Measurements of transcallosally mediated cortical inhibition for differentiating parkinsonian syndromes.

Clinicopathologic evidence suggests differential involvement of cortex and corpus callosum (CC) in various disorders presenting with a parkinsonian syndrome. We tested the hypothesis of whether neurophysiologic and morphometric assessments of CC as surrogate parameters of cortical involvement could be helpful in differential diagnosis of parkinsonian disorders. The integrity of CC was assessed neurophysiologically by measuring the ipsilateral silent period (iSP) evoked by transcranial magnetic stimulation (TMS) in a total of 25 patients with idiopathic parkinsonian syndromes (IPS), corticobasal ganglionic degeneration (CBD), progressive supranuclear palsy (PSP), or multiple system atrophy (MSA). Additionally, morphometric analyses of magnetic resonance imaging (MRI) measurements of CC was carried out in all patients. iSP was abnormal in all 5 CBD and all 5 PSP patients, whereas it was intact in all 10 IPS patients and all 5 MSA patients. Among various MRI parameters of CC, testing between different groups revealed a significant difference only for measurements of the middle part of the truncus. CBD and PSP patients exhibited a significant atrophy as compared with control subjects. These data suggest impairment of callosal integrity in patients with CBD and PSP. iSP measurements may be a useful clinical neurophysiologic test in differential diagnosis of patients with parkinsonian syndromes.     

Disturbed transcallosally mediated motor inhibition in children with attention deficit hyperactivity disorder (ADHD).

OBJECTIVE: The aim of this study was to investigate mechanisms of motor-cortical excitability and inhibition which may contribute to motor hyperactivity in children with attention deficit hyperactivity disorder (ADHD). METHODS: Using transcranial magnetic stimulation (TMS), involvement of the motor cortex and the corpus callosum was analysed in 13 children with ADHD and 13 sex- and age-matched controls. Contralateral silent period (cSP) and transcallosally mediated ipsilateral silent period (iSP) were investigated. RESULTS: Resting motor threshold (RMT), amplitudes of motor evoked potentials (MEP) and cSP were similar in both groups whereas iSP-latencies were significantly longer (p<0.05) and their duration shorter (p<0.01) in the ADHD group. For the ADHD group iSP duration tended to increase and iSP latency to decrease with age (n.s.). Conners-Scores did neither correlate with iSP-latencies and -duration nor with children's age. CONCLUSIONS: The shortened duration of iSP in ADHD children could be explained by an imbalance of inhibitory and excitatory drive on the neuronal network between cortex layer III-the projection site of transcallosal motor-cortical fibers-and layer V, the origin of the pyramidal tract. The longer iSP-latencies might be the result of defective myelination of fast conducting transcallosal fibers in ADHD. iSP may be a useful supplementary diagnostic tool to discriminate between ADHD and normal children.     

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.     

Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: a functional and anatomical study

Functional MRI (fMRI) studies have shown increased activation of ipsilateral motor areas during hand movement in patients with multiple sclerosis (MS). We hypothesized that these changes could be due to disruption of transcallosal inhibitory pathways. We studied 18 patients with relapsing-remitting MS. Conventional T1- and T2-weighted images were acquired and lesion load (LL) measured. Diffusion tensor imaging (DTI) was performed to estimate fractional anisotropy (FA) and mean diffusivity (MD) in the body of the corpus callosum (CC). fMRI was obtained during a right-hand motor task. Patients were studied to evaluate transcallosal inhibition (TCI, latency and duration) and central conduction time (CCT). Eighteen normal subjects were studied with the same techniques. Patients showed increased MD (P < 0.0005) and reduced FA (P < 0.0005) in the body of the CC. Mean latency and duration of TCI were altered in 12 patients and absent in the others. Between-group analysis showed greater activation in patients in bilateral premotor, primary motor (M1), and middle cingulate cortices and in the ipsilateral supplementary motor area, insula, and thalamus. A multivariate analysis between activation patterns, structural MRI, and neurophysiological findings demonstrated positive correlations between T1-LL, MD in the body of CC, and activation of the ipsilateral motor cortex (iM1) in patients. Duration of TCI was negatively correlated with activation in the iM1. Our data suggest that functional changes in iM1 in patients with MS during a motor task partially represents a consequence of loss of transcallosal inhibitory fibers.     

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.     

Altered callosal function in cerebral microangiopathy

Callosal dysfunction is known to be evident in a variety of neurodegenerative and inflammatory diseases of the central nervous system. Cerebral microangiopathy (CMA) may also affect callosal pathways by chronic demyelination. The aim of the present study was to investigate callosal function with respect to the extent of CMA. Callosal function was tested by a bimanual tapping task and by analysis of the ipsilateral silent period (iSP) and the transcallosal conduction time (TCT) using transcranial magnetic stimulation. Results were correlated to the extent of CMA measured by cranial magnetic resonance imaging (cMRI) in 44 patients with CMA compared to 10 control subjects. The extent of CMA was quantified by a cMRI score. Additionally, callosal atrophy was quantified by cMRI morphometry. Frequency of pathological iSP findings or disturbed bimanual tapping was significantly correlated to a higher CMA score. Moreover, the extent of CMA was significantly correlated to the degree of callosal atrophy. It is concluded that CMA considerably affects callosal pathways, possibly by chronic demyelination of callosal fibres. As the extent of CMA and atrophy of the corpus callosum is correlated to callosal dysfunction, analysis of the iSP can be used to assess the clinical impact of CMA detected by cMRI.     

Interhemispheric inhibition in patients with multiple sclerosis

Objectives: A single focal magnetic stimulus applied to the motor cortex of normal subjects can suppress ongoing voluntary electromyographic activity in ipsilateral small hand muscles. This inhibition is mediated from one motor cortex to the contralateral side via a transcallosal pathway. Methods: We have investigated transcallosal inhibition in 24 patients with definite multiple sclerosis (MS) and in 24 healthy volunteers. A focal magnetic stimulus was applied to the hand area of the motor cortex and the onset latency of the inhibition of the ongoing EMG activity of the ipsilateral first dorsal interosseus muscle was evaluated. Cortico-motor conduction time to the same muscle was revealed, using a magnetic stimulus over the contralateral motor cortex. The difference between these values was calculated as transcallosal conduction time. Cerebral magnetic resonance imaging (MRI) scans including sagittal T2-weighted images were performed in 18 patients. Results: The depth of inhibition (maximal inhibition as percentage of the baseline EMG) in the MS patients was comparable to normal values, but the transcallosal conduction time was significantly delayed (patients 17.2±6.4 ms; normal subjects 12.2±2.6 ms; P<0.001). The duration of the inhibition was significantly prolonged in MS patients (patients 47.9±20.9 ms; normal subjects 38.9±10.1 ms; P=0.02). Transcallosal conduction time was delayed in 11 (46%) of 24 patients, compared with normal subjects. It exceeded the normal range (mean±2.5 SD) in one normal subject (specifity 96%). No correlation could be found between the size or extent of the lesions obtained from the MRI scan and the onset latency or the depth of the inhibition. Conclusions: We conclude that conduction over transcallosal connections is significantly slower in patients with MS.     

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.     

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.     

Transcranial magnetic stimulation shows impaired transcallosal inhibition in Marchiafava–Bignami syndrome

A case of Marchiafava–Bignami (MB) syndrome with selective callosal involvement was evaluated by clinical examination and magnetic resonance imaging (MRI) in the acute phase and 6 months after the onset of symptoms; at the same time, the corticospinally and transcallosally mediated effects elicited by transcranial magnetic stimulation (TMS) were investigated. The first MRI study showed the presence of extensive abnormal signal intensity throughout the entire corpus callosum. After high-dose corticosteroid administration her symptoms rapidly resolved, in parallel with the reversion of MRI changes, except for severe cognitive impairment. Follow-up TMS examination revealed persistent transcallosal inhibition (TI) abnormalities. This report indicates that the measurement of TI during the course of MB syndrome is useful for evaluating functional changes to the corpus callosum, including their evaluation with time and after treatment and for elucidating the pathophysiology of MB syndrome.     

Abnormalities of inhibitory neuronal mechanisms in the motor cortex of patients with schizophrenia

BACKGROUND: Focal transcranial magnetic stimulation (TMS) of the motor cortex was used to study two cortically activated inhibitory neuronal mechanisms that suppress ongoing tonic voluntary electromyographic activity in contralateral (postexcitatory inhibition [PI]) and ipsilateral (transcallosal inhibition [TI]) hand muscles. The PI follows the corticospinally mediated excitatory motor response (MEP) and is influenced by dopaminergic neurotransmission. TI reflects transcallosally mediated inhibition of the contralateral motor cortex, leading to motor inhibition in muscles ipsilateral to stimulation. PI and TI were studied to explore whether dopaminergic neurotransmission or interhemispheric transfers are altered in schizophrenia. METHODS: TMS was performed in 16 patients with this disease and in 16 healthy control subjects. Surface electromyographic activity was recorded bilaterally from the first dorsal interosseous muscle during a sustained strong isometric contraction. RESULTS: When compared with the findings in healthy subjects, patients with schizophrenia had a significantly longer PI and TI. The changes of the PI support the notion of an overactivity of the central dopaminergic system in schizophrenia. CONCLUSION: The prolonged TI suggests an abnormal activation of interhemispheric connections between the motor cortices and may be related to previously reported pathology of the corpus callosum in schizophrenic patients.     

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.     

Callosal and corticospinal tract function in patients with hydrocephalus: a morphometric and transcranial magnetic stimulation study

In 15 patients with symptomatic hydrocephalus, pressure-induced morphological changes of the brain and the function of callosal and corticospinal fibres were studied. Morphometry of the corpus callosum (CC) was performed on midsagittal MR images. Focal transcranial magnetic stimulation of the motor cortex was used to assess simultaneously excitatory motor responses in contralateral hand muscle (corticospinally mediated effect) and inhibition of tonic EMG activity in ipsilateral hand muscles (transcallosal inhibition (TI) of the contralateral motor cortex). Before a shunt operation, the midsagittal area of the CC was reduced by 34% on average. The height and, to a lesser degree the length, of the CC were increased before the shunt operation. Thresholds and central motor latencies of corticospinally mediated responses were normal, response amplitudes were smaller than in normal subjects. Motor thresholds increased from 38, SD 5 to 52, SD 8% (P<0.01) within 7 days after ventricular drainage, reflecting the increase in the distance between stimulation coil and brain. The threshold increase paralleled a restoration of normal anatomical conditions within 7 days after shunt operation and the improvement of motor symptoms and might be a predictor of successful decompression. Transcallosal inhibition could be elicited in all patients. The measurements of TI lay within the normal range except the duration, which was prolonged in 73% of 15 patients before shunt operation as a probable indicator of an increased dispersion of callosal conduction. The normalization of the area and shape of the CC after shunt operation and the normal corticospinal and callosal conduction times exclude degeneration, demyelination or functional block of a large proportion of callosal or corticospinal tract fibres or a substantial loss of nerve cells in motor cortex. Received: 22 October 1997 Received in revised form: 13 January 1998 Accepted: 17 January 1998     

Creutzfeldt-Jakob disease presenting as corticobasal degeneration: a neurophysiological study

Abstract Creutzfeldt-Jakob disease (CJD) can occasionally present with a clinical picture resembling a corticobasal degeneration (CBD). Transcallosal inhibition, as tested by focal transcranial magnetic stimulation, is frequently absent or highly disrupted in CBD patients. We report a case of CJD presenting at the beginning of the disease as a CBD in which the ipsilateral silent period (iSP) was present and well detectable. This brief report shows that study of the iSP may be a useful diagnostic tool in order to differentiate CBD from syndromes presenting with similar clinical features.     

The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia

Transcranial magnetic stimulation (TMS) is emerging as a promising tool to non-invasively assess specific cortical circuits in neurological diseases. A number of studies have reported the abnormalities in TMS assays of cortical function in dementias. A PubMed-based literature review on TMS studies targeting primary and secondary dementia has been conducted using the key words “transcranial magnetic stimulation” or “motor cortex excitability” and “dementia” or “cognitive impairment” or “memory impairment” or “memory decline”. Cortical excitability is increased in Alzheimer’s disease (AD) and in vascular dementia (VaD), generally reduced in secondary dementias. Short-latency afferent inhibition (SAI), a measure of central cholinergic circuitry, is normal in VaD and in frontotemporal dementia (FTD), but suppressed in AD. In mild cognitive impairment, abnormal SAI may predict the progression to AD. No change in cortical excitability has been observed in FTD, in Parkinson’s dementia and in dementia with Lewy bodies. Short-interval intracortical inhibition and controlateral silent period (cSP), two measures of gabaergic cortical inhibition, are abnormal in most dementias associated with parkinsonian symptoms. Ipsilateral silent period (iSP), which is dependent on integrity of the corpus callosum is abnormal in AD. While single TMS measure owns low specificity, a panel of measures can support the clinical diagnosis, predict progression and possibly identify earlier the “brain at risk”. In dementias, TMS can be also exploited to select and evaluate the responders to specific drugs and, it might become a rehabilitative tool, in the attempt to restore impaired brain plasticity.     

Dysfunction of transcallosally mediated motor inhibition and callosal morphology in patients with schizophrenia

OBJECTIVE: In order to assess the functional integrity of motor pathways through the corpus callosum (CC) in patients with schizophrenia transcallosally mediated inhibition (TI) of voluntary tonic EMG activity of first dorsal interosseus muscle following ipsilateral focal transcranial magnetic stimulation (fTMS) was investigated. In addition thickness and length of CC were calculated. METHOD: Twelve patients suffering from schizophrenia and 12 healthy controls were investigated. CC morphology was measured in mid-sagittal MRI-slices. Latency and duration of TI were calculated. RESULTS: In schizophrenics the duration of TI was significantly prolonged, whereas latencies were not. In addition, a lack of TI was found unilaterally in three patients. Measurements of CC revealed a significantly reduction of the length and thickness in the anterior part of CC in patients. CONCLUSION: These findings indicate that measurement of TI could be used to detect clinical silent affection of transcallosal motor pathways in schizophrenics. The effect of neuroleptic drugs has to be explored.     

Demyelination and axonal degeneration in corpus callosum assessed by analysis of transcallosally mediated inhibition in multiple sclerosis.

OBJECTIVE: Following focal transcranial magnetic cortex stimulation (fTMS), inhibition of voluntary EMG activity in the ipsilateral first dorsal interosseus (FDI) muscle was studied, in order to assess the functional integrity of the corpus callosum in patients with multiple sclerosis (MS). METHODS AND RESULTS: Thirty-four patients suffering from definite MS and 12 healthy, age-matched normal subjects were examined. In mid-sagittal slices, 29 patients showed lesions within the truncus corporis callosi in T2-weighted MRI. In 20 patients, all areas (anterior, middle and posterior parts), in one both the anterior and posterior part, in 3 exclusively the anterior, in 4 the middle and in one the posterior area were affected. In 5 patients, lesions of corpus callosum were lacking. In normal subjects, fTMS elicited a transient inhibition (TI) of preactivated (50% of maximal force) isometric voluntary ipsilateral FDI muscle activity. Mean onset latencies of TI were 35.5+/-5.4 ms in right and 36.1+/-4.2 ms in left FDI. Mean duration of TI amounted to 23.0+/-8.4 ms for right and 24.6+/-8.4 ms for left FDI. In the MS group, TI latencies were significantly increased in 23 and TI durations in 16 cases, whereas a lack of TI was found in 5 patients bilaterally and in 6 unilaterally. In patients, mean onset latencies of TI were 40.4+/-13.8 ms in right and 43.3+/-14.4 ms in left FDI, TI duration amounted to 30.5+/-17.4 ms for right and 31.0+/-25.2 ms for left FDI. Increase of onset latencies and durations of TI were positively correlated with the summed area of lesions of corpus callosum in representative mid-sagittal MRI slices. Significant correlations between TI onset latencies and duration on the one hand, and central motor conduction latencies along corticospinal tracts (CML) on the other hand, were not found. CONCLUSION: The present investigation indicates that measurement of TI elicited by fTMS seems to be a sensitive method for an assessment of demyelination and axonal degeneration within corpus callosum in MS patients.     

Correlation between antemortem magnetic resonance imaging findings and pathologically confirmed corticobasal degeneration

BACKGROUND: Slowly progressive asymmetric parkinsonism and cortical dysfunction clinically characterize corticobasal syndrome (CBS). Various pathologic findings, including corticobasal degeneration (CBD), progressive supranuclear palsy, and frontotemporal degenerations, underlie CBS. OBJECTIVE: To determine if regional cortical and corpus callosum atrophy and subcortical and periventricular white matter (SPWM) signal changes on head magnetic resonance imaging were specific to CBD. DESIGN: Historical review of autopsy cases. SETTING: Subspecialized behavioral neurology and movement disorder clinics within a neurology department of a tertiary referral center. PATIENTS: Seventeen patients with CBS who had an autopsy-confirmed diagnosis of CBD or another neurodegenerative disease. MAIN OUTCOME MEASURES: Regional cerebral cortical atrophy, regional corpus callosum atrophy, and SPWM signal changes. RESULTS: Similar patterns of regional atrophy and SPWM signal changes were found in the patients with autopsy-proven CBD and in the patients with other neurodegenerative diseases. CONCLUSION: Neither cortical nor corpus callosum atrophy nor SPWM signal changes on head magnetic resonance imaging are specific to CBD.     

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     

Intra- and inter-cortical motor excitability in Alzheimer’s disease

Transcranial magnetic stimulation (TMS) provides evidence for facilitatory and inhibitory motor dysfunctions in Alzheimer's disease (AD). The corpus callosum (CC) is affected in AD already at early stages consistent with the hypothesis that AD patients exhibit alterations in transcallosally mediated motor inhibition (ipsilateral silent period, iSP). Therefore, here we aimed at investigating the integrity not only of intra-, but also of inter-hemispheric mechanisms of cortical motor excitability in AD. We determined the iSP, the resting motor threshold (RMT), and the amplitude of motor evoked potentials (MEP) in 19 AD patients and 19 healthy controls using single-pulse TMS. Furthermore, we used paired-pulse TMS to study the intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF). All subjects underwent comprehensive neuropsychologic, clinical, and laboratory testing, and neuroimaging to exclude significant co-morbidity. In AD patients, the RMT was significantly reduced (Oneway-ANOVA). An analysis of covariance (ANCOVA) revealed a strong group specific interaction of the inhibitory interstimulus intervals (p = 0.005) with a reduced ICI in AD. Furthermore, we found a significantly prolonged iSP-latency (p = 0.003) in AD compared to controls, whereas the iSP-duration was not different. The iSP-latency correlated significantly with the ICI (ANCOVA) (p = 0.02). The ICF did not differ significantly between groups. Our data suggest comprehensive but still subclinical dysfunctions of motor cortical inhibition in mild to moderate clinical stages of AD with strong interactions of intra- and inter-hemispheric inhibitory phenomena. Future studies are needed to show the potential prognostic relevance of these findings for the further course of the disease.