Reward and punishment are potent modulators of associative learning in instrumental and classical conditioning. However, the effect of reward and punishment on procedural learning is not known. The striatum is known to be an important locus of reward-related neural signals and part of the neural substrate of procedural learning. Here, using an implicit motor learning task, we show that reward leads to enhancement of learning in human subjects, whereas punishment is associated only with improvement in motor performance. Furthermore, these behavioral effects have distinct neural substrates with the learning effect of reward being mediated through the dorsal striatum and the performance effect of punishment through the insula. Our results suggest that reward and punishment engage separate motivational systems with distinctive behavioral effects and neural substrates.

Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial.

No abstract

This study provides Class IV evidence that long-term GPi-DBS improves dystonia in patients with DYT1, DYT6, and non-DYT dystonia.

Twenty non-demented patients with idiopathic Parkinson's disease (PD) underwent single photon emission computed tomography (SPECT) with [123I]beta-CIT to further investigate the contribution of nigrostriatal dysfunction to cognitive and motor deficits. Compared to matched controls PD patients showed normal verbal intelligence, short-term memory and phasic alertness. There were significant (p < 0.05) deficits in tests of verbal working memory (digit ordering, reading span), strategic memory (story recall) and executive functions (card sorting), indicating a "prefrontal" cognitive deficit. Significant (p < 0.05) correlations were observed between dopamine transporter (DAT) density in the putamen and motor deficits as well as between DAT density in both striatal compartments (head of the caudate nucleus and putamen) and prefrontal functioning. Age was a major contributing factor to both cognitive status and nigrostriatal integrity as measured by [123I]beta-CIT SPECT. These results support the view that the striatum is part of a neuronal network that is mediating prefrontal cognitive functions.

ObjectiveTo investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications.MethodsWe performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-up with disease-specific QOL (39-item Parkinson's Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson’s Disease Rating Scale (UPDRS) (UPDRS-III “off” and “on” medications, UPDRS-IV) were conducted to determine predictors of change in PDQ-39-SI.ResultsPDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups (p < 0.05). The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group.ConclusionImpaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS.Clinicaltrials.gov identifierNCT00354133.

No abstract

Severe gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages [1,2] with an important impact on quality of life [3][4][5]. While segmental symptoms generally respond well to dopaminergic medication and high-frequent deep brain stimulation of the subthalamic nucleus (STN-DBS), treatment of gait disturbances often remains unsatisfactory [5][6][7]. DBS of the pedunculopontine area is currently under investigation to treat gait disturbances and imbalance in PD; however, appropriate targeting and patient selection remain controversial [8][9][10]. Here, we describe a novel stimulation paradigm of simultaneous stimulation on distant electrode contacts located in the STN and the caudal border zone between the STN and substantia nigra pars reticulata (SNr) in a patient with a severe hypokinetic gait disturbance.A 72-year-old female patient with PD (Hoehn & Yahr IV, disease duration 20 years) with severe dopaminergic motor fluctuations including wearing off, peak-dose dyskinesias since 2007, and severe hypokinetic gait disturbance was referred to our center for deep brain stimulation and, therefore, considered for STN-DBS. A quadripolar electrode (type 3389, Medtronic, Minneapolis, MN, USA) was inserted into each STN and connected to an implantable pulse stimulator (Activa PC, Medtronic, Minneapolis, MN, USA). Localizations of the active electrode contacts were determined from the postoperative MR imaging and co-registration between pre-and postoperative imaging.Stimulation pulses can be delivered more selectively on distant contacts of a lead using a novel paradigm of the socalled 'interleaved pulses', i.e., impulses are delivered simultaneously on two different contacts in alternating order (e.g., 125 Hz on each contact). Importantly, each of the contacts can be programmed with specific parameters (e.g., amplitude, pulse width). Short-term effects of three different stimulator settings on a timed walking test [11] were tested 6 months after DBS surgery after 30 minutes of constant settings: (1) stimulation off [StimOff], (2) conventional stimulation on proximal STN contacts [STNmono], and (3) combined [STN ? SNr] using interleaving pulses on contacts located in both the STN area and the caudal border zone of STN and SNr (detailed parameters in Table 1). Dopaminergic medications were withdrawn overnight. In order to limit the patient's knowledge of the current stimulator settings, DBS was switched on and off several times before the final parameters were maintained. Further follow-up examinations on both [STNmono] and [STN ? SNr] were performed after 2 weeks of constant stimulation on either setting. The freezing of gait questionnaire (FOG-Q) [12], PD-Q 39, and axial UPDRS subscores (UPDRS II, items 13-15 and Electronic supplementary material The online version of this article (