Dopamine-dependent scaling of subthalamic gamma bursts with movement velocity in patients with Parkinson’s disease

Gamma synchronization increases during movement and scales with kinematic parameters. Here, disease-specific characteristics of this synchronization and the dopamine-dependence of its scaling in Parkinson’s disease are investigated. In 16 patients undergoing deep brain stimulation surgery, movements of different velocities revealed that subthalamic gamma power peaked in the sensorimotor part of the subthalamic nucleus, correlated positively with maximal velocity and negatively with symptom severity. These effects relied on movement-related bursts of transient synchrony in the gamma band. The gamma burst rate highly correlated with averaged power, increased gradually with larger movements and correlated with symptom severity. In the dopamine-depleted state, gamma power and burst rate significantly decreased, particularly when peak velocity was slower than ON medication. Burst amplitude and duration were unaffected by the medication state. We propose that insufficient recruitment of fast gamma bursts during movement may underlie bradykinesia as one of the cardinal symptoms in Parkinson’s disease

Error signals in the subthalamic nucleus and its significance for adaptive behavior

Die Funktion des menschlichen Gehirns, Handlungen zu überwachen, umfasst die Fähigkeiten, Handlungsfehler zu detektieren und das Verhalten den aktuellen Umweltanforderungen anzupassen. Patientenstudien haben gezeigt, dass der anteriore mittlere zinguläre Kortex in Interaktion mit den Basalganglien wesentlich an der Implementierung von Handlungsüberwachungsfunktionen beteiligt ist. Es wird angenommen, dass der Nucleus subthalamicus (STN), ein Kerngebiet der Basalganglien und Ziel für diverse neuronale Projektionen, einen Nexus für emotionale, kognitive und motorische Informationsverarbeitungs-prozesse bildet. Eine wichtige Verhaltensadaptation bildet das so genannte post-error slowing, eine Geschwindigkeitsreduktion der Antwortabgabe im Durchgang nach einer fehlerhaften Antwort, die mit motorischen Inhibitionsprozessen in Verbindung gebracht wird. Der STN scheint Studien zufolge eine wichtige Position in diesem Inhibitionsnetzwerk einzunehmen. Eine direkte Beteiligung des STN an Fehlerverarbeitungsprozessen wurde bisher nicht gezeigt. Ziel unserer Studie bildete der Nachweis fehlerassoziierter Aktivität im STN sowie deren Zusammenhang mit fehlerassoziierter Verhaltensadaptation. Über die zur Tiefen Hirnstimulation implantierten Elektroden leiteten wir lokale Feldpotentiale (LFP) aus dem STN und ein Elektro-enzephalogramm von 17 Parkinsonpatienten ab, während diese eine Flankierreizaufgabe bearbeiteten. Die Analyse der elektrophysiologischen Daten fokussierte sich auf die ereigniskorrelierten Potentiale. Da bisherige Studien mit Parkinsonpatienten uneinheitliche Befunde zum Einfluss der dopaminergen Medikation auf Fehlerverarbeitung ergaben, führten wir die Untersuchung jeweils mit und ohne dopaminerge Medikation durch. Neben der typischen kortikalen Fehlernegativität konnten wir fehlerassoziierte Aktivität im STN in Form einer positiven Deflektion in den LFP 260-450 ms nach einer fehlerhaften Antwort nachweisen. Diese fehlerassoziierte Positivierung im STN (STN-Pe) zeigte sich in Zusammenhang mit erfolgreichem post-error slowing. Ein Effekt der dopaminergen Medikation ergab sich in den Daten der Gesamtstichprobe nicht. Interessanterweise fanden wir jedoch zwei Subgruppen mit gegensätzlichen Verhaltenseffekten. Die Gruppe jüngerer Patienten zeigte ohne Medikation signifikant niedrigere Fehlerraten als unter Medikation, wohingegen die Gruppe älterer Patienten umgekehrt niedrigere Fehlerraten unter Medikation erreichte. Diese Befunde suggerieren einen medikamentösen Überdosierungseffekt bei jungen Patienten in Abhängigkeit der vom dopaminergen Neuronenuntergang betroffenen Gehirnareale. Entsprechend der behavioralen Ergebnisse fanden wir dopaminerge Modulationen der kortikalen Fehlernegativität und der STN-Pe in beiden Gruppen. Statistische Signifikanz erreichten die Effekte jedoch nur in der älteren, unter Medikation gute Leistungen zeigenden Gruppe, die entsprechend höhere Amplituden der kortikalen Fehlernegativität und der STN-Pe unter Medikation im Vergleich zum Durchgang ohne Medikation aufwiesen. Zusammenfassend konnten wir mit dieser Studie zeigen, dass der STN in Fehlerverarbeitungsprozesse involviert ist und Dopamin einen modulatorischen Einfluss auf jene Prozesse ausübt.The human brain function of performance monitoring relies on the ability to detect errors and subsequently adapt the behavior to current environmental requirements. Patient studies revealed interactions of the anterior midcingulate cortex and the basal ganglia for the implementation of performance monitoring. It is assumed that the subthalamic nucleus (STN), an input nucleus of the basal ganglia, targeted by a diversity of neural projections, builds a nexus for emotional, cognitive, and motor information processes. An important behavioral adaptation to errors is the so called post- error slowing, a prolongation of the reaction time, observed in the trials after erroneous responses which is associated with motor inhibition. According to previous studies the STN is a pivotal node of the neural networks of motor and cognitive inhibition. However, a direct involvement of the STN in error processing has not been shown so far. Here we investigated error-related activity in the STN and its influence on behavioral adaptation. We simultaneously recorded local field potentials (LFP) of the STN and an electroencephalogram in 17 patients undergoing DBS for Parkinson's disease while performing a flanker task. We primarily analysed event-related potentials. Notably, as patient studies so far yielded inconsistent results regarding the influence of dopamine on error processing, we studied the patients both with and without dopaminergic medication. In addition to the previously reported cortical error-related negativity, we found error-related activity in the STN which was characterized by a positive deflection in the LFP within 260-450 ms after an erroneous response. This so called STN error positivity (STN-Pe) was related to successful post-error slowing. We did not find a main effect of dopaminergic medication in our data. However we detected two subgroups showing an opposite effect of dopaminergic medication on their behavior. The younger patients showed significantly lower error rates while without medication compared to the medicated state, whereas the older patients showed lower error rates under medication. These findings suggest a dopaminergic overdose effect in young patients depending on the dopamine depletion. In agreement with the behavioral results, we found dopaminergic modulations of the error-related negativity and the STN-Pe in both groups. However, statistical significance of these effects was obtained only in the group of the older “ON-good-performing“ patients, which showed higher amplitudes of both components when on medication. In this study we demonstrated that the STN is involved in error processing and that dopamine exerts a modulatory influence on these processes

Expanding the Phenotype of the FAM149B1-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family

Biallelic truncating FAM149B1 variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known FAM149B1 c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in FAM149B1-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the FAM149B1-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of FAM149B1-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes

Rituximab treatment in pediatric-onset multiple sclerosis

Background and purpose: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk–benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. Methods: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. Results: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38–0.92) to 0.03 (95% CI 0.02–0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70–2.48) to 0.08 (95% CI 0.03–0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30–3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. Conclusion: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis

Error signals in the subthalamic nucleus are related to post-error slowing in patients with Parkinson's disease

Error monitoring is essential for optimizing motor behavior. It has been linked to the medial frontal cortex, in particular to the anterior midcingulate cortex (aMCC). The aMCC subserves its performance-monitoring function in interaction with the basal ganglia (BG) circuits, as has been demonstrated in patients suffering from BG lesions or from Parkinson's disease (PD). The subthalamic nucleus (STN) has been assumed an integrative structure for emotional, cognitive and motor processing. Error-related behavioral adaptation such as post-error slowing has been linked to motor inhibition involving activation of an inhibitory network including the STN. However, direct involvement of the STN in error monitoring and post-error behavioral adjustment has not yet been demonstrated. Here, we used simultaneous scalp electroencephalogram (EEG) and local field potential (LFP) recordings from the BG in 17 patients undergoing deep brain stimulation (DBS) for PD to investigate error-related evoked activity in the human STN, its relation to post-error behavioral adjustment and the influence of dopamine during the performance of a speeded flanker task