Motor Sequence Learning Deficits in Idiopathic Parkinson’s Disease Are Associated With Increased Substantia Nigra Activity

Previous studies have shown that persons with Parkinson’s disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-thalamo-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however, unsuccessfully. Finally, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differences between the groups were found during sequence learning. We speculate that learning-specific SN recruitment leads to a relative increase in SN- > putamen connectivity, which returns to a pathological reduced state when no learning takes plac

NFκB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP

Fas (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NFκB via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NFκB signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NFκB was activated by overexpressed FLIPL and FLIPS in a cell type–specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NFκB activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NFκB target gene IL8. As NFκB signaling is inhibited during apoptosis, FasL-induced NFκB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NFκB-related response

Dual-Site Transcranial Magnetic Stimulation for the Treatment of Parkinson's Disease

Abnormal oscillatory activity in the subthalamic nucleus (STN) may be relevant for motor symptoms in Parkinson's disease (PD). Apart from deep brain stimulation, transcranial magnetic stimulation (TMS) may be suitable for altering these oscillations. We speculated that TMS to different cortical areas (primary motor cortex, M1, and dorsal premotor cortex, PMd) may activate neuronal subpopulations within the STN via corticofugal neurons projecting directly to the nucleus. We hypothesized that PD symptoms can be ameliorated by a lasting decoupling of STN neurons by associative dual-site repetitive TMS (rTMS). Associative dual-site rTMS (1 Hz) directed to PMd and M1 (“ADS-rTMS”) was employed in 20 PD patients treated in a blinded, placebo-controlled cross-over design. Results: No adverse events were noted. We found no significant improvement in clinical outcome parameters (videography of MDS-UPDRS-III, finger tapping, spectral tremor power). Variation of the premotor stimulation site did not induce beneficial effects either. A single session of ADS-rTMS was tolerated well, but did not produce a clinically meaningful benefit on Parkinsonian motor symptoms. Successful treatment using TMS targeting subcortical nuclei may require an intervention over several days or more detailed physiological information about the individual brain state and stimulation-induced subcortical effects

Automatic covariance pattern analysis outperforms visual reading of 18 F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) in variant progressive supranuclear palsy

Background: To date, studies on positron emission tomography (PET) with F-18-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS). Objectives: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. Methods: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern. Results: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample. Conclusions: Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. (C) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome

Purpose: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. Methods: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). Results: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). Conclusion: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression

Mechanisms of TRAIL-induced cell signaling

TRAIL (TNF Related Apoptosis Inducing Ligand), ein Mitglied der TNF-Ligandenfamilie, wurde bislang hauptsächlich hinsichtlich seiner dominanten Funktion als Auslöser des apoptotischen Programms untersucht. In neueren Untersuchungen konnte allerdings gezeigt werden, dass TRAIL unter bestimmten Bedingungen auch eine starke Aktivierung nicht-apoptotischer Signalwege induzieren kann. Um die Mechanismen der TRAIL-induzierten nicht-apoptotischen Signaltransduktion genauer zu untersuchen, wurde in der hier vorliegenden Arbeit besonderes Augenmerk auf die TRAIL-vermittelte Aktivierung des Transkriptionsfaktors NFkB und deren Modulation durch Interferon gamma und FLIP gelegt. Hierbei konnte gezeigt werden, dass Interferon gamma, neben einer synergistischen Wirkung hinsichtlich der TRAIL-induzierten Apoptose, unter nicht-apoptotischen Bedingungen, die durch Caspase-Inhibition oder Bcl2-Überexpression geschaffen wurden, auch eine verstärkende Wirkung auf die TRAIL-induzierten NFkB-Aktivierung in KB-Zellen entfaltet. Weiterhin konnte gezeigt werden, dass FLIP, ein Inhibitor der Caspase-8-Aktivierung, dessen Expression unter anderem durch Interferon gamma reguliert wird, neben einer Apoptose-inhibierenden Wirkung auch die TRAIL-induzierte NFkB-Aktivierung in KB-Zellen inhibiert, was auf eine gemeinsame Regulation beider Mechanismen auf der Ebene des DISC (Death Inducin Signaling Complex) hindeutet.TRAIL (TNF Related Apoptosis Inducing Ligand) is a member of the TNF superfamily and is primarily known for its strong apoptosis inducing capability. However, it could be shown that besides its strong apoptotic potential, TRAIL can also induce non-apoptotic signaling pathways under certain conditions. In this dissertation it is shown that interferon gamma synergistically enhances the TRAIL induced activation of NFkB under non-apoptotic conditions, which were achieved by inhibition of caspases or stable expression of Bcl2 in KB-cells. Furthermore, FLIP, an inhibitor of caspase-8-activation, which is amongst others regulated by interferon gamma, is shown not only to block TRAIL-induced apoptosis but also to inhibit TRAIL-induced NFkB-activation in KB-cells, indicating that both mechanisms are coregulated at the level of the DISC (Death Inducing Signaling Complex)

Posttraining Alpha Transcranial Alternating Current Stimulation Impairs Motor Consolidation in Elderly People

The retention of a new sequential motor skill relies on repeated practice and subsequent consolidation in the absence of active skill practice. While the early phase of skill acquisition remains relatively unaffected in older adults, posttraining consolidation appears to be selectively impaired by advancing age. Motor learning is associated with posttraining changes of oscillatory alpha and beta neuronal activities in the motor cortex. However, whether or not these oscillatory dynamics relate to posttraining consolidation and how they relate to the age-specific impairment of motor consolidation in older adults remains elusive. Transcranial alternating current stimulation (tACS) is a noninvasive brain stimulation technique capable of modulating such neuronal oscillations. Here, we examined whether tACS targeting M1 immediately following explicit motor sequence training is capable of modulating motor skill consolidation in older adults. In two sets of double-blind, sham-controlled experiments, tACS targeting left M1 was applied at either 10 Hz (alpha-tACS) or 20 Hz (beta-tACS) immediately after termination of a motor sequence training with the right (dominant) hand. Task performance was retested after an interval of 6 hours to assess consolidation of the training-acquired skill. EEG was recorded over left M1 to be able to detect local after-effects on oscillatory activity induced by tACS. Relative to the sham intervention, consolidation was selectively disrupted by posttraining alpha-tACS of M1, while posttraining beta-tACS of M1 had no effect on delayed retest performance compared to the sham intervention. No significant postinterventional changes of oscillatory activity in M1 were detected following alpha-tACS or beta-tACS. Our findings point to a frequency-specific interaction of tACS with posttraining motor memory processing and may suggest an inhibitory role of immediate posttraining alpha oscillations in M1 with respect to motor consolidation in healthy older adults

Motor Performance But Neither Motor Learning Nor Motor Consolidation Are Impaired in Chronic Cerebellar Stroke Patients

The capacity to acquire and retain new motor skills is essential for everyday behavior and a prerequisite to regain functional independence following impairments of motor function caused by brain damage, e.g., ischemic stroke. Learning a new motor skill requires repeated skill practice and passes through different online and offline learning stages that are mediated by specific dynamic interactions between distributed brain regions including the cerebellum. Motor sequence learning is an extensively studied paradigm of motor skill learning, yet the role of the cerebellum during online and offline stages remains controversial. Here, we studied patients with chronic cerebellar stroke and healthy control participants to further elucidate the role of the cerebellum during acquisition and consolidation of sequential motor skills. Motor learning was assessed by an ecologically valid explicit sequential finger tapping paradigm and retested after an interval of 8 h to assess consolidation. Compared to healthy controls, chronic cerebellar stroke patients displayed significantly lower motor sequence performance independent of whether the ipsilesional or contralesional hand was used for task execution. However, the ability to improve performance during training (i.e., online learning) and to consolidate training-induced skill formation was similar in patients and controls. Findings point to an essential role of the cerebellum in motor sequence production that cannot be compensated, while its role in online and offline motor sequence learning seems to be either negligible or amenable to compensatory mechanisms. This further suggests that residual functional impairments caused by cerebellar stroke may be mitigated even months later by additional skill training

Delirium Screening in Neurocritical Care and Stroke Unit Patients: A Pilot Study on the Influence of Neurological Deficits on CAM-ICU and ICDSC Outcome

Background/objective!#!Delirium is a common complication in critically ill patients with a negative impact on hospital length of stay, morbidity, and mortality. Little is known on how neurological deficits affect the outcome of commonly used delirium screening tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) in neurocritical care patients.!##!Methods!#!Over a period of 1 month, all patients admitted to a neurocritical care and stroke unit at a single academic center were prospectively screened for delirium using both CAM-ICU and ICDSC. Tool-based delirium screening was compared with delirium evaluation by the treating clinical team. Additionally, ICD-10 delirium criteria were assessed.!##!Results!#!One hundred twenty-three patients with a total of 644 daily screenings were included. Twenty-three patients (18.7%) were diagnosed with delirium according to the clinical evaluation. Delirium incidence amounted to 23.6% (CAM-ICU) and 26.8% (ICDSC). Sensitivity and specificity of both screening tools were 66.9% and 93.3% for CAM-ICU and 69.9% and 93.9% for ICDSC, respectively. Patients identified with delirium by either CAM-ICU or ICDSC presented a higher proportion of neurological deficits such as impaired consciousness, expressive aphasia, impaired language comprehension, and hemineglect. Subsequently, generalized estimating equations identified a significant association between impaired consciousness (as indexed by Richmond Agitation and Sedation Scale) and a positive delirium assessment with both CAM-ICU and ICDSC, while impaired language comprehension and hemineglect were only associated with a positive CAM-ICU result.!##!Conclusions!#!A positive delirium screening with both CAM-ICU and ICDSC in neurocritical care and stroke unit patients was found to be significantly associated with the presence of neurological deficits. These findings underline the need for a more specific delirium screening tool in neurocritical care patients

Assessment of brainstem function with auricular branch of vagus nerve stimulation in Parkinson’s disease

Background: The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact