A population model of deep brain stimulation in movement disorders from circuits to cells

Copyright © 2020 Yousif, Bain, Nandi and Borisyuk.For more than 30 years, deep brain stimulation (DBS) has been used to target the symptoms of a number of neurological disorders and in particular movement disorders such as Parkinson's disease (PD) and essential tremor (ET). It is known that the loss of dopaminergic neurons in the substantia nigra leads to PD, while the exact impact of this on the brain dynamics is not fully understood, the presence of beta-band oscillatory activity is thought to be pathological. The cause of ET, however, remains uncertain, however pathological oscillations in the thalamocortical-cerebellar network have been linked to tremor. Both of these movement disorders are treated with DBS, which entails the surgical implantation of electrodes into a patient's brain. While DBS leads to an improvement in symptoms for many patients, the mechanisms underlying this improvement is not clearly understood, and computational modeling has been used extensively to improve this. Many of the models used to study DBS and its effect on the human brain have mainly utilized single neuron and single axon biophysical models. We have previously shown in separate models however, that the use of population models can shed much light on the mechanisms of the underlying pathological neural activity in PD and ET in turn, and on the mechanisms underlying DBS. Together, this work suggested that the dynamics of the cerebellar-basal ganglia thalamocortical network support oscillations at frequency range relevant to movement disorders. Here, we propose a new combined model of this network and present new results that demonstrate that both Parkinsonian oscillations in the beta band and oscillations in the tremor frequency range arise from the dynamics of such a network. We find regions in the parameter space demonstrating the different dynamics and go on to examine the transition from one oscillatory regime to another as well as the impact of DBS on these different types of pathological activity. This work will allow us to better understand the changes in brain activity induced by DBS, and allow us to optimize this clinical therapy, particularly in terms of target selection and parameter setting.Peer reviewe

A robot model of the basal ganglia: Behavior and intrinsic processing

The existence of multiple parallel loops connecting sensorimotor systems to the basal ganglia has given rise to proposals that these nuclei serve as a selection mechanism resolving competitions between the alternative actions available in a given context. A strong test of this hypothesis is to require a computational model of the basal ganglia to generate integrated selection sequences in an autonomous agent, we therefore describe a robot architecture into which such a model is embedded, and require it to control action selection in a robotic task inspired by animal observations. Our results demonstrate effective action selection by the embedded model under a wide range of sensory and motivational conditions. When confronted with multiple, high salience alternatives, the robot also exhibits forms of behavioral disintegration that show similarities to animal behavior in conflict situations. The model is shown to cast light on recent neurobiological findings concerning behavioral switching and sequencing

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

The External Globus Pallidus: Bidirectional Control Over Anxiety-Related Behavior Mediated by CRFR1

Abstract THE EXTERNAL GLOBUS PALLIDUS: BIDIRECTIONAL CONTROL OVER ANXIETY-RELATED BEHAVIOR MEDIATED BY CRFR1 Albert Lee Joseph Hunt, Jr., B.S. Advisory Professor: Shane Cunha, Ph.D. Corticotropin-releasing factor receptor 1 (CRFR1), the principle receptor responsible for the anxiogenic activity of the stress peptide CRF, is abundantly expressed in the external globus pallidus (GPe) raising the question whether activity in the GPe is altered in response to stress. I show that CRFR1 expressing neurons are of the “prototypic” subtype of GPe neurons. I provide evidence of novel circuits from CRF neurons in stress-responsive nuclei, including the paraventricular nucleus of the hypothalamus (PVN) and the central nucleus of the amygdala (CeA), that provide excitatory input to the GPe. Additionally, I show that activation of CRFR1 neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) increases anxiety-related behavior and movement. I show that anxiety-related behavior and movement are decreased in response to activation of Npas1+ neurons, a class of neuron in the GPe that are primarily of the “arkypallidal” subtype. My evidence indicates that CRF neurons may project to the GPe to modulate anxiety-related behavior and movement through differential synaptic input to distinct GPe neuronal subtypes. CRF to GPe circuits provide possible therapeutic avenues to treat anxiety disorders comorbid with basal ganglia neurodegenerative diseases that cause aberrant activity in the GPe such as Parkinson’s disease

Neural signatures of hyperdirect pathway activity in Parkinson’s disease

Parkinson’s disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with ‘hyperdirect pathway’ fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD

Action selection in the striatum: Implications for Huntington's disease

Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role that the striatal microcircuit plays in action selection in the basal ganglia-cortical-thalamic loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-cortical-thalamic loop, to asses the computational role the striatum plays in action selection. We identify robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. I propose a mechanistic underpinning to a novel neural compensatory mechanism, responsible for improved cognition in severe neuro-degeneration. Thus, our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients, which is consistent with recent behavioural data

Investigating the mechanism of action of Deep Brain Stimulation using functional magnetic resonance imaging

Depleted of dopamine, the dynamics of the Parkinsonian brain impact on both “action” and “resting” motor behaviour. Subthalamic nucleus deep brain stimulation (STN DBS) has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Functional magnetic resonance imaging (fMRI) using the blood oxygen level dependent (BOLD) contrast provides the opportunity to study the human brain in vivo, collecting indirect measures of neural activity across the whole brain. To date, technical difficulties and safety concerns have precluded the use of fMRI in DBS patients. Previous work from this department has demonstrated that scanning patients with certain DBS systems and MRI equipment is both safe and feasible. This thesis explores the neuromodulatory actions of STN DBS on both action and resting motor behaviours in patients with Parkinson’s disease (PD) using fMRI. In brief, I present two fMRI studies conducted on STN DBS patients, one task-based, and one resting, collected under a previously approved protocol. I then present experiments exploring the safety of scanning DBS patients using an improved protocol, and then detail two further experiments collected under this new protocol, again one task-based, and one resting. Specifically, I employ statistical parametric mapping to determine DBS-induced changes in motor evoked responses. Using dynamic causal modelling (DCM) and Bayesian model selection, I compare generative models of cortico-subcortical interactions to explain the observed data, inferring which connections DBS may be affecting, and which modulations predict efficacy. I proceed to use stochastic DCM to model the modulatory effects of DBS on endogenous (resting-state) dynamics. Abstract | 4 4 This work casts DBS in terms of modulating effective connectivity within the cortico-basal ganglia motor loops. I discuss how this may explain its current usage in PD, as well as exploratory uses to treat other pathological brain states

Unified neural field theory of brain dynamics underlying oscillations in Parkinson's disease and generalized epilepsies

The mechanisms underlying pathologically synchronized neural oscillations in Parkinson's disease (PD) and generalized epilepsies are jointly explored via a neural field model of the corticothalamic-basal ganglia (CTBG) system. The basal ganglia (BG) are approximated as a single effective population and their roles in modulating oscillatory corticothalamic (CT) dynamics and vice versa are analyzed. Besides normal EEG rhythms, enhanced activity around 4 Hz and 20 Hz exists in the model, consistent with characteristic frequencies in PD. These rhythms result from resonances in loops between the BG and CT populations, analogous to those underlying epileptic oscillations in a previous CT model. Dopamine depletion is argued to weaken the dampening of these resonances in PD, and network connections explain the significant coherence between BG, thalamic, and cortical activity around 4-8 Hz and 20 Hz. Parallels between the afferent and efferent connection sites of the thalamic reticular nucleus (TRN) and BG predict low dopamine to correspond to a reduced likelihood of tonic-clonic (grand mal) seizures, agreeing with experimental findings. Further, the model predicts an increased likelihood of absence (petit mal) seizure resulting from low dopamine levels matching experimental findings. Suppression of absence seizure activity is shown when afferent and efferent BG connections to the CT system are strengthened, consistent with other CTBG modeling studies. The BG are demonstrated to suppress activity of the CTBG system near tonic-clonic seizure states, providing insight into the reported efficacy of current treatments in BG circuits. Sleep states of the TRN are also found to suppress pathological PD activity matching observations. Overall, the findings demonstrate strong parallels between coherent oscillations in generalized epilepsies and PD, and provide insights into possible comorbidities