scholarly journals Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Florence Morin-Parent ◽  
Camille Champigny ◽  
Angelina Lacroix ◽  
François Corbin ◽  
Jean-François Lepage
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Short Interval ◽  
Silent Period ◽  
Intracortical Inhibition ◽  
Primary Objective ◽  
Healthy Controls ◽  
Intracortical Facilitation ◽  
Cortical Hyperexcitability ◽  
Resting Motor Threshold

AbstractFragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.

scholarly journals Increase in Short-Interval Intracortical Facilitation of the Motor Cortex after Low-Frequency Repetitive Magnetic Stimulation of the Unaffected Hemisphere in the Subacute Phase after Stroke

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Eduardo Arruda Mello ◽  
Leonardo G. Cohen ◽  
Sarah Monteiro dos Anjos ◽  
Juliana Conti ◽  
Karina Nocelo F. Andrade ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Magnetic Stimulation ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Short Interval ◽  
Low Frequency ◽  
Intracortical Inhibition ◽  
Active Group ◽  
Intracortical Facilitation ◽  
Resting Motor Threshold ◽  
Stimulation Of

Low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere (UH-LF-rTMS) in patients with stroke can decrease interhemispheric inhibition from the unaffected to the affected hemisphere and improve hand dexterity and strength of the paretic hand. The objective of this proof-of-principle study was to explore, for the first time, effects of UH-LF-rTMS as add-on therapy to motor rehabilitation on short-term intracortical inhibition (SICI) and intracortical facilitation (ICF) of the motor cortex of the unaffected hemisphere (M1UH) in patients with ischemic stroke. Eighteen patients were randomized to receive, immediately before rehabilitation treatment, either active or sham UH-LF-rTMS, during two weeks. Resting motor threshold (rMT), SICI, and ICF were measured inM1UHbefore the first session and after the last session of treatment. There was a significant increase in ICF in the active group compared to the sham group after treatment, and there was no significant differences in changes in rMT or SICI. ICF is a measure of intracortical synaptic excitability, with a relative contribution of spinal mechanisms. ICF is typically upregulated by glutamatergic agonists and downregulated by gabaergic antagonists. The observed increase in ICF in the active group, in this hypothesis-generating study, may be related toM1UHreorganization induced by UH-LF-rTMS.

Motor cortical disinhibition with baroreceptor unloading induced by orthostatic stress

2014 ◽  
Vol 111 (12) ◽  
pp. 2656-2664 ◽  
Author(s):  
Vasiliy E. Buharin ◽  
Andrew J. Butler ◽  
Minoru Shinohara
Keyword(s):  
Heart Rate ◽  
Lower Body Negative Pressure ◽  
Short Interval ◽  
Silent Period ◽  
Intracortical Inhibition ◽  
Frequency Component ◽  
Orthostatic Stress ◽  
Intracortical Facilitation ◽  
Arterial Blood ◽  
Intracortical Excitability

Unloading of the baroreceptors due to orthostatic stress increases corticospinal excitability. The purpose of this study was to examine the effects of baroreceptor unloading due to orthostatic stress on intracortical excitatory and inhibitory pathways in the motor cortex. With transcranial magnetic stimulation, measures of intracortical excitability for a hand muscle were tested on 2 days in healthy young adults. Lower body negative pressure (LBNP) of 40 mmHg was applied during one of the days and not during the Control day. During application of LBNP heart rate and the low-frequency component of heart rate variability increased, while mean arterial blood pressure was maintained. In the resting state, LBNP decreased short-interval intracortical inhibition (SICI) and had no effect on intracortical facilitation (ICF) or short-interval intracortical facilitation (SICF) compared with the Control day. During isometric contraction, no effects of LBNP were observed on tested measures of intracortical excitability including SICI, SICF, and cortical silent period. It was concluded that baroreceptor unloading due to orthostatic stress results in diminished intracortical inhibition, at least in the resting muscle.

Effect of fatigue-related group III/IV afferent firing on intracortical inhibition and facilitation in hand muscles

2020 ◽  
Vol 128 (1) ◽  
pp. 149-158 ◽  
Author(s):  
Christopher Latella ◽  
Onno van der Groen ◽  
Cassio V. Ruas ◽  
Janet L. Taylor
Keyword(s):  
Short Interval ◽  
Intracortical Inhibition ◽  
Voluntary Activation ◽  
Intracortical Facilitation ◽  
Group Iii ◽  
Hand Muscles ◽  
Resting Motor Threshold ◽  
Before And After ◽  
Muscle Afferent ◽  
Related Group

Fatiguing exercise causes a reduction in motor drive to the muscle. Group III/IV muscle afferent firing is thought to contribute to this process; however, the effect on corticospinal and intracortical networks is poorly understood. In two experiments, participants performed sustained maximal isometric finger abductions of the first dorsal interosseous (FDI) muscle, with postexercise blood flow occlusion (OCC) to maintain the firing of group III/IV afferents or without occlusion (control; CON). Before and after exercise, single- and paired-pulse transcranial magnetic stimulation (TMS) tested motor evoked potentials (MEPs), intracortical facilitation [ICF (12 ms)], and short-interval intracortical inhibition [SICI2 (2 ms), SICI3 (3 ms)]. Ulnar nerve stimulation elicited maximal M waves (MMAX). For experiment 1 ( n = 16 participants), TMS intensities were 70% and 120% of resting motor threshold (RMT) for the conditioning and MEP stimuli, respectively. For experiment 2 ( n = 16 participants), the MEP was maintained at 1 mV before and after exercise and the conditioning stimulus individualized. In experiment 1, MEP/MMAX was reduced after exercise (~48%, P = 0.007) but was not different between conditions. No changes occurred in ICF or SICI. In experiment 2, MEP/MMAX increased (~27%, P = 0.027) and less inhibition (SICI2: ~21%, P = 0.021) occurred after exercise for both conditions, whereas ICF decreased for CON only (~28%, P = 0.006). MEPs and SICI2 were modulated by fatiguing contractions but not by group III/IV afferent firing, whereas sustained afferent firing appeared to counteract postexercise reductions in ICF in FDI. The findings do not support the idea that actions of group III/IV afferents on motor cortical networks contribute to the reduction in voluntary activation observed in other studies. NEW & NOTEWORTHY This is the first study to investigate, in human hand muscles, the action of fatigue-related group III/IV muscle afferent firing on intracortical facilitation and inhibition. In fatigued and nonexercised hand muscles, intracortical inhibition is reduced after exercise but is not modulated differently by the firing of group III/IV afferents. However, facilitation is maintained for the fatigued muscle when group III/IV afferents fire, but these results are unlikely to explain the reduction in voluntary activation observed in other studies.

scholarly journals Cortical disinhibition in Parkinson’s disease

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3408-3421 ◽  
Author(s):  
Claudia Ammann ◽  
Michele Dileone ◽  
Cristina Pagge ◽  
Valentina Catanzaro ◽  
David Mata-Marín ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Magnetic Stimulation ◽  
Short Interval ◽  
Intracortical Inhibition ◽  
Motor Threshold ◽  
Intracortical Facilitation ◽  
Low Intensity ◽  
Resting Motor Threshold ◽  
Conditioning Stimuli

Abstract In Parkinson’s disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson’s disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson’s disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson’s disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson’s Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson’s disease.

Effects of water immersion on short- and long-latency afferent inhibition, short-interval intracortical inhibition, and intracortical facilitation

2013 ◽  
Vol 124 (9) ◽  
pp. 1846-1852 ◽  
Author(s):  
Daisuke Sato ◽  
Koya Yamashiro ◽  
Takuya Yoshida ◽  
Hideaki Onishi ◽  
Yoshimitsu Shimoyama ◽  
...  
Keyword(s):  
Water Immersion ◽  
Short Interval ◽  
Intracortical Inhibition ◽  
Intracortical Facilitation ◽  
Afferent Inhibition ◽  
Long Latency

scholarly journals Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome

2020 ◽  
Vol 10 (6) ◽  
pp. 361
Author(s):  
Mittal Jasoliya ◽  
Heather Bowling ◽  
Ignacio Cortina Petrasic ◽  
Blythe Durbin-Johnson ◽  
Eric Klann ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Drug Response ◽  
Molecular Level ◽  
Fragile X ◽  
Primary Objective ◽  
Molecular Biomarkers ◽  
Target Engagement ◽  
Targeted Treatments ◽  
Expression Abundance ◽  
Metalloproteinase 9

Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.

scholarly journals Urine-Derived Epithelial Cell Lines: A New Tool to Model Fragile X Syndrome (FXS)

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2240
Author(s):  
Marwa Zafarullah ◽  
Mittal Jasoliya ◽  
Flora Tassone
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Fragile X Syndrome ◽  
Cell Lines ◽  
Behavioral Problems ◽  
Cell Model ◽  
Fragile X ◽  
Healthy Controls ◽  
Full Mutation ◽  
Epithelial Cell Lines

Fragile X syndrome (FXS) is an X-linked neurodevelopmental condition associated with intellectual disability and behavioral problems due to the lack of the Fragile X mental retardation protein (FMRP), which plays a crucial role in synaptic plasticity and memory. A desirable in vitro cell model to study FXS would be one that can be generated by simple isolation and culture method from a collection of a non-invasive donor specimen. Currently, the various donor-specific cells can be isolated mainly from peripheral blood and skin biopsy. However, they are somewhat invasive methods for establishing cell lines from the primary subject material. In this study, we characterized a cost-effective and straightforward method to derive epithelial cell lines from urine samples collected from participants with FXS and healthy controls (TD). The urine-derived cells expressed epithelial cell surface markers via fluorescence-activated cell sorting (FACS). We observed inter, and the intra-tissue CGG mosaicism in the PBMCs and the urine-derived cells from participants with FXS potentially related to the observed variations in the phenotypic and clinical presentation FXS. We characterized these urine-derived epithelial cells for FMR1 mRNA and FMRP expression and observed some expression in the lines derived from full mutation mosaic participants. Further, FMRP expression was localized in the cytoplasm of the urine-derived epithelial cells of healthy controls. Deficient FMRP expression was also observed in mosaic males, while, as expected, no expression was observed in cells derived from participants with a hypermethylated full mutation.

scholarly journals Fatigue-induced changes in short-interval intracortical inhibition and the silent period with stimulus intensities evoking maximal versus submaximal responses

2020 ◽  
Vol 129 (2) ◽  
pp. 205-217
Author(s):  
Callum G. Brownstein ◽  
Loïc Espeit ◽  
Nicolas Royer ◽  
Thomas Lapole ◽  
Guillaume Y. Millet
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Short Interval ◽  
Conditioning Stimulus ◽  
Silent Period ◽  
Single Pulse ◽  
Intracortical Inhibition ◽  
Fatiguing Exercise ◽  
Induced Changes

This study compared the change in silent period (SP) and short-interval intracortical inhibition (SICI) with conditioning stimulus and single-pulse transcranial magnetic stimulation (TMS) intensities (for SICI and SP, respectively) eliciting maximal and submaximal SICI and SP during fatiguing exercise. The results showed that changes in SICI were only detectable with intensities evoking maximal responses, with no difference between intensities for SP. These findings highlight the importance of maximizing SICI with appropriate intensities before measuring SICI during fatiguing exercise.

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