Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Die hochfrequenten Oszillationen in den Basalganglien und deren Rolle bei Willkürbewegungen

What is the function of the basal ganglia in human behaviour? It is known that alterations of basal ganglia function can lead to motor symptoms like bradykinesia, tremor or dystonia. Yet, direct physiological data from human basal ganglia are limited. Recent advances in functional neurosurgery using deep brain stimulation for the treatment of severe movement disorders allow for direct recordings of local field potentials (LFP) from the human basal ganglia. We used this approach in our studies to investigate basal ganglia function and the role of oscillatory activities during rest, sleep and motor tasks. Changes of oscillatory activity in different frequency bands were analysed in relation to the recording condition. We could demonstrate the presence of lateralized movement-related increase in high frequency (~60-80 Hz, gamma) activity in the basal ganglia of patients with dystonia and a positive correlation of this gamma activity with movement speed and amplitude. Gamma band activity was independent of movement direction and did not occur during passive movements. The stepwise increase of gamma activity with movement amplitude and speed suggests a role of neuronal synchronization in this frequency range in the basal ganglia in order to control the scaling of ongoing movements. In a second study we could show that 13 out of 24 patents with four different pathologies had a narrow band activity centred at ~70 Hz in spectra of thalamic LFP recordings. This activity was modulated by movement and varied over the sleep–wake cycle, being suppressed during slow wave sleep and re-emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at 70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Our results support a functional role of gamma activity in small and large scale (between basal ganglia nuclei and thalamus binding), as a possible way of communication between brain areas. More specifically, in the motor system subcortical oscillatory activity at ~70 Hz may be involved in the control of the scaling of ongoing movements and arousal.Was machen eigentlich die Basalganglien und wie sind sie an der Steuerung von willkürlichen Bewegungen beteiligt? Gegenwärtig wird hypothetisch postuliert, dass sie maßgeblich an der Selektion, Initierung und auch Unterdrückung von „motorischen“ und „nicht-motorischen“ Programmen beteiligt sind. Klassische Studien bei Affen zeigten jedoch, dass Neurone im Globus pallidus internus (GPi) spezifisch die Bewegungsrichtung als auch die Bewegungsgeschwindigkeit kodieren. Von Dystonie Patienten wissen wir, dass die therapeutische Hochfrequenzstimulation des GPi zu einer diskreten Bewegungsverlangsamung führen kann. Ziel der Studie war es, die Bedeutung der oszillatorischen Aktivierungsmuster im GPi und ihre Abhängigkeit von Bewegungsparametern wie Richtung und Geschwindigkeit zu charakterisieren. Bei 22 Patienten mit idiopathischer cervikaler oder segmentaler Dystonie ohne Beteiligung der Hand wurden während einer Bewegungsaufgabe von den Kontakten der im GPi zur tiefen Hirnstimulation implantierten Elektrode die lokalen Feldpotentiale gemessen. Die Patienten führten visuell getriggerte Pronationsbewegungen mit dem Arm durch, deren Winkel gestuft 30°, 60° oder 90° betrug. Bewegungskorrelierte Änderung der synchronen oszillatorischen Aktivität wurden separat für die drei Bewegungen berechnet. Eine Synchronisation im Gamma-Frequenzband trat im kontralateralen GPi bei Bewegungsbeginn auf und erreichte das Maximum zum Zeitpunkt der maximalen Bewegungsgeschwindigkeit. Dabei korrelierte die Bewegungsamplitude und -geschwindigkeit mit dem Ausmaß der Gamma- Synchronisation (60-80 Hz). Die Modulation der oszillatorischen Aktivität in Abhängigkeit von den Bewegungsparametern Amplitude und Geschwindigkeit deutet auf einen regulatorischen Einfluss des GPi bei der Skalierung von Bewegungen hin, der über die reine Selektion und Initiierung des Bewegungsprogramms hinauszugehen scheint

Subthalamic nucleus stimulation impairs emotional conflict adaptation in Parkinson’s disease

The subthalamic nucleus (STN) occupies a strategic position in the motor network, slowing down responses in situations with conflicting perceptual input. Recent evidence suggests a role of the STN in emotion processing through strong connections with emotion recognition structures. As deep brain stimulation (DBS) of the STN in patients with Parkinson’s disease (PD) inhibits monitoring of perceptual and value-based conflict, STN DBS may also interfere with emotional conflict processing. To assess a possible interference of STN DBS with emotional conflict processing, we used an emotional Stroop paradigm. Subjects categorized face stimuli according to their emotional expression while ignoring emotionally congruent or incongruent superimposed word labels. Eleven PD patients ON and OFF STN DBS and eleven age-matched healthy subjects conducted the task. We found conflict-induced response slowing in healthy controls and PD patients OFF DBS, but not ON DBS, suggesting STN DBS to decrease adaptation to within-trial conflict. OFF DBS, patients showed more conflict-induced slowing for negative conflict stimuli, which was diminished by STN DBS. Computational modelling of STN influence on conflict adaptation disclosed DBS to interfere via increased baseline activity

Beta-band amplitude oscillations in the human internal globus pallidus support the encoding of sequence boundaries during initial sensorimotor sequence learning

Sequential behavior characterizes both simple everyday tasks, such as getting dressed, and complex skills, such as music performance. The basal ganglia (BG) play an important role in the learning of motor sequences. To study the contribution of the human BG to the initial encoding of sequence boundaries, we recorded local field potentials in the sensorimotor area of the internal globus pallidus (GPi) during the early acquisition of sensorimotor sequences in patients undergoing deep brain stimulation for dystonia. We demonstrated an anticipatory modulation of pallidal beta-band neuronal oscillations that was specific to sequence boundaries, as compared to within sequence elements, and independent of both the movement parameters and the initiation/termination of ongoing movement. The modulation at sequence boundaries emerged with training, in parallel with skill learning, and correlated with the degree of long-range temporal correlations (LRTC) in the dynamics of ongoing beta-band amplitude oscillations. The implication is that LRTC of beta-band oscillations in the sensorimotor GPi might facilitate the emergence of beta power modulations by the sequence boundaries in parallel with sequence learning. Taken together, the results reveal the oscillatory mechanisms in the human BG that contribute at an initial learning phase to the hierarchical organization of sequential behavior as reflected in the formation of boundary delimited representations of action sequences

Repeating patterns : Predictive processing suggests an aesthetic learning role of the basal ganglia in repetitive stereotyped behaviors

Recurrent, unvarying, and seemingly purposeless patterns of action and cognition are part of normal development, but also feature prominently in several neuropsychiatric conditions. Repetitive stereotyped behaviors (RSBs) can be viewed as exaggerated forms of learned habits and frequently correlate with alterations in motor, limbic, and associative basal ganglia circuits. However, it is still unclear how altered basal ganglia feedback signals actually relate to the phenomenological variability of RSBs. Why do behaviorally overlapping phenomena sometimes require different treatment approaches−for example, sensory shielding strategies versus exposure therapy for autism and obsessive-compulsive disorder, respectively? Certain clues may be found in recent models of basal ganglia function that extend well beyond action selection and motivational control, and have implications for sensorimotor integration, prediction, learning under uncertainty, as well as aesthetic learning. In this paper, we systematically compare three exemplary conditions with basal ganglia involvement, obsessive-compulsive disorder, Parkinson’s disease, and autism spectrum conditions, to gain a new understanding of RSBs. We integrate clinical observations and neuroanatomical and neurophysiological alterations with accounts employing the predictive processing framework. Based on this review, we suggest that basal ganglia feedback plays a central role in preconditioning cortical networks to anticipate self-generated, movement-related perception. In this way, basal ganglia feedback appears ideally situated to adjust the salience of sensory signals through precision weighting of (external) new sensory information, relative to the precision of (internal) predictions based on prior generated models. Accordingly, behavioral policies may preferentially rely on new data versus existing knowledge, in a spectrum spanning between novelty and stability. RSBs may then represent compensatory or reactive responses, respectively, at the opposite ends of this spectrum. This view places an important role of aesthetic learning on basal ganglia feedback, may account for observed changes in creativity and aesthetic experience in basal ganglia disorders, is empirically testable, and may inform creative art therapies in conditions characterized by stereotyped behaviors.publishe

CLOVER-DBS: Algorithm-Guided Deep Brain Stimulation-Programming Based on External Sensor Feedback Evaluated in a Prospective, Randomized, Crossover, Double-Blind, Two-Center Study

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

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

Encoding of sequence boundaries in the subthalamic nucleus of patients with Parkinson's disease

Sequential behaviour is widespread not only in humans but also in animals, ranging in different degrees of complexity from locomotion to birdsong or music performance. The capacity to learn new motor sequences relies on the integrity of basal ganglia-cortical loops. In Parkinson's disease the execution of habitual action sequences as well as the acquisition of novel sequences is impaired partly due to a deficiency in being able to generate internal cues to trigger movement sequences. In addition, patients suffering from Parkinson's disease have difficulty initiating or terminating a self-paced sequence of actions. Direct recordings from the basal ganglia in these patients show an increased level of beta (14-30 Hz) band oscillatory activity associated with impairment in movement initiation. In this framework, the current study aims to evaluate in patients with Parkinson's disease the neuronal activity in the subthalamic nucleus related to the encoding of sequence boundaries during the explicit learning of sensorimotor sequences. We recorded local field potential activity from the subthalamic nucleus of 12 patients who underwent deep brain stimulation for the treatment of advanced Parkinson's disease, while the patients in their usual medicated state practiced sequences of finger movements on a digital piano with corresponding auditory feedback. Our results demonstrate that variability in performance during an early phase of sequence acquisition correlates across patients with changes in the pattern of subthalamic beta-band oscillations; specifically, an anticipatory suppression of beta-band activity at sequence boundaries is linked to better performance. By contrast, a more compromised performance is related to attenuation of beta-band activity before within-sequence elements. Moreover, multivariate pattern classification analysis reveals that differential information about boundaries and within-sequence elements can be decoded at least 100 ms before the keystroke from the amplitude of oscillations of subthalamic nucleus activity across different frequency bands, not just from the beta-band. Additional analysis was performed to assess the strength of how much the putative signal encoding class of ordinal position (boundaries, within-sequence elements) is reflected in each frequency band. This analysis demonstrates that suppression of power in the beta-band contains the most class-related information, whereas enhancement of gamma band (31-100 Hz) activity is the second main contributor to the encoding. Our findings support the hypothesis that subthalamic nucleus-mediated gating of salient boundary elements during sequence encoding may be a prerequisite for the adequate acquisition of action sequences and the transition to habitual behaviour