Increased intracortical facilitation in patients with autosomal dominant pure spastic paraplegia linked to chromosome 2p

There are at least seven clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP). In this study we investigated electrophysiological characteristics in patients with ADPSP linked to chromosome 2p (SPG4). Twelve patients from six different families with ADPSP linked to chromosome 2p and 15 control persons were included. Electromyography (EMG), motor and sensory nerve conduction, and motor evoked potentials using single and paired transcranial magnetic stimulation (PTMS) was performed. From the peripheral nervous system we found signs of motor and sensory axonal neuropathy. Motor evoked potentials disclosed greatly reduced corticospinal tract conduction velocity and amplitude of evoked potentials to the lower extremities indicating that the very marked spasticity predominantly seems to rely on dysfunction of the fast conducting axons of the pyramidal tract. PTMS showed an increased intracortical facilitation (ICF), which may reflect an impaired function of gamma-aminobutyric acid (GABA)-controlled interneuronal circuits in the motor cortex, alternatively an increased glutamatergic transmission or a compensatory recruitment of a larger number of neurones with corticospinal projections.     

Reliability of corticospinal excitability and intracortical inhibition in biceps femoris during different contraction modes

This study aimed to determine the test–retest reliability of a range of transcranial magnetic stimulation (TMS) outcomes in the biceps femoris during isometric, eccentric and concentric contractions. Corticospinal excitability (active motor threshold 120% [AMT120%] and area under recruitment curve [AURC]), short- and long-interval intracortical inhibition (SICI and LICI) and intracortical facilitation (ICF) were assessed from the biceps femoris in 10 participants (age 26.3 ± 6.0 years; height 180.2 ± 6.6 cm, body mass 77.2 ± 8.0 kg) in three sessions. Single- and paired-pulse stimuli were delivered under low-level muscle activity (5% ± 2% of maximal isometric root mean squared surface electromyography [rmsEMG]) during isometric, concentric and eccentric contractions. Participants were provided visual feedback on their levels of rmsEMG during all contractions. Single-pulse outcomes measured during isometric contractions (AURC, AMT110%, AMT120%, AMT130%, AMT150%, AMT170%) demonstrated fair to excellent reliability (ICC range, .51 to .92; CV%, 21% to 37%), whereas SICI, LICI and ICF demonstrated good to excellent reliability (ICC range, .62 to .80; CV%, 19 to 42%). Single-pulse outcomes measured during concentric contractions demonstrated excellent reliability (ICC range, .75 to .96; CV%, 15% to 34%), whereas SICI, LICI and ICF demonstrated good to excellent reliability (ICC range, .65 to .76; CV%, 16% to 71%). Single-pulse outcomes during eccentric contractions demonstrated fair to excellent reliability (ICC range, .56 to .96; CV%, 16% to 41%), whereas SICI, LICI and ICF demonstrated good to excellent (ICC range, .67 to .86; CV%, 20% to 42%). This study found that both single- and paired-pulse TMS outcomes can be measured from the biceps femoris muscle across all contraction modes with fair to excellent reliability. However, coefficient of variation values were typically greater than the smallest worthwhile change which may make tracking physiological changes in these variables difficult without moderate to large effect sizes.     

Intracortical inhibition and facilitation are impaired in patients with early Parkinson''s disease: a paired TMS study

Twelve patients with early Parkinson's disease (PD), none of whom had received any previous L-DOPA treatment, but using other antiparkinsonian drugs, were studied using transcranial magnetic stimulation (TMS). Contralateral and ipsilateral hemispheres were examined, with a focus on the more pronounced parkinsonian symptoms. The conditioning-test TMS paradigm (with a subthreshold conditioning stimulus and a suprathreshold test stimulus) was used through a stimulating round coil. Paired stimuli of short (3, 5 and 7 ms), medium (10, 15 and 20 ms), and long (100, 150, 200 and 250 ms) interstimulus intervals (ISI) were pseudo-randomly mixed with a single stimulus. The first interosseus muscle was used for the motor-evoked potential recordings. Ten healthy subjects (age and sex matched) were studied in the same manner to obtain normative data. When both groups were compared, the significant difference (reduction of the intracortical inhibition and facilitation) between the PD patients and the control group was found at the short and the medium ISI (3, 5, 7, 10, 15 and 20 ms) in both hemispheres (P < 0.05). The longer ISI produced non-significant differences between the two groups in intracortical excitability. There was a non-significant difference in the motor threshold. In conclusion, it can be supposed that both intracortical inhibition and facilitation are impaired in patients with early PD using other antiparkinsonian treatments than L-DOPA or dopamine agonists.     

Task-dependent intracortical inhibition is impaired in focal hand dystonia.

We tested whether task-dependent modulation of inhibition within the motor cortex is impaired in patients with dystonia. Paired-pulse transcranial magnetic stimulation (TMS) at an interstimulus interval of 2 msec was used to measure the effect of two different tasks on short ISI intracortical inhibition (SICI) in dystonic and normal subjects. In two experiments, SICI of the fourth dorsal interosseus (4DIO) and abductor pollicis brevis (APB) muscles were measured before and at the end of the training task. In the first experiment, subjects performed a nonselective task consisting of abducting the thumb, where the APB acted as agonist and the 4DIO as synergist. In the second experiment, the function of the 4DIO was changed as the subjects were asked to consciously inhibit this muscle while abducting the thumb (selective task). Therefore, while the APB was activated in both tasks, the 4DIO was activated in the nonselective task but was in the inhibitory surround in the selective task. We found that performance of the selective but not the nonselective task resulted in increased SICI in the 4DIO of normal but not in dystonic subjects. We conclude that task-dependent SICI is disturbed in patients with dystonia.     

Elevated threshold for intracortical inhibition in focal hand dystonia.

Differences between control and focal hand dystonia (FHD) subject groups in short interval intracortical inhibition (SICI) as determined by paired transcranial magnetic stimulation (TMS) can be difficult to demonstrate, due to interindividual differences. The purpose of this study was to compare two TMS methods for assessing SICI in 8 control and 7 FHD subjects. Electromyographic (EMG) data were recorded from the first dorsal interosseous (FDI) muscle of the dominant hands of the control subjects and affected hands of the FHD subjects. The first method used a conventional approach of setting conditioning stimulus intensity to 80% of rest threshold (RTh) and test stimulus intensity to 120% RTh. Three interstimulus intervals (ISIs) were used: 2 msec, 3 msec, and the ISI between 2 and 3 msec that produced optimal SICI. The second method was novel in that test stimulus intensity was set to 150% active threshold (ATh), and conditioning stimulus intensity was varied between 50% and 100% ATh. The latter was determined at the threshold for SICI and expressed as a ratio of ATh. There was no difference between the subject groups in the degree of SICI produced using the first method, at the three ISIs studied. However, using the second method, the SICI threshold:ATh ratio was found to be significantly higher for FHD subjects. This finding suggests that determining the SICI threshold:ATh ratio may be a more sensitive measure of intracortical inhibitory function than more conventional methods.     

Intracortical inhibition and facilitation upon awakening from different sleep stages: a transcranial magnetic stimulation study

Intracortical facilitation and inhibition, as assessed by the paired-pulse transcranial magnetic stimulation technique with a subthreshold conditioning pulse followed by a suprathreshold test pulse, was studied upon awakening from REM and slow-wave sleep (SWS). Ten normal subjects were studied for four consecutive nights. Intracortical facilitation and inhibition were assessed upon awakening from SWS and REM sleep, and during a presleep baseline. Independently of sleep stage at awakening, intracortical inhibition was found at 1-3-ms interstimulus intervals and facilitation at 7-15-ms interstimulus intervals. Motor thresholds were higher in SWS awakenings, with no differences between REM awakenings and wakefulness, while motor evoked potential amplitude to unconditioned stimuli decreased upon REM awakening as compared to the other conditions. REM sleep awakenings showed a significant increase of intracortical facilitation at 10 and 15 ms, while intracortical inhibition was not affected by sleep stage at awakening. While the dissociation between motor thresholds and motor evoked potential amplitudes could be explained by the different excitability of the corticospinal system during SWS and REM sleep, the heightened cortical facilitation upon awakening from REM sleep points to a cortical motor activation during this stage.     

Evidence for impaired cortical inhibition in patients with unipolar major depression.

BACKGROUND: Several lines of evidence suggest that central cortical inhibitory mechanisms, especially associated with gamma-aminobutyric acid (GABA) neurotransmission, may play a role in the pathophysiology of major depression. Transcranial magnetic stimulation is a useful tool for investigating central cortical inhibitory mechanisms associated with GABAergic neurotransmission in psychiatric and neurological disorders. METHODS: By means of transcranial magnetic stimulation, different parameters of cortical excitability, including motor threshold, the cortical silent period, and intracortical inhibition/facilitation, were investigated in 20 medication-free depressed patients and 20 age- and gender-matched healthy volunteers. RESULTS: Silent period and intracortical inhibition were reduced in depressed patients, consistent with a reduced GABAergic tone. Moreover, patients showed a significant hemispheric asymmetry in motor threshold. CONCLUSIONS: This study provides evidence of reduced GABAergic tone and motor threshold asymmetry in patients with major depression.     

Enhanced intracortical inhibition in cerebellar patients

OBJECTIVE: The aim of the study was to examine intracortical excitability in cerebellar patients. METHODS: Short-latency intracortical inhibition (SICI), long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) to paired transcranial magnetic stimulation (TMS) were investigated in 8 patients with 'pure' cerebellar syndromes and in 14 age-matched normal controls. The conditioning stimulus for short-latency intracortical inhibition and intracortical facilitation was set at 70% of the resting motor threshold (RMT) and preceded the test stimulus (110-120% of the resting motor threshold) by interstimulus intervals (ISIs) of 1-30 ms. For the long-latency intracortical inhibition determinations, the conditioning stimulus was set at 120% of the resting motor threshold and preceded the test stimulus (also 120% of the resting motor threshold) by interstimulus intervals of 30-500 ms. RESULTS: No statistically significant differences were found between patients and controls as regards either short-latency intracortical inhibition or intracortical facilitation. A significant prevalence of long-latency intracortical inhibition was present in cerebellar patients at interstimulus intervals of 200-500 ms (conditioned MEP amplitude=29-41% of test MEP) as compared to controls (71-96% of test MEP). The amplitude of conditioned MEPs was persistently less than 45% of the test MEP in six patients, who were studied at interstimulus intervals up to 1000 ms. CONCLUSIONS: Long-latency intracortical inhibition was prevalent and abnormally longer-lasting in patients. Tonic hyperactivation of a subpopulation of GABAergic interneurons in the motor cortex of patients may be the mechanism responsible for this abnormality. Our findings seem to be specific to cerebellar diseases and are the opposite of those found in movement disorders such as dystonia and Parkinson's disease. These data suggest that the cerebellum and the basal ganglia may have opposite influences in tuning the excitability of the motor cortex.     

Restoration of disturbed intracortical motor inhibition and facilitation in attention deficit hyperactivity disorder children by methylphenidate.

BACKGROUND: Previous investigations using transcranial magnetic stimulation (TMS) have shown that neural inhibitory motor circuits are disturbed in ADHD children. We sought to investigate the influence of methylphenidate (MPH) on inhibitory and facilitatory motor circuits of ADHD children with TMS paired pulse protocols using surplus long interval inter-stimulus intervals (ISI) not investigated so far. METHODS: Motorcortical modulation was tested with TMS paired pulse protocols employing ISI of 3, 13, 50, 100, 200, and 300 msec in 18 ADHD children before and on treatment with MPH. Clinical improvement by MPH was measured by the Conners score. RESULTS: Analysis of variance (ANOVA) revealed a significant three-way interaction "Group x Amplitude x ISI," p = .001. Subsequent two-factorial ANOVAs and t-tests showed group specific differences of motor evoked potential (MEP) amplitudes for inhibitory ISIs of 3 and 100 msec, and for facilitatory ISIs of 13 and 50 msec. Compared to controls, an adjustment of these parameters by MPH could be shown. On MPH, a significant bivariate correlation was found between the Conners score reduction and averaged MEP amplitude changes only for inhibitory ISIs (3 and 100 msec). CONCLUSIONS: In ADHD children, MPH modulates disturbed facilitatory and inhibitory motor circuits, which for the latter is associated with clinical improvement.     

Selective and nonselective benzodiazepine agonists have different effects on motor cortex excitability

Transcranial magnetic stimulation (TMS) is a useful method to study pharmacological effects on motor cortex excitability. Zolpidem is a selective agonist of the benzodiazepine receptor subtype BZ1 and has a distinct pharmacological profile compared to diazepam. To study the different effects of these two drugs on the cortical inhibitory system, TMS was performed before and after administration of a single oral dose of zolpidem (10 mg) and diazepam (5 mg) in six healthy volunteers. TMS tests included the determination of resting and active motor threshold (MT) and measurements of the amplitudes of motor evoked potentials, intracortical facilitation (ICF), short-latency intracortical inhibition (SICI), and long-latency intracortical inhibition (LICI), and determination of the cortical silent period (CSP). Both drugs were without effect on the active or resting MT and decreased the ICF. Prolongation of the CSP and enhancement of LICI only in the presence of zolpidem point to a specific BZ1-related mechanism underlying the long-lasting component of cortical inhibition. This selective modulation of the CSP and the LICI points to a specific role of BZ1 receptors in the control of inhibitory neuronal loops within the primary motor cortex.     

Postexercise facilitation appears durable in normal subjects

Transcranial magnetic stimulation (TMS) was used to study the postexercise facilitation of 11 normal subjects on eight occasions. Between individuals, there was almost a sixfold difference in facilitation. The greatest positive percentage change for any individual was 61%, and the greatest negative percentage change was 51%. The results suggest that facilitation is a durable individual characteristic of normal subjects. Serial studies may therefore be indicated in monitoring individuals suffering relapsing conditions.     

Assessment of postexcitatory inhibition in patients with focal dystonia

The aim of our present study was to detect whether a generalized disturbance of intracortical inhibitory mechanisms as assessed by transcranial magnetic stimulation (TMS) can be observed in a movement disorder with localized clinical expression, that is, in focal cervical dystonia. We measured motor threshold intensity, central motor conduction time and the duration of postexcitatory inhibition evoked by single and paired stimuli TMS from a small hand muscle in 20 patients with idiopathic cervical dystonia, and 21 healthy volunteers. A significant difference could not be found in any of the neurophysiological parameters between patients and controls. These findings are unlike the observations made in Parkinson's disease and Huntington's disease, where significant changes of postexcitatory inhibition after TMS can be observed. This suggests a lack of widespread change in activity of underlying cortical inhibitory mechanisms, as seen in other diseases of the extrapyramidal system with more generalized clinical involvement.     

Influence of repetitive hand movements on intracortical inhibition

Repetitive movements have been reported to induce task-specific changes of intracortical inhibition and facilitation, but the mechanism operating shortly after hand movement is unclear. Transcranial magnetic single and paired stimuli (2 ms) were applied to 15 healthy subjects at rest and 1 s after repetitive (every 6 s) active and passive hand extensions. Motor evoked potentials (MEPs) were recorded from hand extensors (agonists) and flexors (antagonists). A strong overall inhibitory effect was observed after applying paired stimuli. In agonists only, active movements produced significantly larger MEPs. Inhibition, however, did not differ between active or passive movements and rest. This suggests that MEP increases produced by active movements in agonists are not caused by disinhibition, but are rather due to excitation (facilitation). This finding may also have implications for future studies evaluating the preferential activation of target muscles in physiotherapy.     

Reliability of single and paired‐pulse transcranial magnetic stimulation in the vastus lateralis muscle

Introduction: Transcranial magnetic stimulation (TMS) is an important tool to examine neurological pathologies, movement disorders, and central nervous system responses to exercise, fatigue, and training. The reliability has not been examined in a functional locomotor knee extensor muscle. Methods: Within‐ (n = 10) and between‐day (n = 16) reliability of single and paired‐paired pulse TMS was examined from the active vastus lateralis. Results: Motor evoked potential amplitude and cortical silent period duration showed good within‐ and between‐day reliability (intraclass correlation coefficient [ICC] ≥ 0.82). Short‐ and long‐interval intracortical inhibition (SICI and LICI, respectively) demonstrated good within‐day reliability (ICC ≥ 0.84). SICI had moderate to good between‐day reliability (ICC ≥ 0.67), but LICI was not repeatable (ICC = 0.47). Intracortical facilitation showed moderate to good within‐day reliability (ICC ≥ 0.73) but poor to moderate reliability between days (ICC ≥ 0.51). Conclusions: TMS can reliably assess cortical function in a knee extensor muscle. This may be useful to examine neurological disorders that affect locomotion. Muscle Nerve 52: 605–615, 2015     

Normal intracortical excitability in developmental stuttering.

Persistent developmental stuttering (PDS) shares clinical features with task-specific dystonias. In these dystonias, intracortical inhibition is abnormally weak. We therefore sought to determine intracortical inhibition and intracortical facilitation in PDS. In 18 subjects with PDS since childhood (mean age, 39.4 [SD 13.0] years) and 18 speech-fluent controls (43.6 [14.3] years), we investigated resting and active motor thresholds as well as intracortical inhibition and facilitation of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation. In PDS, the resting and active motor thresholds were increased, whereas intracortical inhibition and facilitation were normal. Normal intracortical excitability makes a pathophysiological analogy between focal dystonia and PDS less likely. The enhanced motor threshold suggests reduced motor cortical neuronal membrane excitability in PDS.     

The effect of cutaneous input on intracortical inhibition in focal task‐specific dystonia

In normal subjects short interval intracortical inhibition (SICI) is topographically modulated by cutaneous input, which may be important for focusing muscle activation during tasks. In patients with writer's cramp, a task‐specific focal dystonia characterized by inappropriate and excessive muscle activation of the upper limb during certain motor tasks, intracortical inhibition is reduced at rest and lacks the normal topographically‐specific modulation during motor tasks. In the present study we investigated whether cutaneous input modulated SICI in a group of patients with writer's cramp and a control group of subjects. Electromyographic recordings were made from the right first dorsal interosseous (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles. Brief electrical stimuli were applied to either digit II or digit V with ring electrodes. SICI was investigated using a paired transcranial magnetic stimulation paradigm employing interstimulus intervals of 1–15 ms. Cutaneous input from both digit II and digit V modulated motor evoked potentials and SICI in a topographically‐specific manner in control subjects. In contrast, cutaneous input failed to modulate motor evoked potentials or SICI in the focal hand dystonia patients. These results provide further evidence of abnormal sensorimotor integration in focal hand dystonia. © 2007 Movement Disorder Society     

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials

Background

Inhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2–3 ms (short-interval intracortical inhibition, SICI) or ～100?ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively.Objective/Hypothesis: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI.

Physiology of the motor cortex in polio survivors

We hypothesized that the corticospinal system undergoes functional changes in long-term polio survivors. Central motor conduction times (CMCTs) to the four limbs were measured in 24 polio survivors using transcranial magnetic stimulation (TMS). Resting motor thresholds and CMCTs were normal. In 17 subjects whose legs were affected by polio and 13 healthy controls, single- and paired-pulse TMS was used to assess motor cortex excitability while recording from tibialis anterior (TA) muscles at rest and following maximal contraction until fatigue. In polio survivors the slope of the recruitment curve was normal, but maximal motor evoked potentials (MEPs) were larger than in controls. MEPs were depressed after fatiguing exercise. Three patients with central fatigue by twitch interpolation had a trend toward slower recovery. There was no association with symptoms of post-polio syndrome. These changes occurring after polio may allow the motor cortex to activate a greater proportion of the motor neurons innervating affected muscles.