Neurosystems: brain rhythms and cognitive processing

Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi-modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.098352 - Wellcome Trust; 5R01NS067199 - NINDS NIH HH

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

Computational Study of the Mechanisms Underlying Oscillation in Neuronal Locomotor Circuits

In this thesis we model two very different movement-related neuronal circuits, both of which produce oscillatory patterns of activity. In one case we study oscillatory activity in the basal ganglia under both normal and Parkinsonian conditions. First, we used a detailed Hodgkin-Huxley type spiking model to investigate the activity patterns that arise when oscillatory cortical input is transmitted to the globus pallidus via the subthalamic nucleus. Our model reproduced a result from rodent studies which shows that two anti-phase oscillatory groups of pallidal neurons appear under Parkinsonian conditions. Secondly, we used a population model of the basal ganglia to study whether oscillations could be locally generated. The basal ganglia are thought to be organised into multiple parallel channels. In our model, isolated channels could not generate oscillations, but if the lateral inhibition between channels is sufficiently strong then the network can act as a rhythm-generating ``pacemaker'' circuit. This was particularly true when we used a set of connection strength parameters that represent the basal ganglia under Parkinsonian conditions. Since many things are not known about the anatomy and electrophysiology of the basal ganglia, we also studied oscillatory activity in another, much simpler, movement-related neuronal system: the spinal cord of the Xenopus tadpole. We built a computational model of the spinal cord containing approximately 1,500 biologically realistic Hodgkin-Huxley neurons, with synaptic connectivity derived from a computational model of axon growth. The model produced physiological swimming behaviour and was used to investigate which aspects of axon growth and neuron dynamics are behaviourally important. We found that the oscillatory attractor associated with swimming was remarkably stable, which suggests that, surprisingly, many features of axonal growth and synapse formation are not necessary for swimming to emerge. We also studied how the same spinal cord network can generate a different oscillatory pattern in which neurons on both sides of the body fire synchronously. Our results here suggest that under normal conditions the synchronous state is unstable or weakly stable, but that even small increases in spike transmission delays act to stabilise it. Finally, we found that although the basal ganglia and the tadpole spinal cord are very different systems, the underlying mechanism by which they can produce oscillations may be remarkably similar. Insights from the tadpole model allow us to predict how the basal ganglia model may be capable of producing multiple patterns of oscillatory activity

Propagation of beta/gamma rhythms in the cortico-basal ganglia circuits of the Parkinsonian rat

Much of the motor impairment associated with Parkinson’s disease is thought to arise from pathological activity in the networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in BG networks following dopamine depletion. We recorded local field potentials (LFPs) in the cortex and basal ganglia of rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA) and in dopamine-intact controls. We performed systematic analyses of the networks using a novel tool for estimation of directed interactions (Non-Parametric Directionality, NPD). Additionally, we used a ‘conditioned’ version of the NPD analysis which reveals the dependence of the correlation between two signals upon a third reference signal. We find evidence of the dopamine dependency of both low beta (14-20 Hz) and high beta/low gamma (20-40 Hz) directed interactions within the network. Notably, 6-OHDA lesions were associated with enhancement of the cortical “hyper-direct” connection to the subthalamic nucleus (STN) and its feedback to the cortex and striatum. We find that pathological beta synchronization resulting from 6-OHDA lesioning is widely distributed across the network and cannot be located to any individual structure. Further, we provide evidence that high beta/gamma oscillations propagate through the striatum in a pathway that is independent of STN. Rhythms at high beta/gamma show susceptibility to conditioning that indicates a hierarchical organization when compared to low beta. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in Parkinsonism

Adaptive Parameter Selection for Deep Brain Stimulation in Parkinson’s Disease

Each year, around 60,000 people are diagnosed with Parkinson’s disease (PD) and the economic burden of PD is at least $14.4 billion a year in the United States. Pharmaceutical costs for a Parkinson’s patient can be reduced from$12,000 to $6,000 per year with the addition of neuromodulation therapies such as Deep Brain Stimulation (DBS), transcranial Direct Current Stimulation (tDCS), Transcranial Magnetic Stimulation (TMS), etc. In neurodegenerative disorders such as PD, deep brain stimulation (DBS) is a desirable approach when the medication is less effective for treating the symptoms. DBS incorporates transferring electrical pulses to a specific tissue of the central nervous system and obtaining therapeutic results by modulating the neuronal activity of that region. The hyperkinetic symptoms of PD are associated with the ensembles of interacting oscillators that cause excess or abnormal synchronous behavior within the Basal Ganglia (BG) circuitry. Delayed feedback stimulation is a closed loop technique shown to suppress this synchronous oscillatory activity. Deep Brain Stimulation via delayed feedback is known to destabilize the complex intermittent synchronous states. Computational models of the BG network are often introduced to investigate the effect of delayed feedback high frequency stimulation on partially synchronized dynamics. In this work, we developed several computational models of four interacting nuclei of the BG as well as considering the Thalamo-Cortical local effects on the oscillatory dynamics. These models are able to capture the emergence of 34 Hz beta band oscillations seen in the Local Field Potential (LFP) recordings of the PD state. Traditional High Frequency Stimulations (HFS) has shown deficiencies such as strengthening the synchronization in case of highly fluctuating neuronal activities, increasing the energy consumed as well as the incapability of activating all neurons in a large-scale network. To overcome these drawbacks, we investigated the effects of the stimulation waveform and interphase delays on the overall efficiency and efficacy of DBS. We also propose a new feedback control variable based on the filtered and linearly delayed LFP recordings. The proposed control variable is then used to modulate the frequency of the stimulation signal rather than its amplitude. In strongly coupled networks, oscillations reoccur as soon as the amplitude of the stimulus signal declines. Therefore, we show that maintaining a fixed amplitude and modulating the frequency might ameliorate the desynchronization process, increase the battery lifespan and activate substantial regions of the administered DBS electrode. The charge balanced stimulus pulse itself is embedded with a delay period between its charges to grant robust desynchronization with lower amplitude needed. The efficiency and efficacy of the proposed Frequency Adjustment Stimulation (FAS) protocol in a delayed feedback method might contribute to further investigation of DBS modulations aspired to address a wide range of abnormal oscillatory behaviors observed in neurological disorders. Adaptive stimulation can open doors towards simultaneous stimulation with MRI recordings. We additionally propose a new pipeline to investigate the effect of Transcranial Magnetic Stimulation (TMS) on patient specific models. The pipeline allows us to generate a full head segmentation based on each individual MRI data. In the next step, the neurosurgeon can adaptively choose the proper location of stimulation and transmit accurate magnetic field with this pipeline

Doctor of Philosophy

dissertationParkinson's Disease (PD) motor symptoms, characterized most commonly by bradykinesia, akinesia, rigidity, and tremor, are brought about through the degeneration of dopaminergic neurons in the substantia nigra pars compacta, which leads to changes in electrophysiological activity throughout the basal ganglia. These symptoms are often effectively treated in the early stages of the disease by dopamine replacement therapies. However, as the disease progresses, the therapeutic window of pharmacological approaches reduces and patients develop significant side effects, even under minimally effective doses. When the disease reaches this stage, surgical therapies, such as high-frequency deep brain stimulation (DBS), are considered. DBS of the subthalamic nucleus partially treats the motor symptoms of PD and has been implemented to treat PD over 50,000 times worldwide, but its mechanisms are unclear. In this work, we set out to advance the understanding of the mechanisms, function, and malfunction of DBS as a treatment for PD, keeping in mind the idea that DBS treats PD symptoms without restoring basal ganglia neural activity to that seen under healthy conditions. First, we demonstrated that neuronal information directed from the basal ganglia to the thalamus is pathologically increased in the parkinsonian condition and reduced by DBS in a standard 6-OHDA rat model of PD. Next, we developed a rodent model of DBSs role in the exacerbation of hypokinetic dysarthria, providing a framework for the study of this poorly understood side effect of DBS. Finally, we found that DBS creates action suppression deficits independently from a parkinsonian state, and that PD creates apathy that is not rescued by DBS. Our specific results led to the interpretation that DBS, in its current form, might inherently create side effects that are largely unavoidable. Our work fits into the following overarching idea. DBS successfully treats some motor symptoms of PD through the reduction of pathological information transmission. However, the fact that reducing pathological information does not restore neural activity to that present under healthy conditions underlies some of its failures to improve certain symptoms, as well as its exacerbations and side effects

Mechanisms of High Frequency Stimulation of the Subthalamic Nucleus in Parkinson\u27s Disease: From Local to Distal Effects on the Basal Ganglia Network

No abstract availabl

Global neural rhythm control by local neuromodulation

Neural oscillations are a ubiquitous form of neural activity seen across scales and modalities. These neural rhythms correlate with diverse cognitive functions and brain states. One mechanism for changing the oscillatory dynamics of large neuronal populations is through neuromodulator activity. An intriguing phenomenon explored here is when local neuromodulation of a distinct neuron type within a single brain nucleus exerts a powerful influence on global cortical rhythms. One approach to investigate the impact of local circuits on global rhythms is through optogenetic techniques. My first project involves the statistical analysis of electrophysiological recordings of an optogenetically-mediated Parkinsonian phenotype. Empirical studies demonstrate that Parkinsonian motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the cortico-basal ganglia-thalamic network. However, the mechanism of these aberrant oscillatory dynamics is not well understood. A previous modeling study predicted that cholinergic neuromodulation of medium spiny neurons in the striatum of the basal ganglia may mediate the pathologic beta rhythm. Here, this hypothesis was tested using selective optogenetic stimulation of striatal cholinergic interneurons in normal mice; stimulation robustly and reversibly amplified beta oscillations and Parkinsonian motor symptoms. The modulation of global rhythms by local networks was further studied using computational modeling in the context of intrathalamic neuromodulation. While intrathalamic vasoactive intestinal peptide (VIP) is known to cause long-lasting excitation in vitro, its in vivo dynamical effects have not been reported. Here, biophysical computational models were used to elucidate the impact of VIP on thalamocortical dynamics during sleep and propofol general anesthesia. The modeling results suggest that VIP can form robust sleep spindle oscillations and control aspects of sleep architecture through a novel homeostatic mechanism. This homeostatic mechanism would be inhibited by general anesthesia, representing a new mechanism contributing to anesthetic-induced loss of consciousness. While the previous two projects differed in their use of empirical versus theoretical methods, a challenge common to both domains is the difficulty in visualizing and analyzing large multi-dimensional datasets. A tool to mitigate these issues is introduced here: GIMBL-Vis is a Graphical Interactive Multi-dimensional extensiBLe Visualization toolbox for Matlab. This toolbox simplifies the process of exploring multi-dimensional data in Matlab by providing a graphical interface for visualization and analysis. Furthermore, it provides an extensible open platform for distributed development by the community