Stimulation of the mesencephalic locomotor region for gait recovery after stroke

Malzahn, Uwe; Homola, György A.; Schuhmann, Michael K.; Kleinschnitz, Christoph; Volkmann, Jens

doi:10.1002/ana.25086

Cited by 25 publications

(28 citation statements)

References 42 publications

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“… Wang, Bontempi, et al., 2008 ; Y. Liu et al., 2013 ; Fluri et al., 2017 ). Thus, we used gait analysis as one of the parameters to compare functional deficits in stVAChT-KO mice and littermate controls 7 days after stroke.…”

Section: Discussionmentioning

confidence: 99%

Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

et al. 2020

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Acetylcholine (ACh) has been suggested to facilitate plasticity and improve functional recovery after different types of brain lesions. Interestingly, numerous studies have shown that striatal cholinergic interneurons are relatively resistant to acute ischemic insults, but whether ACh released by these neurons enhances functional recovery after stroke is unknown. We investigated the role of endogenous striatal ACh in stroke lesion volume and functional outcomes following middle cerebral artery occlusion to induce focal ischemia in striatum-selective vesicular acetylcholine transporter-deficient mice (stVAChT-KO). As transporter expression is almost completely eliminated in the striatum of stVAChT-KO mice, ACh release is nearly abolished in this area. Conversely, in other brain areas, VAChT expression and ACh release are preserved. Our results demonstrate a larger infarct size after ischemic insult in stVAChT-KO mice, with more pronounced functional impairments and increased mortality than in littermate controls. These changes are associated with increased activation of GSK-3, decreased levels of β-catenin, and a higher permeability of the blood–brain barrier in mice with loss of VAChT in striatum neurons. These results support a framework in which endogenous ACh secretion originating from cholinergic interneurons in the striatum helps to protect brain tissue against ischemia-induced damage and facilitates brain recovery by supporting blood–brain barrier function.

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Section: Discussionmentioning

confidence: 99%

Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

et al. 2020

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“…Photothrombotic stroke was induced in all rats, as described previously [4]. Briefly, the rats were fixed in a stereotactic frame under deep anesthesia (isoflurane 2.5%).…”

Section: Methodsmentioning

confidence: 99%

“…This might be due to limited neuroplasticity, but it might also be a result of local processes around the infarcted brain area, such as neuroinflammation. Recently, we have shown that high-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) enables gait restoration after photothrombotic lesioning of the sensorimotor cortex in rats [4]. In line with these findings, pharmacological or electrical stimulation of the MLR triggers locomotor behavior in decerebrated animals, such as cats [5], rats [6], and nonhuman primates [7].…”

Section: Introductionmentioning

confidence: 99%

Electrical Stimulation of the Mesencephalic Locomotor Region Attenuates Neuronal Loss and Cytokine Expression in the Perifocal Region of Photothrombotic Stroke in Rats

Schuhmann

Stoll

Bohr

et al. 2019

IJMS

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Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.

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“…The mesencephalic locomotor region (MLR) is a physiologically de ned area in the midbrain tegmentum, where electrical stimulation was found to initiate locomotion in cats (16,17). Since its discovery in 1966, the MLR has been identi ed in multiple species, as a phylogenetically preserved node in the supraspinal locomotor network (18)(19)(20)(21)(22)(23), with studies suggesting therapeutic potential in animal models of gait disorders (24)(25)(26). Electrophysiological and functional imaging evidence also supported its existence in humans (27)(28)(29), encouraging clinical interest in the region as a DBS target to promote gait.…”

Section: Rationale For Dbs Of the Mesencephalic Locomotor Regionmentioning

confidence: 99%

Deep Brain Stimulation of the Cuneiform Nucleus for Levodopa-Resistant Freezing of Gait in Parkinson’s Disease: Study Protocol for a Prospective, Pilot Trial

Chang

Cajigas

Guest

et al. 2020

Preprint

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Background: Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive MLR preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation.Methods: We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow up.Discussion: This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target.Trial Registration: Clinicaltrials.gov Identifier: NCT04218526 (registered January 6, 2020), https://www.clinicaltrials.gov/ct2/show/NCT04218526

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Stimulation of the mesencephalic locomotor region for gait recovery after stroke

Abstract: MLR-HFS can improve disordered locomotor function in a rodent stroke model. It may act by shielding brainstem and spinal locomotor centers from abnormal cortical input after stroke, thus allowing for compensatory and independent action of these circuits. Ann Neurol 2017;82:828-840.

Cited by 25 publications

References 42 publications

Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

Electrical Stimulation of the Mesencephalic Locomotor Region Attenuates Neuronal Loss and Cytokine Expression in the Perifocal Region of Photothrombotic Stroke in Rats

Deep Brain Stimulation of the Cuneiform Nucleus for Levodopa-Resistant Freezing of Gait in Parkinson’s Disease: Study Protocol for a Prospective, Pilot Trial

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