Synaptic reorganization of synchronized neuronal networks with synaptic weight and structural plasticity.

Abnormally strong neural synchronization may impair brain function, as observed in several brain disorders. We computationally study how neuronal dynamics, synaptic weights, and network structure co-emerge, in particular, during (de)synchronization processes and how they are affected by external perturbation. To investigate the impact of different types of plasticity mechanisms, we combine a network of excitatory integrate-and-fire neurons with different synaptic weight and/or structural plasticity mechanisms: (i) only spike-timing-dependent plasticity (STDP), (ii) only homeostatic structural plasticity (hSP), i.e., without weight-dependent pruning and without STDP, (iii) a combination of STDP and hSP, i.e., without weight-dependent pruning, and (iv) a combination of STDP and structural plasticity (SP) that includes hSP and weight-dependent pruning. To accommodate the diverse time scales of neuronal firing, STDP, and SP, we introduce a simple stochastic SP model, enabling detailed numerical analyses. With tools from network theory, we reveal that structural reorganization may remarkably enhance the network's level of synchrony. When weaker contacts are preferentially eliminated by weight-dependent pruning, synchrony is achieved with significantly sparser connections than in randomly structured networks in the STDP-only model. In particular, the strengthening of contacts from neurons with higher natural firing rates to those with lower rates and the weakening of contacts in the opposite direction, followed by selective removal of weak contacts, allows for strong synchrony with fewer connections. This activity-led network reorganization results in the emergence of degree-frequency, degree-degree correlations, and a mixture of degree assortativity. We compare the stimulation-induced desynchronization of synchronized states in the STDP-only model (i) with the desynchronization of models (iii) and (iv). The latter require stimuli of significantly higher intensity to achieve long-term desynchronization. These findings may inform future pre-clinical and clinical studies with invasive or non-invasive stimulus modalities aiming at inducing long-lasting relief of symptoms, e.g., in Parkinson's disease.

Decoupling of interacting neuronal populations by time-shifted stimulation through spike-timing-dependent plasticity.

The synaptic organization of the brain is constantly modified by activity-dependent synaptic plasticity. In several neurological disorders, abnormal neuronal activity and pathological synaptic connectivity may significantly impair normal brain function. Reorganization of neuronal circuits by therapeutic stimulation has the potential to restore normal brain dynamics. Increasing evidence suggests that the temporal stimulation pattern crucially determines the long-lasting therapeutic effects of stimulation. Here, we tested whether a specific pattern of brain stimulation can enable the suppression of pathologically strong inter-population synaptic connectivity through spike-timing-dependent plasticity (STDP). More specifically, we tested how introducing a time shift between stimuli delivered to two interacting populations of neurons can effectively decouple them. To that end, we first used a tractable model, i.e., two bidirectionally coupled leaky integrate-and-fire (LIF) neurons, to theoretically analyze the optimal range of stimulation frequency and time shift for decoupling. We then extended our results to two reciprocally connected neuronal populations (modules) where inter-population delayed connections were modified by STDP. As predicted by the theoretical results, appropriately time-shifted stimulation causes a decoupling of the two-module system through STDP, i.e., by unlearning pathologically strong synaptic interactions between the two populations. Based on the overall topology of the connections, the decoupling of the two modules, in turn, causes a desynchronization of the populations that outlasts the cessation of stimulation. Decoupling effects of the time-shifted stimulation can be realized by time-shifted burst stimulation as well as time-shifted continuous simulation. Our results provide insight into the further optimization of a variety of multichannel stimulation protocols aiming at a therapeutic reshaping of diseased brain networks.

Synaptic reshaping of plastic neuronal networks by periodic multichannel stimulation with single-pulse and burst stimuli.

Synaptic dysfunction is associated with several brain disorders, including Alzheimer's disease, Parkinson's disease (PD) and obsessive compulsive disorder (OCD). Utilizing synaptic plasticity, brain stimulation is capable of reshaping synaptic connectivity. This may pave the way for novel therapies that specifically counteract pathological synaptic connectivity. For instance, in PD, novel multichannel coordinated reset stimulation (CRS) was designed to counteract neuronal synchrony and down-regulate pathological synaptic connectivity. CRS was shown to entail long-lasting therapeutic aftereffects in PD patients and related animal models. This is in marked contrast to conventional deep brain stimulation (DBS) therapy, where PD symptoms return shortly after stimulation ceases. In the present paper, we study synaptic reshaping by periodic multichannel stimulation (PMCS) in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity (STDP). During PMCS, phase-shifted periodic stimulus trains are delivered to segregated neuronal subpopulations. Harnessing STDP, PMCS leads to changes of the synaptic network structure. We found that the PMCS-induced changes of the network structure depend on both the phase lags between stimuli and the shape of individual stimuli. Single-pulse stimuli and burst stimuli with low intraburst frequency down-regulate synapses between neurons receiving stimuli simultaneously. In contrast, burst stimuli with high intraburst frequency up-regulate these synapses. We derive theoretical approximations of the stimulation-induced network structure. This enables us to formulate stimulation strategies for inducing a variety of network structures. Our results provide testable hypotheses for future pre-clinical and clinical studies and suggest that periodic multichannel stimulation may be suitable for reshaping plastic neuronal networks to counteract pathological synaptic connectivity. Furthermore, we provide novel insight on how the stimulus type may affect the long-lasting outcome of conventional DBS. This may strongly impact parameter adjustment procedures for clinical DBS, which, so far, primarily focused on acute effects of stimulation.

Asymmetric adaptivity induces recurrent synchronization in complex networks.

Rhythmic activities that alternate between coherent and incoherent phases are ubiquitous in chemical, ecological, climate, or neural systems. Despite their importance, general mechanisms for their emergence are little understood. In order to fill this gap, we present a framework for describing the emergence of recurrent synchronization in complex networks with adaptive interactions. This phenomenon is manifested at the macroscopic level by temporal episodes of coherent and incoherent dynamics that alternate recurrently. At the same time, the dynamics of the individual nodes do not change qualitatively. We identify asymmetric adaptation rules and temporal separation between the adaptation and the dynamics of individual nodes as key features for the emergence of recurrent synchronization. Our results suggest that asymmetric adaptation might be a fundamental ingredient for recurrent synchronization phenomena as seen in pattern generators, e.g., in neuronal systems.

Perspectives on adaptive dynamical systems.

Adaptivity is a dynamical feature that is omnipresent in nature, socio-economics, and technology. For example, adaptive couplings appear in various real-world systems, such as the power grid, social, and neural networks, and they form the backbone of closed-loop control strategies and machine learning algorithms. In this article, we provide an interdisciplinary perspective on adaptive systems. We reflect on the notion and terminology of adaptivity in different disciplines and discuss which role adaptivity plays for various fields. We highlight common open challenges and give perspectives on future research directions, looking to inspire interdisciplinary approaches.

Impact of number of stimulation sites on long-lasting desynchronization effects of coordinated reset stimulation.

Excessive neuronal synchrony is a hallmark of several neurological disorders, e.g., Parkinson's disease. An established treatment for medically refractory Parkinson's disease is high-frequency deep brain stimulation. However, it provides only acute relief, and symptoms return shortly after cessation of stimulation. A theory-based approach called coordinated reset (CR) has shown great promise in achieving long-lasting effects. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites to counteract neuronal synchrony. Computational studies in plastic neuronal networks reported that synaptic weights reduce during stimulation, which may cause sustained structural changes leading to stabilized desynchronized activity even after stimulation ceases. Corresponding long-lasting effects were found in recent preclinical and clinical studies. We study long-lasting desynchronization by CR stimulation in excitatory recurrent neuronal networks of integrate-and-fire neurons with spike-timing-dependent plasticity (STDP). We focus on the impact of the stimulation frequency and the number of stimulation sites on long-lasting effects. We compare theoretical predictions to simulations of plastic neuronal networks. Our results are important regarding CR calibration for two reasons. We reveal that long-lasting effects become most pronounced when stimulation parameters are adjusted to the characteristics of STDP-rather than to neuronal frequency characteristics. This is in contrast to previous studies where the CR frequency was adjusted to the dominant neuronal rhythm. In addition, we reveal a nonlinear dependence of long-lasting effects on the number of stimulation sites and the CR frequency. Intriguingly, optimal long-lasting desynchronization does not require larger numbers of stimulation sites.

How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation.

Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies. However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered. This work presents the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.

Propagation delays determine neuronal activity and synaptic connectivity patterns emerging in plastic neuronal networks.

In plastic neuronal networks, the synaptic strengths are adapted to the neuronal activity. Specifically, spike-timing-dependent plasticity (STDP) is a fundamental mechanism that modifies the synaptic strengths based on the relative timing of pre- and postsynaptic spikes, taking into account the spikes' temporal order. In many studies, propagation delays were neglected to avoid additional dynamic complexity or computational costs. So far, networks equipped with a classic STDP rule typically rule out bidirectional couplings (i.e., either loops or uncoupled states) and are, hence, not able to reproduce fundamental experimental findings. In this review paper, we consider additional features, e.g., extensions of the classic STDP rule or additional aspects like noise, in order to overcome the contradictions between theory and experiment. In addition, we review in detail recent studies showing that a classic STDP rule combined with realistic propagation patterns is able to capture relevant experimental findings. In two coupled oscillatory neurons with propagation delays, bidirectional synapses can be preserved and potentiated. This result also holds for large networks of type-II phase oscillators. In addition, not only the mean of the initial distribution of synaptic weights, but also its standard deviation crucially determines the emergent structural connectivity, i.e., the mean final synaptic weight, the number of two-neuron loops, and the symmetry of the final connectivity pattern. The latter is affected by the firing rates, where more symmetric synaptic configurations emerge at higher firing rates. Finally, we discuss these findings in the context of the computational neuroscience-based development of desynchronizing brain stimulation techniques.

Coordinated reset stimulation of plastic neural networks with spatially dependent synaptic connections.

Background: Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson's disease (PD), essential tremor, dystonia, and epilepsy. Coordinated reset (CR) stimulation was developed computationally to counteract abnormal neuronal synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites. Computational studies in plastic neural networks reported that CR stimulation drove the networks into an attractor of a stable desynchronized state by down-regulating synaptic connections, which led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed in the brain, shape CR-induced synaptic downregulation and long-lasting effects. Methods: We performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-dependent plasticity and spatially dependent synaptic connections to study and further improve acute and long-term responses to CR stimulation. Results: The characteristic length scale of synaptic connections relative to the distance between stimulation sites plays a key role in CR parameter adjustment. In networks with short synaptic length scales, a substantial synaptic downregulation can be achieved by selecting appropriate stimulus-related parameters, such as the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal sequence of stimulus deliveries is of major importance for synaptic downregulation. In particular, rapid shuffling of the stimulus sequence is advantageous for synaptic downregulation. Conclusion: Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous for long-lasting desynchronization effects. Our work provides important hypotheses on CR parameter selection for future preclinical and clinical studies.

Simulated dataset on coordinated reset stimulation of homogeneous and inhomogeneous networks of excitatory leaky integrate-and-fire neurons with spike-timing-dependent plasticity.

We present simulated data on coordinated reset stimulation (CRS) of plastic neuronal networks. The neuronal network consists of excitatory leaky integrate-and-fire neurons and plasticity is implemented as spike-timing-dependent plasticity (STDP). A synchronized state with strong synaptic connectivity and a desynchronized state with weak synaptic connectivity coexist. CRS may drive the network from the synchronized state into a desynchronized state inducing long-lasting desynchronization effects that persist after cessation of stimulation. This is used to model brain stimulation-induced transitions between a pathological state, with abnormally strong neuronal synchrony, and a physiological state, e.g., in Parkinson's disease. During CRS, a sequence of stimuli is delivered to multiple stimulation sites - called CR sequence. We present simulated data for the analysis of long-lasting desynchronization effects of CRS with shuffled CR sequences versus non-shuffled CR sequences in which the order of stimulus deliveries to the sites remains unchanged throughout the entire stimulation period. Such data are presented for networks with homogeneous synaptic connectivity and networks with inhomogeneous synaptic connectivity. Homogeneous synaptic connectivity refers to a network in which the probability of a synaptic connection does not depend on the pre- and postsynaptic neurons' locations. In contrast, inhomogeneous synaptic connectivity refers to a network in which the probability of a synaptic connection depends on the neurons' locations. The presented neuronal network model was used to analyse the impact of the CR sequences and their shuffling on the long-lasting effects of CRS [1].

Emerging wearable technologies for multisystem monitoring and treatment of Parkinson's disease: a narrative review.

Parkinson's disease (PD) is a chronic movement disorder characterized by a variety of motor and nonmotor comorbidities, including cognitive impairment, gastrointestinal (GI) dysfunction, and autonomic/sleep disturbances. Symptoms typically fluctuate with different settings and environmental factors and thus need to be consistently monitored. Current methods, however, rely on infrequent rating scales performed in clinic. The advent of wearable technologies presents a new avenue to track objective measures of PD comorbidities longitudinally and more frequently. This narrative review discusses and proposes emerging wearable technologies that can monitor manifestations of motor, cognitive, GI, and autonomic/sleep comorbidities throughout the daily lives of PD individuals. This can provide more wholistic insight into real-time physiological versus pathological function with the potential to better assess treatments during clinical trials and allow physicians to optimize treatment regimens. Additionally, this narrative review briefly examines novel applications of wearables as therapy for PD patients.

Impact of acoustic coordinated reset neuromodulation on effective connectivity in a neural network of phantom sound.

Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As recently shown in a proof of concept clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms combined with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas. The objective of the present study was to analyze whether CR therapy caused an alteration of the effective connectivity in a tinnitus related network of localized EEG brain sources. To determine which connections matter, in a first step, we considered a larger network of brain sources previously associated with tinnitus. To that network we applied a data-driven approach, combining empirical mode decomposition and partial directed coherence analysis, in patients with bilateral tinnitus before and after 12 weeks of CR therapy as well as in healthy controls. To increase the signal-to-noise ratio, we focused on the good responders, classified by a reliable-change-index (RCI). Prior to CR therapy and compared to the healthy controls, the good responders showed a significantly increased connectivity between the left primary cortex auditory cortex and the posterior cingulate cortex in the gamma and delta bands together with a significantly decreased effective connectivity between the right primary auditory cortex and the dorsolateral prefrontal cortex in the alpha band. Intriguingly, after 12 weeks of CR therapy most of the pathological interactions were gone, so that the connectivity patterns of good responders and healthy controls became statistically indistinguishable. In addition, we used dynamic causal modeling (DCM) to examine the types of interactions which were altered by CR therapy. Our DCM results show that CR therapy specifically counteracted the imbalance of excitation and inhibition. CR significantly weakened the excitatory connection between posterior cingulate cortex and primary auditory cortex and significantly strengthened inhibitory connections between auditory cortices and the dorsolateral prefrontal cortex. The overall impact of CR therapy on the entire tinnitus-related network showed up as a qualitative transformation of its spectral response, in terms of a drastic change of the shape of its averaged transfer function. Based on our findings we hypothesize that CR therapy restores a silence based cognitive auditory comparator function of the posterior cingulate cortex.

Neuromodulation: selected approaches and challenges.

The brain operates through complex interactions in the flow of information and signal processing within neural networks. The 'wiring' of such networks, being neuronal or glial, can physically and/or functionally go rogue in various pathological states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromodulation are discussed. The use of water-dispersible carbon nanotubes has been proven effective in the modulation of neurite outgrowth in culture and in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biology and analytical engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing 'misfiring' neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real-time measurement of various neurotransmitters as well as electrical activity in the human brain during electrical deep brain stimulation. Such devices can establish the dynamics of electrochemical changes in the brain during stimulation. With increasing application of nanomaterials in devices for electrical and chemical recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us.

Coordinated reset has sustained aftereffects in Parkinsonian monkeys.

Coordinated reset neuromodulation consists of the application of consecutive brief high-frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long-lasting aftereffects on motor function in parkinsonian nonhuman primates. Long-lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients.

Synaptic network structure shapes cortically evoked spatio-temporal responses of STN and GPe neurons in a computational model.

Introduction: The basal ganglia (BG) are involved in motor control and play an essential role in movement disorders such as hemiballismus, dystonia, and Parkinson's disease. Neurons in the motor part of the BG respond to passive movement or stimulation of different body parts and to stimulation of corresponding cortical regions. Experimental evidence suggests that the BG are organized somatotopically, i.e., specific areas of the body are associated with specific regions in the BG nuclei. Signals related to the same body part that propagate along different pathways converge onto the same BG neurons, leading to characteristic shapes of cortically evoked responses. This suggests the existence of functional channels that allow for the processing of different motor commands or information related to different body parts in parallel. Neurological disorders such as Parkinson's disease are associated with pathological activity in the BG and impaired synaptic connectivity, together with reorganization of somatotopic maps. One hypothesis is that motor symptoms are, at least partly, caused by an impairment of network structure perturbing the organization of functional channels. Methods: We developed a computational model of the STN-GPe circuit, a central part of the BG. By removing individual synaptic connections, we analyzed the contribution of signals propagating along different pathways to cortically evoked responses. We studied how evoked responses are affected by systematic changes in the network structure. To quantify the BG's organization in the form of functional channels, we suggested a two-site stimulation protocol. Results: Our model reproduced the cortically evoked responses of STN and GPe neurons and the contributions of different pathways suggested by experimental studies. Cortical stimulation evokes spatio-temporal response patterns that are linked to the underlying synaptic network structure. Our two-site stimulation protocol yielded an approximate functional channel width. Discussion/conclusion: The presented results provide insight into the organization of BG synaptic connectivity, which is important for the development of computational models. The synaptic network structure strongly affects the processing of cortical signals and may impact the generation of pathological rhythms. Our work may motivate further experiments to analyze the network structure of BG nuclei and their organization in functional channels.

Unlearning tinnitus-related cerebral synchrony with acoustic coordinated reset stimulation: theoretical concept and modelling.

Tinnitus is a deafferentation-induced phantom phenomenon characterized by abnormal cerebral synchrony and connectivity. Computationally, we show that desynchronizing acoustic coordinated reset (CR) stimulation can effectively counteract both up-regulated synchrony and connectivity. CR stimulation has initially been developed for the application to electrical deep brain stimulation. We here adapt this approach to non-invasive, acoustic CR stimulation. For this, we use the tonotopic organization of the central auditory system and replace electrical stimulation bursts applied to different brain sites by acoustically delivered tones of different pitch. Based on our simulations, we propose non-invasive acoustic CR stimulation as a possible novel therapy for tinnitus.

Long-Lasting Desynchronization of Plastic Neuronal Networks by Double-Random Coordinated Reset Stimulation.

Hypersynchrony of neuronal activity is associated with several neurological disorders, including essential tremor and Parkinson's disease (PD). Chronic high-frequency deep brain stimulation (HF DBS) is the standard of care for medically refractory PD. Symptoms may effectively be suppressed by HF DBS, but return shortly after cessation of stimulation. Coordinated reset (CR) stimulation is a theory-based stimulation technique that was designed to specifically counteract neuronal synchrony by desynchronization. During CR, phase-shifted stimuli are delivered to multiple neuronal subpopulations. Computational studies on CR stimulation of plastic neuronal networks revealed long-lasting desynchronization effects obtained by down-regulating abnormal synaptic connectivity. This way, networks are moved into attractors of stable desynchronized states such that stimulation-induced desynchronization persists after cessation of stimulation. Preclinical and clinical studies confirmed corresponding long-lasting therapeutic and desynchronizing effects in PD. As PD symptoms are associated with different pathological synchronous rhythms, stimulation-induced long-lasting desynchronization effects should favorably be robust to variations of the stimulation frequency. Recent computational studies suggested that this robustness can be improved by randomizing the timings of stimulus deliveries. We study the long-lasting effects of CR stimulation with randomized stimulus amplitudes and/or randomized stimulus timing in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity. Performing computer simulations and analytical calculations, we study long-lasting desynchronization effects of CR with and without randomization of stimulus amplitudes alone, randomization of stimulus times alone as well as the combination of both. Varying the CR stimulation frequency (with respect to the frequency of abnormal target rhythm) and the number of separately stimulated neuronal subpopulations, we reveal parameter regions and related mechanisms where the two qualitatively different randomization mechanisms improve the robustness of long-lasting desynchronization effects of CR. In particular, for clinically relevant parameter ranges double-random CR stimulation, i.e., CR stimulation with the specific combination of stimulus amplitude randomization and stimulus time randomization, may outperform regular CR stimulation with respect to long-lasting desynchronization. In addition, our results provide the first evidence that an effective reduction of the overall stimulation current by stimulus amplitude randomization may improve the frequency robustness of long-lasting therapeutic effects of brain stimulation.

Spike-Timing-Dependent Plasticity Mediated by Dopamine and its Role in Parkinson's Disease Pathophysiology.

Parkinson's disease (PD) is a multi-systemic neurodegenerative brain disorder. Motor symptoms of PD are linked to the significant dopamine (DA) loss in substantia nigra pars compacta (SNc) followed by basal ganglia (BG) circuit dysfunction. Increasing experimental and computational evidence indicates that (synaptic) plasticity plays a key role in the emergence of PD-related pathological changes following DA loss. Spike-timing-dependent plasticity (STDP) mediated by DA provides a mechanistic model for synaptic plasticity to modify synaptic connections within the BG according to the neuronal activity. To shed light on how DA-mediated STDP can shape neuronal activity and synaptic connectivity in the PD condition, we reviewed experimental and computational findings addressing the modulatory effect of DA on STDP as well as other plasticity mechanisms and discussed their potential role in PD pathophysiology and related network dynamics and connectivity. In particular, reshaping of STDP profiles together with other plasticity-mediated processes following DA loss may abnormally modify synaptic connections in competing pathways of the BG. The cascade of plasticity-induced maladaptive or compensatory changes can impair the excitation-inhibition balance towards the BG output nuclei, leading to the emergence of pathological activity-connectivity patterns in PD. Pre-clinical, clinical as well as computational studies reviewed here provide an understanding of the impact of synaptic plasticity and other plasticity mechanisms on PD pathophysiology, especially PD-related network activity and connectivity, after DA loss. This review may provide further insights into the abnormal structure-function relationship within the BG contributing to the emergence of pathological states in PD. Specifically, this review is intended to provide detailed information for the development of computational network models for PD, serving as testbeds for the development and optimization of invasive and non-invasive brain stimulation techniques. Computationally derived hypotheses may accelerate the development of therapeutic stimulation techniques and potentially reduce the number of related animal experiments.

Dynamics of phase oscillator networks with synaptic weight and structural plasticity.

We study the dynamics of Kuramoto oscillator networks with two distinct adaptation processes, one varying the coupling strengths and the other altering the network structure. Such systems model certain networks of oscillatory neurons where the neuronal dynamics, synaptic weights, and network structure interact with and shape each other. We model synaptic weight adaptation with spike-timing-dependent plasticity (STDP) that runs on a longer time scale than neuronal spiking. Structural changes that include addition and elimination of contacts occur at yet a longer time scale than the weight adaptations. First, we study the steady-state dynamics of Kuramoto networks that are bistable and can settle in synchronized or desynchronized states. To compare the impact of adding structural plasticity, we contrast the network with only STDP to one with a combination of STDP and structural plasticity. We show that the inclusion of structural plasticity optimizes the synchronized state of a network by allowing for synchronization with fewer links than a network with STDP alone. With non-identical units in the network, the addition of structural plasticity leads to the emergence of correlations between the oscillators' natural frequencies and node degrees. In the desynchronized regime, the structural plasticity decreases the number of contacts, leading to a sparse network. In this way, adding structural plasticity strengthens both synchronized and desynchronized states of a network. Second, we use desynchronizing coordinated reset stimulation and synchronizing periodic stimulation to induce desynchronized and synchronized states, respectively. Our findings indicate that a network with a combination of STDP and structural plasticity may require stronger and longer stimulation to switch between the states than a network with STDP only.