Functional and structural plasticity co-express in a left premotor region during early bimanual skill learning

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Untersuchung des Einflusses von subthalaimischer Tiefer Hirnstimulation auf kognitive und affektive Prozesse

As neuromodulatory treatment, subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) undergoes a current paradigm shift, away from being seen as mainly a therapy to improve motor symptoms toward being a window to better understanding of nonmotor networks converging in the basal ganglia. Since the STN is a hub for the integration of cognitive and affective processes into the motor response, DBS impacts interaction of basal ganglia with motor, associative and affective brain regions. STN-DBS leads to cognitive and affective changes that either classify as improvements or disturbances of behaviour when compared to the baseline bias that PD has on nonmotor function per se. This thesis attempted to improve the understanding of mechanisms underlying DBS effects on cognitive and affective processing by assessing nonmotor DBS-effects in understudied domains like decision-making and emotional processing and to relate the findings to computational or anatomical reconstructions of basal ganglia-cortex interactions or STN functional anatomy. To this end, five studies are presented, the results of which are complementary in understanding local and global impact of DBS on the brain and associated nonmotor behavioural changes. Study 1 assessed impact of STN-DBS on emotional conflict processing in a perceptual decision-making task and found that DBS lead to the disability to slow down responses when cognitive control was required and at the same time to a blunting of a PD-inherent bias to process positive information more slowly than negative information. Coherently, Study 4 of this thesis compared response times in automatic movement versus movement that require cognitive control and found that DBS induced a disinhibition that was related to a disruption of cortex-STN coupling via the hyperdirect pathway. Study 2 also assessed changes in decision-making under DBS but in the domain of risk-reward trade-off decisions. Here, it was again found that a PD-specific bias, namely, to take too little risks, could be altered by STN-DBS. Specifically, when motor STN territory was stimulated, risk attitude normalized to a healthy level. This nonmotor benefit of effective STN-DBS is coherent with the results of Study 3 and 4, where impact on the STN motor territory was related to a normalization of depressive symptoms and a functional connectivity that was similar to that of healthy controls. Together, these studies imply that DBS of the STN motor territory induces improvements in value-based decision-making, depression and functional connectivity, while causing impairments in cognitive inhibition during the recruitment of cognitive control. Electrode misplacement however can lead to behavioural disturbances through impact on nonmotor networks like the left prefrontal cortex, the connectivity to which, if disrupted by DBS, explains worsening of depression. The results of this thesis are of high clinical value since they can aid refinement of DBS programming, inform tailored DBS therapy and help to better understand and in the future avoid DBS side effects.Die Tiefe Hirnstimulation des Nucleus subthalamicus (STN-THS) wird bei Morbus Parkinson (PD) zur Verbesserung der motorischen Symptome eingesetzt. Als neuromodulatorische Behandlung bietet sie jedoch auch Zugang zu verbessertem Verständnis nichtmotorischer Netzwerke in den Basalganglien. Da der STN einen Konvergenzpunkt für die Integration kognitiver und affektiver Prozesse in die motorische Reaktion darstellt, beeinflusst die THS die Interaktion der Basalganglien mit motorischen, assoziativen und affektiven Hirnregionen. STN-THS kann daher auch zu kognitiven und affektiven Veränderungen führen, die verglichen mit den krankheitsbedingten nichtmotorischen Veränderungen bei PD entweder als förderlich oder störend für das Verhalten klassifiziert werden können. Diese Dissertation versucht, das Verständnis der Mechanismen zu verbessern, die den Effekten, die THS auf die kognitive und affektive Verarbeitung hat, zugrunde liegen. Hierzu wurden nichtmotorische THS-Effekte in Bereichen wie Entscheidungsfindung und emotionaler Verarbeitung erfasst und die Ergebnisse mit computationalen Modellen, anatomischen Rekonstruktionen von Basalganglien-Kortex-Wechselwirkungen oder der funktionellen Anatomie des STN in Beziehung gesetzt. Es werden fünf Studien vorgestellt, deren Ergebnisse zum Verständnis der lokalen und globalen Auswirkungen von THS auf das Gehirn und der damit verbundenen nichtmotorischen Verhaltensänderungen beitragen. In Studie 1 wurde die Auswirkung von STN-THS auf die Verarbeitung emotional-perzeptiver Konflikte in einer Entscheidungsaufgabe erhoben und festgestellt, dass THS dazu führte, dass die motorischen Reaktionen nicht adäquat verlangsamt werden, wenn kognitive Kontrolle erforderlich ist. Gleichzeitig schwächte STN-THS eine PD-inhärente Tendenz ab, positive Informationen langsamer zu verarbeiten als negative Informationen. Ergänzend dazu wurden in Studie 4 dieser Dissertation Reaktionszeiten bei automatischen Bewegungen mit jenen verglichen, die kognitive Kontrolle erforderten. Hier konnte die DBS-induzierte Disinhibition in kontrollierten Bewegungen mit einer Störung der Cortex-STN-Kopplung über den hyperdirekten Pfad erklärt werden. In Studie 2 wurden auch Änderungen in der Entscheidungsfindung unter THS erhoben, jedoch wurden speziell Entscheidungen betrachtet, in denen zwischen Risiko und Belohnung abgewogen werden musste. Es zeigte sich, dass die PD-spezifische kognitive Einschränkung, in Entscheidungssituationen zu wenig Risiko einzugehen, durch STN-THS ausgeglichen werden konnte. Interessanterweise war der Effekt abhängig von der Elektrodenposition: Wenn der motorische Teil des STN stimuliert wurde, normalisierte sich das Risikoverhalten auf ein gesundes Niveau. Dieser nichtmotorische Nutzen einer motorisch wirksamen STN-THS steht in Einklang mit den Studien 3 und 4, in denen Stimulation des motorischen STN zu einer Normalisierung der depressiven Symptomatik und der funktionellen Konnektivität führte. Zusammengenommen deuten die Ergebnisse der Studien dieser Dissertation darauf hin, dass die THS des motorischen STN zusätzlich zu ihrem motorischen Effekt auch positive Auswirkungen auf nichtmotorische Fähigkeiten haben kann: Sie führt zu einer Normalisierung von wertbasierten Entscheidungen, depressiver Symptomatik und funktioneller Konnektivität. Gleichzeitig vermindert die THS jedoch eine Inhibition der motorischen Antwort in Reaktionszeitaufgaben, die kognitive Kontrolle bedürfen. Zudem kann eine Fehlplatzierung der THS-Elektroden dazu führen, dass nichtmotorische Netzwerke beeinträchtigt werden. Beispielsweise zeigt Studie 3, dass Stimulation von Fasern, die mit dem linken präfrontalen Kortex verbunden sind, zu einer Verschlechterung der depressiven Symptomatik bei PD Patienten führen können. Die Ergebnisse dieser Dissertation haben einen großen klinischen Wert, da sie zu einer Verfeinerung der THS-Programmierung verhelfen und den Weg zu einer individualisierten THS-Therapie, die basierend auf Anatomie und patientenspezifischer Symptomatik eingestellt wird, aufzeigen. Außerdem leisten sie einen Beitrag zum Verständnis der Hintergründe kognitiver und affektiver THS-Effekte und dadurch zur potenziellen Vermeidung von THS-induzierten Nebenwirkungen

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

Pharmacological Dopamine Manipulation Does Not Alter Reward-Based Improvements in Memory Retention during a Visuomotor Adaptation Task

Motor adaptation tasks investigate our ability to adjust motor behaviors to an ever-changing and unpredictable world. Previous work has shown that punishment-based feedback delivered during a visuomotor adaptation task enhances error-reduction, whereas reward increases memory retention. While the neural underpinnings of the influence of punishment on the adaptation phase remain unclear, reward has been hypothesized to increase retention through dopaminergic mechanisms. We directly tested this hypothesis through pharmacological manipulation of the dopaminergic system. A total of 96 young healthy human participants were tested in a placebo-controlled double-blind between-subjects design in which they adapted to a 40° visuomotor rotation under reward or punishment conditions. We confirmed previous evidence that reward enhances retention, but the dopamine (DA) precursor levodopa (LD) or the DA antagonist haloperidol failed to influence performance. We reason that such a negative result could be due to experimental limitations or it may suggest that the effect of reward on motor memory retention is not driven by dopaminergic processes. This provides further insight regarding the role of motivational feedback in optimizing motor learning, and the basis for further decomposing the effect of reward on the subprocesses known to underlie motor adaptation paradigms

A computational model‐based analysis of basal ganglia pathway changes in Parkinson’s disease inferred from resting‐state fMRI

Previous computational model-based approaches for understanding the dynamic changes related to Parkinson's disease made particular assumptions about Parkinson's disease-related activity changes or specified dopamine-dependent activation or learning rules. Inspired by recent model-based analysis of resting-state fMRI, we have taken a data-driven approach. We fit the free parameters of a spiking neuro-computational model to match correlations of blood oxygen level-dependent signals between different basal ganglia nuclei and obtain subject-specific neuro-computational models of two subject groups: Parkinson patients and matched controls. When comparing mean firing rates at rest and connectivity strengths between the control and Parkinsonian model groups, several significant differences were found that are consistent with previous experimental observations. We discuss the implications of our approach and compare its results also with the popular “rate model” of the basal ganglia. Our study suggests that a model-based analysis of imaging data from healthy and Parkinsonian subjects is a promising approach for the future to better understand Parkinson-related changes in the basal ganglia and corresponding treatments

Functional connectivity maps of theta/alpha and beta coherence within the subthalamic nucleus region

The subthalamic nucleus (STN) is a primary target for deep brain stimulation in Parkinson's disease (PD). Although small in size, the STN is commonly partitioned into sensorimotor, cognitive/associative, and limbic subregions based on its structural connectivity profile to cortical areas. We investigated whether such a regional specialization is also supported by functional connectivity between local field potential recordings and simultaneous magnetoencephalography. Using a novel data set of 21 PD patients, we replicated previously reported cortico-STN coherence networks in the theta/alpha and beta frequency ranges, and looked for the spatial distribution of these networks within the STN region. Although theta/alpha and beta coherence peaks were both observed in on-medication recordings from electrode contacts at several locations within and around the STN, sites with theta/alpha coherence peaks were situated at significantly more inferior MNI coordinates than beta coherence peaks. Sites with only theta/alpha coherence peaks, i.e. without distinct beta coherence, were mostly located near the border of sensorimotor and cognitive/associative subregions as defined by a tractography-based atlas of the STN. Peak coherence values were largely unaltered by the medication state of the subject, however, theta/alpha peaks were more often identified in recordings obtained after administration of dopaminergic medication. Our findings suggest the existence of a frequency-specific topography of cortico-STN coherence within the STN, albeit with considerable spatial overlap between functional networks. Consequently, optimization of deep brain stimulation targeting might remain a trade-off between alleviating motor symptoms and avoiding adverse neuropsychiatric side effects