Anatomical and Electrophysiological Manifestations in a Patient with Congenital Corpus Callosum Agenesis
Yi-Ting Hsu1, Jeng-Ren Duann2,6, Chun-Ming Chen3, Yu-Wan Yang1,4, Chon-Haw
Tsai1,4,5*, Ming-Kuei Lu1,4*
1Neuroscience Laboratory, Department of Neurology; 2Biomedical Engineering
Research Center and Graduate Institute of Clinical and Medical Science; 3Department
of Radiology, China Medical University Hospital; 4School of Medicine, Medical
College; 5Graduate Institute of Neural and Cognitive Sciences, China Medical
University, Taichung, Taiwan, 6Institute of Neural Computation, University of
California, San Diego, 92093, USA
* Correspondence to Dr. Ming-Kuei Lu or Dr. Chon-Haw Tsai
Address: Department of Neurology, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan
TEL: 886-4-22062121 EXT. 2004 FAX: 886-4-22344055
E-mail: d4297@mail.cmuh.org.tw (Dr. Lu) or d8079@mail.cmuh.org.tw (Dr. Tsai)
Word count: abstract: 226; text: 1,975; characters: 12,700; 2 figures Running title: Anatomical and electrophysiological findings in ACC
imaging (DTI), interhemispheric inhibition (IHI), movement-related cortical potential (MRCP)
Abstract
The corpus callosum is the major brain structure responsible for the transferring of information between the two hemispheres. In congenital agenesis of the corpus callosum (ACC), an alternative functional connection might exist between the hemispheres; however, this has yet to be demonstrated. The present study evaluated a 27-year-old man with ACC but no detectable motor function deficits using diffusion tensor imaging (DTI), movement-related cortical potential (MRCP), and interhemispheric inhibition (IHI). The MRCP was analyzed at the electrodes of C3, FCZ, and C4. Interhemispheric inhibition was measured using paired transcranial magnetic stimulation over the hand area of the primary motor cortex at both hemispheres. Data of the patient were compared with those of an age-matched healthy control group (n = 8, mean age: 27.6 ± 2.5 years). Diffusion tensor imaging showed absence of the callosal fibers and the presence of enhanced transcommissual fibers in the ACC patient. The mean fractional anisotropy of the transcommissual fibers revealed a significant difference between the patient and the control group (0.62 vs. 0.43, p < 0.01). The MRCP and IHI, supposed to be highly relevant to the transcallosal pathway, were present in the patient though they occurred to a relatively low degree compared to the control group. Findings suggest that in the ACC patient, the abnormal transcommissual fibers might be functional and serve as an alternative
Introduction
The corpus callosum connects homologous cortical areas of the bilateral cerebral hemispheres and plays a critical role in the transfer of sensory, cognitive, and motor information in humans. Congenital development deficits of the corpus callosum are relevant to a wide spectrum of neuropsychological disorders (Paul et al. 2007). However, some patients with congenital agenesis of the corpus callosum (ACC) are clinically asymptomatic (Paul et al. 2007; Taylor and David 1998). The integrity of the functional connectivity of the bilateral hemispheres in these patients, and the possibility of an alternative connection between the two hemispheres are, therefore, of research interest. The present study adopted diffusion tensor imaging (DTI) and two electrophysiological tests, movement-related cortical potential (MRCP) and interhemispheric inhibition (IHI), evoked by transcranial magnetic stimulation (TMS), to evaluate a patient with congenital ACC. Findings were compared with those of an age-matched healthy group.
The MRCP is a cortical negativity time-locked to the onset of a volitional movement (Shibasaki and Hallett 2006). Previous studies have revealed that the simultaneous activation of the motor-related cortices in the bilateral hemispheres for a simple unilateral hand movement is probably mediated by the transcallosal projections (Allison et al. 2000; Gerloff et al. 1998). The manifestation of the MRCP
in an ACC patient could, therefore, provide opportunity for investigation of the role of the corpus callosum in the preparatory process of volitional movement. IHI can be investigated by a paired TMS technique in which a single TMS conditioning shock to the primary motor cortex (M1) in one hemisphere produces an inhibition of the test response evoked from the M1 in the other hemisphere (Ferbert et al. 1992). Motor-evoked potential (MEP) is depressed at two condition-test interstimulus intervals. The short one is around 8-10 ms and the longer one is around 40 ms (Chen et al. 2003). The IHI evoked by the short interval paired TMS (i.e. 10 ms) has been found with a significant correlation to the fractional anisotropy (FA), an DTI-based measure of microstructural integrity, of callosal motor fibers (Wahl et al. 2007). IHI can also be studied by measuring the silent period of the tonic voluntary muscle activity ipsilateral to a single TMS at M1 (Chen et al. 2003; Meyer et al. 1995). Though the physiological mechanism may be distinct between these two IHI protocols, the phenomenon of IHI is thought to be mediated through the transcallosal motor pathway (Chen et al. 2003; Giovannelli et al. 2009). By studying the ipsilateral silent period, Meyer et al. reported abnormal IHI in patients with ACC (Meyer et al. 1995). In this study we adopted short interval paired TMS to investigate IHI in the ACC patient. In addition, previous studies have observed noncallosal commissures or aberrant projections using DTI in ACC patients (Lee et al. 2004; Tovar-Moll et al. 2007;
Utsunomiya et al. 2006). Using the combined study of DTI, MRCP and IHI, the functional relationship between the anatomical abnormalities and the physiological presentations in the ACC patient can be further investigated.
Subjects
A 27-year-old right-handed (Oldfield 1971) man visited the outpatient department after experiencing episodic dizziness and slight anxiety for several days. He did not have any limitations or difficulties with daily life activities. A history of mood disorder was mentioned by his relatives; however, there was no family history of motor disabilities, mental retardation, or epilepsy. Neurological examination showed intact intelligence, full muscle power, normal muscle tone, and intact cerebellar function. He displayed no movement disorder such as mirror movement, intermanual conflict, or apraxic limb. Anatomic T1-weighted imaging showed complete agenesis of the corpus callosum (Figure 1, left panel). The patient and eight age-matched right-handed (Oldfield 1971) healthy subjects (27.6 ± 2.5 years, 6 men) all provided written informed consent to participate in this study. The study procedures were in accordance with the Declaration of Helsinki and followed the safety guidelines for TMS (Rossi et al. 2009) and separate MRI examinations.
DTI
The DTI parameters are described in the Appendix. Vector maps were assigned to red (x element; left-right), green (y element; anteroposterior) and blue (z element; superior-inferior) by the FA-based proportional intensity scale. Tractography of the healthy participants demonstrated sparse connecting fibers between the bilateral anterior commissures (AC) and abundant callosal fibers (Figure 1, middle and right panels). In the ACC patient, absence of the callosal fibers was noted. Thick bundles in the anteroposterior direction (green in the vector map and the fiber tractography) and within the same hemisphere, called Probst bundles (Tovar-Moll et al. 2007), were also observed. The tractography of this patient also showed enhanced connecting fibers between the bilateral AC (i.e. transcommissual fibers, see Figure 1, right panel). The mean FA value calculated from the same position of the transcommissual fibers revealed a significant difference between the patient and the healthy control group (0.62 vs 0.43, p < 0.01) (see the boxplot in Figure 1).
MRCP
The MRCP was recorded by requesting the ACC patient and the healthy participants to perform a self-paced wrist extension movement (see Appendix for the detailed settings). The MRCP of the C3, FCZ, and C4, the maximal activity over the whole scalp, were recorded for comparison (Figure 2A). The MRCP, determined by
calculating the mean amplitude between 1500 ms to 0 ms prior to movement onset, was present in both the healthy control group and in the ACC patient. In the control group, the mean amplitude of MRCP at C3, FCZ, C4 is -1.62 ± 2.37, -2.56 ± 3.37, -2.13 ± 2.94 µV for right hand movement and -3.23 ± 3.72, -4.27 ± 4.36, -3.33 ± 2.58 µV for left hand movement, respectively. In the patient, the mean amplitude of MRCP at C3, FCZ, C4 is 0.39, 0.49, -0.31 µV for right hand movement and -1.05, -2.13, -1.52 µV for left hand movement, respectively (Figure 2A). The patient showed relatively low MRCP amplitude as compared to the healthy control group. However, the difference of the MRCP amplitude between the patient and the control group did not show statistical significance (all p > 0.2 by nonparametric Mann-Whitney U test, Figure 2A boxplot).
IHI
A paired conditioning-test TMS technique was adopted to assess the IHI (Ferbert et al. 1992) (see Appendix for the stimuli parameters). In this study, left-to-right IHI represented the effect of conditioning stimuli at left M1 on the test stimuli at right M1, and vice versa for right-to-left IHI. The right-to-left IHI was 50.2 ± 19.2 ％ in the control group and 69.3% in the ACC patient; the left-to-right IHI was 61.8 ± 21.6 % in the control group and 76.6% in the ACC patient (Figure 2B). Still, the IHI induced slightly lower suppression effects to the ACC patient as compared to the healthy
control group, however, the result did not survive under significance test (both p > 0.3 by nonparametric Mann-Whitney U test, Figure 2B boxplot).
Discussion
The corpus callosum plays an important role in motor control in humans. However, the current ACC patient did not present any significant motor symptoms. One possible explanation is the existence of an alternative noncallosal pathway connecting the patient’s bilateral motor-related brain areas. Previous DTI studies in patients with defective corpus callosum showed at least 2 abnormal long fiber tracts, including a Probst bundle and a sigmoid asymmetrical aberrant bundle (Lee et al. 2004; Tovar-Moll et al. 2007; Utsunomiya et al. 2006). In ACC patients, the AC is usually hypoplastic though it can be normal or enlarged (Meyer et al. 1998a). The current ACC patient demonstrated abnormally enhanced fibers connecting the bilateral AC. It is possible that the enhanced transcommissural fibers form an alternative route connecting the two hemispheres.
The generation of MRCP involves the activation of bilateral supplementary motor areas (SMA) and M1 (Shibasaki and Hallett 2006). It is unclear whether the bilateral cortical activations for movement preparation are relevant to the transcallosal pathway. In the current ACC patient, the analyses observed MRCP, though with a low
explain this observation. One is that the corpus callosum did not mediate the MRCP generation. However, previous research has identified that the size of the corpus callosum correlated with the lateralization of the MRCP and functional activation of the medial motor cortical areas which are thought as the MRCP generators (Stancák et al. 2000; Stancák et al. 2003). Alternatively, a compensatory mechanism could have developed. Considering the relatively low amplitude of MRCP in the ACC patient (Figure 2A), it is likely that the compensatory mechanism, probably through the enhanced transcommissural fibers, did occur but compensate incompletely the functional deficiency caused by the ACC. The reason why the MRCP amplitude was reduced in the ACC patient could be also explained by the presence of the aberrant subcortical bundles. Since MRCP is not only affected by the cortical areas but also the deep brain structures such as basal ganglia and cerebellum (Rektor et al. 2001; Lu et al. 2008), it would be possible that the abnormal subcortical bundles perturb the synergy of the cortical activation for the voluntary hand movements.
Similar to the MRCP findings, less suppression caused by IHI was found in the current ACC patient. Impairment to IHI in ACC patients is relevant to the topography of the ACC (Meyer et al. 1998b). In the previous research applying silent period measurement, patients with agenesis of the anterior trunk of the corpus callosum displayed absent or delayed IHI; IHI showed normal if the anterior trunk of the corpus
callosum was spared (Meyer et al. 1995). The finding is consistent to the current result which showed preserved IHI in the ACC patient with an intact AC, though we applied the short interval paired TMS to measure IHI. Previous studies suggested that IHI measured by the ipsilateral silent period and the short interval paired TMS may be attributed to different mechanisms (Chen et al. 2003; Giovannelli et al. 2009). Since a close relationship exists between the IHI evoked by the short interval paired TMS and FA of the corpus callosum (Wahl et al. 2007), we suppose that the short interval paired TMS would be a more direct way to evaluate the transcallosal IHI compared to the ipsilateral silent period measurement. No prior study has evaluated IHI in patients with ACC and enhanced AC. The presence of IHI in the current ACC patient supports the notion that there might be an alternative inhibitory pathway connecting the bilateral motor cortices. Based on the DTI findings, the enhanced transcommissural fibers might serve as an alternative pathway. The reason why the observed IHI is weak in the ACC patient is unknown. Given the fact that the enhanced AC fibers in the patient are less than the transcallosal fibers in the healthy subjects, it is possible that the alternative inhibitory pathway through the AC is not as efficient as the transcallosal pathway.
Despite of applying the multiple approaches, there are limitations in this study. The functional role of the AC in the ACC patient is still speculative. A combination of
the functional and anatomical imaging study focusing on the transcommissural fibers can be helpful in clarifying the assumption. In addition, it is difficult to entirely rule out the possibility that the electrophysiological findings observed in the ACC patient were relevant to other subcortical circuits instead of the transcommissural fibers. Data from more similar patients are needed to make a solid conclusion.
Conclusion
This study observed abnormally enhanced transcommissual fibers in a patient with ACC. Findings from electrophysiological tests, including MRCP and IHI, support the notion that the abnormal transcommissual fibers might be functional and serve as an alternative route connecting the patient’s bilateral hemispheres.
Acknowledgments
This work has been supported by the grants from the National Science Council (99-2314-B-039-017-MY2), Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004) and "Aim for the Top University Plan" of the National Chiao Tung University and Ministry of Education, Taiwan.
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Figure Legends Figure 1.
Anatomical findings of one representative healthy participant (upper row) and the ACC patient (lower row). The sagittal view T1-weighted MRI shows complete agenesis of the corpus callosum in the ACC patient (lower left panel). Diffusion tensor image tractography is presented in vector maps, which are assigned to the colors of red (left-right direction), green (anteroposterior direction), and blue (superior-inferior direction). These demonstrate dense transcallosal fibers in the healthy participant and the absence of such fibers in the ACC patient. Thick bundles in the anteroposterior direction (Probst bundle) occur in both hemispheres in the ACC patient (middle panel). Tractography of the anterior commissure shows sparse transcommissual fibers in the healthy participant. However, the transcommissual fibers are enhanced in the ACC patient (lower right panel). Mean fractional anisotropy (FA) values of the AC regions (marked with the white asterisk) were calculated and illustrated by the boxplot (rightmost panel). ‘X’ indicates the mean FA value from the ACC patient, which locates 3.2 standard deviations outside the group median of the mean FA values calculated from eight healthy control subjects.
Figure 2.
each hand movement. The control group demonstrates the grand average from 8 age-matched healthy subjects. The short vertical lines denote the onset of the surface electromyographic signal at the extensor carpi radialis muscle. The baseline for each EEG epoch was shown as the horizontal dot-line. The mean amplitude of the MRCP (1500 to 0 ms prior to the movement onset) was plotted in boxplots at the bottom to illustrate the data distribution for the healthy control subjects (horizontal line in the boxes: the median value; box margins: the 25% and the 75% ranking value of the dataset; whiskers: 1.5 standard deviation; plus sign: outlier). The value of the ACC patient was plotted with the ‘cross’, which is, in most cases, located near the lower margin of the box.
(B) The averaged motor-evoked potentials of the 12 paired conditioning-test TMS stimuli (red line) over the primary motor cortex (M1) at both hemispheres and of the 12 single TMS stimuli (black line) over each M1. The control group showed the grand average from 8 age-matched healthy subjects. Interhemispheric inhibition (IHI) was shown as a ratio of the former value to the latter one. The right to left IHI represents the suppression effects brought to the test stimuli on the left M1 by the conditioning stimuli applied to the right M1, and vice versa for the left-to-right IHI. The IHI data were plotted in the boxplots at the bottom using the same display conventions as used in Figure 2A. The IHI value of the ACC patient is located near the lower margin of
