Paired-pulse Stimulation Research Articles

Okadaic acid attenuates short-term and long-term synaptic plasticity of hippocampal dentate gyrus neurons in rats.

Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) have a critical effect on various regulatory mechanisms involved in synaptic plasticity, learning and memory. Okadaic acid (OKA), a potent inhibitor of PP1 and PP2A, reportedly leads to cognitive decline and Alzheimer's disease (AD)-like pathology. The aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons in vivo. Male Wistar rats were divided into two control and OKA groups. OKA was injected intracerebroventricularly (i.c.v.) into lateral ventricles and after two weeks the long-term potentiation (LTP) and paired-pulse responses recorded from hippocampal perforant path-DG synapses in order to assess short-term and long-term synaptic plasticity. Results of this study revealed that OKA-induced inhibition of PP1 and PP2A activity drastically attenuates the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude following paired pulse and high frequency stimulation (HFS) of hippocampal DG neurons indicating pre- and post-synaptic involvement in electrical activity of these neurons. Administration of OKA impaired the short-term and long-term spatial memories conducted by Y-maze and passive avoidance tests, respectively. OKA-induced attenuation in electrophysiological activity and consequent memory deficits also provide a beneficial tool for studying neurodegenerative disorders such as AD.

Short Intracortical Inhibition During Voluntary Movement Reveals Persistent Impairment Post-stroke.

Objective: Short intracortical inhibition (SICI) is a GABAA-mediated phenomenon, argued to mediate selective muscle activation during coordinated motor activity. Markedly reduced SICI has been observed in the acute period following stroke and, based on findings in animal models, it has been posited this disinhibitory phenomenon may facilitate neural plasticity and contribute to early motor recovery. However, it remains unresolved whether SICI normalizes over time, as part of the natural course of stroke recovery. Whether intracortical inhibition contributes to motor recovery in chronic stroke also remains unclear. Notably, SICI is typically measured at rest, which may not fully reveal its role in motor control. Here we investigated SICI at rest and during voluntary motor activity to determine: (1) whether GABAA-mediated inhibition recovers, and (2) how GABAA-mediated inhibition is related to motor function, in the chronic phase post-stroke.Methods: We studied 16 chronic stroke survivors (age: 64.6 ± 9.3 years; chronicity: 74.3 ± 52.9 months) and 12 age-matched healthy controls. We used paired-pulse transcranial magnetic stimulation (TMS) to induce SICI during three conditions: rest, submaximal grip, and performance of box-and-blocks. Upper-extremity Fugl-Meyer Assessment and Box-and-Blocks tests were used to evaluate motor impairment in stroke survivors and manual dexterity in all participants, respectively.Results: At rest, SICI revealed no differences between ipsilesional and contralesional hemispheres of either cortical or subcortical stroke survivors, or healthy controls (P's > 0.05). During box-and-blocks, however, ipsilesional hemisphere SICI was significantly reduced (P = 0.025), especially following cortical stroke (P < 0.001). SICI in the ipsilesional hemisphere during box-and-blocks task was significantly related to paretic hand dexterity (r = 0.56, P = 0.039) and motor impairment (r = 0.56, P = 0.037).Conclusions: SICI during motor activity, but not rest, reveals persistent impairment in chronic stroke survivors indicating that inhibitory brain circuits responsible for motor coordination do not fully normalize as part of the natural history of stroke recovery. Observation that reduced SICI (i.e., disinhibition) is associated with greater motor impairment and worse dexterity in chronic hemiparetic individuals suggests the response considered to promote neuroplasticity and recovery in the acute phase could be maladaptive in the chronic phase post-stroke.

Are age-related changes in cortical motor representations linked with facilitation/inhibition in the primary motor cortex?

Are age-related changes in cortical motor representations linked with facilitation/inhibition in the primary motor cortex?

Early motor resonance differentiates schizophrenia patients from healthy subjects and predicts social cognition performance.

Diminished motor resonance (facilitation of motor potentials during action observation) is possibly related to social cognition deficits in schizophrenia. Adequate social cognition requires the successful moment-to-moment appraisal of social stimuli over a temporal window. However, similar changes in motor resonance with successive action observation stimuli are unknown. We compared the time-course of motor resonance evoked during successive action observation stimuli between schizophrenia patients (antipsychotic-naïve and medicated) and healthy subjects and examined its association with social cognition performance. Fifty-four schizophrenia patients (33 antipsychotic-naive) and 45 healthy subjects underwent 10-recordings (T1 to T10) of cortical reactivity, using two single (sp)- and two paired-pulse (pp) transcranial magnetic stimulation (TMS) paradigms, while they observed goal-directed actions and a static image. They also underwent comprehensive social cognition assessments. Sp-motor resonance revealed a significant quadratic time effect (initial fall and then rise) in patients and healthy subjects [F=12.21, P=0.001]. Such a pattern was not observed for pp-motor resonance. We categorized motor resonance as early (T1-T3), middle (T4-T7) and late (T8-T10) based on pair-wise comparisons. Early, but not middle or late sp-motor resonance was reduced in antipsychotic naïve patients compared to the medicated patients and healthy subjects (F=3.41, P=0.037). Social cognition composite score had significant correlations with both early sp-motor resonance (r=0.34, P=0.01) and early pp-motor resonance (r=0.314, P=0.02) in the combined patient group. Motor resonance time-courses did not vary across groups. The magnitude of early motor resonance was reduced in the antipsychotic-naïve schizophrenia group, compared to healthy subjects. Early phase motor resonance was associated with social cognition deficits in patients.

Ceftriaxone Treatment Preserves Cortical Inhibitory Interneuron Function via Transient Salvage of GLT-1 in a Rat Traumatic Brain Injury Model.

Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a β-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression.

Priming of LTP in amygdala and hippocampus by prior paired pulse facilitation paradigm in mice lacking brain serotonin.

This study focuses on analyzing long-term potentiation (LTP) changes in the lateral nucleus of the amygdala (LA) and in the CA1 region of the hippocampus in slices derived from mice deficient in tryptophan hydroxylase 2 (TPH2-/- ), the rate-limiting enzyme for 5-HT synthesis in the brain. We found a reduced LTP in both brain structures in TPH2-/- mice. However, we found no changes in the magnitude of LTP in TPH2-/- mice compared to wildtype mice when it was preceded by a paired pulse protocol. Whereas the magnitude of long-term depression (LTD) did not differ between wildtype and TPH2-/- mice, priming synapses by LTD-induction facilitated subsequent CA1-LTP in wildtype mice to a greater extent than in TPH2-/- mice. In the LA we found no differences between the genotypes in this protocol of metaplasticity. These data show that, unlike exogenous 5-HT application, lack of 5-HT in the brain impairs cellular mechanisms responsible for induction of LTP. It is supposed that suppression of LTP observed in TPH2-/- mice might be compensated by mechanisms of metaplasticity induced by paired pulse stimulation or low frequency stimulation before the induction of LTP.

Cortical excitability affects mood state in patients with idiopathic generalized epilepsies (IGEs)

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = −2.12; T (50) = −2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = −2.12; T (50) = −2.47, p = 0.04) and Fatigue (MD = −3.42; T (50) = −2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted.

Neuromuscular Fatigue and Recovery after Heavy Resistance, Jump, and Sprint Training.

Training methods that require maximal intensity efforts against light and heavy resistance are commonly used for athletic development. Typically, these sessions are separated by at least 48 h recovery on the assumption that such efforts elicit marked fatigue of the central nervous system (CNS), but this posit has not been well studied. The aim of the study was to assess the etiology and recovery of fatigue after heavy-resistance (strength), jump, and sprint training methods. Ten male athletes completed three training sessions requiring maximal efforts that varied in their loading characteristics: (i) heavy-resistance exercise (10 × 5 back squats at 80% one-repetition maximum [1RM]) (STR), (ii) jumping exercise (10 × 5 jump squats) (JUMP), and (iii) maximal sprinting (15 × 30 m) (SPR). Preparticipants, postparticipants, and 24-, 48-, and 72-h postparticipants completed a battery of tests to measure neuromuscular function using electrical stimulation of the femoral nerve, and single- and paired-pulse magnetic stimulation of the motor cortex, with evoked responses recorded from the knee extensors. Fatigue was self-reported at each time point using a visual analog scale. Each intervention elicited fatigue that resolved by 48 (JUMP) and 72 h (STR and SPR). Decrements in muscle function (reductions in the potentiated quadriceps twitch force) persisted for 48 h after all exercise. Reductions in voluntary activation were present for 24 h after JUMP and SPRINT, and 48 h after STR. No other differences in CNS function were observed as a consequence of training. Strength, jump, and sprint training requiring repeated maximum efforts elicits fatigue that requires up to 72 h to fully resolve, but this fatigue is not primarily underpinned by decrements in CNS function.

The glutamine-glutamate cycle regulates synaptic glutamate release in the ventrolateral ventromedial nucleus of the hypothalamus of perinatal female rats.

The astrocytic glutamine (Gln)-glutamate (Glu) cycle (GGC) supplies Gln for the regulation of glutamatergic synaptic transmission (GST) in the adult hippocampus. Increased synaptic Glu release in the perinatal ventrolateral ventromedial nucleus of the hypothalamus (vlVMH) modulates sexual differentiation, however, whether GGC regulates GST in the perinatal vlVMH has not been determined. Sex differences in oestradiol (E2 ) levels exist in the neonatal hypothalamus, and E2 increases levels of glutamine synthetase and glutaminase, two key enzymes involved in the GGC. Thus, it is hypothesised that sexually dimorphic phenotypes may exist in glutamatergic synapses associated with the GGC in the vlVMH in perinatal rats. Whole-cell voltage-clamp recordings in vlVMH neurones in brain slices from male and female pups revealed that pharmacological disruption of the GGC by α-(methylamino) isobutyric acid (5 mmol L-1 ), which blocks neuronal Gln uptake; or by l-methionine sulphoximine (1.5 mmol L-1 ), which inhibits astrocytic Gln synthesis, decreased miniature excitatory postsynaptic current (mEPSC) amplitudes in female but not male pups. By contrast, GGC interruptions decreased evoked (e)EPSC amplitudes in both sexes following increased synaptic activity produced by a period of stimulation. In male pups, the decreased eEPSCs were attributable to reduced Glu release, as assessed by paired-pulse stimulations, whereas, in female pups, they were attributable to decreased Glu content in the synaptic vesicles, as measured by strontium-evoked mEPSCs. The l-methionine sulphoximine-mediated decrease in eEPSCs was rapidly rescued by exogenous Gln in female but not male pups. The reductions in mEPSCs and eEPSCs in female pups were accompanied by enhanced blocking effects of the low-affinity Glu AMPA receptor antagonist, γ-d-glutamylglycine, consistent with diminished Glu release. In conclusion, female, but not male pups, rely on constitutive astrocytic Gln for sustained synaptic Glu release in the vlVMH. This glutamatergic synaptic phenotype may be associated with brain and behaviour feminisation and/or defeminisation in rats.

An optimal protocol for measurement of corticospinal excitability, short intracortical inhibition and intracortical facilitation in the rectus femoris

The study aimed to determine the optimal application of single- and paired-pulse transcranial magnetic stimulation (TMS) in the rectus femoris. Twenty-nine male adults participated in the study, which involved 5 separate experiments. Experiments 1 to 3 assessed the effect of conditioning stimulus (CS) intensity (60, 70, 80 and 90% active motor threshold, AMT), contraction strength (5, 10, 20 and 50% maximum voluntary contraction, MVC), and inter-stimulus interval (ISI, 2–5 ms for short-interval intracortical inhibition, SICI and 10–15 ms for intracortical facilitation, ICF) on SICI and ICF. In Experiment 4, 30 measurements of corticospinal excitability (CSE), SICI and ICF were recorded, with the minimum number of consecutive measurements required as a probability of falling within the 95% CI determined. In Experiment 5, within- and between-day reliability of CSE, SICI and ICF was assessed. The results suggest that for SICI, a CS of 70% AMT, ISI of 2 ms, and contraction strength of 5 or 10% MVC induces the greatest level of inhibition. Negligible differences in ICF were seen across stimulus variables. The minimum number of measurements required to obtain an accurate estimate of CSE, SICI and ICF was 21, 18 and 17, respectively. Using the optimal stimulus variables and number of measurements, CSE, SICI and ICF can be measured reliably both within- and between-days (intraclass correlation coefficient, ICC ≥ 0.87, ≥0.74, and ≥0.61, respectively). The current findings can be used to guide future investigations using single- and paired-pulse TMS to elicit responses in the rectus femoris.

Fatigue-related group III/IV muscle afferent feedback facilitates intracortical inhibition during locomotor exercise.

This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise. Firing of these interneurons probably contributes to the development of central fatigue during physical activity. We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n=11) cycled at a comparable vastus-lateralis EMG signal (∼0.26mV) before (PRE; 100W) and immediately after (POST; 90±2W) fatiguing constant-load cycling exercise (80% Wpeak; 221±10W; ∼8min). During, PRE and POST cycling, single and paired-pulse (100ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor-evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100ms interval) cervicomedullary motor-evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P<0.05). This paralleled a reduction in conditioned MEP (P<0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P>0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABAB intracortical interneurons.

Changes in Intracortical Excitability of Affected and Unaffected Hemispheres After Stroke Evaluated by Paired-Pulse Transcranial Magnetic Stimulation.

ObjectiveTo assess the altered pattern of intracortical excitability of the affected and unaffected hemispheres in stroke patients using paired-pulse transcranial magnetic stimulation (TMS).MethodsWe evaluated intracortical inhibition (ICI) and intracortical facilitation (ICF) in both hemispheres at acute and subacute stages of 103 stroke patients using paired-pulse TMS. The patients were divided into two groups: mild-to-moderate patients whose motor evoked potential (MEP) was recorded in the affected hemisphere; and severe patients whose MEP was not recorded in the affected hemisphere.ResultsIn mild-to-moderate patients, the value of ICI in the affected hemisphere was increased from 70.3% to 77.9% and the value of ICI in the unaffected hemisphere was decreased from 74.8% to 70.3% with eventual progression in acute to subacute stages of stroke. In severe patients, the value of ICI in the unaffected hemisphere was increased from 65.4% to 75.6%. The changes in ICF were not significantly different in this study.ConclusionWe conclude that the unaffected hemisphere was more disinhibited than the affected hemisphere in acute phase of mild-to-moderate stroke, and the affected hemisphere was more disinhibited in the subacute stage. The unaffected hemisphere was inhibited in severe cases in acute-to-subacute phases of stroke. This finding facilitates appropriate neuromodulation of acute-to-subacute phases in mild-to-severe stroke patients.

Muscle-selective disinhibition of corticomotor representations using a motor imagery-based brain-computer interface

Bridging between brain activity and machine control, brain-computer interface (BCI) can be employed to activate distributed neural circuits implicated in a specific aspect of motor control. Using a motor imagery-based BCI paradigm, we previously found a disinhibition within the primary motor cortex contralateral to the imagined movement, as evidenced by event-related desynchronization (ERD) of oscillatory cortical activity. Yet it is unclear whether this BCI approach does selectively facilitate corticomotor representations targeted by the imagery. To address this question, we used brain state-dependent transcranial magnetic stimulation while participants performed kinesthetic motor imagery of wrist movements with their right hand and received online visual feedback of the ERD. Single and paired-pulse magnetic stimulation were given to the left primary motor cortex at a low or high level of ERD to assess intracortical excitability. While intracortical facilitation showed no modulation by ERD, short-latency intracortical inhibition was reduced the higher the ERD. Intracortical disinhibition was only found in the agonist muscle targeted by motor imagery at high ERD level, but not in the antagonist muscle. Single pulse motor-evoked potential was also increased the higher the ERD. However, at high ERD level, this facilitatory effect on overall corticospinal excitability was not selective to the agonist muscle. Analogous results were found in two independent experiments, in which participants either performed kinesthetic motor imagery of wrist extension or flexion. Our results showed that motor imagery-based BCI can selectively disinhibit the corticomotor output to the agonist muscle, enabling effector-specific training in patients with motor paralysis.

Adaptive threshold hunting reveals differences in interhemispheric inhibition between young and older adults.

Interhemispheric inhibition between bilateral motor cortices is important for the performance of unimanual activities and may be compromised with advancing age. Conventionally, interhemispheric inhibition is assessed using paired-pulse transcranial magnetic stimulation (TMS) with constant conditioning and test stimulation parameters. Adaptive threshold hunting TMS, whereby a target motor-evoked potential amplitude is maintained in the presence of the conditioning, may provide an alternative means of assessment. Furthermore, interhemispheric inhibition may suppress late indirect-waves more so than early indirect-waves which can be preferentially elicited using anterior-posterior (AP) and posterior-anterior (PA) induced currents, respectively. The aim of this study was to assess age-related effects on interhemispheric inhibition using both conventional and threshold hunting techniques with PA- and AP-induced current. In 15 young and 15 older adults, short (10ms) and long (40ms) interval interhemispheric inhibition was examined in the nondominant extensor carpi radialis muscle at rest and during voluntary extension of the contralateral wrist. With the conventional technique, there were no age-related differences in short-interval interhemispheric inhibition. With threshold hunting and AP-induced current, young adults exhibited greater short-interval interhemispheric inhibition during contralateral activation compared with rest and compared with older adults. Furthermore, long-interval interhemispheric inhibition was greater in older adults compared with young for both conventional and threshold hunting techniques. Age-related differences in interhemispheric inhibition are evident with threshold hunting using PA- and AP-induced current.

Intracortical facilitation within the migraine motor cortex depends on the stimulation intensity. A paired-pulse TMS study

IntroductionConnectivity within the primary motor cortex can be measured using the paired-pulse transcranial magnetic stimulation (TMS) paradigm. This evaluates the effect of a first conditioning stimulus on the motor evoked potential (MEP) elicited by a second test stimulus when different interstimulus intervals are used. Aim of the present study was to provide, in patients suffering from migraine without aura (MwoA), additional information on intracortical facilitation (ICF), short intracortical inhibition (SICI), and long intracortical inhibition (LICI), using different intensities of the test stimulus (TS).MethodsWe enrolled 24 patients with episodic MwoA and 24 age- and sex-matched healthy volunteers. Both patients and controls were randomly assigned to two different experimental groups: the first group underwent evaluation of ICF, while in the second group we assessed SICI and LICI. All these measures were assessed by using three different suprathreshold intensities of the TS (110%, 130% and 150% of the resting motor threshold, RMT). Interstimulus intervals (ISIs) of 10 ms were used for testing ICF, while SICI and LICI were carried out by using 2 ms and 100 ms ISIs respectively. All migraine patients underwent the experimental protocol while in the interictal pain-free state.ResultsA main finding of the study was that an increased ICF could be seen in migraineurs as compared to the healthy subjects only by using a 110% intensity of the TS. Instead, no significant differences were observed between patients and controls as regards both measures of intracortical inhibition.ConclusionWe show that hyperresponsivity of the glutamatergic intracortical circuits can be detected in the migraine motor cortex only by applying a low suprathreshold intensity of stimulation. Our results strengthen the notion that, to be reliable, the assessment of cortical excitability in migraine should always include evaluation of the cortical response to different stimulation intensities.

Individual characterization of fast intracortical facilitation with paired biphasic-wave transcranial magnetic stimulation.

We characterized the short-interval intracortical facilitation (SICF) via modulation of transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEPs) using paired-pulse stimulation, and analyzed the interactions with known SICF I-wave behavior. The objective was to optimize individual SICF to enhance TMS effects in motor mapping and therapeutic stimulations. We applied navigated TMS in nine healthy volunteers to study SICF. MEPs were measured for baseline using single-pulse TMS, and subsequently, paired-pulse TMS was applied to study SICF. The interstimulus interval (ISI) between the pulses was varied between 1.2 and 4.3 ms at 0.1 ms intervals. Ten MEPs were measured from three muscles (FDI, APB and ADM) in the dominant hand of the volunteer. We then fitted a 3-peak Gaussian model to the individual paired-pulse MEP vs. ISI curves to characterize each peak by latency, amplitude and width. Individual SICF I-wave interaction characteristics were successfully determined. The average peak latencies were 1.36 (I1-wave), 2.80 (I2-wave) and 4.29 (I3-wave) for the targeted FDI muscle. The peak amplitudes differed depending on the muscle (p = 0.001), with ADM muscle exhibiting greatest SICF effect, but no significant difference between the three peaks. In addition, the peak widths differed between all muscles (p<0.001), second peak being the widest. In conclusion, the individual SICF I-wave interaction characteristics were successfully determined revealing significant differences in peak features. This could enable application of SICF for enhancement of TMS effects in therapy, cortical mapping and basic neuroscience applications.

Motor cortical and corticospinal function differ during an isometric squat compared with isometric knee extension

What is the central question of this study? In order to discern information about testing modalities when assessing neuroplastic responses to squat resistance training, the present study investigated whether corticospinal and intracortical function was different between a joint-angle-matched isometric squat and isometric knee extension. What is the main finding and its importance? The present data show poor agreement of corticospinal and intracortical function between the isometric squat and isometric knee extension. The data reinforce the notion that task specificity is of the utmost importance for assessing neuroplasticity. It has been suggested that task-specific changes in neurophysiological function (neuroplasticity) should be assessed using testing modalities that replicate the characteristics of the intervention. The squat is a commonly prescribed resistance exercise that has been shown to elicit changes in CNS function. However, previous studies have assessed squat-induced neuroplasticity using isometric knee extension, potentially confounding the results. The aim of the present study was to assess the agreement between corticospinal and intracortical activity relating to the knee extensors during isometric knee extension compared with an isometric squat task. Eleven males completed a neurophysiological assessment in an isometric squat (IS) and knee-extension (KE) task matched for joint angles (hip, knee and ankle). Single- and paired-pulse transcranial magnetic stimulation was delivered during isometric contractions at a range of intensities to assess short-interval cortical inhibition (SICI) and corticospinal excitability. Group mean values for SICI (70±14versus 63±12% of unconditioned motor evoked potential during IS and KE, respectively) and corticospinal excitability (mean differences 2-5% of the maximal compound muscle action potential at 25, 50, 75 and 100% maximal voluntary contraction between the IS and KE) were not different between the two tasks (P>0.05) in the vastus lateralis. However, limits of agreement were wide, with poor-to-moderate average intraclass correlation coefficients (ICCs) (SICI, ICC3,1 =0.15; corticospinal excitability, average ICC3,1 range=0.0-0.63), indicating disparate corticospinal and intracortical activity between the IS and KE. These data highlight the importance of task specificity when assessing the modulation of corticospinal excitability and SICI in response to interventions resulting in neuroplastic changes.

Neuromuscular Dysfunction and Cortical Impairment in Sleep Apnea Syndrome.

Lower muscle strength and endurance have been reported in severe obstructive sleep apnea (OSA). Increased intracortical inhibition previously reported at rest in OSA suggests central neuromuscular impairments in these patients. We hypothesized that (i) OSA patients demonstrate reduced knee extensor strength and endurance due to central impairments and (ii) continuous positive airway pressure (CPAP) treatment improves neuromuscular function in these patients. Twelve OSA patients and 11 healthy controls performed intermittent knee extensions until task failure before and after 8 wk of CPAP treatment or control period. Maximal voluntary contraction, voluntary activation and corticospinal excitability and inhibition assessed by single- and paired-pulse transcranial magnetic stimulation were measured before and during the fatiguing task. Time to exhaustion was lower in OSA (before CPAP treatment: 1008 ± 549 s; after CPAP treatment: 975 ± 378 s) compared with controls (before control period: 1476 ± 633 s; after control period: 1274 ± 506 s; P = 0.017). Obstructive sleep apnea patients had reduced maximal voluntary contraction and VATMS compared with controls throughout the fatiguing task as well as increased intracortical inhibition (all P < 0.05). Continuous positive airway pressure treatment did not induce any changes in neuromuscular function (P > 0.05 for all parameters). This study demonstrates that severe OSA patients have cortical impairments which are likely contributing to their reduced knee extensors strength and endurance. Both cortical impairments and neuromuscular function are not improved after 8 wk of CPAP treatment.

Conventional or threshold-hunting TMS? A tale of two SICIs

BackgroundIn human primary motor cortex (M1), the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI) can be expressed conventionally as a percent change in the relative amplitude of a conditioned motor evoked potential to non-conditioned; or adaptive threshold-hunting a target motor evoked potential amplitude in the absence or presence of a conditioning stimulus, and noting the relative change in stimulation intensity. The suitability of each approach may depend on the induced current direction, which probe separate M1 interneuronal populations. ObjectiveTo examine the influence of conditioning stimulus intensity, interstimulus interval (ISI) and current direction for adaptive threshold-hunting and conventional SICI using equivalent TMS intensities. MethodsIn 16 participants (21–32 years), SICI was examined using adaptive threshold-hunting and conventional paired-pulse TMS with posterior-anterior and anterior-posterior stimulation, ISIs of 2 and 3 ms, and a range of conditioning intensities. ResultsInhibition with adaptive threshold-hunting was greater for anterior-posterior stimulation with an ISI of 3 ms (23.6 ± 9.0%) compared with 2 ms (7.5 ± 7.8%, P < 0.001) and posterior-anterior stimulation at both ISIs (2 ms 8.6 ± 8.7%, 3 ms 5.9 ± 4.8%; P < 0.001). There was an association between inhibition obtained with conventional and adaptive threshold-hunting for posterior-anterior but not anterior-posterior stimulation (2 ms only, r = 0.68, P = 0.03). ConclusionsMore inhibition was evident with anterior-posterior than posterior-anterior current for both adaptive threshold-hunting and conventional paired-pulse TMS. Assessment of SICI with anterior-posterior stimulation was not directly comparable between the two approaches. However, the amount of inhibition was dependent on conditioning stimulus intensity and ISI for both SICI techniques.

Effects of propofol on IPSCs in CA1 and dentate gyrus cells of rat hippocampus: Propofol effects on hippocampal cells’ IPSCs

Propofol (2, 6-diisopropylphenol) is one of the most popular intravenous anesthetic agents. In this study, we compared the effects of propofol on inhibitory postsynaptic currents (IPSCs) induced by single and paired electrical stimulations in CA1 pyramidal cells (CA1-PCs) and dentate gyrus granule cells (DG-GCs) in rat hippocampal slices using the whole cell patch-clamp technique. In the absence of propofol, the amplitude of evoked IPSC by single stimulation and decay time constants were stable in both CA1-PCs and DG-GCs for 30 min. Propofol (1 μM and 10 μM) increased both IPSC amplitude in CA1-PCs, but not in DG-GCs. Further, using a paired pulse stimulation protocol, the ratio of IPSC amplitudes (the second response: A2/the first response: A1) was increased by propofol in CA1, but not in DG-GCs. These results suggest that propofol selectively affects IPSCs in CA1-PCs, which is similar to previously reported actions of benzodiazepines.