Reduction Of Short Intracortical Inhibition Research Articles

Impaired intracortical transmission in G2019S leucine rich-repeat kinase Parkinson patients.

A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects. Paired pulse transcranial magnetic stimulation was used to investigate short intracortical inhibition and facilitation and short afferent inhibition. Intermittent theta burst stimulation, a form of repetitive transcranial magnetic stimulation, was used to test long-term potentiation-like cortical plasticity. Leucine-rich repeat kinase 2 and idiopathic PD were tested both in ON and in OFF l-dopa therapy. When compared with idiopathic PD and healthy subjects, leucine-rich repeat kinase 2 PD patients showed a remarkable reduction of short intracortical inhibition in both ON and in OFF l-dopa therapy. This reduction was paralleled by an increase of intracortical facilitation in OFF l-dopa therapy. Leucine-rich repeat kinase 2 PD showed abnormal long-term potentiation-like cortical plasticity in ON l-dopa therapy. The motor cortex in leucine-rich repeat kinase 2 mutated PD patients is strongly disinhibited and hyperexcitable. These abnormalities could be a result of an impairment of inhibitory (gamma-Aminobutyric acid) transmission eventually related to altered neurotransmitter release. © 2017 International Parkinson and Movement Disorder Society.

Abstract TP144: Intracortical Circuits Reveal Muscle- and Task-specific Dysfunction Contributing to Weakness Following Stroke

Introduction: Weakness is a prominent clinical manifestation following stroke. While central factors, including activation impairment, contribute to hemiparetic weakness, specific mechanisms remain poorly understood. Here we probed functioning of the corticospinal pathway and intracortical circuits mediating dynamic force production. Hypothesis: We hypothesized that impairments of intracortical inhibition and excitation contribute to deficits in plantarflexor (PF) force production capacity following stroke. Methods: We studied 19 chronic stroke survivors (age: 66.0±9.6 yrs; chronicity: 77.3±60.9 mo) and 7 controls (age: 61.3±9.7 yrs) and used the Short Physical Performance Battery to group stroke survivors by functional ability (i.e., HIGH, MED, LOW). We obtained peak isometric PF force during a series of maximal voluntary contractions. Single and paired pulse transcranial magnetic stimulation (TMS) was delivered over the ipsilesional hemisphere during isometric and dynamic PF contractions to assess corticomotor excitability, short intracortical inhibition (SICI), and short intracortical facilitation (SICF). Results: Peak isometric force (p=0.04) and cortical excitability in both medial gastrocnemius (MG) and soleus (SO) were progressively reduced across functional levels post-stroke (p’s<0.01). Controls revealed task-dependent modulation of motor evoked responses (MEPs) between isometric and dynamic contractions in MG, but not SOL while the MED and LOW groups failed to modulate MEPs. SICF revealed no differences between muscles, contraction type, or groups. In SO, controls revealed attenuation of SICI during movement. Stroke survivors revealed a progressive reduction in SICI during isometric PF across functional level while SICI increased during dynamic PF, resulting in a pattern reversal between controls and LOW (p=0.02). Conclusion: Deficits in dynamic PF post-stroke appear to be driven by changes in SICI rather than SICF, suggesting dysregulation of GABA-A. Impaired intracortical inhibition could reduce PF capacity by interfering with selective muscle recruitment during dynamic tasks.

Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis

Amyotrophiclateralsclerosis(ALS) isadevastatingdiseaseofthe motornervoussystem.Whilemost casesare sporadic, approximately5%to10%ofcasesare familial andresult frommutation in1ofmorethan25knownALS genes.Thesegenesspanasurprisingly broad range of molecular functions, including RNA metabolism, oxidative stress, axonal transport, autophagy, excitability, and immunity.Oneof thegreatmysteries in the field is thatmotorneurondiseaseresultsasaconvergentphenotypefrommutations in this diverse group of genes. Understanding this puzzle is likely keytooptimizingbothclinicaltrialsandpatienttreatmentbecause differentdrugsmayultimatelybenecessaryfortargetingspecific disease variants. Despitethemolecularheterogeneity, theclinicalmotorneuronphenotypesresultingfromthevariousgeneticmutationsand sporadic casesdifferonlymodestly. So toohasbeen thecaseon theneurophysiological level, inwhichBaeandcolleagues1have performedanimpressiveassemblyofstudiesshowingaxonaland cortical hyperexcitability in ALS. Lowermotor neuron studies useaspecializednerveconductionstudyprotocolcalled threshold tracking,whichwasdevelopedbyMogyoroset al.2Changes instimulus intensitynecessarytogeneratecompoundmotoractionpotentialsofapredeterminedamplitudearemonitoredduring the course of a recording, andprepulses and recovery cycle analysisareusedtomeasuredifferentcomponentsofaxonalexcitability.Cortical hyperexcitability inALShasbeen repeatedly demonstrated using transcranial magnetic stimulation (TMS), bothusing the traditional constant stimulus technique toelicit motor-evokedpotentials (MEPs)andbyadaptingthethresholdtracking approach to TMS. Inthis issueofJAMANeurology,Geevasingaandcolleagues3 extendedtheirobservationstoshowcorticalhyperexcitability in patients with familial ALS due to chromosome 9 open reading frame72(c9orf72)hexanucleotidegenerepeatexpansion,which is themost commongenetic causeofALSand is responsible for about5%ofapparentsporadicALSand40%offamilialALScases. The findings are quite similar to those in sporadic and superoxidedismutase(SOD1)genefamilialALS,with increasedexcitabilitymanifestedmost clearlyusingpaired testing. Short intracortical inhibitionreferstotheincreaseinMEPthreshold(ordecrease inMEPamplitude) resulting fromaconditioningprepulsea few millisecondsbefore a test pulse. In contrast, intracortical facilitationisthereductioninthreshold(orincreaseinMEPamplitude) whentheconditioningprepulseprecedesthetestpulsebyabout 15milliseconds.4The reduction in short intracortical inhibition and increase in intracortical facilitationare2of themostprominentTMSfindings inALS.Otherdisease featuressharedbyboth sporadicandc9orf72 familialALS includereducedrestingmotor threshold, increased MEP amplitude, decreased cortical silent periodduration, and increased centralmotor conduction time. Thecorticalandaxonalexcitabilitystudieshaveshownaremarkableconsistencyof findings inbothpatientswithsporadic ALSandpatientswithfamilialALSand,thus,raisequestionsabout how different molecular mechanisms converge to produce changes inneuronalexcitability inALSandwhether researchers can leverage the consistent neurophysiological hyperexcitabilityphenotypetoreveal informationandpotential targetsthatare broadlyrelevantacrossALSvariants.Theclinical resultssuggest anopportunitytoreexaminehyperexcitabilityusinganimalmodelsandmore-reductionistsystemstoaddressexcitabilitymechanisms.Suchworkcouldpotentially reveal specific ionchannels or cellular pathways that underlie the neurophysiological phenotype.Thecomplexityofdifferentneuronal andnonneuronal cellularsubtypesthatgiverisetoandmodulatethedifferentTMS and nerve conduction study measurements justify additional basic exploration.However, technical considerationshave limited theuseof theneurophysiological techniques inmice, both with regard to challenges inperforming tests aswell as artifacts owing to sedation in interpreting test results. In animalmodels of SOD1 ALS, most studies have supported increased motor neuronactivity5;however,others, includingastudyusinginvivo recordings of specificmotor neuron pools, have not.6 Inmotor neuronsmadefromALS-inducedpluripotent stemcells,hyperexcitability ispresentbut thendecreaseswith longcultureperiods, potentially because of worsening neuronal health and a depolarization-inducedblockofmotorneuronfiring.7-9 Invitro studies have identified roles of persistent sodium currents and delayed-rectifierpotassiumcurrents in increasingmotorneuron excitability in ALS. Futurework using specific channelmodifiers may help elucidate the channels, receptors, andmolecular scaffolding underlying clinical neurophysiological cortical and axonal hyperexcitability. Webelievethebulkoftheevidencesupportshyperexcitability as aprimaryprocess inALSasopposed toanadaptiveone.10 Thepresenceofsignsofhyperexcitability,suchasfasciculations, beforeotherclinicalsymptomsismoreconsistentwithaprimary roleforhyperexcitability.Similarly,thehyperexcitabilityobserved inbothprenatalSOD1motorneuronsandALSstemcell–derived motorneuronsofmultiplegeneticvariants, inwhichdecreasing excitability improvesmotorneuronsurvival andreducesendoplasmicreticulumstressinvitro,bothsupportaprimaryupstream Author Audio Interview at jamaneurology.com

Reduced intra-cortical inhibition after sleep deprivation: A transcranial magnetic stimulation study

Sleep deprivation has multiple effects on brain function. It increases the risk for epileptic seizures both in healthy individuals and in patients with epilepsy. Furthermore it represents an effective antidepressive intervention with rapid onset. However, the mechanisms underlying these effects are still largely unknown [2]. Transcranial magnetic stimulation (TMS) can be used as a non-invasive method for the measurement of motor cortex excitability. Here we used TMS for assessing sleep deprivation effects on cortical excitability in healthy individuals. Before and after 24 h of sleep deprivation, parameters of cortical excitability (resting motor threshold, short intracortical inhibition, intracortical facilitation, cortical silent period) were measured in a sample of 15 healthy volunteers (11 women, 4 men, aged between 21 and 30 years with a mean of 24.3 ± 2.7 years). We detected a significant ( p = 0.042) reduction of short intracortical inhibition (SICI) after sleep deprivation. Motor threshold, intracortical facilitation and contralateral silent period remained unchanged. Our results confirm previous studies which have demonstrated changes of SICI after sleep deprivation. Our findings further suggest that the increased risk for epileptic seizures after sleep deprivation is mediated by a reduction of intracortical inhibition. Whether this mechanism is also involved in mediating the antidepressant effect of sleep deprivation has to be addressed by further studies in depressive patients.

Short and long interval cortical inhibition in patients with Unverricht-Lundborg and Lafora body disease

Myoclonus has different clinical and neurophysiological features in patients with Unverricht-Lundborg (ULD) and Lafora body disease (LBD), probably because of a different cortical hyperexcitability profile. To investigate the role of intracortical inhibition in such different presentations, we used paired-pulse transcranial magnetic stimulation (TMS) in ten ULD and five LBD patients, all with a positive molecular diagnosis. All of the patients were treated with antiepileptic drugs (AEDs). In comparison with healthy subjects, both patient groups had significantly defective short intracortical inhibition (SICI), however LBD patients, but not ULD and healthy subjects, had a clear inhibition at ISI 6 ms and ISI 10 ms. Moreover, defective long interval cortical inhibition (LICI) was found in LBD but not ULD patients. The substantial reduction in SICI suggests that both ULD and LBD patients have impaired inhibitory interneuron pools which are involved in the generation of cortical reflex myoclonus, whereas the inhibition found in LBD patients at ISI 6 and 10 ms, as well the reduced inhibition found at long intervals, suggest a more complex circuitry dysfunction possibly involving both excitatory and inhibitory systems. These findings are probably related to the high epileptogenic propensity characterizing LBD with respect to ULD and to the more severely distorted neuronal network resulting from the pathogenesis of LBD.

RETRACTED: Allelic Variation in the Serotonin Transporter Promoter Modulates Cortical Excitability

Transcranial magnetic stimulation (TMS) is a noninvasive procedure that may be used to study individual differences in motor cortex excitability. Such differences are assumed to reflect serotonergic and other inputs to the motor cortex. Here we investigate the impact of a functional polymorphism in the promoter region of the 5-hydroxytryptamine transporter gene (5-HTTLPR) on measures of motor cortex excitability. Sixty healthy subjects carrying one or two copies of the short 5-HTTLPR allele (s/s and s/l) showed a significant reduction in short intracortical inhibition (SICI, p = .012) and an increased cortical silent period (p = .042) compared with 60 age- and sex-matched individuals homozygous for the long allele (l/l). In contrast, motor threshold and intracortical facilitation did not differ significantly between groups. These results provide further evidence of a role for serotonergic transmission in the modulation of cortical excitability. Differential effects on the measures under study suggest a pattern of prioritization in bioamine regulation of cortical inhibition.

Short Intracortical and Surround Inhibition Are Selectively Reduced during Movement Initiation in Focal Hand Dystonia

In patients with focal hand dystonia (FHD), pathological overflow activation occurs in muscles not involved in the movement. Surround inhibition is a neural mechanism that can sharpen desired movement by inhibiting unwanted movement in adjacent muscles. To further establish the phenomenon of surround inhibition and to determine whether short intracortical inhibition (SICI) reflecting inhibition from the local interneurons in primary motor cortex (M1), might play a role in its genesis, single- and paired-pulse transcranial magnetic stimulation (TMS), and Hoffmann reflex testing were applied to evaluate the excitability of the relaxed abductor pollicis brevis muscle (APB) at various intervals during a movement of the index finger in 16 patients with FHD and 20 controls. Whereas controls showed inhibition of APB motor-evoked potential (MEP) size during movement initiation and facilitation of APB MEP size during the maintenance phase, FHD patients did not modulate APB MEP size. In contrast, SICI remained constant in controls, but FHD patients showed reduced SICI during movement initiation. The H(max)/M(max) ratio in control subjects increased during movement initiation. The results provide additional evidence for the presence of surround inhibition in M1, where it occurs only during movement initiation, indicating that different mechanisms underlie movement initiation and maintenance. Thus, surround inhibition is sculpted both in time and space and may be an important neural mechanism during movement initiation to counteract increased spinal excitability. SICI may contribute to its generation, because in patients with FHD, the lack of depression of APB MEP size is accompanied by a reduction in SICI.

Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum

Objective The cerebellum takes part in several motor functions through its influence on the motor cortex (M1). Here, we applied the theta burst stimulation (TBS) protocol, a novel form of repetitive Transcranial Magnetic Stimulation (rTMS) over the lateral cerebellum. The aim of this study was to test whether TBS of the lateral cerebellum could be able to modulate the excitability of the contralateral M1 in healthy subjects. Methods Motor-evoked potentials (MEPs) amplitude, short intracortical inhibition (SICI), long intracortical inhibition (LICI) and short intracortical facilitation (SICF) were tested in the M1 before and after cerebellar continuous TBS (cTBS) or intermittent TBS (iTBS). Results We found that cTBS induced a reduction of SICI and an increase of LICI. On the other hand, cerebellar iTBS reduced LICI. MEPs amplitude also differently vary following cerebellar stimulation with cTBS or iTBS, resulting in a decrease by the former and an increase by the latter. Conclusions Although the interpretation of these data remains highly speculative, these findings reveal that the cerebellar cortex undergoes bidirectional plastic changes that modulate different intracortical circuits within the contralateral primary motor cortex. Significance Long-lasting modifications of these pathways could be useful to treat various pathological conditions characterized by an altered cortical excitability.