Course of neuropsychological impairment during natalizumab-associated progressive multifocal leukoencephalopathy

$\textbf {Background and purpose}$ Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system from the John Cunningham virus (JCV), is a side effect of natalizumab (NTZ) treatment for relapsing–remitting multiple sclerosis (RRMS), potentially leading to a substantial increase of physical and mental disability. Nevertheless, data of neuropsychological impairment during the NTZ-PML disease course are missing. Our objective was to evaluate the neuropsychological disease course of NTZ-PML patients and to compare neuropsychological deficits of NTZ-PML patients with two different non-PML multiple sclerosis (MS) cohorts. $\bf Methods$ Neuropsychological examinations of 28 NTZ-PML patients performed during different phases of the disease ([i] at PML diagnosis, [ii] during immune reconstitution inflammatory syndrome [IRIS], and [iii] post-IRIS/PML) were retrospectively analyzed and compared to those of NTZ-treated RRMS or secondary progressive MS patients with and without immunotherapy. $\bf Results$ Compared to controls, NTZ-PML patients performed worse in neuropsychological examinations during all stages of disease, mainly affecting visuospatial ability and working memory. Furthermore, failure to eliminate the JCV from the central nervous system was associated with a progredient decline of cognition, especially working memory. $\bf Conclusions$ Working memory and visuospatial abilities are the core neuropsychological deficits of NTZ-PML patients in long-term follow-up. Our findings should be implemented in neurorehabilitation strategies

Cortical and subcortical grey and white matter atrophy in myotonic dystrophies type 1 and 2 is associated with cognitive impairment, depression and daytime sleepiness

$\textbf {Objectives:}$ Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). $\textbf {Methods:}$ 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. $\textbf {Results:}$ Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. $\textbf {Conclusion:}$ GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks

Temporal dynamics of diffusion metrics in early multiple sclerosis and clinically isolated syndrome

$\bf Background:$ Tract-based spatial statistics (TBSS) is suitable for the assessment of voxel-wise changes in fiber integrity in WM tracts in the entire brain. Longitudinal TBSS analyses of early multiple sclerosis (MS) using 3 Tesla magnetic resonance imaging (MRI) are not common. $\bf Objective:$ To characterize microstructural WM alterations at initial diagnosis in clinically isolated syndrome (CIS) and early MS at baseline and longitudinally over 2 years. $\bf Methods:$ DTI (Diffusion tensor imaging) at 3 Tesla was used to evaluate 106 therapy-naive patients with CIS or definite MS at baseline and at 1-year ($\it N$ = 83) and 2-year ($\it N$ = 43) follow-up compared to healthy controls (HC, $\it N$ = 49). TBSS was used for voxel-wise analyses of the DTI indices of fractional anisotropy (FA) and radial, mean, and axial diffusivity (RD, MD, AD) for cross-sectional and longitudinal comparisons. Mean values of FA, RD, and cluster voxel numbers were extracted from significant clusters using an atlas-based approach. Correlations with disability (EDSS) were calculated for FA and RD changes related to affected brain regions. $\bf Results:$ Reductions in FA compared to HC were found at baseline in patients with CIS and RRMS and involved most supra- and infratentorial WM tracts. In the cerebellum and cerebral peduncles, these changes negatively correlated with EDSS after 2 years. FA changes in patients with CIS and RRMS evolved in the second year, particularly in the descending projection pathways and the cerebellum, and were significantly associated with EDSS. RD alterations compared to HC were undetectable in patients at baseline but were observed after 1 year and were exacerbated during the second year in all major supratentorial WM tracts, the corpus callosum, and the cerebellum. FA did not change between baseline and year 1 follow-up, but longitudinal investigation between the first and second year revealed combined dynamic FA and RD changes in the corpus callosum and corona radiata. $\bf Conclusion:$ TBSS of diffusion metrics at initial diagnosis and at 2-year follow-up showed microstructural WM pathology and associations between FA reduction and future disability, respectively. Combined longitudinal changes in FA and RD occurred in specific structures, where RD increases likely reflected progressing axonal degeneration. The distinct temporal dynamics of FA and RD, implying constancy during the first year, supports early therapeutic intervention for CIS and RRMS

Characterization of iron accumulation in deep gray matter in myotonic dystrophy type 1 and 2 using quantitative susceptibility mapping and R2* relaxometry

Quantitative mapping of the magnetic susceptibility and the effective transverse relaxation rate (R2*) are suitable to assess the iron content in distinct brain regions. In this prospective, explorative study the iron accumulation in deep gray matter nuclei (DGM) in myotonic dystrophy type 1 (DM1) and 2 (DM2) and its clinical and neuro-cognitive relevance using susceptibility and R2* mapping was examined. Twelve classical DM1, four childhood-onset DM1 (DM1$_{c.o.}$), twelve DM2 patients and twenty-nine matched healthy controls underwent MRI at 3 Tesla, neurological and neuro-cognitive tests. Susceptibility, R2* and volumes were determined for eleven DGM structures and compared between patients and controls. Twelve classical DM1, four childhood-onset DM1, and 12 DM2 patients as well as 29 matched healthy controls underwent MRI at 3 Tesla, and neurological and neuro-cognitive tests. Susceptibility, R2* and volumes were determined for 11 DGM structures and compared between patients and controls. Iron accumulation in DGM reflected by R2* or susceptibility was found in the putamen and accumbens of DM1 and in DM2, but was more widespread in DM1 (caudate, pallidum, hippocampus, subthalamic nucleus, thalamus, and substantia nigra). Opposed changes of R2* or susceptibility were detected in caudate, putamen and accumbens in the childhood-onset DM1 patients compared to classical DM1. R2* or susceptibility alterations in DGM were significantly associated with clinical symptoms including muscular weakness (DM1), daytime sleepiness (DM1), depression (DM2), and with specific cognitive deficits in DM1 and DM2

Medicine in Spine Exercise [MiSpEx]

$\textbf {Idiopathic as well as nonspecific low back pain}$ is relevant in health care systems as well asinleisure and high-performance sports. Neuromuscular and/or structural deficits, mostly accompanied by biopsychological factors,are known risk factors for both the onset and chronification of symptoms. Meta-analytic evidence describes positive effects of physical activity. However, type, dose-response relation, minimum of training required and setting-specific implementation has not been fullyclarified. $\textbf {Since 2011, the national research network}$ „Medicine in Spine Exercise“ [MiSpEx] has beenfollowing a project layout called „Ran Rücken“ focussing on the development and validation of intervention programs including neuromuscular and pain adaptation moderated by individual training status, pain behaviour, allostatic load and social settings. Overall about 8000 patients and athletes have been and are being followed experimentally and clinically in 34 studies. $\textbf {It could be shown}$ that a training program focussing on compensation of external loads elicited by perturbations is effective in prevention and rehabilitation in both athletes and general population. Besides validation of further consecutively developed programs emphasis is put on the evaluation of transfer strategies to medical systems, sports as well as general population. Finally, the evaluation of an efficient dose-response relation is addressed.$\textbf {Idiopathische und unspezifische Rückenschmerzen}$ sind relevant für das Gesundheitssystem sowie für Alltag, Breiten- und Spitzensport. Neuromuskuläre und strukturelle Defizite, häufig begleitet von biopsychosozialen Faktoren, sind ursächlich für den Beginn und die Chronifizierung der Symptome. Evident in Therapie und Prävention ist körperliche Aktivität, wobei nicht abschließend geklärt ist, welche Art und Dosierung effektiv ist, welches Trainingsminimum erreicht werden muss und wie unterschiedliche Adressatenkreise für einen nachhaltigen Effekt angesprochen werden müssen. $\textbf {Das nationale Forschungsnetzwerk}$ „Medicine in Spine Exercise“ [MiSpEx] arbeitet unter dem Projektnamen „Ran Rücken“ seit 2011 an der Entwicklung und Validierung adressatengerechter Interventionsprogramme mit dem Ziel der Adaptation neuromuskulärer Interaktionen und Schmerz, moderiert durch Trainingszustand, Schmerzempfinden, allostatische Last und Versorgungskontext. Insgesamt wurden und werden rund 8000 Gesunde und Patienten mit Rückenschmerzen aus der Allgemeinbevölkerung und dem Spitzensport in 34 Projekten wissenschaftlich und klinisch betreut. $\textbf {Es konnte nachgewiesen werden}$, dass ein Training zur Kompensation externer Störreize (Perturbationen) bei geringem Aufwand präventiv und therapeutisch wirksam ist. Neben der Validierung neuer, konsekutiv auf den Ergebnissen aufgebauter Interventionsmodule, stehen die Evaluation von Transferstrategien in die medizinische Versorgung, die Systeme des Leistungssports und die Gesamtgesellschaft sowie die Analyse von Dosis-Wirkungsbeziehungen im Fokus des Projekte

Effects of active recovery on muscle function following high-intensity training sessions in elite olympic weightlifters

This study investigated whether the repeated use of an active recovery (ACT) program is beneficial for promoting recovery of muscle function during an intensive training phase in elite Olympic weightlifters. Using a crossover design, eight competitive weightlifters (7 male; 1 female) from the German national Olympic team participated in a two-day microcycle, comprising of four high-intensity training sessions, with either ACT or passive recovery (PAS) following the session. Barbell velocity during the clean pull, countermovement jump (CMJ) height, muscle contractile properties using tensiomyography (TMG), creatine kinase activity (CK), muscle soreness (DOMS) and perceived overall recovery and stress were measured. After termination of the microcycle, the sport-specific performance during all clean pull intensities (85% 1RM, ACT: Effect size (ES) = -0.20, PAS: ES = -0.50; 90% 1RM, ACT: ES = -0.29, PAS: ES = -0.35; 95% 1RM, ACT: ES = -0.41, PAS: ES = -020; P > 0.05) decreased. Both CK (ACT: ES = 2.11, PAS: ES = 1.41; P = 0.001) and DOMS (ACT: ES = 1.65, PAS: ES = 2.33; P = 0.052) considerably increased. Similarly, ratings of perceived recovery and stress were adversely affected in ACT and PAS, whereas changes in CMJ height and TMG muscle contractile properties remained trivial in both conditions. No practically meaningful differences in changes of the outcome measures were found between ACT and PAS, however there were variable individual responses to ACT. In conclusion, the short-term implementation of an individualized ACT program does not seem to enhance recovery from training-induced fatigue more effectively than PAS. However, because of the inter-individual variability in responses to ACT, it may be beneficial at the individual level

Effects of different recovery strategies following a half-marathon on fatigue markers in recreational runners

$\bf {Purpose}$ To investigate the effects of different recovery strategies on fatigue markers following a prolonged running exercise. $\bf {Methods}$ 46 recreational male runners completed a half-marathon, followed by active recovery (ACT), cold water immersion (CWI), massage (MAS) or passive recovery (PAS). Countermovement jump height, muscle soreness and perceived recovery and stress were measured 24h before the half-marathon (pre), immediately after the recovery intervention (post$_{rec}$) and 24h after the race (post$_{24}$). In addition, muscle contractile properties and blood markers of fatigue were determined at pre and post$_{24}$. $\bf {Results}$ Magnitude-based inferences revealed substantial differences in the changes between the groups. At post$_{rec}$, ACT was harmful to perceived recovery (ACT vs. PAS: effect size [ES] = −1.81) and serum concentration of creatine kinase (ACT vs. PAS: ES = 0.42), with CWI being harmful to jump performance (CWI vs. PAS: ES = −0.98). It was also beneficial for reducing muscle soreness (CWI vs. PAS: ES = −0.88) and improving perceived stress (CWI vs. PAS: ES = −0.64), with MAS being beneficial for reducing muscle soreness (MAS vs. PAS: ES = −0.52) and improving perceived recovery (MAS vs. PAS: ES = 1.00). At post$_{24}$, both CWI and MAS were still beneficial for reducing muscle soreness (CWI vs. PAS: ES = 1.49; MAS vs. PAS: ES = 1.12), with ACT being harmful to perceived recovery (ACT vs. PAS: ES = −0.68), serum concentration of creatine kinase (ACT vs. PAS: ES = 0.84) and free-testosterone (ACT vs. PAS: ES = −0.91). $\bf {Conclusions}$ In recreational runners, a half-marathon results in fatigue symptoms lasting at least 24h. To restore subjective fatigue measures, the authors recommend CWI and MAS, as these recovery strategies are more effective than PAS, with ACT being even disadvantageous. However, runners must be aware that neither the use of ACT nor CWI or MAS had any beneficial effect on objective fatigue markers

Do oral contraceptives modulate the effects of stress induction on one-session exposure efficacy and generalization in women?

$\bf Rationale$ The administration of glucocorticoids (GC) as an adjunct to exposure represents a promising strategy to improve one-session exposure outcome in anxiety disorders. It remains to be determined whether similar effects can be induced with the use of acute stress. Furthermore, the possible modulation of exposure effects by hormonal factors (e.g., use of oral contraceptives (OCs)) was not explored so far. $\bf Objectives$ We investigated whether acute stress prior to one-session exposure for spider fear affects its efficacy in women using oral contraceptives ($\it OC$) relative to free-cycling ($\it FC$) women. In addition, effects of stress on generalization of exposure therapy effects towards untreated stimuli were examined. $\bf Methods$ Women with fears of spiders and cockroaches were randomly assigned to $\textit {a Stress}$ (n = 24) or $\textit {No-Stress}$ (n = 24) condition prior to one-session exposure. Of these 48 participants, 19 women used OC (n = 9 in the Stress, and n = 10 in the No-Stress group). All $\it FC$ women had a regular menstrual cycle and were tested only in the follicular phase of their menstrual cycle. Pre-exposure stress induction was realized with the socially evaluated cold-pressor test. Exposure-induced changes towards treated and untreated fear stimuli were tested with behavioral approach tests for spiders and cockroaches and subjective fear and self-report measures. $\bf Results$ Acute stress did not influence exposure-induced reduction in fear and avoidance of the treated stimuli (spiders). Similarly, stress had no effect on the generalization of exposure-therapy effects towards untreated stimuli (cockroaches). Exposure-induced reduction in subjective fear and self-report measures for treated stimuli was less evident in women using $\it OC$ specifically after pre-exposure stress. Women using $\it OC$ had higher levels of subjective fear and scored higher in self-report measures at post-treatment (24 h after exposure) and follow-up (4 weeks after exposure). $\bf Conclusions$ OC intake may represent an important confounding factor in augmentation studies using stress or GC

Heart rate variability monitoring during strength and high-intensity interval training overload microcycles

$\bf Objective:$ In two independent study arms, we determine the effects of strength training (ST) and high-intensity interval training (HIIT) overload on cardiac autonomic modulation by measuring heart rate (HR) and vagal heart rate variability (HRV). $\bf Methods:$ In the study, 37 well-trained athletes (ST: 7 female, 12 male; HIIT: 9 female, 9 male) were subjected to orthostatic tests (HR and HRV recordings) each day during a 4-day baseline period, a 6-day overload microcycle, and a 4-day recovery period. Discipline-specific performance was assessed before and 1 and 4 days after training. $\bf Results:$ Following ST overload, supine HR, and vagal HRV (Ln RMSSD) were clearly increased and decreased (small effects), respectively, and the standing recordings remained unchanged. In contrast, HIIT overload resulted in decreased HR and increased Ln RMSSD in the standing position (small effects), whereas supine recordings remained unaltered. During the recovery period, these responses were reversed (ST: small effects, HIIT: trivial to small effects). The correlations between changes in HR, vagal HRV measures, and performance were weak or inconsistent. At the group and individual levels, moderate to strong negative correlations were found between HR and Ln RMSSD when analyzing changes between testing days (ST: supine and standing position, HIIT: standing position) and individual time series, respectively. Use of rolling 2–4-day averages enabled more precise estimation of mean changes with smaller confidence intervals compared to single-day values of HR or Ln RMSSD. However, the use of averaged values displayed unclear effects for evaluating associations between HR, vagal HRV measures, and performance changes, and have the potential to be detrimental for classification of individual short-term responses. $\bf Conclusion:$ Measures of HR and Ln RMSSD during an orthostatic test could reveal different autonomic responses following ST or HIIT which may not be discovered by supine or standing measures alone. However, these autonomic changes were not consistently related to short-termchanges in performance and the use of rolling averages may alter these relationships differently on group and individual level