Low-beta cortico-pallidal coherence decreases during movement and correlates with overall reaction time

Beta band oscillations (13-30 Hz) are a hallmark of cortical and subcortical structures that are part of the motor system. In addition to local population activity, oscillations also provide a means for synchronization of activity between regions. Here we examined the role of beta band coherence between the internal globus pallidus (GPi) and (motor) cortex during a simple reaction time task performed by nine patients with idiopathic dystonia. We recorded local field potentials from deep brain stimulation (DBS) electrodes implanted in bilateral GPi in combination with simultaneous whole-head magneto-encephalography (MEG). Patients responded to visually presented go or stop-signal cues by pressing a button with left or right hand. Although coherence between signals from DBS electrodes and MEG sensors was observed throughout the entire beta band, a significant movement-related decrease prevailed in lower beta frequencies (∼13-21 Hz). In addition, patients' absolute coherence values in this frequency range significantly correlated with their median reaction time during the task (p = 0.003, r = 0.89). These findings corroborate the recent idea of two functionally distinct frequency ranges within the beta band, as well as the anti-kinetic character of beta oscillations

Simultaneous activation of multiple memory systems during learning : insights from electrophysiology and modeling

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2010.Cataloged from PDF version of thesis.Includes bibliographical references.Parallel cortico-basal ganglia loops are thought to give rise to a diverse set of limbic, associative and motor functions, but little is known about how these loops operate and how their neural activities evolve during learning. To address these issues, single-unit activity was recorded simultaneously in dorsolateral (sensorimotor) and dorsomedial (associative) regions of the striatum as rats learned two versions of a conditional T-maze task. The results demonstrate that contrasting patterns of activity developed in these regions during task performance, and evolved with different training-related dynamics. Oscillatory activity is thought to enable memory storage and replay, and may encourage the efficient transmission of information between brain regions. In a second set of experiments, local field potentials (LFPs) were recorded simultaneously from the dorsal striatum and the CAl field of the hippocampus, as rats engaged in spontaneous and instructed behaviors in the T-maze. Two major findings are reported. First, striatal LFPs showed prominent theta-band rhythms that were strongly modulated during behavior. Second, striatal and hippocampal theta rhythms were modulated differently during T-maze performance, and in rats that successfully learned the task, became highly coherent during the choice period. To formalize the hypothesized contributions of dorsolateral and dorsomedial striatum during T-maze learning, a computational model was developed. This model localizes a model-free reinforcement learning (RL) system to the sensorimotor cortico-basal ganglia loop and localizes a model-based RL system to a network of structures including the associative cortico-basal ganglia loop and the hippocampus. Two models of dorsomedial striatal function were investigated, both of which can account for the patterns of activation observed during T-maze training. The two models make differing predictions regarding activation of the dorsomedial striatum following lesions of the model-free system, depending on whether it serves a direct role in action selection through participation in a model-based planning system or whether it participates in arbitrating between the model-free and model-based controllers. Combined, the work presented in this thesis shows that a large network of forebrain structures is engaged during procedural learning. The results suggest that coordination across regions may be required for successful learning and/or task performance, and that the different regions may contribute to behavioral performance by performing distinct RL computations.by Catherine Ann Thorn.Ph.D

The effect of subthalamic deep brain stimulation on motor learning in Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus is an effective and adjustable treatment for Parkinson’s disease patients with (early) motor complications and has been shown to elicit changes in motor and non-motor cortico-basal ganglia circuits through modulation of distributed neural networks. Recent findings on subcortical basal ganglia - cerebellar anatomy have revealed projections from the subthalamic nucleus to cerebellar hemispheres, which might be modulated by subthalamic DBS. Both the basal ganglia and the cerebellum are known to be involved in motor learning and Parkinson’s disease. This study aimed at investigating the effect of subthalamic DBS on motor learning in Parkinson’s disease (PD) and characterizing underlying neural networks. To this end, 20 Parkinson’s disease patients undergoing subthalamic DBS and 20 age-matched healthy controls performed a visuomotor task. Motor learning was assessed as reduction in movement times from beginning to end of task for each group. DBS electrodes were localized and projected to a publicly available normative connectome (1000 healthy subjects) and a connectivity map for DBS induced improvement in motor learning was calculated. Region of interest analysis was performed to assess the role of connectivity to motor cortex (M1) and cerebellar hemispheres in DBS induced learning. Permutation tests and multiple regressions were conducted for the main statistical analyses; for significant regression models and correlations leave one out cross validation (LOOCV) was performed. Motor learning was impaired in Parkinson’s disease patients off DBS comparing with healthy controls (PD off DBS: 12.2±5.4% from 1311±160ms to 1089±118ms; mean ± standard error of mean; healthy controls: 33.48±3.6% from 729±63ms to 473±42ms; off DBS vs. healthy controls P=0.002). STN-DBS led to a statistically significant improvement in motor learning (PD on DBS: 27.7±6.1% from 940±120ms to 615±84ms; on vs. off DBS P=0.01). There was no statistically significant difference between patients on DBS and healthy controls (P=0.4). DBS induced improvement in motor learning was not correlated with improvement in motor deficits (R=-0.02, P=0.5). A specific connectivity profile including the right cerebellar hemisphere was associated with improved motor learning through DBS (R²=0.33, P=0.01; LOOCV: R=0.43, P=0.028). Region of interest analysis revealed the ipsilateral cerebellum to be the best predictor of DBS induced motor learning (R2=0.34, P=0.008; LOOCV: R=0.045, P=0.02). Here, connectivity to the STN was higher than to M1, suggesting a putative role of the recently discovered basal ganglia - cerebellar circuit bypassing the cortex. This study extends current knowledge on motor learning in Parkinson’s disease and highlights the notion of network modulation in DBS.Die Tiefe Hirnstimulation (THS) des Nucleus subthalamicus ist eine effektive Therapiealternative für Patienten mit idiopathischem Parkinson Syndrom (IPS) und (frühen) motorischen Komplikationen, welche zu verschiedenen motorischen und nicht-motorischen Effekten in der Kortex-Basalganglienschleife führt. Es ist lange bekannt, dass die Basalganglien und das Kleinhirn sowohl beim IPS als auch beim motorischen Lernen eine Rolle spielen. Neue anatomische Studien zeigten eine disynaptische subkortikale Verbindung zwischen den Nucleus subthalamicus und den Kleinhirnhemisphären mit bisher unklarer funktioneller Bedeutung. Die vorliegende Studie untersucht den Effekt subthalamischer THS auf motorisches Lernen beim idiopathischen Parkinson Syndrom mit dem Ziel, zugrundeliegende neuronale Netzwerke zu charakterisieren. Hierfür führten 20 Patienten mit IPS unter THS und 20 altersgepaarte gesunde Probanden eine visuomotorische Reaktionszeitaufgabe durch. Motorisches Lernen wurde als Verbesserung der Bewegungszeiten durch Wiederholung der Aufgabe definiert. THS Elektroden wurden lokalisiert und auf ein öffentlich verfügbares normatives funktionelles MRT Konnektom projiziert (1000 gesunde Probanden). Das optimale Konnektivitätsprofil für THS induziertes motorisches Lernen wurde berechnet. Zusätzlich wurde eine Konnektivitätsanalyse durchgeführt, um die Rolle der Verbindung von aktiven THS Kontakten zum motorischen Kortex und zu den Kleinhirnhemisphären für THS induziertes Lernen zu untersuchen. Die statistische Auswertung der Hauptergebnisse erfolgte durch Monte Carlo Permutation und multiple Regressionen; statistisch signifikante Regressionsmodelle und Korrelationen wurden mittels der „Leave one out“ Methode kreuzvalidiert. Patienten mit IPS und ausgeschalteter THS zeigten ein signifikant beeinträchtigtes motorisches Lernen im Vergleich zu gesunden Kontrollen (IPS mit THS OFF: 12.2±5.4%, von 1311±160ms auf 1089±118ms; gesunde Kontrollen: 33.48±3.6%, von 729±63ms auf 473±42ms; P=0.002). Die subthalamische THS führte zu einer statistisch signifikanten Verbesserung des motorischen Lernens in Patienten mit IPS (IPS mit THS ON: 27.7±6.1%, von 940±120ms auf 615±84ms; P=0.01). Es ergab sich kein signifikanter Unterschied zwischen Patienten mit eingeschalteter THS und gesunden Kontrollen (P=0.4). THS induziertes motorisches Lernen korrelierte nicht mit Linderung motorischer Symptome (R=-0.02, P=0.5). Es konnte ein spezifisches fMRT Konnektivitätsprofil von den aktiven THS Kontakten definiert werden, welches prädiktiv für den Effekt der THS auf motorisches Lernen war (R²=0.33, P=0.01; LOOCV: R=0.43, P=0.028). Eine weiterführende Analyse ergab einen gesonderten Einfluss der rechten Kleinhirnhemisphäre als bester Prädiktor für THS induziertes motorisches Lernen (R2=0.34, P=0.008; LOOCV: R=0.045, P=0.02). In diesen Voxels war funktionelle Konnektivität zum Nucleus subthalamicus höher als zum motorischen Kortex, hinweisend auf eine relevante Rolle der beschriebenen direkten Verbindung vom Nucleus subthalamicus zu den Kleinhirnhemisphären. Diese Studie liefert neue Erkenntnisse über den Zusammenhang von motorischem Lernen und der Neuromodulation motorischer Netzwerke beim idiopathischen Parkinson Syndrom und erweitert das Konzept der Netzwerkmodulation als mechanistisches Modell zur Wirksamkeit der THS

Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.DP2 NS082126 - NINDS NIH HHS; R01 NS081716 - NINDS NIH HHS; R21 NS078660 - NINDS NIH HHShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896681/Published versio

Neuroplasticity following pallidal stimulation for dystonia.

Dystonia is a disabling condition characterised by involuntary muscle spasms and abnormal postures. Its pathophysiology is incompletely understood but most lines of evidence point to an underlying defect of basal ganglia function leading to abnormal corticomotor output. Various abnormalities have been shown, including abnormal neuronal activity in basal ganglia output nuclei, defective neural inhibition at the spinal, brainstem, cortical level and sensorimotor misprocessing. More recently, increased neural plasticity has been found in dystonia patients in response to transcranial magnetic stimulation (TMS) protocols which induce motor cortex plasticity. Excessive plasticity might contribute to dystonia by promoting or reinforcing abnormal patterns of connectivity. The most significant advance in the treatment of generalised dystonia has been the development of globus pallidus internus (GPi) deep brain stimulation (DBS). Interestingly its beneficial effects are progressive over weeks to months rather than immediate. A plasticity effect has been implicated but physiological evidence has been lacking. Furthermore it is unknown what impact GPi DBS has on the underlying pathophysiology such as defective inhibition or excessive plasticity. The aim of the present work was to examine the impact of GPi DBS on underlying pathophysiological features such as disinhibition and abnormal motor cortical plasticity. In this thesis, studies in a consecutive series of dystonia patients, mainly those with primary generalised dystonia, who underwent bilateral GPi DBS, are presented. Patients were studied in a prospective, longitudinal manner with both clinical assessment of dystonia using a validated rating scale and electrophysiological studies including blink reflex excitability and forearm H-reflex reciprocal inhibition. In addition, once stable improvement had been achieved, the impact of GPi DBS on motor cortex plasticity was studied using TMS paired associative stimulation (PAS). The clinical study of these patients confirmed the therapeutic efficacy of GPi DBS and provided direct evidence of the superiority of the posteroventral globus pallidus as the optimal target. The longitudinal studies of blink and H-reflex, showed progressive normalisation of brainstem and spinal excitability, which correlated with the time-course of clinical improvement. These data provide the first evidence of reversal of underlying dystonia pathophysiology by GPi DBS and are compatible with progressive long-term neural reorganisation (plasticity) playing a role in the mechanism of action of GPi DBS. Furthermore, the result of TMS PAS experiments demonstrated that GPi DBS reduces the short-term plasticity of the motor cortex, the magnitude of this effect also correlated with therapeutic effect. This result is compatible with the concept that excessive plasticity promotes dystonia and reversal of these abnormalities may be another mechanism by which GPi DBS acts. In conclusion, work presented in this thesis provides the first electrophysiological correlates of clinical improvement in dystonia after GPi DBS, which collectively supports the notion that both long and short-term plasticity within the central nervous system are involved in the mechanism of GPi DBS action

The role of oscillation population activity in cortico-basal ganglia circuits.

The basal ganglia (BG) are a group of subcortical brain nuclei that are anatomically situated between the cortex and thalamus. Hitherto, models of basal ganglia function have been based solely on the anatomical connectivity and changes in the rate of neurons mediated by inhibitory and excitatory neurotransmitter interactions and modulated by dopamine. Depletion of striatal dopamine as occurs in Parkinson's Disease (PD) however, leads primarily to changes in the rhythmicity of basal ganglia neurons. The general aim of this thesis is to use frontal electrocorticogram (ECoG) and basal ganglia local field potential (LFP) recordings in the rat to further investigate the putative role for oscillations and synchronisation in these structures in the healthy and dopamine depleted brain. In the awake animal, lesion of the SNc lead to a dramatic increase in the power and synchronisation of P-frequency band oscillations in the cortex and subthalamic nucleus (STN) compared to the sham lesioned animal. These results are highly similar to those in human patients and provide further evidence for a direct pathophysological role for p-frequency band oscillations in PD. In the healthy, anaesthetised animal, LFPs recorded in the STN, globus pallidus (GP) and substantia nigra pars reticulata (SNr) were all found to be coherent with the ECoG. A detailed analysis of the interdependence and direction of these activities during two different brain states, prominent slow wave activity (SWA) and global activation, lead to the hypothesis that there were state dependant changes in the dominance of the cortico-subthalamic and cortico-striatal pathways. Multiple LFP recordings in the striatum and GP provided further evidence for this hypothesis, as coherence between the ECoG and GP was found to be dependent on the striatum. Together these results suggest that oscillations and synchronisation may mediate information flow in cortico-basal ganglia networks in both health and disease

Alterations in the amplitude and burst rate of beta oscillations impair reward-dependent motor learning in anxiety

Anxiety results in sub-optimal motor learning, but the precise mechanisms through which this effect occurs remain unknown. Using a motor sequence learning paradigm with separate phases for initial exploration and reward-based learning, we show that anxiety states in humans impair learning by attenuating the update of reward estimates. Further, when such estimates are perceived as unstable over time (volatility), anxiety constrains adaptive behavioral changes. Neurally, anxiety during initial exploration increased the amplitude and the rate of long bursts of sensorimotor and prefrontal beta oscillations (13–30 Hz). These changes extended to the subsequent learning phase, where phasic increases in beta power and burst rate following reward feedback were linked to smaller updates in reward estimates, with a higher anxiety-related increase explaining the attenuated belief updating. These data suggest that state anxiety alters the dynamics of beta oscillations during reward processing, thereby impairing proper updating of motor predictions when learning in unstable environments

Cingulate and cerebellar beta oscillations are engaged in the acquisition of auditory‐motor sequences

Singing, music performance, and speech rely on the retrieval of complex sounds, which are generated by the corresponding actions and are organized into sequences. It is crucial in these forms of behavior that the serial organization (i.e., order) of both the actions and associated sounds be monitored and learned. To investigate the neural processes involved in the monitoring of serial order during the initial learning of sensorimotor sequences, we performed magnetoencephalographic recordings while participants explicitly learned short piano sequences under the effect of occasional alterations of auditory feedback (AAF). The main result was a prominent and selective modulation of beta (13–30 Hz) oscillations in cingulate and cerebellar regions during the processing of AAF that simulated serial order errors. Furthermore, the AAF-induced modulation of beta oscillations was associated with higher error rates, reflecting compensatory changes in sequence planning. This suggests that cingulate and cerebellar beta oscillations play a role in tracking serial order during initial sensorimotor learning and in updating the mapping of the sensorimotor representations. The findings support the notion that the modulation of beta oscillations is a candidate mechanism for the integration of sequential motor and auditory information during an early stage of skill acquisition in music performance. This has potential implications for singing and speech

Deep Brain Stimulation (DBS) Applications

The issue is dedicated to applications of Deep Brain Stimulation and, in this issue, we would like to highlight the new developments that are taking place in the field. These include the application of new technology to existing indications, as well as ‘new’ indications. We would also like to highlight the most recent clinical evidence from international multicentre trials. The issue will include articles relating to movement disorders, pain, psychiatric indications, as well as emerging indications that are not yet accompanied by clinical evidence. We look forward to your expert contribution to this exciting issue

The Behavioral and Neurophysiologic Effects of Acute Dopamine Receptor Blockade in the Macaque Striatum

The pathophysiology of Parkinson's disease (PD) has long been attributed to dopamine (DA) loss in the striatum. However, it remains unclear whether simple underactivation of striatal DA receptors is sufficient to induce parkinsonian signs. To test this hypothesis, we performed unilateral infusions of cis-flupenthixol (cis-flu; D1/D2 antagonist) into the macaque putamen, while the macaque performed a reaching task. Twenty-six cis-flu and three saline infusions were performed across three hemispheres in two macaques. Neuronal and local field potential activity was recorded simultaneously from cortex, globus pallidus externa (GPe), and globus pallidus interna (GPi) during most infusions. The reaching task required each macaque to make visually-cued reaching movements to a target for a reward. The macaque was then required to return its hand to a home position without external cues. Injection-related slowing of movement initiation or execution was thought to reflect akinetic- or bradykinetic-like effects, respectively. Following 8/26 cis-flu infusions, macaques exhibited a marked slowing in the initiation of self-generated return movements (95% increase). This was the most severe behavioral effect of cis-flu infusions. The initiation and execution of externally-cued movements were also prolonged following 9/26 and 6/26 injections, but only by 20% and 15% respectively. In general, akinetic-like effects occurred twice as often as bradykinetic-like effects (p<0.05, 2= 4.1). Interestingly, akinetic and bradykinetic effects could be elicited independently. In addition to affecting behavior, intrastriatal DA receptor blockade also reduced resting and peri-movement activity in the cortex and suppressed resting GPe activity. Burstiness, synchrony, and oscillatory activity in cortex were increased following intrastriatal DA receptor blockade as well. Oscillatory activity was also increased in the GPe and GPi. In conclusion, suppression of striatal DA activity was sufficient to induce akinetic-like signs, most severely affecting movement initiation during self-generated movements. Furthermore, distinct parkinsonian-like signs could be elicited independently, suggesting that separate signs may have unique pathophysiologic substrates. Intrastriatal DA receptor blockade also induced changes in cortical and BG activity that were consistent with findings in the parkinsonian state. Interestingly, many of these neuronal activity changes were specific to cortex, implicating an important role for cortical activity in the development of akinetic parkinsonian signs