Hyperdirect Pathway Research Articles

S84 Subthalamic and GPI stimulation and cortical plasticity

Objectives Review the effects of subthalamic (STN) and internal globus pallidus (GPi) stimulation on cortical plasticity. Methods Several relevant studies are reviewed. Results Using paired associative stimulation, most studies found decreased plasticity in Parkinson’s disease (PD). Dopaminergic medications restored plasticity in patients without levodopa-induced dyskinesia but not in patients with dyskinesia. Early, drug naive PD patients had decreased plasticity on the more affected side but had exaggerated plasticity on the less affected side. This asymmetry in plastsicity decreased over 12 months, which may reflect reduced compensation. In dyskinetic PD patients treated with STN deep brain stimulation (DBS), cortical plasticity was deficient in the off medication state but was restored in the medication on state with the stimulator turned on. STN DBS increases motor cortical excitability at about 3 ms likely through antidromic activation of the hyperdirect pathway, and at 23 ms likely through the indirect pathway. Repeated pairing STN DBS and cortical magnetic stimulation at these specific intervals induced motor cortical plasticity in PD patients. Similarly, repeated pairing of GPi stimulation and cortical magnetic stimulation at specific intervals induced cortical plasticity in dystonia patients. Discussion Cortical plasticity appears to be decreased in PD patients and is partially restored in some patients on medications while increased plasticity may be a compensatory mechanism in early PD. Cortical plasticity is strongly influenced by the basal ganglia. Conclusion DBS can modulate and induce cortical plasticity in PD and dystonia. Significance Modulation of cortical plasticity may be involved in mediating the effects of DBS.

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats.

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the pathophysiological basis of these diseases, it is necessary to precisely characterize in which way the processing of information is disturbed between the different neuronal parts of the circuit. Using extracellular in vivo electrophysiological recordings, it is possible to accurately delineate neuronal activity within a neuronal network. The application of this method has several advantages over alternative techniques, e.g., functional magnetic resonance imaging and calcium imaging, as it allows a unique temporal and spatial resolution and does not rely on genetically engineered organisms. However, the use of extracellular in vivo recordings is limited since it is an invasive technique that cannot be universally applied. In this article, a simple and easy to use method is presented with which it is possible to simultaneously record extracellular potentials such as local field potentials and multiunit activity at multiple sites of a network. It is detailed how a precise targeting of subcortical nuclei can be achieved using a combination of stereotactic surgery and online analysis of multi-unit recordings. Thus, it is demonstrated, how a complete network such as the hyperdirect cortico-basal ganglia loop can be studied in anesthetized animals in vivo.

Acute <em>In Vivo</em> Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

Acute <em>In Vivo</em> Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

Creating and parameterizing patient-specific deep brain stimulation pathway-activation models using the hyperdirect pathway as an example.

BackgroundDeep brain stimulation (DBS) is an established clinical therapy and computational models have played an important role in advancing the technology. Patient-specific DBS models are now common tools in both academic and industrial research, as well as clinical software systems. However, the exact methodology for creating patient-specific DBS models can vary substantially and important technical details are often missing from published reports.ObjectiveProvide a detailed description of the assembly workflow and parameterization of a patient-specific DBS pathway-activation model (PAM) and predict the response of the hyperdirect pathway to clinical stimulation.MethodsIntegration of multiple software tools (e.g. COMSOL, MATLAB, FSL, NEURON, Python) enables the creation and visualization of a DBS PAM. An example DBS PAM was developed using 7T magnetic resonance imaging data from a single unilaterally implanted patient with Parkinson’s disease (PD). This detailed description implements our best computational practices and most elaborate parameterization steps, as defined from over a decade of technical evolution.ResultsPathway recruitment curves and strength-duration relationships highlight the non-linear response of axons to changes in the DBS parameter settings.ConclusionParameterization of patient-specific DBS models can be highly detailed and constrained, thereby providing confidence in the simulation predictions, but at the expense of time demanding technical implementation steps. DBS PAMs represent new tools for investigating possible correlations between brain pathway activation patterns and clinical symptom modulation.

Resting State fMRI Reveals Increased Subthalamic Nucleus and Sensorimotor Cortex Connectivity in Patients with Parkinson's Disease under Medication.

Functional connectivity (FC) between the subthalamic nucleus (STN) and the sensorimotor cortex is increased in off-medication patients with Parkinson’s disease (PD). However, the status of FC between STN and sensorimotor cortex in on-medication PD patients remains unclear. In this study, resting state functional magnetic resonance imaging was employed on 31 patients with PD under medication and 31 healthy controls. Two-sample t-test was used to study the change in FC pattern of the STN, the FC strength of the bilateral STN was correlated with overall motor symptoms, while unilateral STN was correlated with offside motor symptoms. Both bilateral and right STN showed increased FC with the right sensorimotor cortex, whereas only right STN FC was correlated with left-body rigidity scores in all PD patients. An additional subgroup analysis was performed according to the ratio of mean tremor scores and mean postural instability and gait difficulty (PIGD) scores, only the PIGD subgroup showed the increased FC between right STN and sensorimotor cortex under medication. Increased FC between the STN and the sensorimotor cortex was found, which was related to motor symptom severity in on-medication PD patients. Anti-PD drugs may influence the hyperdirect pathway to alleviate motor symptoms with the more effect on the tremor subtype.

Semi-mechanistic computer simulation of psychotic symptoms in schizophrenia with a model of a humanized cortico-striatal-thalamocortical loop

Despite new insights into the pathophysiology of schizophrenia and clinical trials with highly selective drugs, no new therapeutic breakthroughs have been identified. We present a semi-mechanistic Quantitative Systems Pharmacology (QSP) computer model of a biophysically realistic cortical-striatal-thalamo-cortical loop. The model incorporates the direct, indirect and hyperdirect pathway of the basal ganglia and CNS drug targets that modulate neuronal firing, based on preclinical data about their localization and coupling to voltage-gated ion channels. Schizophrenia pathology is introduced using quantitative human imaging data on striatal hyperdopaminergic activity and cortical dysfunction. We identified an entropy measure of neuronal firing in the thalamus, related to the bandwidth of information processing that correlates well with reported historical clinical changes on PANSS Total with antipsychotics after introduction of their pharmacology (42 drug-dose combinations, r2=0.62). This entropy measure is further validated by predicting the clinical outcome of 28 other novel stand-alone interventions, 14 of them with non-dopamine D2R pharmacology, in addition to 8 augmentation trials (correlation between actual and predicted clinical scores r2=0.61). The platform predicts that most combinations of antipsychotics have a lower efficacy over what can be achieved by either one; negative pharmacodynamical interactions are prominent for aripiprazole added to risperidone, haloperidol, quetiapine and paliperidone. The model also recapitulates the increased probability for psychotic breakdown in a supersensitive environment and the effect of ketamine in healthy volunteers.This QSP platform, combined with similar readouts for motor symptoms, negative symptoms and cognitive impairment has the potential to improve our understanding of drug effects in schizophrenia patients.

Sixty-hertz stimulation improves bradykinesia and amplifies subthalamic low-frequency oscillations.

The objective of this study was to investigate the hypothesis that attenuation of subthalamic nucleus (STN) alpha-/beta-band oscillations is causal to improvement in bradykinesia. STN local field potentials from a sensing neurostimulator (Activa® PC+S; Medtronic, Inc.) and kinematics from wearable sensors were recorded simultaneously during 60- and 140-Hz deep brain stimulation (DBS) in 9 freely moving PD subjects (15 STNs) performing repetitive wrist flexion-extension. Kinematics were recorded during 20-Hz DBS in a subgroup. Both 60- and 140-Hz DBS improved the angular velocity and frequency of movement (P=0.002 and P=0.029, respectively, for 60 Hz; P<0.001 and P<0.001, respectively, for 140 Hz), but 60-Hz DBS did not attenuate beta-band power (13-30 Hz). In fact, 60-Hz DBS amplified alpha/low-beta (11-15 Hz, P=0.007) and attenuated high-beta power (19-27 Hz, P<0.001), whereas 140-Hz DBS broadly attenuated beta power (15-30 Hz, P<0.001). Only 60-Hz DBS improved the regularity of angular range (P=0.046) and 20-Hz DBS did not worsen bradykinesia. There was no correlation between beta-power modulation and bradykinesia. These novel results obtained from freely moving PD subjects demonstrated that both 140- and 60-Hz DBS improved bradykinesia and attenuated high beta oscillations; however, 60-Hz DBS amplified a subband of alpha/low-beta oscillations, and DBS at a beta-band frequency did not worsen bradykinesia. Based on recent literature, we suggest that both 140- and 60-Hz DBS decouple the cortico-STN hyperdirect pathway, whereas 60-Hz DBS increases coupling within striato-STN circuitry. These results inform future algorithms for closed-loop DBS in PD. © 2016 International Parkinson and Movement Disorder Society.

EP 21. Neuromodulation of the hyperdirect pathway to study flexibility as an endophenotype of obsessive compulsive disorders

Obsessive-Compulsive Disorder (OCD) is a mental disorder featuring obsessions (intrusive ideas) and compulsions which are repetitive behaviors performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients have diminished behavioral flexibility. The pathophysiology of OCD support this hypothesis with dysfunctional cortico-basal ganglia loops including two specific structures connected together through the hyperdirect pathway: the subthalamic nucleus and the orbitofrontal cortex, both also involved in behavioral flexibility. Thus, our objective is twofold: to verify the involvement of behavioral flexibility in the compulsive behavior and to explore the neurobiological bases underlying flexibility in patients and an animal model of OCD (SAPAP3-KO). We aim at developing similar behavioral tasks in both species where we could chronically modulate neural activity using deep brain stimulation and optogenetic. Behavioral flexibility may be challenged in reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. When the association has been learned, reward contingencies are inverted. This task has been implemented easily for neuropsychological studies in human. However, the adaptation of non-spatial reversal learning task in rodents is much more laborious due to the high number of trials required for the acquisition. To overcome this issue, we developed automated behavioral cages where animals could live and be exposed continuously to the reversal learning task. Our protocol is based on 5 main successive stages of training and allow to perform multiple reversal within one session. This experimental setup has also be designed to integrate chronic neuronal stimulation device to automatically modulate neural activity in the hyperdirect pathway during relevant events of the task. We succeeded in designing a similar reversal learning task to explore the behavioral flexibility both in humans and rodents. With our automatic ecological behavioral setup for mice, we reduced very significantly the time necessary to perform visual reversal learning task compared to more classical paradigm. Moreover we obtained preliminary results which are in line with the hypothesis of an impaired behavioral flexibility in compulsive subjects. Indeed, we observed that both OCD patients and SAPAP3-KO mice showed perseverative maladaptive behaviors in our task. These preliminary results suggest that OCD conditions could be associated with a diminished behavioral flexibility. The development of a translational behavioral task is the first step of our aim to explore the neural basis of the behavioral flexibility and its link with compulsive behavior. For this purpose, our innovative designs will allow us to modulate the cortico-basal ganglia pathways both in patients (with DBS) and OCD mouse model (with optogenetic) during behavioral tasks to study their implications in compulsive behaviors.

Corrigendum: Changing pattern in the basal ganglia: motor switching under reduced dopaminergic drive.

Scientific Reports 6: Article number: 23327; published online: 23 March 2016; updated: 19 August 2016. This Article contains an error in the Introduction section. “The standard model predicts that a normal balance between competing BG pathways can be restored by decreasing indirect and hyperdirect pathway activity, for example via lesions of the globus pallidus pars externa (GPe) or the STN.

Ultra-High Field MRI Post Mortem Structural Connectivity of the Human Subthalamic Nucleus, Substantia Nigra, and Globus Pallidus.

Introduction: The subthalamic nucleus, substantia nigra, and globus pallidus, three nuclei of the human basal ganglia, play an important role in motor, associative, and limbic processing. The network of the basal ganglia is generally characterized by a direct, indirect, and hyperdirect pathway. This study aims to investigate the mesoscopic nature of these connections between the subthalamic nucleus, substantia nigra, and globus pallidus and their surrounding structures.Methods: A human post mortem brain specimen including the substantia nigra, subthalamic nucleus, and globus pallidus was scanned on a 7 T MRI scanner. High resolution diffusion weighted images were used to reconstruct the fibers intersecting the substantia nigra, subthalamic nucleus, and globus pallidus. The course and density of these tracks was analyzed.Results: Most of the commonly established projections of the subthalamic nucleus, substantia nigra, and globus pallidus were successfully reconstructed. However, some of the reconstructed fiber tracks such as the connections of the substantia nigra pars compacta to the other included nuclei and the connections with the anterior commissure have not been shown previously. In addition, the quantitative tractography approach showed a typical degree of connectivity previously not documented. An example is the relatively larger projections of the subthalamic nucleus to the substantia nigra pars reticulata when compared to the projections to the globus pallidus internus.Discussion: This study shows that ultra-high field post mortem tractography allows for detailed 3D reconstruction of the projections of deep brain structures in humans. Although the results should be interpreted carefully, the newly identified connections contribute to our understanding of the basal ganglia.

Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease.

Chronic dopamine depletion in Parkinson's disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus-cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the possibility that cortical connectivity with the subthalamic nucleus in the high and low beta bands may reflect coupling mediated predominantly by the hyperdirect and indirect pathways to subthalamic nucleus, respectively, and that subthalamic nucleus deep brain stimulation predominantly suppresses the former. Yet only the change in strength of local subthalamic nucleus oscillations correlates with the degree of improvement during deep brain stimulation, compatible with the current view that a strengthened hyperdirect pathway is a prerequisite for locally generated beta activity but that it is the severity of the latter that may determine or index motor impairment.

The Striatum and Subthalamic Nucleus as Independent and Collaborative Structures in Motor Control.

The striatum and the subthalamic nucleus (STN) are two separate input structures into the basal ganglia (BG). Accordingly, research to date has primarily focused on the distinct roles of these structures in motor control and cognition, often through investigation of Parkinson’s disease (PD). Both structures are divided into sensorimotor, associative, and limbic subdivisions based on cortical connectivity. The more recent discovery of the STN as an input structure into the BG drives comparison of these two structures and their respective roles in cognition and motor control. This review compares the role of the striatum and STN in motor response inhibition and execution, competing motor programs, feedback based learning, and response planning. Through comparison, it is found that the striatum and STN have highly independent roles in motor control but also collaborate in order to execute desired actions. There is also the possibility that inhibition or activation of one of these structures indirectly contributes to the function of other connected anatomical structures. Both structures contribute to selective motor response inhibition, which forms the basis of many tasks, but the STN additionally contributes to global inhibition through the hyperdirect pathway. Research is warranted on the functional connectivity of the network for inhibition involving the rIFG, preSMA, striatum, and STN.

Tractographical model of the cortico-basal ganglia and corticothalamic connections: Improving Our Understanding of Deep Brain Stimulation.

The cortico-basal ganglia and corticothalamic projections have been extensively studied in the context of neurological and psychiatric disorders. Deep brain stimulation (DBS) is known to modulate many of these pathways to produce the desired clinical effect. The aim of this work is to describe the anatomy of the main circuits of the basal ganglia using tractography in a surgical planning station. We used imaging studies of 20 patients who underwent DBS for movement and psychiatric disorders. We segmented the putamen, caudate nucleus (CN), thalamus, and subthalamic nucleus (STN), and we also segmented the cortical areas connected with these subcortical areas. We used tractography to define the subdivisions of the basal ganglia and thalamus through the generation of fibers from the cortical areas to the subcortical structures. We were able to generate the corticostriatal and corticothalamic connections involved in the motor, associative and limbic circuits. Furthermore, we were able to reconstruct the hyperdirect pathway through the corticosubthalamic connections and we found subregions in the STN. Finally, we reconstructed the cortico-subcortical connections of the ventral intermediate nucleus, the nucleus accumbens and the CN. We identified a feasible delineation of the basal ganglia and thalamus connections using tractography. These results could be potentially useful in DBS if the parcellations are used as targets during surgery.

Painting a global picture of basal ganglia network: from past to present!

Since the 70s it has been thought that basal ganglia integrated sensorimotor, associative and limbic inputs and then projected this information through the thalamus to the motor cortex, supplementary motor area and frontal cortex, thus playing a relevant role in planning movement. Recent literature on basal ganglia networks is going beyond the classical “dogma” of dorsal striatum as the main station for cortical inputs in basal ganglia loops and several neurophysiological studies have suggested a more segregated organization of these neural circuits. In the classical view, various tract-tracing methods combined with immunohistochemistry and in situ hybridization demonstrated that the cortical information flows through the basal ganglia via a dual-network model, based on the “direct” and “indirect” routes. However, in addition to these two major projection systems, a glutamatergic hyper-direct pathway between cerebral cortex and subthalamic nucleus has been demonstrated first in monkeys and then in humans. Furthermore, we have recently shown a i) cortico-pallidal connection; ii) a cerebello-pallidal connection; iii) a cerebello nigral connection [1, 2]. Herein, we extensively examined basal ganglia network of fifteen healthy subjects by using probabilistic constrained spherical deconvolution tractography on magnetic resonance diffusion weighted imaging data and we also performed weighted connectivity analysis for each of the subcortical nuclei. In addition, we demonstrated for the first time tractographic evidences of the existence of a direct cortico-nigral pathway in humans. We found that substantia nigra is connected with cerebral cortex as a whole, with the most representative connections involving prefrontal cortex, precentral and postcentral gyri and superior parietal lobule. These findings would strength the hypothesis that the cortico-basal ganglia network consists of several, parallel, segregated, and functionally distinct, but homologous loop, and may be relevant for the comprehension of the pathophysiology of several basal ganglia disorders.

Competing basal ganglia pathways determine the difference between stopping and deciding not to go.

The architecture of corticobasal ganglia pathways allows for many routes to inhibit a planned action: the hyperdirect pathway performs fast action cancellation and the indirect pathway competitively constrains execution signals from the direct pathway. We present a novel model, principled off of basal ganglia circuitry, that differentiates control dynamics of reactive stopping from intrinsic no-go decisions. Using a nested diffusion model, we show how reactive braking depends on the state of an execution process. In contrast, no-go decisions are best captured by a failure of the execution process to reach the decision threshold due to increasing constraints on the drift rate. This model accounts for both behavioral and functional MRI (fMRI) responses during inhibitory control tasks better than alternative models. The advantage of this framework is that it allows for incorporating the effects of context in reactive and proactive control into a single unifying parameter, while distinguishing action cancellation from no-go decisions.

A new paradigm and computational framework to estimate stop-signal reaction time distributions from the inhibition of complex motor sequences.

Inhibitory control is an important component of executive function that allows organisms to abort emerging behavioral plans or ongoing actions on the fly as new sensory information becomes available. Current models treat inhibitory control as a race between a Go- and a Stop process that may be mediated by partially distinct neural substrates, i.e., the direct and the hyper-direct pathway of the basal ganglia. The fact that finishing times of the Stop process (Stop-Signal Reaction Time, SSRT) cannot be observed directly has precluded a precise comparison of the functional properties that govern the initiation (GoRT) and inhibition (SSRT) of a motor response. To solve this problem, we modified an existing inhibitory paradigm and developed a non-parametric framework to measure the trial-by-trial variability of SSRT. A series of simulations verified that the non-parametric approach is on par with a parametric approach and yields accurate estimates of the entire SSRT distribution from as few as ~750 trials. Our results show that in identical settings, the distribution of SSRT is very similar to the distribution of GoRT albeit somewhat shorter, wider and significantly less right-skewed. The ability to measure the precise shapes of SSRT distributions opens new avenues for research into the functional properties of the hyper-direct pathway that is believed to mediate inhibitory control.

Relationship between subthalamic nucleus neuronal activity and electrocorticogram is altered in the R6/2 mouse model of Huntington's disease.

Neural synchrony between the subthalamic nucleus (STN) and cortex is critical for proper information processing in basal ganglia circuits. Using in vivo extracellular recordings in urethane-anaesthetized mice, we demonstrate that single units and local field potentials from the STN exhibit oscillatory entrainment to low-frequency (0.5-4Hz) rhythms when the cortex is in a synchronized state. Here we report novel findings in the R6/2 transgenic mouse model of Huntington's disease (HD) by demonstrating that STN activity is reduced and less phase-locked to cortical low-frequency oscillations. The spectral power of low-frequency oscillations in ECoG recordings of R6/2 mice is diminished while the spectral power of higher frequencies is augmented and such altered cortical patterning could lead to decreased synchrony in corticosubthalamic circuits. Our data establish that cortical entrainment of STN neural activity is disrupted in R6/2 mice and may be one of the mechanisms contributing to disordered motor control in HD. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder in which impairments in the processing of information between the cortex and basal ganglia are fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a pivotal role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in a hyperkinetic movement syndrome, similar to the HD phenotype. The aim of the present study was to examine the relationship between neuronal activity in the STN and cortex in an animal model of HD. We performed in vivo extracellular recordings in the STN to measure single-unit activity and local field potentials in the R6/2 transgenic mouse model of HD. These recordings were obtained during epochs of simultaneously acquired electrocorticogram (ECoG) in discrete brain states representative of global cortical network synchronization or desynchronization. Cortically patterned STN neuronal activity was less phase-locked in R6/2 mice, which is likely to result in less efficient coding of cortical inputs by the basal ganglia. In R6/2 mice, the power of the ECoG in lower frequencies (0.5-4Hz) was diminished while the power expressed in higher frequencies (13-100Hz) was increased. In addition, the spontaneous activity of STN neurons in R6/2 mice was reduced and neurons exhibited a more irregular firing pattern. Glutamatergic STN neurons provide the major excitatory drive to the output nuclei of the basal ganglia and altered discharge patterns could lead to aberrant basal ganglia output and disordered motor control in HD.

Combined lesions of direct and indirect basal ganglia pathways but not changes in dopamine levels explain learning deficits in patients with Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disease of the basal ganglia that causes severe motor, cognitive and emotional dysfunctions. In the human basal ganglia, these dysfunctions are accompanied by a loss of striatal medium spiny neurons, dysfunctions of the subthalamic nucleus and globus pallidus, and changes in dopamine receptor binding. Here, we used a neuro-computational model to investigate which of these basal ganglia dysfunctions can explain patients' deficits in different stimulus-response learning paradigms. We show that these paradigms are particularly suitable for scrutinising the effects of potential changes in dopamine signaling and of potential basal ganglia lesions on overt behavior in HD. We find that combined lesions of direct and indirect basal ganglia pathways, but none of these lesions alone, reproduce patients' learning impairments. Degeneration of medium spiny neurons of the direct pathway accounts for patients' deficits in facilitating correct responses, whereas degeneration of indirect pathway medium spiny neurons explains their impairments in inhibiting dominant but incorrect responses. The empirical results cannot be explained by lesions of the subthalamic nucleus, which is part of the hyperdirect pathway, or by changes in dopamine levels. Overall, our simulations suggest combined lesions of direct and indirect pathways as a major source of HD patients' learning impairments and, tentatively, also their motor and cognitive deficits in general, whereas changes in dopamine levels are suggested to not be causally related to patients' impairments.

Age-dependent alterations in the cortical entrainment of subthalamic nucleus neurons in the YAC128 mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that results in motor, cognitive and psychiatric abnormalities. Dysfunction in neuronal processing between the cortex and the basal ganglia is fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a crucial role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in hyperkinetic movement abnormalities, similar to the motor symptoms associated with HD. The aim of the present study was to examine whether changes in the fidelity of information transmission between the cortex and the STN emerge as a function of phenotypic severity in the YAC128 mouse model of HD. We obtained in vivo extracellular recordings in the STN and concomitant electrocorticogram (ECoG) recordings during discrete brain states that reflected global cortical network synchronization or desynchronization. At early ages in YAC128 mice, both the cortex and the STN exhibited patterns of hyperexcitability. As symptom severity progressed, cortical entrainment of STN activity was disrupted and there was an increase in the proportion of non-oscillating, tonically firing STN neurons that were less phase-locked to cortical activity. Concomitant to the dissipation of STN entrainment, there was a reduction in the evoked response of STN neurons to focal cortical stimulation. The spontaneous discharge of STN neurons in YAC128 mice also decreased with age and symptom severity. These results indicate dysfunction in the flow of information within the corticosubthalamic circuit and demonstrate progressive age-related disconnection of the hyperdirect pathway in a transgenic mouse model of HD.

A Biologically Inspired Computational Model of Basal Ganglia in Action Selection.

The basal ganglia (BG) are a subcortical structure implicated in action selection. The aim of this work is to present a new cognitive neuroscience model of the BG, which aspires to represent a parsimonious balance between simplicity and completeness. The model includes the 3 main pathways operating in the BG circuitry, that is, the direct (Go), indirect (NoGo), and hyperdirect pathways. The main original aspects, compared with previous models, are the use of a two-term Hebb rule to train synapses in the striatum, based exclusively on neuronal activity changes caused by dopamine peaks or dips, and the role of the cholinergic interneurons (affected by dopamine themselves) during learning. Some examples are displayed, concerning a few paradigmatic cases: action selection in basal conditions, action selection in the presence of a strong conflict (where the role of the hyperdirect pathway emerges), synapse changes induced by phasic dopamine, and learning new actions based on a previous history of rewards and punishments. Finally, some simulations show model working in conditions of altered dopamine levels, to illustrate pathological cases (dopamine depletion in parkinsonian subjects or dopamine hypermedication). Due to its parsimonious approach, the model may represent a straightforward tool to analyze BG functionality in behavioral experiments.