Role of the subthalamic and pedonculopontine nuclei in gait and postural control in humans : electrophysiological, anatomical and behavioral approach

Les études neurophysiologiques de la locomotion ont été en très grande majorité conduites chez l’animal. Elles ont permis de mettre en évidence une région locomotrice dans le mésencéphale, dans laquelle le noyau pédonculopontin (NPP) joue un rôle prépondérant. Des troubles de la marche et de l’équilibre dans la maladie de Parkinson sont en lien avec la perte de neurones cholinergiques dans le NPP, mais également avec la dysfonction dopaminergique dans les ganglions de la base. L’activité du noyau subthalamique (NST) est impactée par la perte dopaminergique. Recevant de nombreuses afférences corticales et ayant une connectivité réciproque forte avec le PPN, la connectivité du NST suggère son importance pour le contrôle locomoteur. Néanmoins, il existe peu de données sur le rôle du NST et du NPP dans le contrôle de la marche et de l’équilibre chez l’Homme. Ce manuscrit regroupe des enregistrements électrophysiologiques du NST pendant l’initiation de la marche, une étude de l’effet de la fréquence de la stimulation cérébrale profonde du NST sur l’initiation de la marche en contexte de charge cognitive, une étude par immunohistochimie de la région du NPP chez l’Homme, et des données préliminaires d’activité électrophysiologique du NPP pendant une tâche de marche imaginaire et l’initiation de la marche. Ensemble, ces données participent à une meilleure compréhension des bases anatomo-fonctionnelles du contrôle de la marche et de l’équilibre chez l’Homme. De plus, la mise en évidence de marqueurs électrophysiologiques des troubles de la marche et de l’équilibre laisse à penser que la prise en charge de ces troubles est possible par stimulation cérébrale profonde.Neurophysiological studies of locomotion have been in majority driven on animal models. These approaches led to the identification of a mesencephalic locomotor region in which the pedonculopontin nucleus (PPN) plays a preponderant role. Gait and posture disabilities in Parkinson’s disease were linked with a loss of cholinergic neurons in the PPN as well as a dopaminergic dysfunction in the basal ganglia. The activity in the subthalamic nucleus (STN) is impacted by the dopaminergic loss. The STN receives numerous cortical inputs and is reciprocally connected with the PPN, suggesting an important role of the STN in the locomotor control. However, few data exist on the role of the STN and the PPN in gait and balance control in humans. This manuscript regroups electrophysiological recordings of the STN during gait initiation, a study of the effect of deep brain stimulation frequency of gait initiation in the context of cognitive load, an immunochemistry study of the region of the PPN in human, and preliminary results of the electrophysiological activity of the PPN during virtual gait and real gait initiation. Together, these data participate to a better understanding of the anatomo-functional basis of the gait and balance control in human. Moreover, the identification of electrophysiological markers of gait and balance dysfunction suggest that a deep brain stimulation may be relevant for their alleviation

Effets de la stimulation cérébrale profonde sur l’équilibre et la marche chez les patients atteints de la maladie de Parkinson : une revue systématique neurophysiologique

International audienceDeep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) provides an efficient treatment for the alleviation of motor signs in patients with Parkinson's disease. The effects of DBS on gait and balance disorders are less successful and may even lead to an aggravation of freezing of gait and imbalance. The identification of a substantia nigra pars reticulata (SNr)-mesencephalic locomotor region (MLR) network in the control of locomotion and postural control and of its dysfunction/lesion in PD patients with gait and balance disorders led to suggestion that DBS should be targeting the SNr and the pedunculopontine nucleus (part of the MLR) for PD patients with these disabling axial motor signs. However, the clinical results to date have been disappointing. In this review, we discuss the effects of DBS of these basal ganglia and brainstem structures on the neurophysiological parameters of gait and balance control in PD patients. Overall, the data suggest that both STN and GPi-DBS improve gait parameters and quiet standing postural control in PD patients, but have no effect or may even aggravate dynamic postural control, in particular with STN-DBS. Conversely, DBS of the SNr and PPN has no effect on gait parameters but improves anticipatory postural adjustments and gait postural control.La stimulation cérébrale profonde du noyau sous-thalamique (NST) ou du globus pallidum interne (GPi) représente un traitement efficace des troubles moteurs de la maladie de Parkinson. Les effets de la stimulation cérébrale profonde (SCP) sur les troubles de la marche et de l’équilibre sont moins probants avec parfois une aggravation postopératoire du freezing de la marche et/ou des chutes. L’identification du circuit substantia nigra pas reticulata (SNr) – région locomotrice mésencéphalique (RLM), qui comprend le noyau pédunculopontin (NPP) comme ayant un rôle majeur dans le contrôle postural et la locomotion et de leur dysfonctionnement/lésion chez les patients parkinsoniens souffrant de troubles de la marche et de l’équilibre a permis d’envisager la SCP de ces régions cérébrales pour améliorer ces signes moteurs invalidants. Toutefois, les résultats cliniques ont été assez décevants. Dans cette revue, nous rapportons les effets de la SCP des ganglions de la base et du NPP sur les paramètres neurophysiologiques de la marche et du contrôle postural chez les patients parkinsoniens. En moyenne, la SCP du NST et du GPi améliore les paramètres locomoteurs et le contrôle postural en position statique, mais semble avoir peu ou pas d’effet sur le contrôle postural dynamique avec peut-être une aggravation, en particulier avec la SCP-NST. Inversement, la SCP de la SNr ou du PPN ne modifie pas les paramètres locomoteurs mais pourrait améliorer les ajustements posturaux anticipatoires et le contrôle postural dynamique

Direct stimulation of anterior insula and ventromedial prefrontal cortex disrupts economic choices

International audienceNeural activity within the ventromedial prefrontal cortex (vmPFC) and anterior insula (aIns) is often associated with economic choices and confidence. However, it remains unclear whether these brain regions are causally related to these processes. To address this issue, we leveraged intracranial electrical stimulation (iES) data obtained from patients with epilepsy performing an economic choice task. Our results reveal opposite effects of stimulation on decision-making depending on its location along a dorso-ventral axis within each region. Specifically, stimulation of the ventral subregion within aIns reduces risk-taking by increasing participants' sensitivity to potential losses, whereas stimulation of the dorsal subregion of aIns and the ventral portion of the vmPFC increases risk-taking by reducing participants' sensitivity to losses. Moreover, stimulation of the aIns consistently decreases participants' confidence, regardless of its location within the aIns. These findings suggest the existence of functionally dissociated neural subregions and circuits causally involved in accepting or avoiding challenges

Decreasing subthalamic deep brain stimulation frequency reverses cognitive interference during gait initiation in Parkinson’s disease

International audienceFreezing of gait (FOG) represents a major burden for Parkinson's disease (PD) patients. High-frequency (130-Hz) subthalamic deep-brain-stimulation (STN-DBS) has been reported to aggravate FOG whereas lowering the frequency to 60-80 Hz improves FOG. To further understand the effects of STN-DBS on FOG, we assessed the effects of 80-Hz and 130-Hz STN-DBS on gait initiation performance, in relation to motor and executive function processing

Freezing of gait depends on cortico-subthalamic network recruitment following STN-DBS in PD patients

Introduction: Subthalamic deep-brain-stimulation (STN-DBS) is an effective means to treat Parkinson's disease (PD) symptoms. Its benefit on gait disorders is variable, with freezing of gait (FOG) worsening in about 30% of cases. Here, we investigate the clinical and anatomical features that could explain postoperative FOG. Methods: Gait and balance disorders were assessed in 19 patients, before and after STN-DBS using clinical scales and gait recordings. The location of active stimulation contacts were evaluated individually and the volumes of activated tissue (VAT) modelled for each hemisphere. We used a whole brain tractography template constructed from another PD cohort to assess the connectivity of each VAT within the 39 Brodmann cortical areas (BA) to search for correlations between postoperative PD disability and cortico-subthalamic connectivity. Results: STN-DBS induced a 100% improvement to a 166% worsening in gait disorders, with a mean FOG decrease of 36%. We found two large cortical clusters for VAT connectivity: one "prefrontal", mainly connected with BA 8,9,10,11 and 32, and one "sensorimotor", mainly connected with BA 1-2-3,4 and 6. After surgery, FOG severity positively correlated with the right prefrontal VAT connectivity, and negatively with the right sensorimotor VAT connectivity. The right prefrontal VAT connectivity also tended to be positively correlated with the UPDRS-III score, and negatively with step length. The MDRS score positively correlated with the right sensorimotor VAT connectivity. Conclusion: Recruiting right sensorimotor and avoiding right prefrontal cortico-subthalamic fibres with STN-DBS could explain reduced post-operative FOG, since gait is a complex locomotor program that necessitates accurate cognitive control

Human thalamic low-frequency oscillations correlate with expected value and outcomes during reinforcement learning

International audienceAbstract Reinforcement-based adaptive decision-making is believed to recruit fronto-striatal circuits. A critical node of the fronto-striatal circuit is the thalamus. However, direct evidence of its involvement in human reinforcement learning is lacking. We address this gap by analyzing intra-thalamic electrophysiological recordings from eight participants while they performed a reinforcement learning task. We found that in both the anterior thalamus (ATN) and dorsomedial thalamus (DMTN), low frequency oscillations (LFO, 4-12 Hz) correlated positively with expected value estimated from computational modeling during reward-based learning (after outcome delivery) or punishment-based learning (during the choice process). Furthermore, LFO recorded from ATN/DMTN were also negatively correlated with outcomes so that both components of reward prediction errors were signaled in the human thalamus. The observed differences in the prediction signals between rewarding and punishing conditions shed light on the neural mechanisms underlying action inhibition in punishment avoidance learning. Our results provide insight into the role of thalamus in reinforcement-based decision-making in humans

Pedunculopontine and Cuneiform Nuclei Deep Brain Stimulation for Severe Gait and Balance Disorders in Parkinson’s Disease: Interim Results from a Randomized Double-Blind Clinical Trial

International audienceBackground: Dopa-resistant freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced Parkinson's disease (PD).Objective: We investigate the effects of deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), comprised of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, for treating gait and balance disorders, in a randomized double-blind cross-over trial.Methods: Six PD patients with dopa-resistant FOG and/or falls were operated for MLR-DBS. Patients received three DBS conditions, PPN, CuN, or sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory-postural-adjustments (APAs) during gait initiation on a force platformResults:The anteroposterior APAs were not significantly different between the DBS conditions (median displacement [1st-3rd quartile] of 3.07 [3.12-4.62] cm with sham-DBS, 1.95 [2.29-3.85] cm with PPN-DBS and 2.78 [1.66-4.04] cm with CuN-DBS; p = 0.25). Step length and velocity were significantly higher with CuN-DBS vs. both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs. sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs. inclusion. We did not find any significant change in clinical scales between DBS conditions or one year after surgery.Conclusion: Two months of PPN-DBS or CuN-DBS does not effectively improve clinically dopa-resistant gait and balance disorders in PD patients