MEDIAN METHOD FOR DETERMINING CORTICAL BRAIN ACTIVITY IN A NEAR INFRARED SPECTROSCOPY IMAGE

Near-InfraRed-Spectroscopy (NIRS) is a neuroimaging method of brain cortical activity using low-energy optical radiation to detect local changes in (de)oxyhaemoglobin concentration. A methodology consisting of a raw signal pre-processing phase, followed by statistical analysis based on a general linear model, is currently being used to determine signal activity. The aim of this research is to define the median modification of the standard method usually used for the estimation of cortical activity from the NIRS signal and to verify its applicability in measuring motor tasks for patients with Parkinson's disease. Individual examinations were conducted in 10 cycles, during which finger tapping, and rest phases were alternating. Changes in oxyhaemoglobin concentration were calculated from the native NIRS signal using the modified Lambert-Beer equation. The signals were filtered in the 0.015–0.3 Hz band and fitted by the physiological response function of the brain tissue for each finger tapping cycle separately. The median value from the 10 cycles was then computed. Activity values obtained in individual subjects have been used in Brain Mapping visualizations. These describe motor task patterns during the ON and OFF deep brain stimulation of the subthalamic nucleus in Parkinson's disease, which demonstrates activation in accordance with the current state of knowledge in functional imaging

Concomitant Medication Usage with Levodopa-Carbidopa Intestinal Gel : Results from the COSMOS Study

Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels.The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD.The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter.Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment.LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

A loud auditory stimulus overcomes voluntary movement limitation in cervical dystonia

Background Patients with cervical dystonia (CD) present with an impaired performance of voluntary neck movements, which are usually slow and limited. We hypothesized that such abnormality could involve defective preparation for task execution. Therefore, we examined motor preparation in CD patients using the StartReact method. In this test, a startling auditory stimulus (SAS) is delivered unexpectedly at the time of the imperative signal (IS) in a reaction time task to cause a faster execution of the prepared motor programme. We expected that CD patients would show an abnormal StartReact phenomenon. Methods Fifteen CD patients and 15 age matched control subjects (CS) were asked to perform a rotational movement (RM) to either side as quick as possible immediately after IS perception (a low intensity electrical stimulus to the II finger). In randomly interspersed test trials (25%) a 130 dB SAS was delivered simultaneously with the IS. We recorded RMs in the horizontal plane with a high speed video camera (2.38 ms per frame) in synchronization with the IS. The RM kinematic-parameters (latency, velocity, duration and amplitude) were analyzed using video-editing software and screen protractor. Patients were asked to rate the difficulty of their RMs in a numerical rating scale. Results In control trials, CD patients executed slower RMs (repeated measures ANOVA, p<0.10−5), and reached a smaller final head position angle relative to the midline (p<0.05), than CS. In test trials, SAS improved all RMs in both groups (p<0.10−14). In addition, patients were more likely to reach beyond their baseline RM than CS (χ2, p<0.001) and rated their performance better than in control trials (t-test, p<0.01). Conclusion We found improvement of kinematic parameters and subjective perception of motor performance in CD patients with StartReact testing. Our results suggest that CD patients reach an adequate level of motor preparation before task execution

Multi-centre classification of functional neurological disorders based on resting-state functional connectivity.

BACKGROUND Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a "rule-in" procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting. METHODS This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross-validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation). RESULTS FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%). CONCLUSIONS The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms

Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G \u3e A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Background: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. Objective: We sought to characterize the role of EIF4A2 variants in dystonic conditions. Methods: We undertook an unbiased search for likely deleterious variants in mutation-constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient-derived fibroblasts. Results: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence- to adulthood-onset dystonia with tremor. In patient-derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4-Not, the complex that interacts with eIF4A2 to mediate microRNA-dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4-Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia-affected pedigrees. Conclusions: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia-tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later-onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Weight Gain Is Associated with Medial Contact Site of Subthalamic Stimulation in Parkinson's Disease

The aim of our study was to assess changes in body-weight in relation to active electrode contact position in the subthalamic nucleus. Regular body weight measurements were done in 20 patients with advanced Parkinson's disease within a period of 18 months after implantation. T1-weighted (1.5T) magnetic resonance images were used to determine electrode position in the subthalamic nucleus and the Unified Parkinson's disease rating scale (UPDRS-III) was used for motor assessment. The distance of the contacts from the wall of the third ventricle in the mediolateral direction inversely correlated with weight gain (r = −0.55, p<0.01) and with neurostimulation-related motor condition expressed as the contralateral hemi-body UPDRS-III (r = −0.42, p<0.01). Patients with at least one contact within 9.3 mm of the wall experienced significantly greater weight gain (9.4±(SD)4.4 kg, N = 11) than those with both contacts located laterally (3.9±2.7 kg, N = 9) (p<0.001). The position of the active contact is critical not only for motor outcome but is also associated with weight gain, suggesting a regional effect of subthalamic stimulation on adjacent structures involved in the central regulation of energy balance, food intake or reward

The sensitivity of ECG contamination to surgical implantation site in brain computer interfaces.

BACKGROUND Brain sensing devices are approved today for Parkinson's, essential tremor, and epilepsy therapies. Clinical decisions for implants are often influenced by the premise that patients will benefit from using sensing technology. However, artifacts, such as ECG contamination, can render such treatments unreliable. Therefore, clinicians need to understand how surgical decisions may affect artifact probability. OBJECTIVES Investigate neural signal contamination with ECG activity in sensing enabled neurostimulation systems, and in particular clinical choices such as implant location that impact signal fidelity. METHODS Electric field modeling and empirical signals from 85 patients were used to investigate the relationship between implant location and ECG contamination. RESULTS The impact on neural recordings depends on the difference between ECG signal and noise floor of the electrophysiological recording. Empirically, we demonstrate that severe ECG contamination was more than 3.2x higher in left-sided subclavicular implants (48.3%), when compared to right-sided implants (15.3%). Cranial implants did not show ECG contamination. CONCLUSIONS Given the relative frequency of corrupted neural signals, we conclude that implant location will impact the ability of brain sensing devices to be used for "closed-loop" algorithms. Clinical adjustments such as implant location can significantly affect signal integrity and need consideration

Skuteczność i bezpieczeństwo leczenia toksyną botulinową typu A (abobotulinum toxin A) pacjentów ze spastycznością kończyny dolnej. Randomizowane badanie kliniczne

Cel: Wykazanie skuteczności jednorazowego wstrzyknięcia toksy­ny botulinowej typu A (abobotulinum toxin A [Dysport]) podawanej do mięśni kończyny dolnej w porównaniu z placebo u dorosłych z przewlekłym niedowładem połowiczym. Ocena długotrwałego bezpieczeństwa i skuteczności wielokrotnych wstrzyknięć. Metody: W wieloośrodkowym badaniu klinicznym prowadzonym metodą podwójnie ślepej próby, z randomizacją, kontrolą placebo i pojedynczym cyklem leczenia dorośli uczestnicy po co najmniej 6 miesiącach od udaru/uszkodzenia mózgu otrzymali pojedynczą iniekcję badanego leku (abobotulinum toxin A 1000 j., 1500 j., placebo) do mięśni kończyny dolnej. Po badaniu zasadniczym badanie przedłużono o rok w fazie otwartej, w trakcie której uczestnicy otrzymywali nie więcej niż 4 cykle leczenia (1000 j., 1500 j.) podawane w co najmniej 12-tygodniowych odstępach. Skuteczność leczenia oceniano według zmodyfikowanej skali Ashwortha (MAS, Modified Ashworth Scale) dla kompleksu mięśnia trójgłowego łydki (GSC, gastrocnemius-soleus complex; pierwszorzędowy punkt końcowy badania metodą podwójnie śle­pej próby). W badaniu określono również odpowiedź na leczenie w łącznej ocenie lekarzy (PGA, physician global assessment), a także szybkość swobodnego chodu boso. Bezpieczeństwo leczenia stanowiło pierwszorzędowy punkt końcowy badania prowadzonego metodą próby otwartej. Wyniki: Średnia zmiana (95-proc. przedział ufności) wartości MAS GSC w okresie od początku do 4. tygodnia (faza leczenia metodą podwójnie ślepej próby, n = 381) po jednokrotnym podaniu leku wyniosła: –0,5 (od –0,7 do –0,4) (placebo, n = 128), –0,6 (od –0,8 do –0,5) (toksyna botulinowa typu A 1000 j., n = 125; p = = 0,28 wobec placebo) i –0,8 (od –0,9 do –0,7) (toksyna abobotu­linowa typu A 1500 j., n = 128; p = 0,009 wobec placebo). Średnie wartości oceny PGA w 4. tygodniu były następujące: 0,7 (0,5–0,9) (placebo), 0,9 (0,7–1,1) (1000 j.; p = 0,067 wobec placebo) i 0,9 (0,7–1,1) (1500 j.; p = 0,067). Szybkość chodu nie poprawiła się statystycznie znamiennie w porównaniu z placebo. W 4. tygodniu 4. cyklu leczenia (faza otwarta) średnia zmiana oceny MAS GSC wyniosła –1,0. W cyklach badania w fazie otwartej odnotowano stopniową poprawę oceny PGA i szybkości chodu. W 4. tygodniu 4. cyklu leczenia średnia ocena PGA wyniosła 1,9, a szybkość chodu wzrosła o 25,3% (17,5–33,2), przy czym 16% uczestni­ków badania osiągnęło szybkość ponad 0,8 m/s (odpowiadającą chodowi samodzielnemu; 0% na początku badania). Tolerancja leczenia była dobra i zgodna ze znanym profilem bezpieczeństwa toksyny abobotulinowej typu A. Wnioski: Wśród pacjentów z przewlekłym niedowładem po­łowiczym jednokrotne podanie toksyny abobotulinowej typu A (Dysport, Ipsen) spowodowało obniżenie napięcia mięśniowego. Wielokrotne podanie leku w fazie rocznego przedłużenia badania zasadniczego było dobrze tolerowane oraz przyczyniło się do zwiększenia szybkości chodu i prawdopodobieństwa osiągnięcia chodu samodzielnego. Numery identyfikacyjne na portalu Clinicaltrial.gov: NCT01249404, NCT01251367. Klasyfikacja dowodu naukowego: z fazy badania prowadzonej metodą podwójnie ślepej próby uzyskano dane naukowe klasy I, na podstawie których stwierdza się, że jednokrotne wstrzyknięcie toksyny botulinowej typu A u dorosłych z przewlekłym niedowładem spastycznym zmniejsza napięcie mięśniowe w kończynie dolnej. Neurology® 2017; 89: 2245–225