Transcallosal sensorimotor fiber tract structure‐function relationships

Recent studies have demonstrated neuroanatomically selective relationships among white matter tract microstructure, physiological function, and task performance. Such findings suggest that the microstructure of transcallosal motor fibers may reflect the capacity for interhemispheric inhibition between the primary motor cortices, although full characterization of the transcallosal inhibitory sensorimotor network is lacking. Thus, the goal of this study was to provide a comprehensive description of transcallosal fibers connecting homologous sensorimotor cortical regions and to identify the relationship(s) between fiber tract microstructure and interhemispheric inhibition during voluntary cortical activity. To this end, we assessed microstructure of fiber tracts connecting homologous sensorimotor regions of the cortex with diffusion tensor imaging. We also assessed interhemispheric inhibition by eliciting the ipsilateral silent period (iSP) within the same participants. We mapped mutually exclusive transcallosal connections between homologous sensorimotor regions and computed quantitative metrics of each fiber tract. Paralleling work in non‐human primates, we found the densest interhemispheric sensorimotor connections to be between the medial motor areas. Additionally, we provide a midsagittal callosal atlas in normalized Montreal Neurological Institute (MNI) space for future studies to use when investigating callosal fiber tracts connecting primary and secondary sensorimotor cortices. Finally, we report a strong, positive relationship (r = 0.76) between strength of interhemispheric inhibition (iSP) and microstructure of interhemispheric fibers that is specific to tracts connecting the primary motor cortices. Thus, increased fiber microstructure in young adults predicts interhemispheric inhibitory capacity. Hum Brain Mapp, 2013.

Related papers:

title: Neural pathways mediating bilateral interactions between the upper limbs
abstract: The ease with which we perform tasks such as opening the lid of a jar, in which the two hands execute quite different actions, belies the fact that there is a strong tendency for the movements of the upper limbs to be drawn systematically towards one another. Mirror movements, involuntary contractions during intended unilateral engagement of the opposite limb, are considered pathological, as they occur in association with specific disorders of the CNS. Yet they are also observed frequently in normally developing children, and motor irradiation, an increase in the excitability of the (opposite) homologous motor pathways when unimanual movements are performed, is a robust feature of the mature motor system. The systematic nature of the interactions that occur between the upper limbs has also given rise to the expectation that functional improvements in the control of a paretic limb may occur when movements are performed in a bimanual context. In spite of the ubiquitous nature of these phenomena, there is remarkably little consensus concerning the neural basis of their mediation. In the present review, consideration is given to the putative roles of uncrossed corticofugal fibers, branched bilateral corticomotoroneuronal projections, and segmental networks. The potential for bilateral interactions to occur in various brain regions including the primary motor cortex, the supplementary motor area, non-primary motor areas, the basal ganglia, and the cerebellum is also explored. This information may provide principled bases upon which to evaluate and develop task and deficit-specific programs of movement rehabilitation and therapy.

title: Callosotomy patients exhibit temporal uncoupling during continuous bimanual movements
abstract: Rhythmic bimanual movements are highly constrained in the temporal domain, with the gestures of the two hands tightly synchronized. Previous studies have implicated a subcortical locus for temporal coupling based on the observation that these constraints persist in callosotomy patients. We now report that such coupling is restricted to movements entailing a discrete event (such as a movement onset). Three callosotomy patients exhibited a striking lack of temporal coupling during continuous movements, with the two hands oscillating at non-identical frequencies. We propose a subcortical locus of temporal coupling for movements involving discrete events. In contrast, synchronization between the hands during continuous movements depends on interhemispheric transmission across the corpus callosum.

title: Ipsilateral motor cortex activation on functional magnetic resonance imaging during unilateral hand movements is related to interhemispheric interactions
abstract: Distal, unilateral hand movements can be associated with activation of both sensorimotor cortices on functional MRI. The neurophysiological significance of the ipsilateral activation remains unclear. We examined 10 healthy right-handed subjects with and without activation of the ipsilateral sensorimotor area during unilateral index-finger movements, to examine ipsilateral, uncrossed-descending pathways and interhemispheric interaction between bilateral motor areas, using transcranial magnetic stimulation (TMS). No subject showed ipsilateral activation during right hand movement. Five subjects showed ipsilateral sensorimotor cortical activation during left hand movement (IpsiLM1). In these subjects, paired-pulse TMS revealed a significant interhemispheric inhibition of the left motor cortex by the right hemisphere that was not present in the 5 subjects without IpsiLM1. Neither ipsilateral MEPs nor ipsilateral silent periods were evoked by TMS in any subjects. Our observation suggests that IpsiLM1 is not associated with the presence of ipsilateral uncrossed-descending projections. Instead, IpsiLM1 may reveal an enhanced interhemispheric inhibition from the right hemisphere upon the left to suppress superfluous, excessive activation.

title: Environmentally-specified patterns of movement coordination in normal and split-brain subjects
abstract: SummaryRhythmic movement patterns between the hands in response to environmental signals are studied in normal (musicians and nonmusicians) and split-brain subjects. Only two phase-locked states — in-phase and anti-phase — are shown to be stable for all subjects. Split-brain subjects show an even greater attraction to these patterns, thus providing no support for the notion that reduced cortical interaction between the hemispheres allows for independent visuomotor control of the hands in such tasks. Moreover, differences in trajectories produced by normal individuals and those without an intact corpus callosum are remarkable. The resultant patterns of coordination afford 1) a generalization of previous results on intrisincally generated rhythmic behavior to environmentally-specified movement patterns; and 2) a discussion of neural mechanisms underlying stable phase relations.

title: Hand and sex differences in the isthmus and genu of the human corpus callosum. A postmortem morphological study.
abstract: The midsagittal area of the corpus callosum was measured in its entirety and in seven subdivisions in a sample of 50 brains consecutively obtained from autopsies of individuals who had neuropsychological testing before death. A 12-item test of hand preference was used as an index of the pattern of interhemispheric functional asymmetry. Callosal size was analysed for two factors: hand preference, classified as consistent-right-hand preference (CRH) versus non consistent-right-hand preference, and sex. The group of nCRH (n = 18) was found to have a larger overall callosal area, with the greatest difference occurring in the posterior body segments, especially the isthmus. The isthmus probably includes interhemispheric fibres from posterior parietal and superior temporal cortex which involves cortical regions related to functional asymmetry. The results of variation in callosal morphology are discussed as part of a possible substrate of functional asymmetry and due to variation in axonal elimination in early brain development. Sex differences were found in several aspects of callosal anatomy. (1) The difference between hand groups in the posterior body occurred in interaction with sex:handedness was a factor in callosal size in males (n = 15), but not in females (n = 35). This result is consistent with the general hypothesis of females having less clear lateralization than males. (2) Females did not have a larger overall callosum or a larger splenium, either in absolute size or size proportional to brain weight. The latter measure was considered since callosal area correlated with cerebrum weight (r = 0.48). In contrast, female of both hand groups were found to have a larger proportional isthmus compared to CRH males. (3) Of all callosal regions, only the genu and a part of the anterior body were found to be larger in absolute size in males than females. (4) Callosal size decreased with chronological age in males, but not in females.

title: Differential Callosal Contributions to Bimanual Control in Young and Older Adults
abstract: Our recent work has shown that older adults are disproportionately impaired at bimanual tasks when the two hands are moving out of phase with each other [Bangert, A. S., Reuter-Lorenz, P. A., Walsh, C. M., Schachter, A. B., & Seidler, R. D. Bimanual coordination and aging: Neurobehavioral implications. Neuropsychologia, 48, 1165–1170, 2010]. Interhemispheric interactions play a key role during such bimanual movements to prevent interference from the opposite hemisphere. Declines in corpus callosum (CC) size and microstructure with advancing age have been well documented, but their contributions to age deficits in bimanual function have not been identified. In the current study, we used structural magnetic resonance and diffusion tensor imaging to investigate age-related changes in the relationships between callosal macrostructure, microstructure, and motor performance on tapping tasks requiring differing degrees of interhemispheric interaction. We found that older adults demonstrated disproportionately poorer performance on out-of-phase bimanual control, replicating our previous results. In addition, older adults had smaller anterior CC size and poorer white matter integrity in the callosal midbody than their younger counterparts. Surprisingly, larger CC size and better integrity of callosal microstructure in regions connecting sensorimotor cortices were associated with poorer motor performance on tasks requiring high levels of interhemispheric interaction in young adults. Conversely, in older adults, better performance on these tasks was associated with larger size and better CC microstructure integrity within the same callosal regions. These findings implicate age-related declines in callosal size and integrity as a key contributor to bimanual control deficits. Further, the differential age-related involvement of transcallosal pathways reported here raises new questions about the role of the CC in bimanual control.

title: Age Differences in Interhemispheric Interactions: Callosal Structure, Physiological Function, and Behavior
abstract: There is a fundamental gap in understanding how brain structural and functional network connectivity are interrelated, how they change with age, and how such changes contribute to older adults’ sensorimotor deficits. Recent neuroimaging approaches including resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) have been used to assess brain functional (fcMRI) and structural (DTI) network connectivity, allowing for more integrative assessments of distributed neural systems than in the past. Declines in corpus callosum size and microstructure with advancing age have been well documented, but their contributions to age deficits in unimanual and bimanual function are not well defined. Our recent work implicates age-related declines in callosal size and integrity as a key contributor to unimanual and bimanual control deficits. Moreover, our data provide evidence for a fundamental shift in the balance of excitatory and inhibitory interhemispheric processes that occurs with age, resulting in age differences in the relationship between functional and structural network connectivity. Training studies suggest that the balance of interhemispheric interactions can be shifted with experience, making this a viable target for future interventions.

title: The size of corpus callosum correlates with functional activation of medial motor cortical areas in bimanual and unimanual movements.
abstract: Effects of the size of corpus callosum measured from in vivo magnetic resonance imaging (MRI) recordings on cortical activations evaluated using functional MRI (fMRI) were analyzed during motor tasks. Twelve right-handed men performed unilateral finger movements and bilateral movements either with or without a temporal delay between left and right fingers. The size of the rostral part of corpus callosum and the anterior and posterior callosal truncus explained 11.9 and 15.2% of activation in the mesial frontal cortex in unimanual left and right finger movements, respectively. In bimanual simultaneous movements, 34.2% of the activated voxels in the mesial frontal cortex were related to the size of corpus callosum. In bimanual movements in which left finger movement preceded the onset of the right finger movement, the callosal size accounted for 88.7% of activation in the mesial frontal cortex. In contrast, when the right finger movement preceded the left, callosal size accounted for only 31.3% of the mesial frontal cortex activation. The correlations between callosal parameters and activation over the lateral cortex were sparse and occurred only in bimanual movements. The results suggest that corpus callosum modulates the activity of the supplementary motor and cingulate cortical areas depending on temporal complexity of bimanual movements.

title: Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: Relations to timed performance
abstract: The integrity of white matter, as measured in vivo with diffusion tensor imaging (DTI), is disrupted in normal aging. A current consensus is that in adults advancing age affects anterior brain regions disproportionately more than posterior regions; however, the mainstay of studies supporting this anterior-posterior gradient is based primarily on measures of the corpus callosum. Using our quantitative fiber tracking approach, we assessed fiber tract integrity of samples of major white matter cortical, subcortical, interhemispheric, and cerebellar systems (11 bilateral and 2 callosal) on DTI data collected at 1.5T magnet strength. Participants were 55 men (age 20-78 years) and 65 women (age 28-81 years), deemed healthy and cognitively intact following interview and behavioral testing. Fiber integrity was measured as orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, which was quantified separately for longitudinal diffusivity (lambdaL), an index of axonal length or number, and transverse diffusivity (lambdaT), an index of myelin integrity. Aging effects were more evident in diffusivity than FA measures. Men and women, examined separately, showed similar age-related increases in longitudinal and transverse diffusivity in fibers of the internal and external capsules bilaterally and the fornix. FA was lower and diffusivity higher in anterior than posterior fibers of regional paired comparisons (genu versus splenium and frontal versus occipital forceps). Diffusivity with older age was generally greater or FA lower in the superior than inferior fiber systems (longitudinal fasciculi, cingulate bundles), with little to no evidence for age-related degradation in pontine or cerebellar systems. The most striking sex difference emerged for the corpus callosum, for which men showed significant decline in FA and increase in longitudinal and transverse diffusivity in the genu but not splenium. By contrast, in women the age effect was present in both callosal regions, albeit modestly more so in the genu than splenium. Functional meaningfulness of these age-related differences was supported by significant correlations between DTI signs of white matter degradation and poorer performance on cognitive or motor tests. This survey of multiple fiber systems throughout the brain revealed a differential pattern of age's effect on regional FA and diffusivity and suggests mechanisms of functional degradation, attributed at least in part to compromised fiber microstructure affecting myelin and axonal morphology.

title: Integrity of white matter in the corpus callosum correlates with bimanual co-ordination skills
abstract: Variation in brain structure may reflect variation in functional properties of specific brain systems. Structural variation may therefore reflect variation in behavioural performance. Here, we use diffusion-weighted magnetic resonance imaging to show that variation in white matter integrity in a specific region in the body of the corpus callosum is associated with variation in performance of a bimanual co-ordination task. When the callosal region showing this association is used as a seed for probabilistic tractography, inter-hemispheric pathways are generated to the supplementary motor area and caudal cingulate motor area. This provides further evidence for the role of medial wall motor areas in bimanual co-ordination and supports the idea that variation in brain structure reflects inter-individual differences in skilled performance.

title: Callosal dysfunction in amyotrophic lateral sclerosis correlates with diffusion tensor imaging of the central motor system
abstract: We investigated the frequency and functional relevance of corpus callosum degeneration in amyotrophic lateral sclerosis (ALS). A total of 22 ALS patients and 29 healthy controls performed the newly developed Contralateral Co-Movement Test as indicator of callosal dysfunction. Diffusion tensor imaging was applied to determine fractional anisotropy values in the callosal area containing the crossing motor fibers and in the pyramidal tracts in 13 subjects of each group. ALS patients had more than twice the amount of co-movements as compared to healthy subjects. Contralateral co-movements correlated with fractional anisotropy values of the corpus callosum motor region as did ALS Functional Rating Scale as measure of disease progression. In both groups, contralateral co-movements correlated with the central motor index (ratio of the mean of fractional anisotropy values of both pyramidal tracts and corpus callosum motor region). Neuropsychological test results failed to show correlations with functional or morphological parameters. Combining Contralateral Co-Movement Test and diffusion tensor imaging in ALS revealed the close relation between functional and morphological impairment in the degenerating central motor-neuronal network. The Contralateral Co-Movement Test delivers simple means of symptom quantification, independent of ALS Functional Rating Scale, for future neuroprotective trials.

title: Callosal Contributions to Simultaneous Bimanual Finger Movements
abstract: Corpus callosum (CC) is involved in the performance of bimanual motor tasks. We asked whether its functional role could be investigated by combining a motor behavioral study on bimanual movements in multiple sclerosis (MS) patients with a quantitative magnetic resonance diffusion tensor imaging (DTI) analysis of CC, which is shown to be damaged in this disease. MS patients and normal subjects were asked to perform sequences of bimanual finger opposition movements at different metronome rates; then we explored the structural integrity of CC by means of DTI. Significant differences in motor performance, mainly referred to timing accuracy, were observed between MS patients and control subjects. Bimanual motor coordination was impaired in MS patients as shown by the larger values of the interhand interval observed at all the tested metronome rates with respect to controls. Furthermore, DTI revealed a significant reduction of fractional anisotropy (FA), indicative of microstructural tissue damage, in the CC of MS patients. By correlating the mean FA values with the different motor behavior parameters, we found that the degree of damage in the anterior callosal portions mainly influences the bimanual coordination and, in particular, the movement phase preceding the finger touch. Finally, the described approach, which correlates quantitative measures of tissue damage obtained by advanced magnetic resonance imaging tools with appropriate behavioral measurements, may help the exploration of different aspects of motor performance impairment attributable to the disease.

title: Organization of ipsilateral excitatory and inhibitory pathways in the human motor cortex.
abstract: Motor cortex stimulation has both excitatory and inhibitory effects on ipsilateral muscles. Excitatory effects can be assessed by ipsilateral motor-evoked potentials (iMEPs). Inhibitory effects include an interruption of ipsilateral voluntary muscle activity known as the silent period (iSP) and a reduction in corticospinal excitability evoked by conditioning stimulation of the contralateral motor cortex (interhemispheric inhibition, IHI). Both iSP and IHI may be mediated by transcallosal pathways. Their relationship to the contralateral corticospinal projection and whether iSP and IHI represent the same phenomenon remain unclear. The neuronal population activated by transcranial magnetic stimulation (TMS) is highly dependent on the direction of the induced current in the brain. We examined the relationship among iMEP, iSP, IHI, and the contralateral corticospinal system by examining the effects of different stimulus intensities and current directions. Surface electromyography (EMG) was recorded from both first dorsal interosseous (FDI) muscles. The iSP in the right FDI muscle was obtained by right motor cortex stimulation during voluntary muscle contraction. IHI was examined by conditioning stimulation of the right motor cortex followed by test stimulation of the left motor cortex at interstimulus intervals (ISIs) of 2-80 ms. The induced current directions tested in the right motor cortex were anterior medial (AM), posterior medial (PM), posterior lateral, and anterior lateral (AL). Contralateral MEPs (cMEPs) had the lowest threshold with the AM direction and the shortest latency with the PM direction. iMEPs were present in 8 of 10 subjects. Both iMEP and IHI did not show significant directional preference. iSP was observed in all subjects with the highest threshold for the AL direction and the longest duration for the AM direction. cMEP, iSP, and IHI all increased with stimulus intensity up to approximately 75% stimulator output. Target muscle activation decreased IHI at 8-ms ISI but had little effect on IHI at 40-ms ISI. iSP and IHI at 8-ms ISI did not correlate at any stimulus intensities and current directions tested, and factor analysis showed that they are explained by different factors. However, active IHI at 40-ms ISI was explained by the same factor as iSP. The different directional preference for cMEP compared with iMEP and IHI suggests that these ipsilateral effects are mediated by populations of cortical neurons that are different from those activating the corticospinal neurons. iSP and IHI do not represent the same phenomenon and should be considered complementary measures of ipsilateral inhibition.

title: Handedness is mainly associated with an asymmetry of corticospinal excitability and not of transcallosal inhibition
abstract: The study aims to compare transcallosal inhibition (TI), as assessed by the paired-pulse transcranial magnetic stimulation (TMS) technique, in a sample of right-handed subjects (RH) and left-handed subjects (LH). Motor thresholds (MTs) and motor evoked potential (MEP) amplitudes were also measured in the two groups, as an index of corticospinal activity.



Thirty-two normal subjects (16 RH and 16 LH) were recorded with a paired-pulse TMS paradigm (intensity of both pulses=120% of MT). The inter-stimulus intervals (ISIs) were 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 ms for both motor cortices, and MEP responses were recorded from the abductor digiti minimi muscles.



Both groups showed a clear TI centred around the 12 ms ISI, but no difference was found as a function of handedness or of hemisphere. On the other hand, the two groups differed in terms of corticospinal activity, since the hand motor dominant hemisphere had lower MTs than the non-dominant one in LH, and larger MEP amplitudes for the right hand were found in RH.



Results point to a functional asymmetry of the motor cortex on the hand-dominant versus the non-dominant hemisphere, while handedness does not seem associated with functional differences in callosal inhibition, as measured by the inter-hemispheric paired-pulse TMS technique.

title: Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: A functional and anatomical study
abstract: 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.

title: Interactions between inhibitory and excitatory circuits in the human motor cortex
abstract: Cortical activity depends on the balance between excitatory and inhibitory influences. Several different excitatory and inhibitory systems in the human motor cortex can be tested by transcranial magnetic stimulation (TMS). While considerable information is known about these different inhibitory and excitatory phenomena individually, how they are related to each other and how they interact is not well understood. Several recent studies have investigated the interactions between some of these circuits by applying them together. It has been found that short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) are mediated by different circuits. LICI appears to inhibit SICI, which may occur through presynaptic GABAB receptors. Interhemispheric inhibition elicited by stimulation of the contralateral motor cortex also inhibits SICI and may share inhibitory mechanisms with LICI. Long-interval afferent inhibition induced by median nerve stimulation inhibits LICI but does not interact with SICI. Based on these results, a model of interactions between different inhibitory systems that can be tested and refined in the future is proposed. Further studies of the interaction between different cortical inhibitory and excitatory circuits should improve our understanding of the functional organization of the motor cortex and allow better interpretation of abnormal findings in disease states. It may also be developed into a new way of studying the pathophysiology of diseases and the effects of intervention.

title: Cortical projection to erector spinae muscles in man as assessed by focal transcranial magnetic stimulation.
abstract: We stimulated the motor cortex in 9 subjects using focal transcranial magnetic stimulation with a figure of 8 coil in order to examine the cortical representation of the erector spinae muscles. Recordings were made from the erector spinae 3.5 cm lateral to the third lumbar vertebra. In 5 subjects clearly reproducible responses could be obtained which had a latency compatible with transmission via fast conducting fibers in a mono- or oligosynaptic pathway. In the remaining 4 subjects responses were poorly defined. Latencies in surface recordings varied between 13 and 24 msec but were longer when needle recordings were used. Mapping of the motor cortex was performed by moving the coil in 2 cm steps on either side of Cz. Different patterns of hemispheric representation were found ranging from a contralateral projection in either hemisphere to a representation of both back muscles in one hemisphere (2 subjects). Responses were followed by a silent period. The latter was interrupted or terminated by a response between 52 and 85 msec post stimulus which was found predominantly in the muscle ipsilateral to the side of stimulation.

title: Inhibitory and excitatory interhemispheric transfers between motor cortical areas in normal humans and patients with abnormalities of the corpus callosum.
abstract: Transcranial magnetic stimulation of the motor cortex was performed in 10 normal subjects and 10 patients with radiographical abnormalities of the corpus callosum. Seven patients had a complete or partial agenesis or hypoplasia of the corpus callosum, two had a thin corpus callosum due to hydrocephalus or white matter degeneration and one had a circumscript contusion lesion of the corpus callosum. The patients served as a clinical model to investigate transcallosal influences on excitatory and inhibitory effects of motor cortex stimulation and to assess the potential diagnostic use of interhemispheric conduction studies and the contribution of interhemispheric interaction on transcranially elicited contralateral excitatory and inhibitory motor responses. Stimulation over one motor cortex suppressed tonic voluntary electromyographic activity in ipsilateral hand muscles in all subjects with preserved anterior half of the trunk of the corpus callosum. Since this suppression was lacking or had a delayed onset latency in patients with absence or abnormalities of the anterior half of the trunk of the corpus callosum it can be concluded that it is due to a transcallosal inhibition (Ti) of the opposite motor cortex mediated by fibres passing through this part of the corpus callosum. In normal subjects Ti had an mean onset latency of 36.1 +/- 3.5 ms (SD) and a duration of 24.5 +/- 3.9 ms. The calculated mean transcallosal conduction time was 13 ms. The threshold of Ti recorded in muscles ipsilateral to stimulation tended to be higher than the one for eliciting excitatory contralateral motor responses (56 +/- 6% versus 46 +/- 10% maximum stimulator output). Cortical thresholds (at rest) for contralateral excitatory hand motor responses were higher in patients with developmental abnormalities of the corpus callosum than in normals (66 +/- 17% versus 46 +/- 10% maximum stimulator output), which probably reflects also a facilitatory transcallosal interaction of both motor cortices in normals. In contrast, facilitation of cortically elicited motor responses in one hand by strong contraction of the other hand was the same in the patients with agenesis of the corpus callosum and normals, which suggests that this facilitatory spread takes place on a spinal rather than on a cortical level. Central motor latencies and amplitudes of contralateral hand motor responses were the same in patients with developmental abnormalities of the corpus callosum and normals (6.1 +/- 0.7 ms versus 6.3 +/- 0.7 ms and 6.7 +/- 2.4 mV versus 6.6 +/- 2.9 mV) so that callosal transfers do not seem to influence corticospinal conduction properties.(ABSTRACT TRUNCATED AT 400

title: Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans
abstract: 1 Blockade of uptake carriers of γ‐aminobutyric acid (GABA) has been shown to modulate inhibition in cortical slices of experimental animals, although little is known about this mechanism in vivo and, in particular, in humans. 2 The effects of blockade of GABA uptake were studied using transcranial magnetic stimulation (TMS) in humans. In eight healthy volunteers several measures of cortical excitation and inhibition were obtained before and ≈2 h after ingestion of 5‐15 mg of tiagabine (TGB). 3 After TGB ingestion, the duration of the TMS‐induced silent period observable in the electromyogram of the voluntarily contracted target muscle was prolonged. Similarly, paired‐pulse inhibition of the motor‐evoked potential (MEP), as tested by delivering two magnetic shocks of equal suprathreshold intensities at 160 ms interstimulus interval (ISI), was more pronounced. In apparent contradistinction, paired‐pulse inhibition of the MEPs produced by a subthreshold conditioning stimulus delivered 3 ms prior to a suprathreshold stimulus was reduced. Paired‐pulse facilitation elicited by the same double‐shock protocol at an ISI of 10 ms was increased. 4 The prolongation of the GABAB receptor‐mediated component of the inhibitory postsynaptic potential observed with TGB in in vitro studies probably underlies the increase in cortical silent period duration. The reduction of the paired‐pulse inhibition at 3 ms, in turn, probably reflects inhibition of GABAA receptor‐mediated inhibition via presynaptic GABAB receptors. 5 These data provide in vivo evidence of differential modulation of cortical inhibition by blockade of GABA uptake. Presynaptic GABA autoreceptors may be involved in modulating cortical inhibition in the human motor cortex.

title: Modulation of interhemispheric inhibition by volitional motor activity: an ipsilateral silent period study
abstract: Brief interruption of voluntary EMG in a hand muscle by focal transcranial magnetic stimulation (TMS) of the ipsilateral primary motor cortex (M1), the so‐called ipsilateral silent period (ISP), is a measure of interhemispheric motor inhibition. However, little is known about how volitional motor activity would modulate the ISP. Here we tested in 30 healthy adults to what extent and under what conditions voluntary activation of the stimulated right M1 by moving the left hand strengthens interhemispheric inhibition as indexed by an enhancement of the ISP area in the maximally contracting right first dorsal interosseous (FDI). Left index finger abduction, already at low levels of contraction, significantly enhanced the ISP compared to left hand at rest. Even imagination of left index finger movement enhanced the ISP compared to rest or mental calculation. This enhancement occurred in the absence of motor‐evoked potential amplitude modulation in the left FDI, thus excluding a non‐specific contribution from an increase in right M1 corticospinal excitability. Contraction of the left extensor indicis, but not contraction of more proximal left upper limb or left or right lower limb muscles also enhanced the ISP. A reaction time experiment showed that the ISP enhancement developed at a late stage of movement preparation just before or at movement onset. Interhemispheric inhibition of the motor‐evoked potential as tested by a bifocal paired‐pulse TMS protocol and thought to be mediated via a neuronal circuit different to the ISP was not enhanced when tested under identical motor task conditions. Finally, ISP enhancement by contraction of the left FDI correlated inversely with EMG mirror activity in the right FDI during phasic abductions of the left index finger. Our findings strongly suggest that voluntary M1 activation by real or imagined movement of the contralateral hand increases interhemispheric motor inhibition of the opposite M1. This phenomenon shows substantial topographical, temporal and neuronal circuit specificity, and has functional significance as it probably plays a pivotal role in suppressing mirror activity.

title: Structural integrity of callosal midbody influences intermanual transfer in a motor reaction‐time task
abstract: Training one hand on a motor task results in performance improvements in the other hand, also when stimuli are randomly presented (nonspecific transfer). Corpus callosum (CC) is the main structure involved in interhemispheric information transfer; CC pathology occurs in patients with multiple sclerosis (PwMS) and is related to altered performance of tasks requiring interhemispheric transfer of sensorimotor information. To investigate the role of CC in nonspecific transfer during a pure motor reaction‐time task, we combined motor behavior with diffusion tensor imaging analysis in PwMS. Twenty‐two PwMS and 10 controls, all right‐handed, were asked to respond to random stimuli with appropriate finger opposition movements with the right (learning) and then the left (transfer) hand. PwMS were able to improve motor performance reducing response times with practice with a trend similar to controls and preserved the ability to transfer the acquired motor information from the learning to the transfer hand. A higher variability in the transfer process, indicated by a significantly larger standard deviation of mean nonspecific transfer, was found in the PwMS group with respect to the control group, suggesting the presence of subtle impairments in interhemispheric communication in some patients. Then, we correlated the amount of nonspecific transfer with mean fractional anisotropy (FA) values, indicative of microstructural damage, obtained in five CC subregions identified on PwMS's FA maps. A significant correlation was found only in the subregion including posterior midbody (Pearson's r = 0.74, P = 0.003), which thus seems to be essential for the interhemispheric transfer of information related to pure sensorimotor tasks.

title: Direction information coordinated via the posterior third of the corpus callosum during bimanual movements
abstract: We examined bimanual coordination in a patient before and after each stage of callosotomy surgery. We tested how well the patient coordinated movement direction between the hands. The patient drew symmetrical or asymmetrical figures simultaneously with both hands. Before surgery, symmetrical figures were drawn well and asymmetrical figures were drawn poorly. Following anterior callosotomy, the drawings improved slightly. Symmetrical figures were still drawn well, and asymmetrical ones were still drawn poorly. Thus, spatial integration remained intact despite the loss of interhemispheric communication between frontal cortical sites. After posterior callosotomy, spatial coordination deteriorated significantly. Mirror-image drawings became less symmetrical, while asymmetrical drawings improved. These data indicate that the posterior callosum mediates the coordination of direction information between the hands during bimanual movements. Given the topographical organization of the corpus callosum, this integration is likely carried out by parietal cortex.

title: Anterior and posterior callosal contributions to simultaneous bimanual movements of the hands and fingers.
abstract: In order to study the role of the corpus callosum in two-handed coordination we tested callosotomy subjects while they attempted to initiate simultaneous discrete movements with both hands. We observed four split-brain patients, including one pre- and post-operatively, as well as normal and epileptic control subjects. Split-brain patients made button presses that were less synchronous than either normal or epileptic controls. Although split-brain patients' average performance did not always differ from control subjects, callosotomy resulted in a 3-fold increase in the variability with which 'simultaneous' movements were initiated. The one subject tested pre- and post-callosotomy showed distinct changes in movement initiation synchrony after both the anterior and the posterior stages of the surgery. These changes suggest that anterior and posterior callosal fibres may make unique contributions to bimanual synchronization, depending on whether responses are self-initiated or in reaction to a visual stimulus. This study demonstrates that neural communication across anterior and posterior fibres of the corpus callosum strongly influences the temporal precision of bimanual coordination. Specifically, callosal transmission affects the degree of bilateral synchrony with which simple simultaneous hand and finger movements are initiated.

title: Dynamic intra- and interhemispheric interactions during unilateral and bilateral hand movements assessed with fMRI and DCM
abstract: Any motor action results from a dynamic interplay of various brain regions involved in different aspects of movement preparation and execution. Establishing a reliable model of how these areas interact is crucial for a better understanding of the mechanisms underlying motor function in both healthy subjects and patients. We used fMRI and dynamic causal modeling to reveal the specific excitatory and inhibitory influences within the human motor system for the generation of voluntary hand movements. We found an intrinsic balance of excitatory and inhibitory couplings among core motor regions within and across hemispheres. Neural coupling within this network was specifically modulated upon uni- and bimanual movements. During unimanual movements, connectivity towards the contralateral primary motor cortex was enhanced while neural coupling towards ipsilateral motor areas was reduced by both transcallosal inhibition and top-down modulation. Bimanual hand movements were associated with a symmetric facilitation of neural activity mediated by both increased intrahemispheric connectivity and enhanced transcallosal coupling of SMA and M1. The data suggest that especially the supplementary motor area represents a key structure promoting or suppressing activity in the cortical motor network driving uni- and bilateral hand movements. Our data demonstrate that fMRI in combination with DCM allows insights into intrinsic properties of the human motor system and task-dependent modulations thereof.

title: Repetitive transcranial magnetic stimulation of the supplementary motor area (SMA) degrades bimanual movement control in humans
abstract: Moving the upper limbs at a common tempo according to an in-phase or anti-phase mode represents elementary coordination dynamics. Previously, the role of the supplementary motor area (SMA) has been emphasized for successful production of these patterns. The objective of this study was to investigate whether repetitive transcranial magnetic stimulation (rTMS) of the SMA at 5 Hz can interfere with these isofrequency configurations in the post-stimulation stage. Results showed a deterioration of temporal control as a function of coordinative complexity. This effect was associated with a decrease in the functional coupling between the primary motor cortices, as measured by electroencephalographic coherence. These data suggest that rTMS of the SMA can modify interhemispheric communication and accordingly modulate interlimb behavior.

title: Role of the right dorsal premotor cortex in “physiological” mirror EMG activity
abstract: A distributed cortical network enables the lateralization of intended unimanual movements, i.e., the transformation from a default mirror movement to a unimanual movement. Little is known about the exact functional organization of this “non-mirror transformation” network. Involvement of the right dorsal premotor cortex (dPMC) was suggested because its virtual lesion by high-frequency repetitive transcranial magnetic stimulation (rTMS) increased the excitability of the left primary motor cortex (M1) during unilateral isometric contraction of a left hand muscle (Cincotta et al.,  2004). However, no behavioural effects were observed in that experimental protocol. Here we tested behaviourally twelve healthy volunteers to find out whether focal disruption of the right dPMC by “off-line” One Hz rTMS (900 pulses, 115% of resting motor threshold) enhances “physiological” mirroring.This was measured by an established protocol (Mayston et al.,  1999) that quantifies the mirror increase in the electromyographic (EMG) level in the isometrically contracting abductor pollicis brevis (APB) muscle of one hand during brief phasic contractions performed with the APB of the other hand. Mirroring in the right APB significantly increased after real rTMS of the right dPMC. In contrast, no change in mirroring was seen with sham rTMS of the right dPMC, real rTMS of the right M1, or real rTMS of the left dPMC. These findings strongly support the hypothesis that the right dPMC is part of the non-mirror transformation cortical network.

title: Hemispheric asymmetries of the premotor cortex are task specific as revealed by disruptive TMS during bimanual versus unimanual movements.
abstract: The premotor cortex (PMC) is functionally lateralized, such that the left PMC is activated for unimanual movements of either hand, whereas the right PMC is particularly active during complex bimanual movements. Here we ask the question whether the high activation of right PMC in the bimanual context reflects either hemispheric specialization or handedness. Left- and right-handed subjects performed a bimanual antiphase tapping task at different frequencies while transcranial magnetic stimulation (TMS) was used to temporarily disrupt left versus right PMC during complex bimanual movements. For both handedness groups, more disruptions were induced when TMS was applied over the motor nondominant PMC than over the motor dominant PMC or when sham-TMS was used. In a second experiment, right-handers performed complex unimanual tapping with either hand, while TMS was applied to the PMC in both hemispheres. The novel result was that the high susceptibility of the motor nondominant PMC was specific to the bimanual context, indicating that hemispheric asymmetries of the PMC depend on the bimanual versus unimanual nature of the motor task. We hypothesize that asymmetries of PMC involvement in bimanual control reflect interhemispheric interactions, whereby the motor nondominant PMC appears to prevent motor cross talk arising from the dominant hemisphere.

title: Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function
abstract: The corpus callosum (CC) is the principal white matter fiber bundle connecting neocortical areas of the two hemispheres. Although an object of extensive research, important details about the anatomical and functional organization of the human CC are still largely unknown. Here we focused on the callosal motor fibers (CMFs) that connect the primary motor cortices (M1) of the two hemispheres. Topography and somatotopy of CMFs were explored by using a combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure. CMF microstructure was assessed by fractional anisotropy (FA), and CMF functional connectivity between the hand areas of M1 was measured by interhemispheric inhibition using paired-pulse transcranial magnetic stimulation. CMFs mapped onto the posterior body and isthmus of the CC, with hand CMFs running significantly more anteriorly and ventrally than foot CMFs. FA of the hand CMFs but not FA of the foot CMFs correlated linearly with interhemispheric inhibition between the M1 hand areas. Findings demonstrate that CMFs connecting defined body representations of M1 map onto a circumscribed region in the CC in a somatotopically organized manner. The significant and topographically specific positive correlation between FA and interhemispheric inhibition strongly suggests that microstructure can be directly linked to functional connectivity. This provides a novel way of exploring human brain function that may allow prediction of functional connectivity from variability of microstructure in healthy individuals, and potentially, abnormality of functional connectivity in neurological or psychiatric patients.

title: Anisotropy of Callosal Motor Fibers in Combination With Transcranial Magnetic Stimulation in the Course of Motor Development
abstract: The corpus callosum (CC) represents a key structure for hand motor development and is accessible to investigation by diffusion tensor magnetic resonance imaging (DTI) and transcranial magnetic stimulation (TMS). To identify quantifiable markers for motor development, we combined DTI with TMS. We examined groups of 11 healthy preschool-aged children, 10 healthy adolescents, and 10 healthy adults with both, DTI and TMS/ipsilateral silent period (iSP). DTI-values for fractional anisotropy (FA) were calculated for areas I to V of the CC. ISP-values for latency, duration, and extent of electromyography suppression were calculated. FA was significantly lower in areas II to IV of the CC in children as compared with adults (P < 0.05). In area III, where callosal motor fibers cross the CC, FA differed significantly between children and adolescents (P < 0.05). TMS parameters demonstrated significant age-related differences in duration and extent of iSP (P < 0.05). No significant differences were detected regarding latency of iSP. The maturation of callosal motor fiber connectivity seems to reflect the degree of interhemispheric inhibition between the motor cortices with anisotropy of callosal motor fibers being a potential marker for motor development.

title: ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data
abstract: Diffusion tensor imaging (DTI) is becoming a standard addition to routine MR imaging for investigating microstructural tissue properties (e.g., see  for a recent review). With this research field rapidly evolving, the need for efficient and user-friendly diffusion MR processing/analysis software packages is also increasing. Here, a new MR diffusion toolbox – dubbed ExploreDTI – is officially presented for the first time. ExploreDTI is a non-commercial package that combines many of the key MR diffusion processing tools that have appeared in the recent literature, but which have not necessarily been widely available. The package will be made freely available to academic institutions following the ISMRM meeting in Hawaii. The main features of ExploreDTI are summarized in the following sections. Platform ExploreDTI is written in Matlab (The Mathworks Inc., Natick, Massachusetts, USA) and, as such, works across multiple platforms (Windows PC, Unix, Mac). The focus of ExploreDTI is on interactive display and manipulation of data, such as WM fiber tracts , brain surface renderings , and diffusion glyphs (principal diffusion directions (PDD), cuboids, ellipsoids, and fiber orientation distribution (FOD) objects – Fig. 3). While many aspects of the processing have been vectorized, optimal results will be obtained with a high-performance graphics card.   ExploreDTI can take, as input, raw diffusion-weighted (DW) data in multiple formats including Dicom, Analyze, NIFTI, and Matlab formats – and is easily adapted to handle others. The diffusion tensor can be estimated by linear, weighted linear, and non-linear least squares methods with (or without) the RESTORE method . Q-ball Imaging (QBI)  and Constrained Spherical Deconvolution (CSD)  reconstructions are integrated as are overlays of other modalities, such as T1 structural data (Figs. 4, 5) or atlas labels . • Motion / Eddy Current Correction: This pre-processing step corrects the DW images for subject motion and Eddy-current-induced distortions, incorporating the Bmatrix rotation to preserve the orientational information correctly . • Quality Assessment Tools: ExploreDTI contains quality assessment tools to investigate artefacts (due to motion, distortions, signal dropouts, etc.) based on analyses of residuals and outliers of the diffusion tensor fit [6] .  Both deterministic [7] (Figs. 1, 4) and wild bootstrap (Figs. 8, 9)  streamline tracking algorithms are supported for DTI, QBI, and CSD [2, 3]. Atlas labels and ROIs (‘AND’, ‘OR/SEED’, ‘NOT’) can be defined to select fiber tracts of interest (or segments thereof – Fig. 10), such as described, for instance, in . ExploreDTI also incorporates the PASTA tools  so that quantitative measures along the tracts, such as fractional and relative anisotropy, the ‘Westin’-measures [11], mean/longitudinal/transverse diffusivity, or other modality information can be calculated. • Synthetic fiber phantoms: ExploreDTI allows for the generation of synthetic MR diffusion fiber phantoms with a wide range of architectural complexity given a set of predefined parameters, such as the b-value, voxel size, number of gradient directions, mean diffusivity, width of the fiber bundle(s) etc.  .  In addition to brain surface renderings, diffusion glyphs for DTI/CSD/QBI, and image maps (FA, mean diffusivity, etc.), hyper-streamtubes (streamtubes with variable width – Fig. 12) are integrated to visualize specific local fiber tract properties, such as the 95% “cone of uncertainty” . Snapshot and Movie tools are included for rapid and easy export of key results into presentations.  Although developed in Matlab, ExploreDTI can be compiled as a standalone application, obviating the need for a Matlab licence. ExploreDTI can take output from other tracking packages – and provide a way of navigating through them in an efficient manner. ExploreDTI incorporates a detailed manual, with worked examples and screenshots to enable you to get quickly acquainted with its many features. More information can be found on http://www.ExploreDTI.com.

title: Three-dimensional locations and boundaries of motor and premotor cortices as defined by functional brain imaging: A meta-analysis
abstract: The mesial premotor cortex (pre-supplementary motor area and supplementary motor area proper), lateral premotor cortex (dorsal premotor cortex and ventral premotor cortex), and primary sensorimotor cortex (primary motor cortex and primary somatosensory cortex) have been identified as key cortical areas for sensorimotor function. However, the three-dimensional (3-D) anatomic boundaries between these regions remain unclear. In order to clarify the locations and boundaries for these six sensorimotor regions, we surveyed 126 articles describing pre-supplementary motor area, supplementary motor area proper, dorsal premotor cortex, ventral premotor cortex, primary motor cortex, and primary somatosensory cortex. Using strict inclusion criteria, we recorded the reported normalized stereotaxic coordinates (Talairach and Tournoux or MNI) from each experiment. We then computed the probability distributions describing the likelihood of activation, and characterized the shape, extent, and area of each sensorimotor region in 3-D. Additionally, we evaluated the nature of the overlap between the six sensorimotor regions. Using the findings from this meta-analysis, along with suggestions and guidelines of previous researchers, we developed the Human Motor Area Template (HMAT) that can be used for ROI analysis. HMAT is available through e-mail from the corresponding author.

title: Assessing the effects of age on long white matter tracts using diffusion tensor tractography
abstract: Aging is associated with significant white matter deterioration and this deterioration is assumed to be at least partly a consequence of myelin degeneration. The present study investigated specific predictions of the myelodegeneration hypothesis using diffusion tensor tractography. This technique has several advantages over other methods of assessing white matter architecture, including the possibility of isolating individual white matter tracts and measuring effects along the whole extent of each tract. The study yielded three main findings. First, age-related white matter deficits increased gradually from posterior to anterior segments within specific fiber tracts traversing frontal and parietal, but not temporal cortex. This pattern inverts the sequence of myelination during childhood and early development observed in previous studies and lends support to a "last-in-first-out" theory of the white matter health across the lifespan. Second, both the effects of aging on white matter and their impact on cognitive performance were stronger for radial diffusivity (RD) than for axial diffusivity (AD). Given that RD has previously been shown to be more sensitive to myelin integrity than AD, this second finding is also consistent with the myelodegeneration hypothesis. Finally, the effects of aging on select white matter tracts were associated with age difference in specific cognitive functions. Specifically, FA in anterior tracts was shown to be primarily associated with executive tasks and FA in posterior tracts mainly associated with visual memory tasks. Furthermore, these correlations were mirrored in RD, but not AD, suggesting that RD is more sensitive to age-related changes in cognition. Taken together, the results help to clarify how age-related white matter decline impairs cognitive performance.

title: Topography of the human corpus callosum revisited—Comprehensive fiber tractography using diffusion tensor magnetic resonance imaging
abstract: Several tracing studies have established a topographical distribution of fiber connections to the cortex in midsagittal cross-sections of the corpus callosum (CC). The most prominent example is Witelson's scheme, which defines five vertical partitions mainly based on primate data. Conventional MRI of the human CC does not reveal morphologically discernable structures, although microscopy techniques identified myelinated axons with a relatively small diameter in the anterior and posterior third of the CC as opposed to thick fibers in the midbody and posterior splenium. Here, we applied diffusion tensor imaging (DTI) in conjunction with a tract-tracing algorithm to gain cortical connectivity information of the CC in individual subjects. With DTI-based tractography, we distinguished five vertical segments of the CC, containing fibers projecting into prefrontal, premotor (and supplementary motor), primary motor, and primary sensory areas as well as into parietal, temporal, and occipital cortical areas. Striking differences to Witelson's classification were recognized in the midbody and anterior third of the CC. In particular, callosal motor fiber bundles were found to cross the CC in a much more posterior location than previously indicated. Differences in water mobility were found to be in qualitative agreement with differences in the microstructure of transcallosal fibers yielding the highest anisotropy in posterior regions of the CC. The lowest anisotropy was observed in compartments assigned to motor and sensory cortical areas. In conclusion, DTI-based fiber tractography of healthy human subjects suggests a modification of the widely accepted Witelson scheme and a new classification of vertical CC partitions.

title: New graphical method to measure silent periods evoked by transcranial magnetic stimulation
abstract: Manual methods of measuring duration of cortical silent periods (CSP) evoked by transcranial magnetic stimulation (TMS) depend upon subjective visual estimation of onset and offset. Because of this, the measurements are susceptible to poor rater reliability. We describe a graphical method to measure silent periods with greater precision. The statistical process underlying this new method is simple and particularly suited to signal detection in serially dependent data.



TMS-evoked silent periods were recorded in 13 healthy subjects. Two investigators subjectively measured silent period duration on each subject to estimate rater reliability. Using the graphical method, the mean and 99.76% variation limits of pre-stimulus electromyogram (EMG) activity were computed. Each averaged trial was displayed and CSP onset and offset detected when post-stimulus EMG activity moved outside the 99.76% limits.



Maximum variation in silent period duration was 21.8 ms between the two investigators' subjective measurements. Silent period duration measured with the graphical method closely approximated measurements obtained using the manual method. It was possible to automate the procedure.



This graphical method allowed precise measurement of CSP duration, independent of subjective estimations of onset or offset points. Further studies are necessary to determine if this method can provide a framework for other physiologic measures.

title: Relationships between motor unit size and recruitment threshold in older adults: implications for size principle
abstract: As a part of the aging process, motor unit reorganization occurs in which small motoneurons reinnervate predominantly fast-twitch muscle fibers that have lost their innervation. We examined the relationship between motor unit size and the threshold force for recruitment in two muscles to determine whether older individuals might develop an alternative pattern of motor unit activation. Young and older adults performed isometric contractions ranging from 0 to 50% of maximal voluntary contraction in both the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. Muscle fiber action potentials were recorded with an intramuscular needle electrode and motor unit size was computed using spike-triggered averaging of the global EMG signal (macro EMG), which was also obtained from the intramuscular needle electrode. As expected, older individuals exhibited larger motor units than young subjects in both the FDI and the TA. However, moderately strong correlations were obtained for the macro EMG amplitude versus recruitment threshold relationship in both the young and older adults within both muscles, suggesting that the size principle of motor unit recruitment seems to be preserved in older adults.

title: Physiological motor asymmetry in human handedness: evidence from transcranial magnetic stimulation
abstract: We hypothesized that human handedness might be associated with measurable differences in the excitability of the motor system. We compared the thresholds for electromyographic activation of the left and right abductor pollicis brevis (APB) and biceps muscles in 30 left-handers and 30 right-handers, by varying the direction of a brief monophasic pulse in a circular electromagnetic coil centered over the vertex of the scalp. In right-handers, we found that the threshold for activation of muscles in the right arm was lower than the threshold for activation of corresponding muscles in the left arm. In left-handers, the reverse was true. Threshold asymmetry was influenced significantly by the consistency with which each subject used the writing hand to perform other motor tasks, and was not significant between non-consistent left-handers and right-handers. Our results indicate that human handedness, and in particular, consistency of hand preference, are associated with lateralized differences in the excitability of motor system projections activated by transcranial magnetic stimulation. Our findings might reflect physiological differences in corticospinal tract function or cortical motor representation.

title: Differences of the ipsilateral silent period in small hand muscles
abstract: 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. Muscle Nerve, 2006

title: Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. 1996.
abstract: Quantitative-diffusion-tensor MRI consists of deriving and displaying parameters that resemble histological or physiological stains, i.e., that characterize intrinsic features of tissue microstructure and microdynamics. Specifically, these parameters are objective, and insensitive to the choice of laboratory coordinate system. Here, these two properties are used to derive intravoxel measures of diffusion isotropy and the degree of diffusion anisotropy, as well as intervoxel measures of structural similarity, and fiber-tract organization from the effective diffusion tensor, D , which is estimated in each voxel. First, D is decomposed into its isotropic and anisotropic parts, 〈D〉 I and D – 〈D〉 I , respectively (where 〈D〉 = Trace( D )/3 is the mean diffusivity, and I is the identity tensor). Then, the tensor (dot) product operator is used to generate a family of new rotationally and translationally invariant quantities. Finally, maps of these quantitative parameters are produced from high-resolution diffusion tensor images (in which D is estimated in each voxel from a series of 2D-FT spin-echo diffusion-weighted images) in living cat brain. Due to the high inherent sensitivity of these parameters to changes in tissue architecture (i.e., macromolecular, cellular, tissue, and organ structure) and in its physiologic state, their potential applications include monitoring structural changes in development, aging, and disease.

title: Interhemispheric connections of the ventral premotor cortex in a new world primate
abstract: This study describes the pattern of interhemispheric connections of the ventral premotor cortex (PMv) distal forelimb representation (DFL) in squirrel monkeys. Our objectives were to describe qualitatively and quantitatively the connections of PMv with contralateral cortical areas. Intracortical microstimulation techniques (ICMS) guided the injection of the neuronal tract tracers biotinylated dextran amine or Fast blue into PMv DFL. We classified the interhemispheric connections of PMv into three groups. Major connections were found in the contralateral PMv and supplementary motor area (SMA). Intermediate interhemispheric connections were found in the rostral portion of the primary motor cortex, the frontal area immediately rostral and ventral to PMv (FR), cingulate motor areas (CMAs), and dorsal premotor cortex (PMd). Minor connections were found inconsistently across cases in the anterior operculum (AO), posterior operculum/inferior parietal cortex (PO/IP), and posterior parietal cortex (PP), areas that consistently show connections with PMv in the ipsilateral hemisphere. Within‐case comparisons revealed that the percentage of PMv connections with contralateral SMA and PMd are higher than the percentage of PMv connections with these areas in the ipsilateral hemisphere; percentages of PMv connections with contralateral M1 rostral, FR, AO, and the primary somatosensory cortex are lower than percentages of PMv connections with these areas in the ipsilateral hemisphere. These studies increase our knowledge of the pattern of interhemispheric connection of PMv. They help to provide an anatomical foundation for understanding PMv's role in motor control of the hand and interhemispheric interactions that may underlie the coordination of bimanual movements.  2007.

title: Transcallosal connections of the distal forelimb representations of the primary and supplementary motor cortical areas in macaque monkeys
abstract: The goal of the present neuroanatomical study in macaque monkeys was twofold: (1) to clarify whether the hand representation of the primary motor cortex (M1) has a transcallosal projection to M1 of the opposite hemisphere; (2) to compare the topography and density of transcallosal connections for the hand representations of M1 and the supplementary motor area (SMA). The hand areas of M1 and the SMA were identified by intracortical microstimulation and then injected either with retrograde tracer substances in order to label the neurons of origin in the contralateral motor cortical areas (four monkeys) or, with an anterograde tracer, to establish the regional distribution and density of terminal fields in the opposite motor cortical areas (two monkeys). The main results were: (1) The hand representation of M1 exhibited a modest homotopic callosal projection, as judged by the small number of labeled neurons within the region corresponding to the contralateral injection. A modest heterotopic callosal projection originated from the opposite supplementary, premotor, and cingulate motor areas. (2) In contrast, the SMA hand representation showed a dense callosal projection to the opposite SMA. The SMA was found to receive also dense heterotopic callosal projections from the contralateral rostral and caudal cingulate motor areas, moderate projections from the lateral premotor cortex, and sparse projections from M1. (3) After injection of an anterograde tracer (biotinylated dextran amine) in the hand representation of M1, only a few small patches of axonal label were found in the corresponding region of M1, as well as in the lateral premotor cortex; virtually no label was found in the SMA or in cingulate motor areas. Injections of the same anterograde tracer in the hand representation of the SMA, however, resulted in dense and widely distributed axonal terminal fields in the opposite SMA, premotor cortex, and cingulate motor areas, while labeled terminals were clearly less dense in M1. It is concluded that the hand representations of the SMA and M1 strongly differ with respect to the strength and distribution of callosal connectivity with the former having more powerful and widespread callosal connections with a number of motor fields of the opposite cortex than the latter. These anatomical results support the proposition of the SMA being a bilaterally organized system, possibly contributing to bimanual coordination.

title: Transcallosal inhibition in cortical and subcortical cerebral vascular lesions
abstract: The excitability of the motor cortex after transcranial magnetic stimulation was investigated in 10 patients with purely subcortical, and in 22 patients with cortical-subcortical cerebrovascular lesions. In the first investigation we applied magnetic double stimuli over both motor cortices with different inter-stimulus intervals. The first (conditioning) stimulus was applied to the affected hemisphere and the second stimulus (test stimulus) to the unaffected side. The responses of the first dorsal interosseal (FDI) muscle, contralateral to the test stimulus, were recorded after applying the test stimulus alone and at inter-stimulus intervals of 5 ms, 7 ms, 15 ms, 30 ms and 60 ms. In a second investigation the patients were asked to activate their non-paretic first dorsal interosseus muscle and the magnetic stimulus was applied over the affected hemisphere. The EMG responses were rectified and averaged. Patients with subcortical cerebral lesions below the centrum semiovale (i.e., having no effect on the transcallosal fibres) displayed a pronounced inhibition of one motor cortex after the stimulation of the contralateral side, comparable with normal subjects. Patients with cortical-subcortical cerebral lesions displayed only partly less inhibition of their motor cortex but the results in this group were not uniform. Since inhibition was preserved in patients with subcortical lesions, which had destroyed the corticospinal tract, we conclude that this inhibition is not mediated through an ipsilateral projection but via a transcallosal route.

title: Conduction deficits of callosal fibres in early multiple sclerosis
abstract: To study the diagnostic usefulness of transcallosal inhibition (TI) elicited by transcranial magnetic stimulation (TMS) in detecting central conduction deficits in early multiple sclerosis. Corticospinally mediated excitatory responses evoked by TMS are accepted as a sensitive diagnostic tool in multiple sclerosis. Recently, TI evoked by TMS has been introduced as a new paradigm to test the function of callosal fibres interconnecting both hand associated motor cortices.  Focal TMS of the motor cortex was performed in 50 patients with early relapsing-remitting multiple sclerosis. Corticospinally mediated (central motor latencies, amplitudes) and transcallosally mediated (onset latency and duration of TI) stimulation effects were investigated.  TMS disclosed abnormalities of corticospinally mediated responses in 62% and of TI in 80% of the patients.  The assessment of TI allows the discovery of lesions within the periventricular white matter that were not accessible by neurophysiological techniques before. This new paradigm increases the sensitivity of TMS with which to detect central conduction deficits in early multiple sclerosis.

title: Absence of transcallosal inhibition following focal mangnetic stimulation in preschool children
abstract: Focal transcranial magnetic stimulation of the hand‐associated motor cortex was used to study normal healthy preschool children (n = 7; mean age, 4.6 years) and adults (n = 7; mean age, 29.4 years) under the conditions of standardized tonic voluntary contraction of small hand muscles. Callosally mediated inhibitory as well as corticospinally mediated inhibitory and excitatory motor effects were investigated. Although children had no detectable transcallosal inhibition, their corticospinally mediated postexcitatory silent period was present (mean, 140.8 ± 30.2 msec). It was significantly shorter then in adults (mean, 192.5 ± 32.0 msec). The motor thresholds of the cortically elicited muscle responses, measured as the lowest stimulus intensity, were significantly higher in children (mean, 89 ± 5%) than in adults (mean, 46 ± 6%). The corticomuscular latency of transcranially elicited motor responses revealed no difference between children and adults. These observations may reflect maturation processes in the motor system. Maturation of at least some direct corticospinal fibers occurs early in life and is followed by that of intracortical excitatory and inhibitory connections. The maturation of functionally competent callosal connections appears to occur after the age of 5 years.

title: Local–global interference is modulated by age, sex and anterior corpus callosum size
abstract: To identify attentional and neural mechanisms affecting global and local feature extraction, we devised a global-local hierarchical letter paradigm to test the hypothesis that aging reduces functional cerebral lateralization through corpus callosum (CC) degradation. Participants (37 men and women, 26-79 years) performed a task requiring global, local, or global+local attention and underwent structural MRI for CC measurement. Although reaction time (RT) slowed with age, all participants had faster RTs to local than global targets. This local precedence effect together with greater interference from incongruent local information and greater response conflict from local targets each correlated with older age and smaller callosal genu (anterior) areas. These findings support the hypothesis that the CC mediates lateralized local-global processes by inhibition of task-irrelevant information under selective attention conditions. Further, with advancing age smaller genu size leads to less robust inhibition, thereby reducing cerebral lateralization and permitting interference to influence processing. Sex was an additional modifier of interference, in that callosum-interference relationships were evident in women but not in men. Regardless of age, smaller splenium (posterior) areas correlated with less response facilitation from repetition priming of global targets in men, but with greater response facilitation from repetition priming of local targets in women. Our data indicate the following dissociation: anterior callosal structure was associated with inhibitory processes (i.e., interference from incongruency and response conflict), which are vulnerable to the effects of age and sex, whereas posterior callosal structure was associated with facilitation processes from repetition priming dependent on sex and independent of age.

title: Dorsal premotor cortex exerts state-dependent causal influences on activity in contralateral primary motor and dorsal premotor cortex.
abstract: During voluntary action, dorsal premotor cortex (PMd) may exert influences on motor regions in both hemispheres, but such interregional interactions are not well understood. We used transcranial magnetic stimulation (TMS) concurrently with event-related functional magnetic resonance imaging to study such interactions directly. We tested whether causal influences from left PMd upon contralateral (right) motor areas depend on the current state of the motor system, involving regions engaged in a current task. We applied short bursts (360 ms) of high- or low-intensity TMS to left PMd during single isometric left-hand grips or during rest. TMS to left PMd affected activity in contralateral right PMd and primary motor cortex (M1) in a state-dependent manner. During active left-hand grip, high (vs. low)-intensity TMS led to activity increases in contralateral right PMd and M1, whereas activity decreases there due to TMS were observed during no-grip rest. Analyses of condition-dependent functional coupling confirmed topographically specific stronger coupling between left PMd and right PMd (and right M1), when high-intensity TMS was applied to left PMd during left-hand grip. We conclude that left PMd can exert state-dependent interhemispheric influences on contralateral cortical motor areas relevant for a current motor task.