1 Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92093, , 2 Laboratory for Research on the Neuroscience of Autism, Children's Hospital Research Center, San Diego, CA 92123 and , 3 Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Abstract |
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Introduction |
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While it is likely that a similar topographical relationship exists in humans as in other mammals, few studies have provided direct anatomical evidence that confirms this cortico-callosal mapping in humans. De Lacoste and colleagues reported the relationship between cortical lesion sites in 13 postmortem brains and sites of Wallerian degeneration in each corpus callosum (de Lacoste et al., 1985). To localize the site of axon degeneration, de Lacoste et al. divided the callosum into five subregions that generally corresponded to the genu (including the rostrum), anterior body, mid-body, posterior body and splenium. Six of the brains had circumscribed lesions and resultant degeneration that provided the most specific evidence of cortico-callosal relationships. Two brains with degeneration in the most anterior subregion of the rostrum and genu had lesions in the inferior frontal, prefrontal and inferior anterior parietal regions. In the body of the callosum, degeneration was only seen in cases with more extensive lesions including, but not specific to, the superior frontal area and the superior temporal region. Degeneration in the posterior body of the callosum was evident in one of two brains with lesions in the temporaloccipital junction. Both of these cases showed additional degeneration in the splenium. Abnormalities of the splenium were also seen in a case of a lesion in the superior parietal cortex and in a case with an occipital lesion. The pattern of callosal atrophy and lesion site generally resembled the anterior to posterior, cortico-callosal projection pattern observed in monkeys. Additionally, splenium degeneration that corresponded to single occipital lobe lesions has been reported in four human postmortem brains (Clarke and Miklossy, 1990
).
In addition to anatomical studies, maps based on physiological responses to callosal or transcallosal stimulation provide converging evidence of human callosal topography. Yu-ling and colleagues intraoperatively stimulated 30 commissurotomized patients along 12 anterior to posterior subdivisions of the callosum to produce evoked potentials (EPs) (Yu-ling et al., 1991). EPs were recorded by four electrodes in the cerebral lobes. Stimulation of sectors 14 resulted in EPs in the frontal lobe most often, while excitation of sectors 58 induced EPs in frontal and temporal regions most frequently. Stimulation of posterior sectors 912 induced EPs in parietal and occipital regions exclusively. Meyer and colleagues mapped transcallosal motor neurons with transcranial magnetic stimulation to the motor cortex (Meyer et al., 1998
). In 13 patients with partial surgical transections of the callosum, they measured the transcallosal inhibition of the contralateral hand muscle to identify which lesion site interrupted the normal inhibition response. The lack of transcallosal inhibition in five patients with lesions in the trunk of the callosum suggests that motor axons traverse the body of the callosum. Although topographical relationships reported in the anatomical and physiological studies are generally consistent with those found in primates, these findings are currently based on a small number of adult cases and reflect a limited sample of cortical sites.
The organization of the callosum in the pediatric human brain has yet to be investigated. Yu-ling et al.'s study, for example, included patients as young as six years of age, but they did not analyze the pediatric brains separately or report the age distribution of their subjects. Examination of the callosa in children with perinatal brain injury provides the opportunity to determine whether the pattern of early cortico-callosal relationships resembles the profile seen with lesions acquired after full maturation of the corpus callosum (de Lacoste et al., 1985; Clarke and Miklossy, 1990
). Early lesions, however, introduce an alternative possibility of axon retention or transcallosal reorganization. In the mature brain, a lesion and its corresponding pattern of Wallerian degeneration reflect normal development and topography. In contrast, a pre- or perinatal lesion disrupts the establishment of intercortical connections. The outcome of perturbation during this dynamic phase of connectivity is not wholly predictable and may result in atypical cortico-callosal organization.
In the course of normal development, the perinatal interval constitutes a pivotal period of both expansive and retractive events which shape interhemispheric connections. As early as 1112 weeks gestation, transcallosal axons extend across the callosum. By weeks 1820 at midgestation, the gross morphology of the callosum is formed. It is during the perinatal period that the callosum lengthens further and the subregions thicken at different rates which may correspond to rates of cortical development (Rakic and Yakovlev, 1968; Clarke et al., 1989
; Malinger and Zakut, 1993
; Koshi et al., 1997
). While the callosum continues to increase in size throughout childhood (Rakic and Yakovlev, 1968
; Barkovich and Kjos, 1988
; Witelson and Kigar, 1988
; Clarke et al., 1989
; Hayakawa et al., 1989
; Allen et al., 1991
; Ferrario et al., 1996
; Gabrielli et al., 1996
; Giedd et al., 1996
, 1999
) and into adulthood (Hayakawa et al., 1989
; Pujol et al., 1993
; Rauch and Jinkins, 1994
), the growth is attributable to myelination rather than a commensurate increase in the number of transcallosal axons. Underlying callosal growth during the perinatal period are retractive events that result in a restriction of transcallosal projections. In the rat, cat and monkey, axons initially arise from a greater number and wider distribution of neurons than in the mature state (Innocenti et al., 1977
; Ivy et al., 1979
; Killackey and Chalupa, 1986
). The process of axon retraction eliminates a large portion of the early projections to establish a discrete set of cortico-callosal pathways (O'Leary et al., 1981
; Koppel and Innocenti, 1983
; Chalupa and Killackey, 1989
; LaMantia and Rakic, 1990
; Kadhim et al., 1993
). The magnitude of the progressive and regressive processes has been documented in the rhesus monkey where axon counts increase nearly 50-fold between midgestation and birth. By birth the number of axons exceeds adult levels by threefold. This elevated state is swiftly reduced within the first 3 months of life by the elimination of 70% of the initial axons (LaMantia and Rakic, 1990
). In studies of human callosal development, this regressive process is evidenced by a plateau or modest decline in the cross-sectional area in postmortem fetuses and infants between 33 weeks gestation and the first two postnatal months (Clarke et al., 1989
).
In the case of an early injury, the normal mechanisms of initially profuse axonal projections and subsequent axon retraction may allow for the retention or relocation of otherwise transient projections. Since a loss of cortical tissue alters the balance of competition and connectivity of axons within and between hemispheres, axonal retention may take multiple forms. Transient connections that are normally eliminated from established pathways may be sustained following a reduction in competition. For example, in the mature feline brain the primary sensory area (S1) projects to both the ipsilateral and contralateral secondary sensory areas (S2). Unilateral surgical ablation of S1 during the first postnatal week reduces the number of fibers terminating in S2. As a result, an increased number of projections from the contralesional S1 to the ipsilesional S2 remain (Caminiti and Innocenti, 1981). In addition to augmenting existing pathways, axons may secure connections in atypical locations. In monkeys, for instance, dorsolateral prefrontal neurons usually project to a homotypic site in the contralateral hemisphere. After pre- and perinatal ablation of the dorsolateral prefrontal cortex, however, axons reroute to terminate in the dorsomedial prefrontal cortex (Goldman-Rakic, 1981
). Functional lesions incurred by restricting the normal activity of the sensory systems also lead to the retention of early transient connections. Several different techniques for altering visual input, such as surgically induced strabismus on postnatal days 69, or suturing both eyes closed for the first postnatal month, lead to a stabilization of projections peripheral to the 17/18 border (Innocenti and Frost, 1979
).
While studies have documented the progression of human callosal development, none has examined the underlying topographical organization of the callosum early in development. The objectives of the current study were twofold. First, the study used in vivo magnetic resonance imaging (MRI) to investigate whether or not a profile of lesion site and corresponding callosal decrement in children with preand perinatal insults would be evident and whether it would conform to the pattern documented in animals and adult humans. Second, by examining individual regions of the callosa for possible hyper- or hypoplasia in this group of children, the study investigated whether there would be observable neuroplastic alterations in the development of cortico-callosal maps.
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Materials and Methods |
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Study participants were ten children with unilateral focal brain injury (FL) that had occurred prenatally or within the first 6 weeks of life. The cerebral injuries directly involved gray and white matter or white matter alone. The children were participants in an ongoing study by the Project in Cognitive and Neural Development at the University of California, San Diego. The most common etiology of the injuries was an ischemic or hemorrhagic stroke. The injuries of the children were initially documented with either cranial ultrasound, computer tomography or MRI. Exclusionary criteria consisted of (i) multiple lesions; (ii) disorders that could have lead to diffuse damage including head trauma, congenital viral infection, maternal drug or alcohol use during pregnancy, bacterial meningitis, encephalitis or severe anoxia; (iii) evolving lesions such as arteriovenous malformation or tumors; and (iv) history of neurosurgical procedures. Table 1 describes the lesion sites and summarizes the neuro- logical and behavioral profile of each FL subject. From a database of 123 healthy normal volunteer subjects originally created for a study of the neuroanatomy of autism (Egaas et al., 1995
), MRI scans of 86 children between 2 and 20 years of age were included in the present study. Of these 86 subjects, a subset of 61 children were selected to form sex- and age-matched control groups for individual FL subjects. The age range and number of controls for each FL child appear in Table 2
.
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All subjects were imaged without sedation in a 1.5 T GE Signa magnet. The head was first imaged in the axial plane (TR = 300 ms, TE = 20 ms, 1 NEX, FOV = 20 cm, 256 x 128 matrix, 5 mm slices, skip 2.5 mm) to ensure that the interhemispheric midline was straight and to identify the midsagittal center of the callosum. The images for measuring the cross-section of the corpus callosum were then acquired with a high resolution T1-weighted series (TR = 600 ms, TE = 25 ms, 2 NEX, FOV = 16 cm, 256 x 256 matrix, 390 µm2 in plane resolution, 4 mm contiguous slices). In each case, the image that most clearly delineated both the rostral and caudal ends of the corpus callosum was selected for measurement.
Two sets of whole brain images were acquired for all subjects and served as the basis for assessing the site and extent of the lesions and for obtaining volumetric measures of gray and white matter. The set of high-resolution images used for three-dimensional reconstruction was a T1-weighted protocol, either a three-dimensional SPGR in the coronal plane (TR = 24 ms, TE = 5 ms, 2 NEX, flip angle = 45°, FOV = 21 cm, matrix = 192 x 256, 1.5 mm slice thickness) or a three-dimensional MP-RAGE in the sagittal plane (TR = 30 ms, TE = 5 ms, 2 NEX, flip angle = 10°, FOV = 20 cm, matrix = 192 x 256, 1.2 mm slice thickness). For differentiation and quantification of gray and white matter and cerebrospinal fluid, a dual echo proton density and T2 -weighted axial protocol was acquired (TR = 3000 ms, TE = 30 and 80 ms, 1 NEX, FOV = 20 cm, matrix = 256 x 256, 3 mm consecutive interleaved axial slices).
Image Analysis
All MR data was transferred in digital format to Silicon Graphics workstations for analysis. The images were first enlarged (5x) from 256 x 256 up to 1280 x 1280 by replicating the original pixels. The resulting enlargement was low-pass filtered to remove the blocky appearance by two-dimensional convolution with a small (11 x 11) triangular filter kernel (Egaas et al., 1995). This pre-processing created a smooth rendering of the corpus callosum 2.1 times life-size, with an interpixel distance of only 0.125 mm. The corpus callosum was manually traced with a mouse-controlled cursor and software developed in our laboratory.
The callosa of the FL subjects and control subjects not previously reported were traced three times by an investigator (P.M.) blind to the subjects' identities and lesion sites. Each drawing was measured for total cross-sectional area and digitally stored. An average measurement was derived from the three drawings.
For each subject, all drawings were analyzed with an automatic computer algorithm developed by Egaas and colleagues (Egaas et al., 1995), which was based on the approach of Clarke et al. (Clarke et al., 1989
). The algorithm first identified the average position of all the pixels composing the structure. From this location, 360 rays were projected in all directions in the plane at 1° increments, some of which intersected the callosum. The midpoint of where each ray entered and exited the corpus callosum defined the midline arc of the structure. The midline arc was then divided into 30 equal length segments, with 29 vertices and two endpoints. Figure 1
illustrates how the algorithm was adapted to divide the corpus callosum into five subregions, by drawing dividing lines at the 6th, 12th, 18th and 24th vertices. In this way, we could localize area differences. The algorithm automatically measured each of the five subregions.
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Results |
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The cross-sectional area of the corpus callosum was reduced in nine of the ten FL subjects. Eight of those callosa were 26 SDs below the normal mean. To determine whether the degree of callosal reduction was directly proportional to the size of lesion, we calculated two indices for each FL child: callosal reduction and lesion size. The degree of callosal reduction was expressed as the ratio of the total callosal area to the normal mean. The index of lesion size was represented by the ratio of the volume of the injured hemibrain (gray and white matter) to the volume of the intact hemibrain. Correlation analysis showed that the greater the size of lesion, the greater the degree of callosal reduction (r = 0.78, P < 0.01). Figure 3 illustrates the correspondence between lesion size and callosal thinning in the FL children.
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The subregions with callosal thinning bore a topographical relationship to the sites of the cortical lesions. In Figures 4 and 5, graphs display the measured area of each of the five subregions expressed as a percentage of the normal mean for each FL subject. The corresponding three-dimensional renderings show the location of each subject's lesion and the two-dimensional MR images show the greatest anterioposterior extent of the lesions in the axial plane. We report the findings in a posterior to anterior direction, beginning with cases of small lesions that correspond to callosal reduction in a single subregion, followed by lesions associated with reduction in two or more subregions. A representative selection of midsagittal MR images of the callosa appear in Figure 6
.
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Subregion 5
Reduction specific to callosal subregion 5 was evident in a single subject, 0512, whose 7 cm3 lesion involved the gray matter of the angular gyrus and extended to the lateral aspect of the superior parietal gyrus in the posterior parietal area. The lesion also included the white matter beneath the angular and supramarginal gyri and impinged upon the white matter of the superior parietal gyrus. The measures of 0512's other callosal subregions were within or slightly below the normal range.
Subregion 4
Three subjects with primarily parietal lesions displayed isolated reductions of callosal subregion 4. Subjects 1822 and 1711 had relatively small peri-Sylvian lesions (8 and 14 cm3 respectively) that closely resembled each other. Subject 1822 showed loss of the lateral aspect of the postcentral gyrus, as well as gray and white matter loss in the adjacent precentral and supramarginal gyri. Subject 1711 had loss of all but the most inferior portion of the postcentral gyrus along with loss marginally in the posterior superior temporal gyrus and posterior insula within the Sylvian fissure. The lesion of the third subject, 2313, was a 0.5 cm3 white matter lesion that lay dorsal to the posterior horn of the lateral ventricle, just posterior to the central sulcus.
Reduction in Multiple Subregions
Subregions 35
Subregion 4 was absent from the midsagittal plane and subregions 3 and 5 were diminished in subject 0202 whose white matter lesion was manifest as a dilation of the posterior lateral ventricle. The dilation reflected white matter loss beneath the lateral occipital, lateral parietal, superior temporal and posterior frontal cortex. The three-dimensional reconstruction of the lesion in Figure 4 displays the actual form of the dilated ventricle and a projection of normal ventricle size and position based on the contralesional lateral ventricle. The absence of callosal fibers in subregion 4 and reduction in 5 resembles parietal loss (see above). The more anterior reduction in subregion 3 may be due to disruption of fibers from the precentral and posterior inferior frontal gyri.
Subregions 25
Reduction in callosal subregion 2, in addition to 35, was apparent in subject 0713 who had a white matter lesion beneath the frontal (superior frontal, middle frontal and precentral gyri) and parietal cortex (postcentral, superior parietal and supramarginal gyri). Subject 0713's callosum displayed thinning that was anterior to subject 0202's, and subject 0713's lesion included more anterior frontal white matter as well. Comparison between subject 0713's and 0202's lesion sites suggests that subregion 2 contains transcallosal projections arising from the middle and superior frontal gyri.
Subregions 25 were also affected in four subjects with cortical and subcortical lesions that involved two or more lobes along the posterior to anterior axis of the brain. Subjects 0719, 1610, 1622 and 1919 had lesions characteristic of an infarct in the perfusion territory of the middle cerebral artery. They all showed gray and white matter loss in the inferior parietal and inferior, posterior frontal regions. The lesions included the following common sites: the supramarginal gyrus, postcentral gyrus, insula, precentral gyrus and inferior frontal gyrus (pars opercularis, pars triangularis, pars orbitalis). In addition, subjects 0719, 1610 and 1622's lesions involved the gray matter alone or the gray and white matter in posterior parietal, temporal and occipital regions including the angular gyrus, the superior and middle temporal gyri and the middle occipital gyrus. Subject 0719 showed further loss to the superior occipital gyrus.
Subregion 1
Of the five subjects with extensive lesions described above, three subjects (1610, 1622 and 1919) showed an additional reduction in subregion 1, the genu and rostrum. In the cases of 1622 and 1919 the lesions additionally extended anteriorly to include the lateral and posterior orbital gyri of the inferior frontal lobe. The lesion of 1610 possibly included direct tissue loss or atrophy to the posterior and superior aspects of the posterior and lateral orbital gyri.
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Discussion |
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Callosal Topography
The measurement of individual callosal subregions revealed a distinct pattern between location of callosal size reduction and the site of lesion. This pattern confirms and elaborates the topography previously observed in adults (de Lacoste et al., 1985) and monkeys (Sunderland, 1940
; Pandya and Seltzer, 1986
). Evidence of the most specific topographical mapping was derived from lesions constrained in size. In this study the smallest lesions were located in posterior regions. Within subregion 5, thinning of the splenium was associated with one posterior parietal lesion that primarily involved gray and white matter of the angular gyrus and the white matter underlying the temporaloccipital junction. In subregion 4, this study documented hypoplasia with three anterior parietal lesions, two lesions primarily of the postcentral gyrus and one encapsulated in the white matter just posterior and medial to the central sulcus. These data indicate that transcallosal axons that originate between the central sulcus and the ascending posterior segment of the superior temporal sulcus project through the posterior body of the callosum. Reduction in progressively more anterior subregions, 3, 2 and 1 corresponded with lesions that included increasingly more anterior portions of the frontal lobe. In the present study, there were no focal lesions restricted to the frontal lobe. Instead lesions affecting this anterior region lay in the middle cerebral artery perfusion territory where they also impinged upon the parietal lobe and, in some cases, the temporal and occipital lobes. Consequently reduction in subregions 3, 2 or 1 co-occurred with thinning in multiple posterior subregions. Diminution of subregion 3 coincided with tissue loss in the precentral and posterior inferior frontal gyri. Additional reduction in subregion 2 corresponded with lesion involvement of the middle and superior frontal gyri. Reduction in subregion 1 was apparent with lesions that included the orbital gyri. Additionally, in each of the cases with subregion 1 thinning, the lesions that included the orbital gyri were accompanied by atrophy of white matter in the intact anterior superior and middle frontal gyri. This decrease in frontal lobe white matter, coincident with the direct tissue loss in the posterior orbital region, may also have contributed to hypoplasia in subregion 1.
In the posterior portion of the callosum our topographical mapping coincides with earlier studies. We observed thinning of callosal subregion 5 in the case of a lesion located at the conjunction of the postcentral, superior parietal, supramarginal and angular gyri. This lesion site augments previous studies which have shown axonal degeneration in the splenium following adult acquired lesions in posterior brain areas. Specific adult cases included two temporo-parieto-occipital junction lesions, one superior parietal lesion and five occipital pole lesions (de Lacoste et al., 1985; Clarke and Miklossy, 1990
). The unique focal lesion site we report appears to lie between the cases of superior parietal and temporaloccipital junction lesions. Its location suggests that a continuous superiorinferior band of parietal cortex projects across the splenium. Size reduction specific to subregion 4, the posterior body of the callosum, corresponded to three cases of focal lesions of the postcentral gyrus and the adjacent white matter. In previous studies of adults, discrete lesions in this specific area were not observed. Rather, de Lacoste et al. tentatively associated a single temporo-parietooccipital junction lesion with degeneration in callosal subregion 4 (de Lacoste et al., 1985
). The distinctive lesion sites that we report complement and extend existing callosal topography maps.
In the anterior portion of the callosum, the mapping we observed differs from de Lacoste's work. In both studies reduction and degeneration in subregions 13 were associated with more extensive lesions. In our pediatric cases, subregions 1, 2 and 3 were associated with lesions affecting respectively the orbital gyri, the superior and middle frontal gyri, and the inferior frontal and precentral gyri. Similarly autoradiographic tracing and lesions studies with monkeys demonstrate fibers from the lateral and ventral prefrontal region, including area 46 and the orbital gyri, across the genu and rostrum (Sunderland, 1940; Barbas and Pandya, 1984
). Premotor fibers from areas 4 and 6 cross the anterior callosum body, and projections from sensory and motor cortices traverse the mid-body (Pandya and Seltzer, 1986
). In contrast, de Lacoste and colleagues reported two cases in which the lesions that appeared to involve multiple frontal areas (orbital, inferior frontal, middle frontal and precentral gyri) corresponded with callosal degeneration in region 1 exclusively (de Lacoste et al., 1985
). A factor that may contribute to the different cortico-callosal patterns is the involvement of the insular cortex seen in our pediatric cases. In each of the middle cerebral artery infarctions, the insula was damaged along with the cerebral cortex. Transcallosal axons arising from the insula project through the body of the callosum in nonhuman primates. The additional loss of insular cortex may have accentuated the reduction in subregions 2 and 3 seen in this study. It is not clear whether the lesions reported in de Lacoste et al.'s study show a similar loss of the insula. While the sparing of the insula cannot completely account for the absence of degeneration in regions 2 and 3, it may contribute to the magnitude of difference between the studies. Additional studies with delimited frontal lesions would clarify and refine the mapping of the anterior callosum.
Specification and Neuroplasticity
In addition to cortico-callosal topographical mapping, this study simultaneously investigated the possibility of neuroplastic axon retention manifest as hypertrophic growth in the callosum. In regard to this second objective, the hypoplasia seen in the callosal cross-sectional areas of the FL cases reveals limits of developmental neuroplasticity. Although the overproduction of callosal axons inherent in normal development would appear to provide the potential for compensatory axon retention following an early injury, the current cases consistently showed region- specific thinning without hypertrophy in individual subregions. Even the smallest lesion, which measured 0.5 cm3 of cerebral white matter, was accompanied by callosal thinning. Further, the degree of callosal reduction corresponded directly to the estimated lesion volume. Smaller lesions were associated with callosal reduction limited to a single subregion, while more extensive anterioposterior lesions affected three or more subregions.
In the observed cases, the mechanisms that underlie axon retention and rerouting were insufficient to offset callosal thinning. A simple explanation for callosal attenuation despite the early occurrence of injury is the possibility that axon elimination preceded the onset of the lesions. In this case, the reduction of surplus axons before the injury could have precluded or diminished the opportunity to retain transitory axons in lieu of the fibers directly damaged by the lesion. Since the relative timing of events is not known definitively, this account cannot be dismissed. However, a second, more comprehensive explanation that shifts the focus to earlier developmental processes is also consistent with the findings. Amid the initial profusion of axonal connections, growth patterns observed in individual axons reveal that discrete differences distinguish sustainable and retractable axons prior to axon retraction and perinatal injury (Aggoun-Zouaoui and Innocenti, 1994). An early predictor of axon fate, for example, is the origination site of transcallosal axons. In the visual cortex of the kitten, axons that arise from the border of areas 17 and 18, which supports callosal projections in adulthood, terminate in the contralateral 17/18 supragranular cortex and form sustaining arbors. In constrast, axons that arise from eventually acallosal area 17 project temporarily and indiscriminately across area 17 to the 17/18 border (Aggoun-Zouaoui and Innocenti, 1994
). These early distinctions show that the connective pattern of transient axons is not redundant with that of permanent axons. Encoding intrinsic to the callosal neuron may play an important part in the regulation of the axon's retention. Subsequent mechanisms that underlie axon elimination may perform a lesser role in the determination of axon fate. In the case of an early lesion, transient axons which arise from typically acallosal areas might be unable to establish sustainable connections.
In addition to neuron location as an early indicator of axon retention, termination sites in the contralateral hemisphere also predict the viability of axon projections. Although fibers arise from an initially widespread distribution of callosal neurons, they converge on limited sites in the contralateral gray matter (Innocenti, 1981). The funneling of fibers to restricted sites may confine the spatial extent of subsequent neuroplasticity. Additionally, within the loci of converging projections, transient and permanent axons terminate on different laminar and tangential targets (Innocenti, 1981
). In the visual area of the kitten, axons that project to adult-like sites the 17/18 border, part of area 19 and the suprasylvian area terminate in layers 3 and 4. In contrast, transient axons project more widely across the visual area and terminate in the lower portion of layer 6 or in the underlying white matter without penetrating the cortex (Innocenti, 1981
; Aggoun-Zouaoui and Innocenti, 1994
). These segregated termination patterns demonstrate early differences and imply that transient and permanent projections may not be readily interchangeable. Although the mechanisms that guide axon trajectories are not fully understood, they probably involve a combination of intrinsic and extrinsic factors. In vitro videos documenting the process of sensorimotor axon growth and target-seeking in the hamster show that axons appear to sample and respond to local trophic or inhibitory cues, possibly both, in the white matter beneath the cortical target (Halloran and Kalil, 1994
). The cues that inhibit or limit otherwise transitory axons from entering sustainable cortical sites under normal conditions may also prevent these axons from terminating in alternative sites in instances of early perturbation.
Regardless of the early exuberance of callosal neurons and axons, the brain appears to retain a predictable subset of axons that adhere to particular patterns of axon origination and termination. Which axons are preserved or discarded may be determined primarily by selective projection rather than selective elimination. Consequently, highly specified patterns of connectivity established before the onset of the lesions presently studied may curtail the possibility of sustaining transient projections that might support reorganization. It is important to note, however, that the failure to retain transient axons may be the actual facilitative or protective response to injury. The inhibition of aberrant connections may preserve the integrity of intact brain regions and prevent further compromise of the system's functional organization.
It remains possible that the callosa studied here have some compensatory or aberrant axon retention simultaneous with the callosal thinning. Since it would be secondary to the overall decrease in callosal cross-sectional area, retention on this scale may only be detectable in animal studies employing auto- radiographic techniques. It is also plausible that axon retention in the current study is masked by co-occurring reduction in myelination. In cases of prenatal ischemia in cats, an abnormally high number of fibers can be retained in the callosum yet remain undetectable at the gross morphological level due to reduced myelination (Miller et al., 1993).
The current study reveals a mapping between the cerebral site of tissue loss and the region of callosal thinning that closely resembles the cortico-callosal topography of nonhuman primates. These findings coincide with and advance the current understanding of human callosal topography and extend that topography to a pediatric population. They further demonstrate that in the wake of cortical and subcortical injury in the pre- and perinatal period, children show a persistent thinning of the callosum. While compensatory retention of some of the exuberant axons may occur along with the apparent fiber loss, these developmental changes were not detected with MRI.
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Notes |
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Address correspondence to Pamela Moses, Ph.D., Cognitive Science Department, University of California at San Diego, La Jolla, CA 92093- 0515, USA. Email: pmoses{at}ucsd.edu.
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