Increased motor cortex inhibition as a marker of compensation to chronic pain in knee osteoarthritis

AbstractThis study aims to investigate the associative and multivariate relationship between different sociodemographic and clinical variables with cortical excitability as indexed by transcranial magnetic stimulation (TMS) markers in subjects with chronic pain caused by knee osteoarthritis (OA). This was a cross-sectional study. Sociodemographic and clinical data were extracted from 107 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models per TMS markers: motor threshold (MT), motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). In our multivariate models, the two markers of intracortical inhibition, SICI and CSP, had a similar signature. SICI was associated with age (β: 0.01), WOMAC pain (β: 0.023), OA severity (as indexed by Kellgren–Lawrence Classification) (β: − 0.07), and anxiety (β: − 0.015). Similarly, CSP was associated with age (β: − 0.929), OA severity (β: 6.755), and cognition (as indexed by the Montreal Cognitive Assessment) (β: − 2.106). ICF and MT showed distinct signatures from SICI and CSP. ICF was associated with pain measured through the Visual Analogue Scale (β: − 0.094) and WOMAC (β: 0.062), and anxiety (β: − 0.039). Likewise, MT was associated with WOMAC (β: 1.029) and VAS (β: − 2.003) pain scales, anxiety (β: − 0.813), and age (β: − 0.306). These associations showed the fundamental role of intracortical inhibition as a marker of adaptation to chronic pain. Subjects with higher intracortical inhibition (likely subjects with more compensation) are younger, have greater cartilage degeneration (as seen by radiographic severity), and have less pain in WOMAC scale. While it does seem that ICF and MT may indicate a more acute marker of adaptation, such as that higher ICF and MT in the motor cortex is associated with lesser pain and anxiety.

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Late Cortical Disinhibition in Human Motor Cortex: A Triple-Pulse Transcranial Magnetic Stimulation Study

Journal of Neurophysiology ◽

10.1152/jn.00782.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 511-518 ◽

Cited By ~ 60

Author(s):

R. F. H. Cash ◽

U. Ziemann ◽

K. Murray ◽

G. W. Thickbroom

Keyword(s):

Transcranial Magnetic Stimulation ◽

Motor Cortex ◽

Magnetic Stimulation ◽

Short Interval ◽

Motor Evoked Potential ◽

Silent Period ◽

Intracortical Inhibition ◽

Human Motor Cortex ◽

Acid Type ◽

Human Motor

In human motor cortex transcranial magnetic stimulation (TMS) has been used to identify short-interval intracortical inhibition (SICI) corresponding to γ-aminobutyric acid type A (GABAA) effects and long-interval intracortical inhibition (LICI) and the cortical silent period (SP) corresponding to postsynaptic GABAB effects. Presynaptic GABAB effects, corresponding to disinhibition, can also be identified with TMS and have been shown to be acting during LICI by measuring SICI after a suprathreshold priming stimulus (PS). The duration of disinhibition is not certain and, guided by studies in experimental preparations, we hypothesized that it may be longer-lasting than postsynaptic inhibition, leading to a period of late cortical disinhibition and consequently a net increase in corticospinal excitability. We tested this first by measuring the motor-evoked potential (MEP) to a test stimulus (TS), delivered after a PS at interpulse intervals (IPIs) ≤300 ms that encompassed the period of PS-induced LICI and its aftermath. MEP amplitude was initially decreased, but then increased at IPIs of 190–210 ms, reaching 160 ± 17% of baseline 200 ms after PS ( P < 0.05). SP duration was 181 ± 5 ms. A second experiment established that the onset of the later period of increased excitability correlated with PS intensity ( r2 = 0.99) and with the duration of the SP ( r2 = 0.99). The third and main experiment demonstrated that SICI was significantly reduced in strength at all IPIs ≤220 ms after PS. We conclude that TMS-induced LICI is associated with a period of disinhibition that is at first masked by LICI, but that outlasts LICI and gives rise to a period during which disinhibition predominates and net excitability is raised. Identification of this late period of disinhibition in human motor cortex may provide an opportunity to explore or modulate the behavior of excitatory networks at a time when inhibitory effects are restrained.

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Transcranial focused ultrasound neuromodulation of the human primary motor cortex

10.1101/234666 ◽

2018 ◽

Cited By ~ 1

Author(s):

Wynn Legon ◽

Priya Bansal ◽

Roman Tyshynsky ◽

Leo Ai ◽

Jerel K. Mueller

Keyword(s):

Motor Cortex ◽

Focused Ultrasound ◽

Primary Motor Cortex ◽

Neuronal Excitability ◽

Cortical Excitability ◽

Silent Period ◽

Single Pulse ◽

Intracortical Inhibition ◽

Stimulus Response ◽

Non Invasive

AbstractTranscranial focused ultrasound is a form of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. The effect of ultrasound on human motor cortical excitability is currently unknown. We apply ultrasound to the primary motor cortex in humans using a novel transcranial ultrasound and magnetic stimulation (TUMS) paradigm that allows for concurrent and concentric ultrasound stimulation with transcranial magnetic stimulation (TMS). This allows for non-invasive inspection of the effect of ultrasound on motor neuronal excitability using the motor evoked potential (MEP) generated by TMS. We test the effect of ultrasound on single pulse MEP recruitment curves and paired pulse protocols including short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We also test the longevity of the effect and the effect of ultrasound on the cortical silent period in a small sub-sample of participants. In addition, we test the effect of ultrasound to motor cortex on a stimulus response reaction time task. Results show ultrasound inhibits the amplitude of single-pulse MEPs and attenuates intracortical facilitation but does not affect intracortical inhibition. Early evidence suggests that ultrasound does not affect cortical silent period duration and that the duration of inhibition may be related to the duration of stimulation. Finally, ultrasound reduces reaction time on a simple stimulus response task. This is the first report of the effect of ultrasound on human motor cortical excitability and motor behavior and confirms previous results in the somatosensory cortex that ultrasound results in effective neuronal inhibition that confers a performance advantage.

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High-Frequency Transcranial Magnetic Stimulation on Motor Cortex of Patients Affected by Migraine With Aura: A Way to Restore Normal Cortical Excitability?

Cephalalgia ◽

10.1111/j.1468-2982.2009.01870.x ◽

2009 ◽

Vol 30 (1) ◽

pp. 46-52 ◽

Cited By ~ 35

Author(s):

F Brighina ◽

A Palermo ◽

O Daniele ◽

A Aloisio ◽

B Fierro

Keyword(s):

Transcranial Magnetic Stimulation ◽

Motor Cortex ◽

Migraine With Aura ◽

High Frequency ◽

Magnetic Stimulation ◽

Cortical Excitability ◽

Repetitive Transcranial Magnetic Stimulation ◽

Motor Evoked Potential ◽

Intracortical Inhibition ◽

Healthy Controls

We showed reduced motor intracortical inhibition (ICI) and paradoxical increase of intracortical facilitation (ICF) to 1 Hz repetitive transcranial magnetic stimulation (rTMS) in patients affected by migraine with aura (MA). In conditions of enhanced excitability due to a reduced inhibition, high-frequency rTMS was found to potentiate intracortical inhibition. Here we explored the conditioning effects of high-frequency priming stimulation of motor cortex with the aim of normalizing excitability reverting paradoxical facilitation by 1 Hz rTMS in MA. Nine patients with MA and nine healthy controls underwent a paired-pulse TMS paradigm to evaluate motor intracortical excitability (ICI and ICF) before and after the following rTMS conditions: 1 Hz alone or preceded by a real or sham conditioning high-frequency (10 Hz) rTMS. Sham was used to control for rTMS specificity. In baseline, ICI was significantly lower in migraineurs with respect to controls. One hertz stimulation reduced motor evoked potential amplitude and ICF in healthy controls, while it caused a significant paradoxical ICF increase in migraineurs. High-frequency rTMS conditioning normalized excitability in migraine, increasing short ICI and so reversing the paradoxical effects of 1 Hz rTMS. These findings raise the possibility that the interictal reduced intracortical inhibition in migraine could be normalized by high-frequency rTMS. This would open perspectives for new treatment strategies in migraine prevention.

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Changes in Cortical Excitability and Parkinson Tremor After Botulinum Toxin Therapy

Neurology ◽

10.1212/wnl.0000000000012662 ◽

2021 ◽

Vol 97 (14) ◽

pp. e1413-e1424

Author(s):

Olivia Samotus ◽

Robert Chen ◽

Mandar Jog

Keyword(s):

Botulinum Toxin ◽

De Novo ◽

Cortical Excitability ◽

Botulinum Toxin Type A ◽

Short Interval ◽

Motor Evoked Potential ◽

Botulinum Toxin Type ◽

Intracortical Inhibition ◽

Botulinum Toxin Therapy ◽

Time Point

Background and ObjectivesTo investigate the relationship between botulinum toxin type A (BoNT-A) administration, tremor amplitude, and modulation of intracortical excitability and sensorimotor processing using paired-pulse transcranial magnetic stimulation (pp-TMS) in patients with early, tremor-dominant Parkinson disease (PD).MethodsTwelve de novo (naive to anti-PD medications) and 7 l-dopa (optimized on levodopa) participants with PD with tremor affecting one arm were recruited. All participants received 4 serial BoNT-A treatments for tremor every 12 weeks and peak effect was assessed 6 weeks posttreatment, totaling 8 visits over 42 weeks. Injection measures were based on kinematic tremor analysis. Short interval intracortical inhibition (SICI), intracortical facilitation (ICF), long interval intracortical inhibition (LICI), and measures of sensorimotor interaction (short-latency afferent [SAI] and long-latency afferent [LAI] stimulation) were assessed in both hemispheres using pp-TMS paradigms at each time point. Linear mixed models analyzed the effect of each pp-TMS measure and tremor severity within each cohort and the association between pp-TMS and tremor severity in the de novo cohort over 42 weeks. t Tests compared pp-TMS measures between hemispheres per time point.ResultsBaseline SICI, LICI, and SAI was reduced (higher motor evoked potential [MEP] ratio) on the tremulous/treated side compared to the nontremulous side in de novo participants. On the treated side in the de novo cohort, BoNT-A treatment significantly reduced ICF and increased LICI, SAI, and LAI (lower MEP ratio) at peak BoNT-A time points. The change in tremor severity was significantly associated with changes in SICI, LICI, and LAI.DiscussionOur findings suggest that tremor severity in early PD may be related to impaired intracortical inhibition and defective sensorimotor integration.

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Cortical dysfunction underlies disability in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458511424308 ◽

2011 ◽

Vol 18 (4) ◽

pp. 425-432 ◽

Cited By ~ 39

Author(s):

Steve Vucic ◽

Therese Burke ◽

Kerry Lenton ◽

Sudarshini Ramanathan ◽

Lavier Gomes ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cortical Excitability ◽

Short Interval ◽

Motor Evoked Potential ◽

Intracortical Inhibition ◽

Progressive Multiple Sclerosis ◽

Conduction Time ◽

Cortical Function ◽

Resting Motor Threshold ◽

Cortical Dysfunction

Background: Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance. Objectives: Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS. Methods: Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing–remitting MS patients (RRMS) and 66 controls. Results: Short interval intracortical inhibition (SPMS 3.0 ± 2.1%; RRMS 12.8 ± 1.7%, p < 0.01; controls 10.5 ± 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 ± 2.2%; RRMS 26.3 ± 3.6%, p <0.05; controls 24.7 ± 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 ± 1.9%; RRMS -2.0 ± 1.4, p < 0.05; controls -0.9 ± 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 ± 4.5%; RRMS 56.0 ± 1.5%, p < 0.01; controls 59.0 ± 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 ± 1.2 ms, p < 0.001) and RRMS (7.0 ± 0.9 ms, p < 0.05) patients compared with controls (5.5 ± 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale. Conclusion: Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.

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Paired-pulse measures

10.1093/oxfordhb/9780198568926.013.0011 ◽

2012 ◽

Author(s):

Ritsuko Hanajima ◽

Yoshikazu Ugawa

Keyword(s):

Motor Cortex ◽

Cortical Excitability ◽

Motor Evoked Potential ◽

Paired Pulse ◽

Motor Cortical Excitability ◽

Interhemispheric Connectivity ◽

Conditioned Motor ◽

Human Motor ◽

Motor Cortical ◽

Insight Into

This article reviews the physiology and application of the currently available paired-pulse protocols. Paired-pulse transcranial magnetic stimulation (TMS) techniques study the modulation of human motor cortical excitability. Paired-pulse experiments are designed to give insight into the nature of the cortical circuitry activated by TMS. Changes in motor cortical excitability produced by the conditioning pulse are estimated by changes in the size of the conditioned motor-evoked potential (MEP). It is possible to identify specific abnormalities in the balance between inhibitory and facilitatory processes, even if the pathology lies in abnormal afferent signalling to the motor cortex rather than in the motor cortex itself. The conclusion that emerges from the studies on interhemispheric interactions is that it is now possible by means of TMS protocols to chart long-range functional interhemispheric connectivity of remote areas of the human brain.

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Effect of Paired Associative Stimulation on Corticomotor Excitability in Chronic Smokers

Brain Sciences ◽

10.3390/brainsci9030062 ◽

2019 ◽

Vol 9 (3) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Andrew Lavender ◽

Hiroki Obata ◽

Noritaka Kawashima ◽

Kimitaka Nakazawa

Keyword(s):

Motor Learning ◽

Cortical Excitability ◽

Motor Evoked Potential ◽

Silent Period ◽

Single Pulse ◽

Control Group ◽

Short Term ◽

Paired Associative Stimulation ◽

Negative Effect ◽

Chronic Smoking

Chronic smoking has been shown to have deleterious effects on brain function and is an important risk factor for ischemic stroke. Reduced cortical excitability has been shown among chronic smokers compared with non-smokers to have a long-term effect and so far no study has assessed the effect of smoking on short-term motor learning. Paired associative stimulation (PAS) is a commonly used method for inducing changes in excitability of the motor cortex (M1) in a way that simulates short-term motor learning. This study employed PAS to investigate the effect of chronic cigarette smoking on plasticity of M1. Stimulator output required to elicit a motor-evoked potential (MEP) of approximately 1 mV was similar between the groups prior to PAS. MEP response to single pulse stimuli increased in the control group and remained above baseline level for at least 30 min after the intervention, but not in the smokers who showed no significant increase in MEP size. The silent period was similar between groups at all time points of the experiment. This study suggests that chronic smoking may have a negative effect on the response to PAS and infers that chronic smoking may have a deleterious effect on the adaptability of M1.

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Motor Cortex Excitability in Patients with Migraine with Aura and Hemiplegic Migraine

Cephalalgia ◽

10.1046/j.1468-2982.2000.00011.x ◽

2000 ◽

Vol 20 (1) ◽

pp. 45-50 ◽

Cited By ~ 55

Author(s):

KJ Werhahn ◽

K Wiseman ◽

J Herzog ◽

S Foörderreuther ◽

M Dichgans ◽

...

Keyword(s):

Motor Cortex ◽

Migraine With Aura ◽

Silent Period ◽

Intracortical Inhibition ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Cortical Hyperexcitability ◽

Motor Cortex Excitability ◽

Patient Groups ◽

Intracortical Inhibition And Facilitation

We studied the excitability of the motor cortex using transcranial magnetic stimulation (TMS) in 12 patients with migraine with aura (MA) and nine patients with familial hemiplegic migraine (FHM). Motor thresholds at rest, the duration of the cortical and peripheral silent period and intracortical inhibition and facilitation using paired-pulse TMS at intervals of 2 to 15 ms were measured with patients free of attacks for at least 48 h. In contrast to previous reports we could not find any significant differences between patient groups and compared to controls ( n = 17) in the parameters tested. The results suggest that there are no interictal changes of excitability of the motor cortex in migraine. This study does not support the concept of general cortical hyperexcitability in migraine secondary to a genetic predisposition or a structural alteration of inhibitory interneurones in the cortex due to repeated parenchymal insults during attacks.

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Association of Cortical Hyperexcitability and Cognitive Impairment in Patients with ALS

Neurology ◽

10.1212/wnl.0000000000011798 ◽

2021 ◽

pp. 10.1212/WNL.0000000000011798

Author(s):

Mana Higashihara ◽

Nathan Pavey ◽

Mehdi van den Bos ◽

Parvathi Menon ◽

Matthew C. Kiernan ◽

...

Keyword(s):

Cognitive Impairment ◽

Cortical Excitability ◽

Short Interval ◽

Motor Evoked Potential ◽

Intracortical Inhibition ◽

Cognitively Impaired ◽

Cortical Hyperexcitability ◽

Multivariable Regression ◽

Als Patients ◽

Lateral Sclerosis

Objective:To determine whether cortical hyperexcitability was more prominent in cognitively impaired amyotrophic lateral sclerosis (ALS) patients.Methods:Threshold tracking transcranial magnetic stimulation (TMS) was utilised to assess cortical excitability, while cognitive function determined by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Cognitive impairment was defined by ECAS<105. ALS patients, defined by the Awaji criteria, were prospectively recruited. Patients unable to undergo TMS, or in whom TMS indices were compromised by coexistent medical conditions were excluded. Cortical hyperexcitability was defined by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation (SICF), index of excitability (IE) and motor evoked potential (MEP) amplitude. Student t-test determined differences between groups, while multivariable regression modelling was utilised to assess association between cognitive, clinical and TMS parameters. TMS results were compared to 42 controls.Results:Cognitive impairment was evident in 36% of the 40 ALS patents (23 males, mean age 62.1 years). Cortical hyperexcitability was more prominent in cognitively impaired patients as indicated by an increase in SICF (ECAS≥105 -15.3±1.7%; ECAS<105 -20.6±1.2%, P<0.01), IE (ECAS ≥105 80.9±7.8; ECAS <105 95.0±4.5, P<0.01) and MEP amplitude (ECAS≥105 28.7±3.3%; ECAS<105 43.1±5.9%, P<0.05). SICF was independently associated with the ECAS score (β=2.410, P<0.05). Reduced SICI was evident in ALS, being more prominent in patients with reduced executive score (ECASexecutive score>33 6.2±1.3%; ECASexecutive score<33 1.5±2.1%, P<0.01).Conclusion:Cortical hyperexcitability was more prominent in cognitively impaired ALS patients. Given that ECAS is a valid predictor of TDP-43 pathology, the increase in cortical hyperexcitability may be associated with TDP-43 accumulation.

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Synovial Adiponectin Was More Associated with Clinical Severity than Synovial Leptin in Women with Knee Osteoarthritis

Cartilage ◽

10.1177/1947603520904776 ◽

2020 ◽

pp. 194760352090477 ◽

Cited By ~ 1

Author(s):

Cristóbal Orellana ◽

Joan Calvet ◽

Antoni Berenguer-Llergo ◽

Néstor Albiñana ◽

María García Manrique ◽

...

Keyword(s):

Synovial Fluid ◽

Knee Osteoarthritis ◽

Inflammatory Markers ◽

Cross Sectional Study ◽

Clinical Severity ◽

Womac Pain ◽

Obese Women ◽

Cross Sectional ◽

Total Pain ◽

Tnf Α

Objective Different adipokines have been reported to play a role in the development, progression, and severity of knee osteoarthritis, but this association may be mediated by obesity. The aim of this study was to evaluate separately the associations of leptin and adiponectin with clinical severity and inflammatory markers in nonobese and obese women with knee osteoarthritis. Design Cross-sectional study with systematic inclusion of 115 women with symptomatic primary knee osteoarthritis. Age, physical exercise, symptoms duration, and body mass index were collected. Radiographic severity was evaluated according to Kellgren-Lawrence scale. Pain and disability were assessed by WOMAC-total, -pain, -function subscales. Two adipokines (leptin and adiponectin) and 3 inflammatory markers (TNF-α, hsCRP, and IL-6) were measured by ELISA in synovial fluid and serum. Results Synovial fluid adiponectin was associated with WOMAC pain, function, and total and with synovial fluid IL-6 in nonobese female knee osteoarthritis after controlling by confounders (partial correlation coefficient [PCC] = 0.395, 0.387, 0.427, and 0.649, respectively). Synovial fluid and serum leptin were significantly associated with IL-6 (PCC = 0.354) after controlling by confounders but associations with clinical severity and the rest of inflammatory markers were mitigated after control. Conclusions Adiponectin in synovial fluid was associated with clinical severity and local inflammatory markers in knee osteoarthritis women, while leptin relation was attenuated when controlled by confounders.

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