scholarly journals Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Barbara Commisso ◽  
Lingjun Ding ◽  
Karl Varadi ◽  
Martin Gorges ◽  
David Bayer ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Primary Motor Cortex ◽  
Structural Basis ◽  
Progressive Degeneration ◽  
New Variant ◽  
Als Patients ◽  
The Brain ◽  
Pathogenic Process ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodeling in experimentally tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.

scholarly journals Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

2020 ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Luc Dupuis ◽  
Tobias Boeckers ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Metabolic Phenotype ◽  
Metabolic Disturbances ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractIncreased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.Significance statementWe provide a circuit perspective of the recently identified and medically relevant hyper-metabolic phenotype of Amyotrophic Lateral Sclerosis. We demonstrate the selective involvement of orbitofrontal, insular and motor cortex projections to hypothalamus in murine ALS models and in human patients. The enhanced pipeline for large-scale registration, segmentation projections mapping, the identification of new circuits target of neurodegeneration, and the relevance of these circuits in metabolic disturbances make this work relevant not only for the investigation of ALS but also for other neurodegenerative disease as well as for all conditions characterized by systemic energy imbalances.

scholarly journals Expression and Cellular Distribution of P-Glycoprotein and Breast Cancer Resistance Protein in Amyotrophic Lateral Sclerosis Patients

2019 ◽  
Vol 79 (3) ◽  
pp. 266-276
Author(s):  
Erwin A van Vliet ◽  
Anand M Iyer ◽  
Lucia Mesarosova ◽  
Hilal Çolakoglu ◽  
Jasper J Anink ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Abc Transporters ◽  
Breast Cancer Resistance Protein ◽  
Cellular Distribution ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Als Patients ◽  
The Brain ◽  
Lateral Sclerosis

Abstract For amyotrophic lateral sclerosis (ALS), achieving and maintaining effective drug levels in the brain is challenging due to the activity of ATP-binding cassette (ABC) transporters which efflux drugs that affect drug exposure and response in the brain. We investigated the expression and cellular distribution of the ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) using immunohistochemistry in spinal cord (SC), motor cortex, and cerebellum from a large cohort of genetically well characterized ALS patients (n = 25) and controls (n = 14). The ALS group included 17 sporadic (sALS) and 8 familial (fALS) patients. Strong P-gp expression was observed in endothelial cells in both control and ALS specimens. Immunohistochemical analysis showed higher P-gp expression in reactive astroglial cells in both gray (ventral horn) and white matter of the SC, as well as in the motor cortex of all ALS patients, as compared with controls. BCRP expression was higher in glia in the SC and in blood vessels and glia in the motor cortex of ALS patients, as compared with controls. P-gp and BCRP immunoreactivity did not differ between sALS and fALS cases. The upregulation of both ABC transporters in the brain may explain multidrug resistance in ALS patients and has implications for the use of both approved and experimental therapeutics.

scholarly journals Death Receptors in the Selective Degeneration of Motoneurons in Amyotrophic Lateral Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Julianne Aebischer ◽  
Nathalie Bernard-Marissal ◽  
Brigitte Pettmann ◽  
Cédric Raoul
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune Cells ◽  
Microglial Activation ◽  
Death Receptors ◽  
Strong Body ◽  
Als Patients ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Lateral Sclerosis

While studies on death receptors have long been restricted to immune cells, the last decade has provided a strong body of evidence for their implication in neuronal death and hence neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). ALS is a fatal paralytic disorder that primarily affects motoneurons in the brain and spinal cord. A neuroinflammatory process, associated with astrocyte and microglial activation as well as infiltration of immune cells, accompanies motoneuron degeneration and supports the contribution of non-cell-autonomous mechanisms in the disease. Hallmarks of Fas, TNFR, LT-βR, and p75NTR signaling have been observed in both animal models and ALS patients. This review summarizes to date knowledge of the role of death receptors in ALS and the link existing between the selective loss of motoneurons and neuroinflammation. It further suggests how this recent evidence could be included in an ultimate multiapproach to treat patients.

Motor control: spinal and cortical mechanisms

2016 ◽  
Author(s):  
David Burke
Keyword(s):  
Motor Control ◽  
Motor Cortex ◽  
Voluntary Movement ◽  
Primary Motor Cortex ◽  
Lower Limbs ◽  
Spinal Reflex ◽  
Extensive Literature ◽  
Spinal Level ◽  
Corticospinal System ◽  
The Brain

There is extensive machinery at cerebral and spinal levels to support voluntary movement, but spinal mechanisms are often ignored by clinicians and researchers. For movements of the upper and lower limbs, what the brain commands can be modified or even suppressed completely at spinal level. The corticospinal system is the executive pathway for movement arising largely from primary motor cortex, but movement is not initiated there, and other pathways normally contribute to movement. Greater use of these pathways can allow movement to be restored when the corticospinal system is damaged by, e.g. stroke, but there can be unwanted consequences of this ‘plasticity’. There is an extensive literature on cerebral mechanisms in the control of movement, and an equally large literature on spinal reflex function and the changes that occur during movement, and when pathology results in weakness and/or spasticity.

scholarly journals First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Agessandro Abrahao ◽  
Ying Meng ◽  
Maheleth Llinas ◽  
Yuexi Huang ◽  
Clement Hamani ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Primary Motor Cortex ◽  
Brain Barrier ◽  
Human Trial ◽  
Blood Brain ◽  
Lateral Sclerosis ◽  
Bbb Opening

Abstract MR-guided focused ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS.

scholarly journals Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Rami Saad ◽  
Luc Dupuis ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Diffusion Tensor ◽  
Metabolic Dysfunction ◽  
Projection Mapping ◽  
Magnetic Resonance Imaging Mri ◽  
Als Patients

Abstract Background Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Methods The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. Results Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Conclusion This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

scholarly journals Magnetic susceptibility in the deep layers of the primary motor cortex in Amyotrophic Lateral Sclerosis

2016 ◽  
Vol 12 ◽  
pp. 965-969 ◽  
Author(s):  
M. Costagli ◽  
G. Donatelli ◽  
L. Biagi ◽  
E. Caldarazzo Ienco ◽  
G. Siciliano ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Magnetic Susceptibility ◽  
Motor Cortex ◽  
Primary Motor Cortex ◽  
Deep Layers ◽  
Lateral Sclerosis

scholarly journals Electrode Placement in Transcranial Direct Current Stimulation—How Reliable Is the Determination of C3/C4?

2019 ◽  
Vol 9 (3) ◽  
pp. 69 ◽  
Author(s):  
Tonya Rich ◽  
Bernadette Gillick
Keyword(s):  
Motor Cortex ◽  
Direct Current ◽  
Transcranial Direct Current Stimulation ◽  
Primary Motor Cortex ◽  
Electrode Placement ◽  
Rater Reliability ◽  
Direct Current Stimulation ◽  
Adult Participants ◽  
The Brain ◽  
Absolute Reliability

The 10/20 electroencephalogram (EEG) measurements system often guides electrode placement for transcranial direct current stimulation (tDCS), a form of non-invasive brain stimulation. One targeted region of the brain is the primary motor cortex (M1) for motor recovery after stroke, among other clinical indications. M1 is identified by C3 and C4 of the 10/20 EEG system yet the reliability of 10/20 EEG measurements by novice research raters is unknown. We investigated the reliability of the 10/20 EEG measurements for C3 and C4 in 25 adult participants. Two novice raters were assessed for inter-rater reliability. Both raters received two hours of instruction from a registered neurodiagnostic technician. One of the raters completed the measurements across two testing days for intra-rater reliability. Relative reliability was determined using the intraclass coefficient (ICC) and absolute reliability. We observed a low to fair inter and intra-rater ICC for motor cortex measurements. The absolute reliability was <1.0 cm by different novice raters and on different days. Although a low error was observed, consideration of the integrity of the targeted region of the brain is critical when designing tDCS interventions in clinical populations who may have compromised brain structure, due to a lesion or altered anatomy.

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