Mesencephalic Locomotor Region Research Articles

Electrical stimulation of the cuneiform nucleus enhances the effects of rehabilitative training on locomotor recovery after incomplete spinal cord injury.

Most human spinal cord injuries are anatomically incomplete, leaving some fibers still connecting the brain with the sublesional spinal cord. Spared descending fibers of the brainstem motor control system can be activated by deep brain stimulation (DBS) of the cuneiform nucleus (CnF), a subnucleus of the mesencephalic locomotor region (MLR). The MLR is an evolutionarily highly conserved structure which initiates and controls locomotion in all vertebrates. Acute electrical stimulation experiments in female adult rats with incomplete spinal cord injury conducted in our lab showed that CnF-DBS was able to re-establish a high degree of locomotion five weeks after injury, even in animals with initially very severe functional deficits and white matter lesions up to 80-95%. Here, we analyzed whether CnF-DBS can be used to support medium-intensity locomotor training and long-term recovery in rats with large but incomplete spinal cord injuries. Rats underwent rehabilitative training sessions three times per week in an enriched environment, either with or without CnF-DBS supported hindlimb stepping. After 4 weeks, animals that trained under CnF-DBS showed a higher level of locomotor performance than rats that trained comparable distances under non-stimulated conditions. The MLR does not project to the spinal cord directly; one of its main output targets is the gigantocellular reticular nucleus in the medulla oblongata. Long-term electrical stimulation of spared reticulospinal fibers after incomplete spinal cord injury via the CnF could enhance reticulospinal anatomical rearrangement and in this way lead to persistent improvement of motor function. By analyzing the spared, BDA-labeled giganto-spinal fibers we found that their gray matter arborization density after discontinuation of CnF-DBS enhanced training was lower in the lumbar L2 and L5 spinal cord in stimulated as compared to unstimulated animals, suggesting improved pruning with stimulation-enhanced training. An on-going clinical study in chronic paraplegic patients investigates the effects of CnF-DBS on locomotor capacity.

Mesencephalic Locomotor Region and Presynaptic Inhibition during Anticipatory Postural Adjustments in People with Parkinson's Disease.

Individuals with Parkinson's disease (PD) and freezing of gait (FOG) have a loss of presynaptic inhibition (PSI) during anticipatory postural adjustments (APAs) for step initiation. The mesencephalic locomotor region (MLR) has connections to the reticulospinal tract that mediates inhibitory interneurons responsible for modulating PSI and APAs. Here, we hypothesized that MLR activity during step initiation would explain the loss of PSI during APAs for step initiation in FOG (freezers). Freezers (n = 34) were assessed in the ON-medication state. We assessed the beta of blood oxygenation level-dependent signal change of areas known to initiate and pace gait (e.g., MLR) during a functional magnetic resonance imaging protocol of an APA task. In addition, we assessed the PSI of the soleus muscle during APA for step initiation, and clinical (e.g., disease duration) and behavioral (e.g., FOG severity and APA amplitude for step initiation) variables. A linear multiple regression model showed that MLR activity (R2 = 0.32, p = 0.0006) and APA amplitude (R2 = 0.13, p = 0.0097) explained together 45% of the loss of PSI during step initiation in freezers. Decreased MLR activity during a simulated APA task is related to a higher loss of PSI during APA for step initiation. Deficits in central and spinal inhibitions during APA may be related to FOG pathophysiology.

Revisiting the two rhythm generators for respiration in lampreys.

In lampreys, respiration consists of a fast and a slow rhythm. This study was aimed at characterizing both anatomically and physiologically the brainstem regions involved in generating the two rhythms. The fast rhythm generator has been located by us and others in the rostral hindbrain, rostro-lateral to the trigeminal motor nucleus. More recently, this was challenged by researchers reporting that the fast rhythm generator was located more rostrally and dorsomedially, in a region corresponding to the mesencephalic locomotor region. These contradictory observations made us re-examine the location of the fast rhythm generator using anatomical lesions and physiological recordings. We now confirm that the fast respiratory rhythm generator is in the rostro-lateral hindbrain as originally described. The slow rhythm generator has received less attention. Previous studies suggested that it was composed of bilateral, interconnected rhythm generating regions located in the caudal hindbrain, with ascending projections to the fast rhythm generator. We used anatomical and physiological approaches to locate neurons that could be part of this slow rhythm generator. Combinations of unilateral injections of anatomical tracers, one in the fast rhythm generator area and another in the lateral tegmentum of the caudal hindbrain, were performed to label candidate neurons on the non-injected side of the lateral tegmentum. We found a population of neurons extending from the facial to the caudal vagal motor nuclei, with no clear clustering in the cell distribution. We examined the effects of stimulating different portions of the labeled population on the respiratory activity. The rostro-caudal extent of the population was arbitrarily divided in three portions that were each stimulated electrically or chemically. Stimulation of either of the three sites triggered bursts of discharge characteristic of the slow rhythm, whereas inactivating any of them stopped the slow rhythm. Substance P injected locally in the lateral tegmentum accelerated the slow respiratory rhythm in a caudal hindbrain preparation. Our results show that the fast respiratory rhythm generator consists mostly of a population of neurons rostro-lateral to the trigeminal motor nucleus, whereas the slow rhythm generator is distributed in the lateral tegmentum of the caudal hindbrain.

Hypothalamic Orexinergic Neurons Projecting to the Mesencephalic Locomotor Region Are Activated by Voluntary Wheel Running Exercise in Rats.

Cardiovascular changes during exercise are regulated by a motor volitional signal, called central command, which originates in the rostral portions of the brain and simultaneously regulates somatomotor and autonomic nervous systems. Whereas we recently elucidated mesencephalic locomotor region (MLR) neurons projecting to the rostral ventrolateral medulla as a crucial component of the central circuit responsible for transmitting central command signals, upstream circuits that regulate the MLR neurons remain unknown. Orexinergic neurons, which primarily originate from the perifornical area (PeFA) of the hypothalamus and reportedly play roles in eliciting locomotion and elevating sympathetic activity, send axonal projection to the MLR. The knowledge led us to investigate whether central command signals are relayed through orexinergic neurons projecting to the MLR. We performed anterograde transsynaptic tagging with AAV1 encoding Cre to confirm the presence of MLR neurons postsynaptic to the PeFA in rats. We also conducted retrograde neural tracing with retrograde AAV, combined with immunohistochemical staining, to examine the excitability of MLR-projecting orexinergic neurons in rats that were allowed to freely run on the wheel for 90 min. A significant number of MLR neurons were labeled with Cre, indicating that PeFA neurons make synaptic contacts with MLR neurons. Moreover, immunoreactivities of Fos, a marker of neuronal excitation, were found in many MLR-projecting orexinergic neurons by voluntary wheel running exercise, compared to non-exercising control rats, especially in the intermediate-posterior, rather than anterior, and medial, rather than lateral, portions within the orexinergic neuron-distributing domain. The findings suggest that specifically located orexinergic neurons transmit central command signals onto the MLR for running exercise. Elucidating the role of these MLR-projecting orexinergic neurons in somatomotor control and autonomic cardiovascular control deserves further study to unveil central circuit mechanisms responsible for central command function.

Selective Activation of Subthalamic Nucleus Output Quantitatively Scales Movements.

The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. According to the dominant model, the STN output can suppress movement by enhancing inhibitory basal ganglia (BG) output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson's patients. But the mechanisms underlying STN DBS remain poorly understood, as previous studies usually relied on electrical stimulation, which cannot selectively target STN output neurons. Here, we selectively stimulated STN projection neurons using optogenetics and quantified behavior in male and female mice using 3D motion capture. STN stimulation resulted in movements with short latencies (10-15 ms). A single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematic measures. Unilateral stimulation caused movement in the ipsiversive direction (toward the side of stimulation) and quantitatively determined head yaw and head roll, while stimulation of either STN raises the head (pitch). Bilateral stimulation does not cause turning but raised the head twice as high as unilateral stimulation of either STN. Optogenetic stimulation increased the firing rate of STN neurons in a frequency-dependent manner, and the increased firing is responsible for stimulation-induced movements. Finally, stimulation of the STN's projection to the brainstem mesencephalic locomotor region was sufficient to reproduce the behavioral effects of STN stimulation. These results question the common assumption that the STN suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.SIGNIFICANCE STATEMENT Our results question the common assumption that the subthalamic nucleus (STN) suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem.

The mesencephalic locomotor region recruits V2a reticulospinal neurons to drive forward locomotion in larval zebrafish

The mesencephalic locomotor region (MLR) is a brain stem area whose stimulation triggers graded forward locomotion. How MLR neurons recruit downstream vsx2+ (V2a) reticulospinal neurons (RSNs) is poorly understood. Here, to overcome this challenge, we uncovered the locus of MLR in transparent larval zebrafish and show that the MLR locus is distinct from the nucleus of the medial longitudinal fasciculus. MLR stimulations reliably elicit forward locomotion of controlled duration and frequency. MLR neurons recruit V2a RSNs via projections onto somata in pontine and retropontine areas, and onto dendrites in the medulla. High-speed volumetric imaging of neuronal activity reveals that strongly MLR-coupled RSNs are active for steering or forward swimming, whereas weakly MLR-coupled medullary RSNs encode the duration and frequency of the forward component. Our study demonstrates how MLR neurons recruit specific V2a RSNs to control the kinematics of forward locomotion and suggests conservation of the motor functions of V2a RSNs across vertebrates.

Upregulation of breathing rate during running exercise by central locomotor circuits in mice

While respiratory adaptation to exercise is compulsory to cope with the increased metabolic demand, the neural signals at stake remain poorly identified. Using neural circuit tracing and activity interference strategies in mice, we uncover here two systems by which the central locomotor network can enable respiratory augmentation in relation to running activity. One originates in the mesencephalic locomotor region (MLR), a conserved locomotor controller. Through direct projections onto the neurons of the preBötzinger complex that generate the inspiratory rhythm, the MLR can trigger a moderate increase of respiratory frequency, prior to, or even in the absence of, locomotion. The other is the lumbar enlargement of the spinal cord containing the hindlimb motor circuits. When activated, and through projections onto the retrotrapezoid nucleus (RTN), it also potently upregulates breathing rate. On top of identifying critical underpinnings for respiratory hyperpnea, these data also expand the functional implication of cell types and pathways that are typically regarded as “locomotor” or “respiratory” related.

Neural underpinnings of freezing-related dynamic balance control in people with Parkinson's disease

IntroductionPeople with Parkinson's disease (PD) with freezing of gait (FOG; freezers) show impaired dynamic balance and experience falls more frequently compared to those without (non-freezers). Here, we explore the neural underpinnings of these freezing-related balance problems. Methods12 freezers, 16 non-freezers and 14 controls performed a dynamic balance task in the lab. The next day, the same task was investigated in the MRI-scanner through motor imagery (MI). A visual imagery (VI) control task was also performed. Imagery engagement was determined by comparing the performance times between the dynamic balance task, and its MI- and VI-variants. Balance-related brain activations in regions of interest were contrasted between groups based on an MI > rest versus VI > rest contrast. ResultsFreezers and non-freezers were matched for age, cognition and disease severity. Similar performance times between the balance control task and the MI-conditions revealed excellent imagery engagement. Compared to non-freezers, freezers showed decreased activation in regions of interest located in the left mesencephalic locomotor region (MLR; p = 0.006), right anterior cerebellum (p = 0.017) and cerebellar vermis (p < 0.001). Intriguingly, non-freezers showed higher activations in the cerebellar vermis than controls (p = 0.010). ConclusionOverall, we showed that decreased activation in the left MLR, and cerebellar regions in freezers relative to non-freezers could explain why dynamic balance is more affected in freezers. As non-freezers displayed increased cerebellar vermis activation compared to controls, it is possible that freezers show an inability to recruit sufficient compensatory cerebellar activity for effective dynamic balance control.

Brainstem neural mechanisms controlling locomotion with special reference to basal vertebrates.

Over the last 60 years, the basic neural circuitry responsible for the supraspinal control of locomotion has progressively been uncovered. Initially, significant progress was made in identifying the different supraspinal structures controlling locomotion in mammals as well as some of the underlying mechanisms. It became clear, however, that the complexity of the mammalian central nervous system (CNS) prevented researchers from characterizing the detailed cellular mechanisms involved and that animal models with a simpler nervous system were needed. Basal vertebrate species such as lampreys, xenopus embryos, and zebrafish became models of choice. More recently, optogenetic approaches have considerably revived interest in mammalian models. The mesencephalic locomotor region (MLR) is an important brainstem region known to control locomotion in all vertebrate species examined to date. It controls locomotion through intermediary cells in the hindbrain, the reticulospinal neurons (RSNs). The MLR comprises populations of cholinergic and glutamatergic neurons and their specific contribution to the control of locomotion is not fully resolved yet. Moreover, the downward projections from the MLR to RSNs is still not fully understood. Reporting on discoveries made in different animal models, this review article focuses on the MLR, its projections to RSNs, and the contribution of these neural elements to the control of locomotion. Excellent and detailed reviews on the brainstem control of locomotion have been recently published with emphasis on mammalian species. The present review article focuses on findings made in basal vertebrates such as the lamprey, to help direct new research in mammals, including humans.

The PPN and motor control: Preclinical studies to deep brain stimulation for Parkinson's disease.

The pedunculopontine nucleus (PPN) is the major part of the mesencephalic locomotor region, involved in the control of gait and locomotion. The PPN contains glutamatergic, cholinergic, and GABAergic neurons that all make local connections, but also have long-range ascending and descending connections. While initially thought of as a region only involved in gait and locomotion, recent evidence is showing that this structure also participates in decision-making to initiate movement. Clinically, the PPN has been used as a target for deep brain stimulation to manage freezing of gait in late Parkinson's disease. In this review, we will discuss current thinking on the role of the PPN in locomotor control. We will focus on the cytoarchitecture and functional connectivity of the PPN in relationship to motor control.

Exaggerated renal sympathetic nerve and pressor responses during spontaneously occurring motor activity in hypertensive rats.

Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

Granger causality analysis for calcium transients in neuronal networks, challenges and improvements.

One challenge in neuroscience is to understand how information flows between neurons in vivo to trigger specific behaviors. Granger causality (GC) has been proposed as a simple and effective measure for identifying dynamical interactions. At single-cell resolution however, GC analysis is rarely used compared to directionless correlation analysis. Here, we study the applicability of GC analysis for calcium imaging data in diverse contexts. We first show that despite underlying linearity assumptions, GC analysis successfully retrieves non-linear interactions in a synthetic network simulating intracellular calcium fluctuations of spiking neurons. We highlight the potential pitfalls of applying GC analysis on real in vivo calcium signals, and offer solutions regarding the choice of GC analysis parameters. We took advantage of calcium imaging datasets from motoneurons in embryonic zebrafish to show how the improved GC can retrieve true underlying information flow. Applied to the network of brainstem neurons of larval zebrafish, our pipeline reveals strong driver neurons in the locus of the mesencephalic locomotor region (MLR), driving target neurons matching expectations from anatomical and physiological studies. Altogether, this practical toolbox can be applied on in vivo population calcium signals to increase the selectivity of GC to infer flow of information across neurons.

Functional contribution of mesencephalic locomotor region nuclei to locomotor recovery after spinal cord injury

Spinal cord injury (SCI) results in a disruption of information between the brain and the spinal circuit. Electrical stimulation of the mesencephalic locomotor region (MLR) can promote locomotor recovery in acute and chronic SCI rodent models. Although clinical trials are currently under way, there is still debate about the organization of this supraspinal center and which anatomic correlate of the MLR should be targeted to promote recovery. Combining kinematics, electromyographic recordings, anatomic analysis, and mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus contribute to locomotor recovery by enhancing motor efficacy in hindlimb muscles, and by increasing locomotor rhythm and speed on a treadmill, over ground, and during swimming in chronic SCI mice. In contrast, glutamatergic neurons of the pedunculopontine nucleus slow down locomotion. Therefore, our study identifies the cuneiform nucleus and its glutamatergic neurons as a therapeutical target to improve locomotor recovery in patients living with SCI.

Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia

IntroductionThe leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion. MethodsWe compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [18F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112. ResultsIn HPK-non-LID rats, [18F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT1A receptors. ConclusionThis neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson’s disease.

Levodopa alters resting-state functional connectivity more selectively in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a debilitating motor symptom of Parkinson's disease (PD). Although PD dopaminergic medication (L-DOPA) seems to generally reduce FOG severity, its effect on neural mechanisms of FOG remains to be determined. The purpose of this study was to quantify the effect of L-DOPA on brain resting-state functional connectivity in individuals with FOG. Functional magnetic resonance imaging was acquired at rest in 30 individuals living with PD (15 freezers) in the ON- and OFF- medication state. A seed-to-voxel analysis was performed with seeds in the bilateral basal ganglia nuclei, the thalamus and the mesencephalic locomotor region. In freezers, medication-state contrasts revealed numerous changes in resting-state functional connectivity, not modulated by L-DOPA in non-freezers. In freezers, L-DOPA increased the functional connectivity between the seeds and regions including the posterior parietal, the posterior cingulate, the motor and the medial prefrontal cortices. Comparisons with non-freezers revealed that L-DOPA generally normalizes brain functional connectivity to non-freezers levels but can also increase functional connectivity, possibly compensating for dysfunctional networks in freezers. Our findings suggest that L-DOPA could contribute to a better sensorimotor, attentional, response inhibition and limbic processing to prevent FOG when triggers are encountered but could also contribute to FOG by interfering with the processing capacity of the striatum. This study shows that levodopa taken to control PD symptoms induces changes in functional connectivity at rest, in freezers only. Increases (green) in functional connectivity of GPe, GPi, putamen and thalamus with cognitive, sensorimotor and limbic cortical regions of the Interference model (blue) was observed. Our results suggest that levodopa can normalize connections similar to non-freezers or increases connectivity to compensate for dysfunctional networks.

Freezing of gait, gait initiation, and gait automaticity share a similar neural substrate in Parkinson's disease

Individuals with Parkinson’s disease (PD) and freezing of gait (FOG) have difficulty initiating and maintaining a healthy gait pattern; however, the relationship among FOG severity, gait initiation, and gait automaticity, in addition to the neural substrate of this relationship has not been investigated. This study investigated the association among FOG severity during turning (FOG-ratio), gait initiation (anticipatory postural adjustment [APA]), and gait automaticity (dual-task cost [DTC]), and the neural substrates of these associations. Thirty-four individuals with FOG of PD were assessed in the ON-medication state. FOG-ratio during a turning test, gait automaticity using DTC on stride length and gait speed, and APA during an event-related functional magnetic resonance imaging protocol to assess brain activity from the regions of interest (e.g., dorsolateral prefrontal cortex [DLPFC] and mesencephalic locomotor region [MLR]) were assessed in separated days. Results showed that FOG-ratio, APA amplitude, and DTC on stride length are negatively associated among them (P < 0.05). APA amplitude and DTC on stride length explained 59% of the FOG-ratio variance (P < 0.05). Although the activity of the right DLPFC and right MLR explained 55% of the FOG-ratio variance (P < 0.05) and 30% of the DTC on stride length variance (P ≤ 0.05), only the activity of the right MLR explained 23% of the APA amplitude (P < 0.05). FOG severity during turning, APA amplitude, and stride length automaticity are associated among them and share a similar locomotor substrate, as the MLR activity was a common brain region in explaining the variance of these variables.

Advances in DBS Technology and Novel Applications: Focus on Movement Disorders.

Deep brain stimulation (DBS) is an established treatment in several movement disorders, including Parkinson's disease, dystonia, tremor, and Tourette syndrome. In this review, we will review and discuss the most recent findings including but not limited to clinical evidence. New DBS technologies include novel hardware design (electrodes, cables, implanted pulse generators) enabling new stimulation patterns and adaptive DBS which delivers potential stimulation tailored to moment-to-moment changes in the patient's condition. Better understanding of movement disorders pathophysiology and functional anatomy has been pivotal for studying the effects of DBS on the mesencephalic locomotor region, the nucleus basalis of Meynert, the substantia nigra, and the spinal cord. Eventually, neurosurgical practice has improved with more accurate target visualization or combined targeting. A rising research domain emphasizes bridging neuromodulation and neuroprotection. Recent advances in DBS therapy bring more possibilities to effectively treat people with movement disorders. Future research would focus on improving adaptive DBS, leading more clinical trials on novel targets, and exploring neuromodulation effects on neuroprotection.

Dynamic control of visually guided locomotion through corticosubthalamic projections.

SUMMARYGoal-directed locomotion requires control signals that propagate from higher order areas to regulate spinal mechanisms. The corticosubthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task in which head-fixed mice run to a visual landmark and then stop and wait to collect the reward and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our behavioral modeling, calcium imaging, and optogenetics manipulation results suggest that the M2-STN pathway can be recruited during visually guided locomotion to rapidly and precisely control the pedunculopontine nucleus (PPN) of the mesencephalic locomotor region through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, PPN, and STN, we find that the corticosubthalamic projections potentially control PPN activity by differentiating an M2 error signal to ensure fast input-output dynamics.

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

Background: Parkinson's disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches. We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with FOG response to dopaminergic therapy. In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication). The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r = -0.360, df = 30, p = 0.043) but not overall motor dopa-response. These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior.

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury.

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited.Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats.We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14).This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability.