scholarly journals Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis

Brain ◽  
2020 ◽  
Vol 143 (3) ◽  
pp. 800-810 ◽  
Author(s):  
C Sahara Khademullah ◽  
Afif J Aqrabawi ◽  
Kara M Place ◽  
Zahra Dargaei ◽  
Xinyi Liang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Primary Motor Cortex ◽  
Intracortical Inhibition ◽  
Motor Deficits ◽  
Cortical Interneuron ◽  
Neuronal Populations ◽  
Cortical Hyperexcitability ◽  
Symptom Progression ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

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 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 Histological-MRI correlation in the primary motor cortex of patients with amyotrophic lateral sclerosis

2014 ◽  
Vol 41 (3) ◽  
pp. 665-675 ◽  
Author(s):  
Mark D. Meadowcroft ◽  
Nathan J. Mutic ◽  
Don C. Bigler ◽  
Jian-li Wang ◽  
Zachary Simmons ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Primary Motor Cortex ◽  
Lateral Sclerosis

scholarly journals Semiautomated Evaluation of the Primary Motor Cortex in Patients with Amyotrophic Lateral Sclerosis at 3T

2017 ◽  
Vol 39 (1) ◽  
pp. 63-69 ◽  
Author(s):  
G. Donatelli ◽  
A. Retico ◽  
E. Caldarazzo Ienco ◽  
P. Cecchi ◽  
M. Costagli ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Primary Motor Cortex ◽  
Lateral Sclerosis

Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis

Neurology ◽  
1997 ◽  
Vol 49 (5) ◽  
pp. 1292-1298 ◽  
Author(s):  
Ulf Ziemann ◽  
Martin Winter ◽  
Carl D. Reimers ◽  
Karin Reimers ◽  
Frithjof Tergau ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Silent Period ◽  
Intracortical Inhibition ◽  
Control Group ◽  
Cortical Silent Period ◽  
Healthy Control ◽  
Als Patients ◽  
Period Duration ◽  
Lateral Sclerosis

We investigated 14 patients with amyotrophic lateral sclerosis (ALS) by paired conditioning-test transcranial magnetic stimulation to test the hypothesis that the motor cortex is hyperexcitable in ALS. Intracortical(corticocortical) inhibition was significantly less in the ALS group than in an age-matched healthy control group (85.3 ± 27.0% versus 45.2± 15.5%, respectively; p < 0.0001). In contrast, intracortical facilitation, motor threshold, and cortical silent period duration in the ALS patients were not different from the control group. We suggest that the selective abnormality of intracortical inhibition is best compatible with an impaired function of inhibitory interneuronal circuits in the motor cortex that in turn renders the corticomotoneuron hyperexcitable.

scholarly journals Amyotrophic lateral sclerosis associated mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

2020 ◽  
Author(s):  
MS Dyer ◽  
KE Lewis ◽  
AK Walker ◽  
TC Dickson ◽  
A Woodhouse ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Models ◽  
Rna Binding ◽  
Binding Protein ◽  
Synaptic Function ◽  
Nuclear Localization Sequence ◽  
Mechanisms Of Toxicity ◽  
Cortical Hyperexcitability ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease pathologically characterised by mislocalisation of the RNA binding protein TAR-DNA binding protein 43 (TDP-43) from the nucleus to the cytoplasm. Changes to neuronal excitability and synapse dysfunction in the motor cortex are early pathological changes occurring in people with ALS and mouse models of disease. To investigate the effect of mislocalized TDP-43 on the function of motor cortex neurons we utilised mouse models that express either human wild-type (TDP-43WT) or nuclear localization sequence-deficient TDP-43 (TDP-43ΔNLS) on an inducible promoter that is restricted to the forebrain. Pathophysiology was investigated through immunohistochemistry and whole-cell patch-clamp electrophysiology. Thirty days expression TDP-43ΔNLS in adult mice (60 days of age) does not cause any changes in the number of NeuN positive nor CTIP2 positive neurons in the motor cortex. However at this time-point the expression of TDP-43ΔNLS drives intrinsic hyperexcitability in layer V excitatory neurons of the motor cortex. This hyperexcitability occurs concomitantly with a decrease in excitatory synaptic input to these cells. This pathophysiology is not present when TDP-43WT expression is driven, demonstrating that the localisation of TDP-43 to the cytoplasm is crucial for the altered excitability phenotype. This study has important implications for the mechanisms of toxicity of one of the most notorious proteins linked to ALS, TDP-43. We provide the first evidence that TDP-43 mislocalization causes aberrant synaptic function and a hyperexcitability phenotype in the motor cortex, linking some of the earliest dysfunctions to arise in people with ALS to mislocalisation of TDP-43.

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