor efficacy or stimulation amplitudes between directional and circular DBS in the short-term crossover. Follow-up evaluations 3 to 6 months after implantation revealed improvements in motor outcome and medication reduction comparable to other DBS studies with a majority of patients remaining with a directional setting., Conclusion: Directional DBS can increase side-effect thresholds while achieving clinical benefit comparable to conventional DBS. Whether directional DBS improves long-term clinical outcome needs to be investigated in the future. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)