Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation

Chang, Stephano J.; Cajigas, Iahn; Opriş, Ioan; Guest, James D.; Noga, Brian R.

doi:10.3389/fnsys.2020.00064

Cited by 29 publications

(29 citation statements)

References 60 publications

(108 reference statements)

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“…This supports the idea that distinct brainstem circuits control speed (Lee et al, 2014;Roseberry et al, 2016;Capelli et al, 2017;Caggiano et al, 2018;Josset et al, 2018) and braking/turning movements in mammals (Bouvier et al, 2015;Lemieux and Bretzner, 2019;Cregg et al, 2020;Usseglio et al, 2020; Figure 7). This also suggests that MLR glutamatergic neurons (and especially CnF glutamatergic neurons, Chang et al, 2020) are a relevant target to improve navigation adaptable to the environment in conditions where locomotion is impaired such as Parkinson's disease (Plaha and Gill, 2005;Hamani et al, 2016a,b;Goetz et al, 2019), spinal cord injury (Bachmann et al, 2013;Richardson, 2014;Roussel et al, 2019; for review Chari et al, 2017) and stroke (Fluri et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…It is relevant to determine whether MLR-evoked locomotion can be dynamically adapted to the environment, as MLR stimulation is explored to improve locomotor function in Parkinson’s disease (Plaha and Gill, 2005 ; Hamani et al, 2016a , b ; Goetz et al, 2019 ) and in animal models of spinal cord injury (Bachmann et al, 2013 ; Richardson, 2014 ; Roussel et al, 2019 ; for review Chari et al, 2017 ) and stroke (Fluri et al, 2017 ). We focused on the CnF, which is increasingly considered as the optimal subregion to target within the MLR (Chang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Zouwen

Boutin

Fougère

et al. 2021

Front. Neural Circuits

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A key function of the mesencephalic locomotor region (MLR) is to control the speed of forward symmetrical locomotor movements. However, the ability of freely moving mammals to integrate environmental cues to brake and turn during MLR stimulation is poorly documented. Here, we investigated whether freely behaving mice could brake or turn, based on environmental cues during MLR stimulation. We photostimulated the cuneiform nucleus (part of the MLR) in mice expressing channelrhodopsin in Vglut2-positive neurons in a Cre-dependent manner (Vglut2-ChR2-EYFP) using optogenetics. We detected locomotor movements using deep learning. We used patch-clamp recordings to validate the functional expression of channelrhodopsin and neuroanatomy to visualize the stimulation sites. In the linear corridor, gait diagram and limb kinematics were similar during spontaneous and optogenetic-evoked locomotion. In the open-field arena, optogenetic stimulation of the MLR evoked locomotion, and increasing laser power increased locomotor speed. Mice could brake and make sharp turns (~90°) when approaching a corner during MLR stimulation in the open-field arena. The speed during the turn was scaled with the speed before the turn, and with the turn angle. Patch-clamp recordings in Vglut2-ChR2-EYFP mice show that blue light evoked short-latency spiking in MLR neurons. Our results strengthen the idea that different brainstem neurons convey braking/turning and MLR speed commands in mammals. Our study also shows that Vglut2-positive neurons of the cuneiform nucleus are a relevant target to increase locomotor activity without impeding the ability to brake and turn when approaching obstacles, thus ensuring smooth and adaptable navigation. Our observations may have clinical relevance since cuneiform nucleus stimulation is increasingly considered to improve locomotion function in pathological states such as Parkinson’s disease, spinal cord injury, or stroke.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Zouwen

Boutin

Fougère

et al. 2021

Front. Neural Circuits

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“…7). This also suggests that CnF glutamatergic neurons are a relevant target to improve navigation adaptable to the environment in conditions where locomotion is impaired such as Parkinson’s disease [37, 38, 39, 40] spinal cord injury [41, 42] and stroke [43] (for review [44]).…”

Section: Discussionmentioning

confidence: 99%

“…It is relevant to determine whether MLR-evoked locomotion can be dynamically adapted to the environment, as MLR stimulation is explored to improve locomotor function in Parkinson’s disease [37, 38, 39, 40] and in animal models of spinal cord injury [41, 42] and stroke [43]. We focused on the CnF, which is increasingly considered as the optimal subregion to target within the MLR [44].…”

Section: Introductionmentioning

confidence: 99%

Freely behaving mice can brake and turn during optogenetic stimulation of the Mesencephalic Locomotor Region

Zouwen

Boutin

Fougère

et al. 2020

Preprint

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Background: Stimulation of the Mesencephalic Locomotor Region (MLR) is increasingly considered as a target to improve locomotor function in Parkinson's disease and spinal cord injury. A key function of the MLR is to control the speed of forward symmetrical locomotor movements. However, the ability of freely moving mammals to integrate environmental cues to brake and turn during MLR stimulation is poorly documented. Objective/hypothesis: We investigated whether freely behaving mice could brake or turn based on environmental cues during MLR stimulation. Methods: We stimulated the cuneiform nucleus in mice expressing channelrhodopsin in Vglut2-positive neurons in a Cre-dependent manner (Vglut2-ChR2-EYFP) using optogenetics. We detected locomotor movements using deep learning. We used patch-clamp recordings to validate the functional expression of channelrhodopsin and neuroanatomy to visualize the stimulation sites. Results: Optogenetic stimulation of the MLR evoked locomotion and increasing laser power increased locomotor speed. Gait diagram and limb kinematics were similar during spontaneous and optogenetic-evoked locomotion. Mice could brake and make sharp turns (~90⁰) when approaching a corner during MLR stimulation in an open-field arena. The speed during the turn was scaled with the speed before the turn, and with the turning angle. In a reporter mouse, many Vglut2-ZsGreen neurons were immunopositive for glutamate in the MLR. Patch-clamp recordings in Vglut2-ChR2-EYFP mice show that blue light evoked short latency spiking in MLR neurons. Conclusion: MLR glutamatergic neurons are a relevant target to improve locomotor activity without impeding the ability to brake and turn when approaching an obstacle, thus ensuring smooth and adaptable navigation.

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“…While animal studies have long distinguished between the pedunculopontine nucleus (PPN) and the slightly dorsally positioned cuneiform nucleus (CnF) in debates over the exact structural correlate to the MLR [(see Ferreira-Pinto et al (2018) for a review], with many suggesting the CnF may be more efficacious for gait ( Shik et al, 1966 ; Eidelberg et al, 1981 ; Takakusaki et al, 2016 ; Opris et al, 2019 ; Chang et al, 2021 ; Figure 1 ), neurosurgeons have exclusively targeted the PPN. This raises the possibility that target optimization in this region, including with the use of new directional DBS electrodes, could improve outcomes ( Chang et al, 2020b ).…”

Section: Introductionmentioning

confidence: 99%

MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait

Chang

Cajigas

Guest

et al. 2021

Front. Hum. Neurosci.

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BackgroundFreezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.MethodsAs part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise CartesiaTM) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject.ResultsPost-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia.ConclusionDTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG.Clinical Trial RegistrationClinicaltrials.gov identifier: NCT04218526.

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Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation

Cited by 29 publications

References 60 publications

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region

Freely behaving mice can brake and turn during optogenetic stimulation of the Mesencephalic Locomotor Region

MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait

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