Cortico-basal Ganglia Network Research Articles

Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensembles

Defining spatial synchronisation of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronisation could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifies groups of signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a “beta ensemble”. Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5 ms) synchrony in the raw BUA signal and phase synchronisation with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise of a single synchronisation process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.

Tuned to Tremor: Increased Sensitivity of Cortico-Basal Ganglia Neurons to Tremor Frequency in the MPTP Nonhuman Primate Model of Parkinson's Disease.

Rest tremor is one of the most prominent clinical features of Parkinson's disease (PD). Here, we hypothesized that cortico-basal ganglia neurons tend to fire in a pattern that matches PD tremor frequency, suggesting a resonance phenomenon. We recorded spiking activity in the primary motor cortex (M1) and globus pallidus external segment of 2 female nonhuman primates, before and after parkinsonian state induction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The arm of nonhuman primates was passively rotated at seven different frequencies surrounding and overlapping PD tremor frequency. We found entrainment of the spiking activity to arm rotation and a significant sharpening of the tuning curves in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine state, with a peak response at frequencies that matched the frequency of PD tremor. These results reveal increased sensitivity of the cortico-basal ganglia network to tremor frequency and could indicate that this network acts not only as a tremor switch but is involved in setting its frequency.SIGNIFICANCE STATEMENT Tremor is a prominent clinical feature of Parkinson's disease; however, its underlying pathophysiology is still poorly understood. Using electrophysiological recordings of single cortico-basal ganglia neurons before and after the induction of a parkinsonian state, and in response to passive arm rotation, this study reports increased sensitivity to tremor frequency in Parkinson's disease. We found sharpening of the population tuning to the midrange of the tested frequencies (1-13.3 Hz) in the healthy state that further increased in the parkinsonian state. These results hint at the increased frequency-tuned sensitivity of cortico-basal ganglia neurons and suggest that they tend to resonate with the tremor.

Multivariable closed-loop control of deep brain stimulation for Parkinson’s disease

Objective. Closed-loop deep brain stimulation (DBS) methods for Parkinson’s disease (PD) to-date modulate either stimulation amplitude or frequency to control a single biomarker. While good performance has been demonstrated for symptoms that are correlated with the chosen biomarker, suboptimal regulation can occur for uncorrelated symptoms or when the relationship between biomarker and symptom varies. Control of stimulation-induced side-effects is typically not considered. Approach. A multivariable control architecture is presented to selectively target suppression of either tremor or subthalamic nucleus beta band oscillations. DBS pulse amplitude and duration are modulated to maintain amplitude below a threshold and avoid stimulation of distal large diameter axons associated with stimulation-induced side effects. A supervisor selects between a bank of controllers which modulate DBS pulse amplitude to control rest tremor or beta activity depending on the level of muscle electromyographic (EMG) activity detected. A secondary controller limits pulse amplitude and modulates pulse duration to target smaller diameter axons lying close to the electrode. The control architecture was investigated in a computational model of the PD motor network which simulated the cortico-basal ganglia network, motoneuron pool, EMG and muscle force signals. Main results. Good control of both rest tremor and beta activity was observed with reduced power delivered when compared with conventional open loop stimulation, The supervisor avoided over- or under-stimulation which occurred when using a single controller tuned to one biomarker. When DBS amplitude was constrained, the secondary controller maintained the efficacy of stimulation by increasing pulse duration to compensate for reduced amplitude. Dual parameter control delivered effective control of the target biomarkers, with additional savings in the power delivered. Significance. Non-linear multivariable control can enable targeted suppression of motor symptoms for PD patients. Moreover, dual parameter control facilitates automatic regulation of the stimulation therapeutic dosage to prevent overstimulation, whilst providing additional power savings.

The Effects of Subthalamic Nucleus Deep Brain Stimulation and Retention Delay on Memory-Guided Reaching Performance in People with Parkinson's Disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) improves intensive aspects of movement (velocity) in people with Parkinson's disease (PD) but impairs the more cognitively demanding coordinative aspects of movement (error). We extended these findings by evaluating STN-DBS induced changes in intensive and coordinative aspects of movement during a memory-guided reaching task with varying retention delays. We evaluated the effect of STN-DBS on motor control during a memory-guided reaching task with short and long retention delays in participants with PD and compared performance to healthy controls (HC). Eleven participants with PD completed the motor section of the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and performed a memory-guided reaching task under four different STN-DBS conditions (DBS-OFF, DBS-RIGHT, DBS-LEFT, and DBS-BOTH) and two retention delays (0.5 s and 5 s). An additional 13 HC completed the memory-guided reaching task. Unilateral and bilateral STN-DBS improved the MDS-UPDRS III scores. In the memory-guided reaching task, both unilateral and bilateral STN-DBS increased the intensive aspects of movement (amplitude and velocity) in the direction toward HC but impaired coordinative aspects of movement (error) away from the HC. Furthermore, movement time was decreased but reaction time was unaffected by STN-DBS. Shorter retention delays increased amplitude and velocity, decreased movement times, and decreased error, but increased reaction times in the participants with PD. There were no interactions between STN-DBS condition and retention delay. STN-DBS may affect cognitive-motor functioning by altering activity throughout cortico-basal ganglia networks and the oscillatory activity subserving them.

Exercise alters cortico-basal ganglia network metabolic connectivity: a mesoscopic level analysis informed by anatomic parcellation defined in the mouse brain connectome

The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in metabolic connectivity in the cortico-basal ganglia-thalamic network during the performance of a new motor task, with regions-of-interest defined based on mesoscopic domains recently defined in the mouse brain structural connectome. Mice were trained on a motorized treadmill for six weeks or remained sedentary (control), thereafter undergoing [14C]-2-deoxyglucose metabolic brain mapping during wheel walking. Regional cerebral glucose uptake (rCGU) was analyzed in 3-dimensional brains reconstructed from autoradiographic brain sections using statistical parametric mapping. Metabolic connectivity was assessed by calculating inter-regional correlation of rCGU cross-sectionally across subjects within a group. Compared to controls, exercised animals showed broad decreases in rCGU in motor areas, but increases in limbic areas, as well as the visual and association cortices. In addition, exercised animals showed (i) increased positive metabolic connectivity within and between the motor cortex and caudoputamen (CP), (ii) newly emerged negative connectivity of the substantia nigra pars reticulata with the globus pallidus externus, and CP, and (iii) reduced connectivity of the prefrontal cortex (PFC). Increased metabolic connectivity in the motor circuit in the absence of increases in rCGU strongly suggests greater network efficiency, which is also supported by the reduced involvement of PFC-mediated cognitive control during the performance of a new motor task. Our study delineates exercise-associated changes in functional circuitry at the subregional level and provides a framework for understanding the effects of exercise on functions of the cortico-basal ganglia-thalamic network.

Cortico-basal ganglia networks dysfunction associated with disease severity in patients with idiopathic blepharospasm.

Structural changes occur in brain regions involved in cortico-basal ganglia networks in idiopathic blepharospasm (iBSP); whether these changes influence the function connectivity patterns of cortico-basal ganglia networks remains largely unknown. Therefore, we aimed to investigate the global integrative state and organization of functional connections of cortico-basal ganglia networks in patients with iBSP. Resting-state functional magnetic resonance imaging data and clinical measurements were acquired from 62 patients with iBSP, 62 patients with hemifacial spasm (HFS), and 62 healthy controls (HCs). Topological parameters and functional connections of cortico-basal ganglia networks were evaluated and compared among the three groups. Correlation analyses were performed to explore the relationship between topological parameters and clinical measurements in patients with iBSP. We found significantly increased global efficiency and decreased shortest path length and clustering coefficient of cortico-basal ganglia networks in patients with iBSP compared with HCs, however, such differences were not observed between patients with HFS and HCs. Further correlation analyses revealed that these parameters were significantly correlated with the severity of iBSP. At the regional level, the functional connectivity between the left orbitofrontal area and left primary somatosensory cortex and between the right anterior part of pallidum and right anterior part of dorsal anterior cingulate cortex was significantly decreased in patients with iBSP and HFS compared with HCs. Dysfunction of the cortico-basal ganglia networks occurs in patients with iBSP. The altered network metrics of cortico-basal ganglia networks might be served as quantitative markers for evaluation of the severity of iBSP.

Basal ganglia functional connectivity network analysis does not support the 'noisy signal' hypothesis of Parkinson's disease.

The 'noisy signal' hypothesis of basal ganglia dysfunction in Parkinson's disease (PD) suggests that major motor symptoms of the disorder are caused by the development of abnormal basal ganglia activity patterns resulting in the propagation of 'noisy' signals to target systems. While such abnormal activity patterns might be useful biomarkers for the development of therapeutic interventions, correlation between specific changes in activity and PD symptoms has been inconsistently demonstrated, and raises questions concerning the accuracy of the hypothesis. Here, we tested this hypothesis by considering three nodes of the basal ganglia network, the subthalamus, globus pallidus interna, and cortex during self-paced and cued movements in patients with PD. Interactions between these regions were analyzed using measures that assess both linear and non-linear relationships. Marked changes in the network are observed with dopamine state. Specifically, we detected functional disconnection of the basal ganglia from the cortex and higher network variability in untreated PD, but various patterns of directed functional connectivity with lower network variability in treated PD. When we examine the system output, significant correlation is observed between variability in the cortico-basal ganglia network and muscle activity variability but only in the treated state. Rather than supporting a role of the basal ganglia in the transmission of noisy signals in patients with PD, these findings suggest that cortico-basal ganglia network interactions by fault or design, in the treated Parkinsonian state, are actually associated with improved cortical network output variability.

Reduced D2 /D3 Receptor Binding and Glucose Metabolism in a Macaque Model of Huntington's Disease.

Dopamine system dysfunction and altered glucose metabolism are implicated in Huntington's disease (HD), a neurological disease caused by mutant huntingtin (mHTT) expression. The aim was to characterize alterations in cerebral dopamine D2 /D3 receptor density and glucose utilization in a newly developed AAV-mediated NHP model of HD that expresses mHTT throughout numerous brain regions. Positron emission tomography (PET) imaging was performed using [18 F]fallypride to quantify D2 /D3 receptor density and 2-[18 F]fluoro-2-deoxy-d-glucose ([18 F]FDG) to measure cerebral glucose utilization in these HD macaques. Compared to controls, HD macaques showed significantly reduced dopamine D2 /D3 receptor densities in basal ganglia (P < 0.05). In addition, HD macaques displayed significant glucose hypometabolism throughout the cortico-basal ganglia network (P < 0.05). [18 F]Fallypride and [18 F]FDG are PET imaging biomarkers of mHTT-mediated disease progression that can be used as noninvasive outcome measures in future therapeutic studies with this AAV-mediated HD macaque model. © 2022 International Parkinson and Movement Disorder Society.

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia

L-DOPA-induced dyskinesia (LID) in Parkinson’s disease has been linked to oscillatory neuronal activities in the cortico-basal ganglia network. We set out to examine the pattern of cortico-basal ganglia oscillations induced by selective agonists of D1 and D2 receptors in a rat model of LID. Local field potentials were recorded in freely moving rats using large-scale electrodes targeting three motor cortical regions, dorsomedial and dorsolateral striatum, external globus pallidus, and substantial nigra pars reticulata. Abnormal involuntary movements were elicited by the D1 agonist SKF82958 or the D2 agonist sumanirole, while overall motor activity was quantified using video analysis (DeepLabCut). Both SKF82958 and sumanirole induced dyskinesia, although with significant differences in temporal course, overall severity, and body distribution. The D1 agonist induced prominent narrowband oscillations in the high gamma range (70–110 Hz) in all recorded structures except for the nigra reticulata. Additionally, the D1 agonist induced strong functional connectivity between the recorded structures and the phase analysis revealed that the primary motor cortex (forelimb area) was leading a supplementary motor area and striatum. Following treatment with the D2 agonist, narrowband gamma oscillations were detected only in forelimb motor cortex and dorsolateral striatum, while prominent oscillations in the theta band occurred in the globus pallidus and nigra reticulata. Our results reveal that the dyskinetic effects of D1 and D2 receptor agonists are associated with distinct patterns of cortico-basal ganglia oscillations, suggesting a recruitment of partially distinct networks.

O019 / #949 DEEP BRAIN STIMULATION MODEL NET WORK OF BG AND NEURONAL VARIATIONS OF ENTROPY OF STNS IN PARKINSON`S: TRACK 4: CARDIOVASCULAR DISORDERS / NEURAL ENGINEERING

Deep brain stimulation is an effective treatment for Parkinson disease(PD) which has been shown to have measurable effects on the biomarkers. Computational modeling allows the investigation of network dynamics which may be difficult to access during clinical practice. Here a computational model of the corticobasal ganglia network is utilized to investigate changes in basal ganglia neuronal entropy during DBS. In this study we present the DBS brain model network of basal ganglia (BG) and neuronal variations of entropy of STNs in PD.

Microscale electrophysiological functional connectivity in human cortico-basal ganglia network

ObjectiveWe investigated the electrophysiological relationships in the cortico-basal ganglia network on a sub-centimeter scale to increase our understanding of neural functional relationships in Parkinson’s disease (PD). MethodsData was intraoperatively recorded from 2 sources in the human brain—a microelectrode in the subthalamic nucleus (STN) and a micro-electrocorticography grid on the motor association cortex—during bilateral deep brain stimulation (DBS) electrode placement. STN neurons and local field potential (LFP) were defined as functionally connected when the 99.7% confidence intervals of the action potential (AP)-aligned average LFP and control did not overlap. ResultsAPs from STN neurons were functionally connected to the STN LFP for 18/46 STN neurons. This functional connection was observed between STN neuron APs and cortical LFP for 25/46 STN neurons. The cortical patterns of electrophysiological functional connectivity differed for each neuron. ConclusionsA subset of single neurons in the STN exhibited functional connectivity with electrophysiological activity in the STN and at a distance with the motor association cortex surveyed on a sub-centimeter spatial scale. These connections show a per neuron differential topography on the cortex. SignificanceThe cortico-basal ganglia circuit is organized on a sub-centimeter scale, and plays an important role in the mechanisms of PD and DBS.

Where Actions Meet Outcomes: Medial Prefrontal Cortex, Central Thalamus, and the Basal Ganglia.

Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes.

P 33 Changes in functional connectivity relate to modulation of cognitive control by subthalamic stimulation

Introduction Using cognitive control, humans can flexibly influence behavior based on set goals, which includes overriding impulses by inhibiting automatic responses in a conflicting environment. The basal ganglia have been hypothesized as an integral part in a cortico-subcortical network that modulates inhibitory control in both motor and non-motor domains. Subthalamic (STN) deep brain stimulation (DBS) in Parkinson‘s disease (PD) patients not only improves kinematic parameters of movement but also modulates cognitive control in the motor and non-motor domain, especially in situations of high conflict. Materials & Methods During DBS ON and OFF conditions, we conducted a visuomotor task in 14 PD patients who previously underwent resting-state functional MRI (rs-fMRI) acquisitions DBS ON and OFF. In the task, participants had to move a cursor with a pen on a digital tablet either towards (automatic condition) or in the opposite direction (controlled condition) of a target. Behaviorally, the first main outcome parameter was reaction time, and specifically, the difference in reaction time between automatic and controlled condition that reflects the additional time associated with engagement of cognitive control. Furthermore, average movement velocity ON vs. OFF DBS in automatic and controlled trials was assessed. Analysis of the imaging data focused on STN DBS induced modulation of rs-fMRI connectivity as a function of changes in behavior ON vs. OFF DBS and was estimated using link-wise network-based statistics within an a-priori defined network parcellation with 7 bihemispheric regions of interest (STN, internal/external pallidum (GPi and GPe), striatum, motor thalamus (VAn, VAp, VLd/VLv nuclei combined), motor and premotor cortices, supplementary motor area (SMA) and pre-SMA). Results Behavioral results showed diminished reaction time adaptation under DBS, i.e., PD patients ON DBS slowed down significantly less in the controlled condition compared to the automatic condition than they did OFF DBS. Additionally, pen-to-target movement velocity was increased under DBS in both automatic and controlled condition. Resting-state imaging data analysis revealed that DBS-induced reaction time reduction was associated with attenuated functional connectivity between cortical motor areas, basal ganglia and thalamus. On the other hand, increased movement velocity ON DBS was associated with stronger pallido-thalamic connectivity. Conclusion These findings suggest that DBS-induced decoupling of a motor cortico-basal ganglia network underlies impaired inhibitory control in PD patients undergoing subthalamic DBS and highlight the concept of functional network modulation through DBS. Understanding the connectivity basis of nonmotor changes in PD patients treated with DBS has a high clinical relevance, since network modulation may be fine-tuned with advancing therapeutic developments such as adaptive stimulation.

Consistent Changes in Cortico-Subthalamic Directed Connectivity Are Associated With the Induction of Parkinsonism in a Chronically Recorded Non-human Primate Model.

Parkinson’s disease is a neurological disease with cardinal motor signs including bradykinesia and tremor. Although beta-band hypersynchrony in the cortico-basal ganglia network is thought to contribute to disease manifestation, the resulting effects on network connectivity are unclear. We examined local field potentials from a non-human primate across the naïve, mild, and moderate disease states (model was asymmetric, left-hemispheric dominant) and probed power spectral density as well as cortico-cortical and cortico-subthalamic connectivity using both coherence and Granger causality, which measure undirected and directed effective connectivity, respectively. Our network included the left subthalamic nucleus (L-STN), bilateral primary motor cortices (L-M1, R-M1), and bilateral premotor cortices (L-PMC, R-PMC). Results showed two distinct peaks (Peak A at 5–20 Hz, Peak B at 25–45 Hz) across all analyses. Power and coherence analyses showed widespread increases in power and connectivity in both the Peak A and Peak B bands with disease progression. For Granger causality, increases in Peak B connectivity and decreases in Peak A connectivity were associated with the disease. Induction of mild disease was associated with several changes in connectivity: (1) the cortico-subthalamic connectivity in the descending direction (L-PMC to L-STN) decreased in the Peak A range while the reciprocal, ascending connectivity (L-STN to L-PMC) increased in the Peak B range; this may play a role in generating beta-band hypersynchrony in the cortex, (2) both L-M1 to L-PMC and R-M1 to R-PMC causalities increased, which may either be compensatory or a pathologic effect of disease, and (3) a decrease in connectivity occurred from the R-PMC to R-M1. The only significant change seen between mild and moderate disease was increased right cortical connectivity, which may reflect compensation for the left-hemispheric dominant moderate disease state.

Pallidal and Cortical Oscillations in Freely Moving Patients With Dystonia

ObjectivesTo evaluate the correlation between the pallidal local field potentials (LFPs) activity and the cortical oscillations (at rest and during several motor tasks) in two freely moving patients with generalized dystonia and pallidal deep brain stimulation (DBS). Materials and MethodsTwo women with isolated generalized dystonia were selected for bilateral globus pallidus internus (GPi) DBS. After the electrodes' implantation, cortical activity was recorded by a portable electroencephalography (EEG) system simultaneously with GPi LFPs activity, during several motor tasks, gait, and rest condition. Recordings were not performed during stimulation. EEG and LFPs signals relative to each specific movement were coupled together and grouped in neck/upper limbs movements and gait. Power spectral density (PSD), EEG-LFP coherence (through envelope of imaginary coherence operator), and 1/f exponent of LFP-PSD background were calculated. ResultsIn both patients, the pallidal LFPs PSD at rest was characterized by prominent 4–12 Hz activity. Voluntary movements increased activity in the theta (θ) band (4–7 Hz) compared to rest, in both LFPs and EEG signals. Gait induced a drastic raise of θ activity in both patients' pallidal activity, less marked for the EEG signal. A coherence peak within the 8–13 Hz range was found between pallidal LFPs and EEG recorded at rest. ConclusionsNeck/upper limbs voluntary movements and gait suppressed the GPi-LFPs—cortical-EEG coherence and differently impacted both EEG and LFPs low frequency activity. These findings suggest a selective modulation of the cortico-basal ganglia network activity in dystonia.

Discovery and characterization of benzyloxy piperidine based dopamine 4 receptor antagonists

The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in l-DOPA induced dyskinesias in Parkinson’s disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.

Using cortico-basal ganglia network physiology for chronic embedded adaptive DBS in movement disorders

Using cortico-basal ganglia network physiology for chronic embedded adaptive DBS in movement disorders

Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important.Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures.Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables.We conclude that modulation of the primary motor putamen–posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.

Striatal Oscillations in Parkinsonian Non-Human Primates

Dopamine loss in Parkinson’s disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of striatal neurons in PD remains poorly defined. Here, we analyzed the local field potentials in one untreated and five MPTP-treated non-human primates (NHP) with chronic, advanced parkinsonism. Oscillatory activities in the alpha (8–13 Hz) and low-beta (13–20 Hz) frequency bands were found in the striatum similarly to the motor cortex and globus pallidus of the NHP model of PD. Both alpha and low-beta frequency band oscillations of the striatum were highly coherent with the cortical and pallidal oscillations, confirming the presence of abnormal 8–20 Hz oscillatory activity in the cortico-basal ganglia network in parkinsonian NHPs. The reversal of parkinsonism induced by acute levodopa administration was associated with reduced 8–20 Hz oscillations in the striatum. These findings indicate that pathological oscillations at alpha and low-beta bands are also present in the striatum concordant with basal ganglia network changes in the primate model of PD.

Cortico-Striatal Oscillations Are Correlated to Motor Activity Levels in Both Physiological and Parkinsonian Conditions.

Oscillatory neural activity in the cortico-basal ganglia-thalamocortical (CBGTC) loop is associated with the motor state of a subject, but also with the availability of modulatory neurotransmitters. For example, increased low-frequency oscillations in Parkinson’s disease (PD) are related to decreased levels of dopamine and have been proposed as biomarkers to adapt and optimize therapeutic interventions, such as deep brain stimulation. Using neural oscillations as biomarkers require differentiating between changes in oscillatory patterns associated with parkinsonism vs. those related to a subject’s motor state. To address this point, we studied the correlation between neural oscillatory activity in the motor cortex and striatum and varying degrees of motor activity under normal and parkinsonian conditions. Using rats with bilateral or unilateral 6-hydroxydopamine lesions as PD models, we correlated the motion index (MI)—a measure based on the physical acceleration of the head of rats—to the local field potential (LFP) oscillatory power in the 1–80 Hz range. In motor cortices and striata, we observed a robust correlation between the motion index and the oscillatory power in two main broad frequency ranges: a low-frequency range [5.0–26.5 Hz] was negatively correlated to motor activity, whereas a high-frequency range [35.0–79.9 Hz] was positively correlated. We observed these correlations in both normal and parkinsonian conditions. In addition to these general changes in broad-band power, we observed a more restricted narrow-band oscillation [25–40 Hz] in dopamine-denervated hemispheres. This oscillation, which seems to be selective to the parkinsonian state, showed a linear frequency dependence on the concurrent motor activity level. We conclude that, independently of the parkinsonian condition, changes in broad-band oscillatory activities of cortico-basal ganglia networks (including changes in the relative power of low- and high-frequency bands) are closely correlated to ongoing motions, most likely reflecting he operations of these neural circuits to control motor activity. Hence, biomarkers based on neural oscillations should focus on specific features, such as narrow frequency bands, to allow differentiation between parkinsonian states and physiological movement-dependent circuit modulation.