The ipsilateral silent period in boys with attention-deficit/hyperactivity disorder.

OBJECTIVE: Characterize maturation of transcallosal inhibition (ipsilateral silent period [iSP]) in attention deficit/hyperactivity disorder (ADHD) using transcranial magnetic stimulation (TMS). BACKGROUND: Maturation of the iSP is related to acquisition of fine motor skills in typically developing children suggesting that dexterous fine motor skills depend upon mature interhemispheric interactions. Since neuromotor maturation is abnormal in boys with ADHD we hypothesized that iSP maturation in these children would be abnormal. We studied iSP maturation in 12 boys with ADHD and 12 age-matched, typically developing boys, 7-13 years of age. METHODS: Surface electromyographic activity was recorded from right first dorsal interosseus (FDI). During background activation, focal TMS was delivered at maximal stimulator output over the ipsilateral motor cortex. RESULTS: Maturation of finger speed in boys with ADHD was significantly slower than that in the control group. The iSP latency decreased with age in the control group but not in the ADHD group. CONCLUSIONS: These findings suggest the presence of a complex relationship between abnormalities of certain interhemispheric interactions (as represented by iSP latency) and delayed maturation of neuromotor skills in boys with ADHD. SIGNIFICANCE: These data provide preliminary physiologic evidence supporting delayed or abnormal development of interhemispheric interactions in boys with ADHD.     

Impaired transcallosally mediated motor inhibition in adults with attention-deficit/hyperactivity disorder is modulated by methylphenidate

Using transcranial magnetic stimulation (TMS) in children with ADHD, an impaired transcallosally mediated motor inhibition (ipsilateral silent period, iSP) was found, and its restoration was correlated with improvement of hyperactivity under medication with methylphenidate (MPH). Hyperactivity has been reported to decrease during transition into adulthood, although some motor dysfunction might persist. As one underlying neurophysiological process, a development-dependent normalization of motor cortical excitability might be postulated. In order to test this hypothesis, we measured the iSP in 21 adult ADHD patients and twenty-one sex- and age-matched healthy controls. In 16 of these patients, a second TMS was performed under treatment with MPH. Our results indicate a persistence of impaired transcallosally mediated motor cortical inhibition (shortened duration) in ADHD adults, which was correlated with clinical characteristics of hyperactivity and restlessness, and was restored by MPH. In contrast to ADHD in childhood, the iSP latency was not impaired, suggesting a partial development-dependent normalization of motor cortical excitability in ADHD adults. ISP duration appears to be a sensitive parameter for the assessment of disturbed intercortical inhibition in adults with ADHD.     

Cortical correlates of neuromotor development in healthy children.

OBJECTIVE: To examine the relationship between acquisition of fine motor skills in childhood and development of the motor cortex. METHODS: We measured finger tapping speed and mirror movements in 43 healthy right-handed subjects (6-26 years of age). While recording surface electromyographic activity from right and left first dorsal interosseus, we delivered focal transcranial magnetic stimulation (TMS) over the hand areas of each motor cortex. We measured motor evoked potential (MEP) threshold, and ipsilateral (iSP) and contralateral (CSP) silent periods. RESULTS: As children got older, finger speeds got faster, MEP threshold decreased, iSP duration increased and latency decreased. Finger tapping speed got faster as motor thresholds and iSP latency decreased, but was unrelated to CSP duration. In all subjects right hemisphere MEP thresholds were higher than those on the left and duration of right hemisphere CSP was longer than that on the left. Children under 10 years of age had higher left hand mirror movement scores, and fewer left hemisphere iSPs which were of longer duration. CONCLUSIONS: Maturation of finger tapping skills is closely related to developmental changes in the motor threshold and iSP latency. Studies are warranted to explore the relationship between these measures and other neuromotor skills in children with motor disorders. SIGNIFICANCE: TMS can provide important insights into certain functional aspects of neurodevelopment in children.     

Evidence for normal intracortical inhibitory recruitment properties in cervical dystonia

ObjectiveDystonia is associated with reduced intracortical inhibition as measured by the cortical silent period (cSP); however, this may be due to abnormal cSP threshold or input-output properties. This study evaluated cSP recruitment properties in people with cervical dystonia (CD).MethodsBilateral electromyographic recordings were collected in the upper trapezius muscle in response to transcranial magnetic stimulation of the left and right primary motor cortex in a group with CD (n = 19) and controls (n = 21). cSP threshold, cSP input-output properties at stimulation intensities from 1 to 1.4x the cSP threshold, ipsilateral silent period duration (iSP) and timing and magnitude of the contralateral and ipsilateral motor evoked potential (MEP) were assessed.ResultsThe cSP threshold, input-output properties, and contralateral MEP magnitude were not significantly different between groups (all p > 0.07). Hemispheric symmetry was present in the control group while the CD group had reduced iSP (p < 0.01) and a trend for reduced ipsilateral MEP response (p = 0.053) in the left hemisphere.ConclusionsRecruitment properties of intracortical inhibition are similar between control and CD groups. Transcallosal inhibition is asymmetric between hemispheres in people with CD.SignificanceEvidence of normal intracortical inhibition recruitment properties challenge the commonly held view that cortical inhibition is reduced in dystonia.     

Impairment of transcallosal inhibition in patients with corticobasal degeneration.

OBJECTIVE: To evaluate the motor function of the transcallosal pathways in patients with clinical diagnosis of corticobasal degeneration (CBD). METHODS: In a group of 7 patients (4 males, 3 females; mean age 70.6 years) with clinical diagnosis of probable CBD (and in 8 age-matched normal controls) we evaluated the suppression of the ongoing voluntary EMG activity in the opponens pollicis muscle induced by focal transcranial magnetic stimulation (TMS) of the ipsilateral hand motor cortex. Such ipsilateral silent period (iSP) is mediated from one motor cortex to the contralateral side via a transcallosal pathway. In addition, CBD patients were investigated with magnetic resonance imaging (MRI) and neuropsychological assessment. RESULTS: iSP was normal in 4 CBD patients, while it was bilaterally disrupted in the other 3. MRI showed an atrophy of the corpus callosum (middle-posterior part of the trunk) in the CBD patients with iSP disruption. Neuropsychological evaluation showed in patients with iSP impairment a decrease of verbal fluencies associated with an impairment of attentive function. CONCLUSIONS: A proportion of CBD patients shows physiological evidence of impaired callosal motor function and atrophy of the corpus callosum on MRI, possibly correlated to dysphasic and cognitive disorders.     

Impact of pulse duration in single pulse TMS

Objective

The intensity of transcranial magnetic stimulation (TMS) is typically adjusted by changing the amplitude of the induced electrical field, while its duration is fixed. Here we examined the influence of two different pulse durations on several physiological parameters of primary motor cortex excitability obtained using single pulse TMS.

Methods

A Magstim Bistim² stimulator was used to produce TMS pulses of two distinct durations. For either pulse duration we measured, in healthy volunteers, resting and active motor thresholds, recruitment curves of motor evoked potentials in relaxed and contracting hand muscles as well as contralateral (cSP) and ipsilateral (iSP) cortical silent periods.

Results

Motor thresholds decreased by 20% using a 1.4 times longer TMS pulse compared to the standard pulse, while there was no significant effect on threshold adjusted measurements of cortical excitability. The longer pulse duration reduced pulse-to-pulse variability in cSP.

Conclusions

The strength of a TMS pulse can be adjusted both by amplitude or pulse duration. TMS pulse duration does not affect threshold-adjusted single pulse measures of motor cortex excitability.

Significance

Using longer TMS pulses might be an alternative in subjects with very high motor threshold. Pulse duration might not be relevant as long as TMS intensity is threshold-adapted. This is important when comparing studies performed with different stimulator types.     

Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation

BACKGROUND: Cortical inhibition (CI) deficits have been proposed as a pathophysiologic mechanism in schizophrenia. This study employed 3 transcranial magnetic stimulation (TMS) paradigms to assess CI in patients with schizophrenia. Paired-pulse TMS involves stimulating with a lower-intensity pulse a few milliseconds before a higher-intensity pulse, thereby inhibiting the size of the motor evoked potential produced by the higher-intensity pulse. In the cortical silent period paradigm, inhibition is reflected by the silent period duration (ie, the duration of electromyographic activity cessation following a TMS-induced motor evoked potential). Transcallosal inhibition involves stimulation of the contralateral motor cortex several milliseconds prior to stimulation of the ipsilateral motor cortex, inhibiting the size of the motor evoked potential produced by ipsilateral stimulation. METHODS: We measured CI using these 3 paradigms in 15 unmedicated patients with schizophrenia (14 medication-naive and 1 medication-free for longer than 1 year) (13 were in the transcallosal inhibition paradigm), 15 medicated patients with schizophrenia (11 taking olanzapine, 1 risperidone, 1 quetiapine, 1 methotrimeprazine + perphenazine, 1 quetiapine + loxapine), and 15 healthy controls. RESULTS: Unmedicated patients demonstrated significant CI deficits compared with healthy controls across all inhibitory paradigms whereas medicated patients did not (at all inhibitory intervals, paired-pulse TMS: controls = 59.9%, medicated = 44.3%, unmedicated = 28.7%; cortical silent period: controls = 55.0 milliseconds, medicated = 60.4 milliseconds, unmedicated = 39.7 milliseconds; transcallosal inhibition: controls = 33.6%, medicated = 23.7%, unmedicated = 10.4%; P<.05). CONCLUSIONS: These results suggest that schizophrenia is associated with deficits in CI and that antipsychotic medications may increase CI.     

Motor pathway excitability in ATP13A2 mutation carriers: a transcranial magnetic stimulation study

ObjectiveTo describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS).MethodsFive members of a Chilean family with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short latency afferent inhibition (SAI) as markers of intracortical intrahemispheric inhibition/facilitation and the ipsilateral silent period (iSP) and paired-pulse interhemispheric inhibition (IHI) to probe interhemispheric motor interactions.ResultsCSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC.ConclusionA compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical inhibition. In addition, some aspects of interhemispheric inhibition are increased in the presence of a single ATP13A2 mutation.     

An age-related change in the ipsilateral silent period of a small hand muscle

ObjectiveTo establish the presence or absence of an age effect on the ipsilateral silent period (iSP) for the abductor pollicis brevis (APB) muscle in healthy subjects.MethodsTwenty young adults (10 men, 10 women; age range: 20–40) and 20 older adults (10 men, 10 women; age range: 50–70) were matched by age (+30 years), gender and height (±5 cm). All were right-handed. We investigated the iSP for the APB by applying transcranial magnetic stimulation (TMS) and recording surface electromyograms. The contralateral motor-evoked potential (MEP) onset latency, the iSP onset and end latency (iSPOL and iSPEL) were measured and the iSP duration (iSPD) and transcallosal conduction time (TCT) were calculated. We evaluated the correlation between age and iSP, the latter’s intra- and intersession reproducibility and potential influencing factors.ResultsMean iSPOL, iSPEL and TCT values were significantly greater in older adults (both men and women) than in young adults. Intra- and intersession reproducibility was good. The mean left-side iSPEL and iSPD were longer than the right-side mean values in young adults but not in older adults. In both age groups, women displayed shorter latencies than men.ConclusionsThere is a strong effect of age on iSP parameters.SignificanceOur iSP results may evidence a decrease in transcallosal excitability with age, rather than slowing of the transcallosal interneuron conduction velocity.     

Transcallosal inhibition across the menstrual cycle: a TMS study.

OBJECTIVE: To determine if there are steroid-dependent changes in transcallosal transfer during the menstrual cycle in normal women. METHODS: We tested 13 normally cycling women during the menstrual, follicular and midluteal phases. Blood levels of estradiol (E) and progesterone (P) were determined by radioimmunoassay. Ipsilateral tonic voluntary muscle activity suppression, called ipsilateral silent period (iSP), was evoked by applying transcranial magnetic stimulation (TMS) over the left motor cortex and by measuring the EMG of the ipsilateral first dorsal interosseus (FDI) muscle. Both iSP-duration and transcallosal conduction times were measured and related to cycle phase and steroid levels. RESULTS: Duration of iSPs varied over the cycle with largest differences between follicular and midluteal phases. During the midluteal phase high levels of P were significantly related to short iSPs. This relation also applied to E levels and iSPs during the follicular phase. CONCLUSIONS: Our study shows for the first time that the transcallosal transfer is modulated by E and P and changes over the menstrual cycle. SIGNIFICANCE: It is suggested that gonadal steroid hormones affect the interhemispheric interaction and change the functional cerebral organization sex dependently via its neuromodulatory properties on GABAergic and glutamatergic neurons.     

Differences of the ipsilateral silent period in small hand muscles

The ipsilateral silent period (iSP) is thought to depend on activity transmitted by the corpus callosum but ipsilateral corticospinal pathways may also contribute. Because the presence of ipsilateral corticospinal pathways differs between small hand muscles, we compared the iSP in the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles. The iSP was elicited in 20 healthy subjects by focal transcranial magnetic stimulation of one primary motor cortex during maximal voluntary contraction of the ipsilateral target muscle. The iSP duration was significantly longer in the FDI than APB because of an irregularly occurring second phase of inhibition in the FDI that was absent in the APB. Although the first phase of inhibition is transmitted by the corpus callosum, we provide evidence that the second phase is mediated through ipsilateral corticospinal pathways. Therefore, for specific assessment of callosal conduction, the iSP should be measured in the APB rather than FDI.     

Are there differences in cortical excitability between akinetic-rigid and tremor-dominant subtypes of Parkinson's disease?

ObjectiveTo assess by transcranial magnetic stimulation (TMS) the excitability of various cortical circuits in akinetic-rigid and tremor-dominant subtypes of Parkinson's disease (PD).MethodsThe study included 92 patients with PD according to UK Brain Bank criteria, with akinetic-rigid (n = 64) or tremor-dominant (n = 28) subtype. Cortical excitability study, including resting and active motor thresholds (rMT and aMT), input—output curve of motor evoked potentials, contralateral and ipsilateral silent periods (cSP and iSP), short and long-interval intracortical inhibition (SICI and LICI), and intracortical facilitation (ICF) were measured. The results obtained were compared to a control group of 30 age- and sex-matched healthy subjects.ResultsThe patients in the tremor group had significantly lower rMT and aMT compared to controls and akinetic-rigid patients and significantly shorter iSP duration compared to akinetic-rigid patients, while iSP latency tended to be longer in akinetic-rigid patients compared to controls. There were no significant differences between the two PD subgroups regarding other cortical excitability parameters, including paired-pulse TMS parameters.ConclusionsOnly subtle differences of cortical excitability were found between patients with akinetic-rigid vs. tremor-dominant subtype of PD.SignificanceThe clinical heterogeneity of PD patients probably has an impact on cortical excitability measures, far beyond the akinetic-rigid versus tremor-dominant profile.     

Asymmetric transcallosal conduction delay leads to finer bimanual coordination

It has been theorized that hemispheric dominance and more segregated information processing have evolved to overcome long conduction delays through the corpus callosum (transcallosal conduction delay - TCD) but that this may still impact behavioral performance, mostly in tasks requiring high timing accuracy. Nevertheless, a thorough understanding of the temporal features of interhemispheric communication is lacking.Here, we aimed to assess the relationship between TCD and behavioral performance with a noninvasive directional cortical measure of TCD obtained from transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) in the motor system.Twenty-one healthy right-handed subjects were tested. TEPs were recorded during an ipsilateral silent period (iSP) paradigm and integrated with diffusion tensor imaging (DTI) and an in-phase bimanual thumb-opposition task. Linear mixed models were applied to test relationships between measures.We found TEP indexes of transcallosal communication at ∼15 ms both after primary motor cortex stimulation (M1-P15) and after dorsal premotor cortex stimulation (dPMC-P15). Both M1-and dPMC-P15 were predicted by mean diffusivity in the callosal body. Moreover, M1-P15 was positively related to iSP. Importantly, M1-P15 latency was linked to bimanual coordination with direction-dependent effects, so that asymmetric TCD was the best predictor of bimanual coordination.Our findings support the idea that transcallosal timing in signal transmission is essential for interhemispheric communication and can impact the final behavioral outcome. However, they challenge the view that a short conduction delay is always beneficial. Rather, they suggest that the effect of the conduction delay may depend on the direction of information flow.     

Physical activity and neural correlates of aging: a combined TMS/fMRI study

Aerobic exercise has been suggested to ameliorate aging-related decline in humans. Recently, evidence has indicated chronological aging is associated with decreases in measures of interhemispheric inhibition during unimanual movements, but that such decreases may be mitigated by long-term physical fitness. The present study investigated measures of ipsilateral (right) primary motor cortex activity during right-hand movements using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS). Healthy, right-handed participant groups were comprised of 12 sedentary older adults, 12 physically active older adults, and 12 young adults. Active older adults and younger adults evidenced longer ipsilateral silent periods (iSP) and less positive BOLD of ipsilateral motor cortex (iM1) as compared to sedentary older adults. Across groups, duration of iSP from TMS was inversely correlated with BOLD activity in iM1 during unimanual movement. These findings suggest that increased physical activity may have a role in decreasing aging-related losses of interhemispheric inhibition.     

Ipsilateral silent period: a marker of callosal conduction abnormality in early relapsing-remitting multiple sclerosis?

OBJECTIVE: The corpus callosum (CC) is commonly affected in multiple sclerosis (MS). The ipsilateral silent period (iSP) is a putative electrophysiological marker of callosal demyelination. The purpose of this study was to re-assess, under recently established optimised protocol conditions [Jung P., Ziemann U. Differences of the ipsilateral silent period in small hand muscles. Muscle Nerve in press.], its diagnostic sensitivity in MS, about which conflicting results were reported in previous studies. METHODS: ISP measurements (onset, duration, and depth) were obtained in the abductor pollicis brevis (APB) muscle of either hand in 49 patients with early relapsing-remitting MS (RRMS) (mean EDSS, 1.3). Standard central motor conduction times to the APB (CMCT(APB)) and tibial anterior muscles (CMCT(TA)), and magnetic resonance images (MRI) were also obtained. RESULTS: ISP measurements showed a similar diagnostic sensitivity (28.6%) as CMCT(APB) (24.5%), while diagnostic sensitivities of CMCT(TA) (69.4%) and MRI of the CC (78.6%) were much higher. Prolongation of iSP duration was the most sensitive single iSP measure. ISP prolongation occurred more frequently when CMCT(APB) to the same hand was also prolonged (40.0% vs. 8.4%, p<0.0001). The correlation between iSP duration and CMCT(APB) was significant (Pearson's r=0.24, p<0.02), suggesting that iSP duration can be contaminated by demyelination of the contralateral corticospinal tract. ISP duration did not correlate with MRI abnormalities of the CC. CONCLUSIONS: ISP measures are neither a sensitive nor a specific marker of callosal conduction abnormality in early RRMS.     

Normal interhemispheric inhibition in persistent developmental stuttering

Imaging studies suggest a right hemispheric (pre)motor overactivity in patients with persistent developmental stuttering (PDS). The interhemispheric inhibition (IHI) studied with transcranial magnetic stimulation is an established measure of the interplay between right and left motor areas. We assessed IHI in 15 young male adults with PDS and 15 age‐matched fluent‐speaking subjects. We additionally studied the ipsilateral silent period (iSP) duration. We found no significant between‐group difference for IHI or for iSP duration. We conclude that the interplay between the primary motor cortices is normal in patients with PDS. The abnormal right motor and premotor activity observed in functional imaging studies on PDS are not likely to reflect altered primary motor cortex excitability, but are likely to have a different origin. © 2009 Movement Disorder Society     

Children with comorbid attention-deficit-hyperactivity disorder and tic disorder: evidence for additive inhibitory deficits within the motor system

For children with attention-deficit-hyperactivity disorder (ADHD) or tic disorder (TD), we recently reported deficient inhibitory mechanisms within the motor system by using transcranial magnetic stimulation. These deficits--stated as reduced intracortical inhibition in ADHD and shortened cortical silent period in TD--could be seen as neurophysiological correlates of motor hyperactivity and tics, respectively. To investigate neurophysiological aspects of comorbidity, we measured motor system excitability for the first time also in children with combined ADHD and TD. The findings of a reduced intracortical inhibition as well as a shortened cortical silent period in these comorbid children provide evidence for additive effects at the level of motor system excitability.     

Comparison of Transcallosal Inhibition Between Hemispheres and Its Relationship with Motor Behavior in Patients with Severe Upper Extremity Impairment After Subacute Stroke

ObjectiveTo compare corticospinal excitability and transcallosal inhibition between contralesional primary motor cortex (M1) and ipsilesional M1. We also investigated the correlation between transcallosal inhibition and upper extremity motor behavior.Materials and methods19 individuals with unilateral ischemic subacute stroke who had severe upper extremity impairment participated in this study. Corticospinal excitability was assessed by measuring the resting motor threshold, active motor threshold and motor evoked potential amplitude. Transcallosal inhibition was investigated by measuring the duration and depth of the ipsilateral silent period (ISP). The data from the two hemispheres were compared and the relationships of transcallosal inhibition with upper extremity motor impairment, grip strength and pinch strength were analyzed.ResultsResting motor threshold (p = 0.001) and active motor threshold (p = 0.001) were lower and motor evoked potential amplitude was higher (p = 0.001) in the contralesional M1 compared to the ipsilesional M1. However, there were no differences between the two M1s in ISP duration (p = 0.297) or ISP depth (p =0. 229). Transcallosal inhibition from the contralesional M1 was positively associated with motor impairment (ISP duration, p = 0.003; ISP depth, p = 0.017) and grip strength (ISP duration, p = 0.016; ISP depth, p = 0.045).ConclusionsSymmetric transcallosal inhibition between hemispheres and positive association of transcallosal inhibition from contralesional M1 with upper extremity motor behavior indicate that recruitment of contralesional M1 may be necessary for recovery in patients with severe upper extremity impairment after subacute ischemic stroke.     

Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder

OBJECTIVE: Deficits in motor inhibition may contribute to impulsivity and irritability in children with bipolar disorder. Studies of the neural circuitry engaged during failed motor inhibition in pediatric bipolar disorder may increase our understanding of the pathophysiology of the illness. The authors tested the hypothesis that children with bipolar disorder and comparison subjects would differ in ventral prefrontal cortex, striatal, and anterior cingulate activation during unsuccessful motor inhibition. They also compared activation in medicated versus unmedicated children with bipolar disorder and in children with bipolar disorder and attention deficit hyperactivity disorder (ADHD) versus those with bipolar disorder without ADHD. METHOD: The authors conducted an event-related functional magnetic resonance imaging study comparing neural activation in children with bipolar disorder and healthy comparison subjects while they performed a motor inhibition task. The study group included 26 children with bipolar disorder (13 unmedicated and 15 with ADHD) and 17 comparison subjects matched by age, gender, and IQ. RESULTS: On failed inhibitory trials, comparison subjects showed greater bilateral striatal and right ventral prefrontal cortex activation than did patients. These deficits were present in unmedicated patients, but the role of ADHD in mediating them was unclear. CONCLUSIONS: In relation to comparison subjects, children with bipolar disorder may have deficits in their ability to engage striatal structures and the right ventral prefrontal cortex during unsuccessful inhibition. Further research should ascertain the contribution of ADHD to these deficits and the role that such deficits may play in the emotional and behavioral dysregulation characteristic of bipolar disorder.