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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 5  |  Issue : 3  |  Page : 81-89

Special anatomy series: Updates in structural, functional, and clinical relevance of the corpus callosum: What new imaging techniques have revealed


1 H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Baylor St. Luke's Medical Center, Houston, Texas, USA
2 W. G. (Bill) Hefner VA Healthcare System, Research and Academic Affairs, Salisbury; Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, USA
3 H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Center for Trauma Rehabilitation Research, Harris Health System, Houston, Texas, USA

Date of Submission31-Jan-2022
Date of Decision13-May-2022
Date of Acceptance18-May-2022
Date of Web Publication22-Aug-2022

Correspondence Address:
Dr. Faye Y Chiou-Tan
H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, McNair Campus 7200 Cambridge Steet, Suite 10C, Houston, TX 77030
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisprm.JISPRM-000159

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  Abstract 


Introduction: The human corpus callosum (CC) is a primary commissural tract in the brain and serves as a major communication pathway between the cerebral hemispheres. Objective: The objective of this paper is to enhance understanding of the anatomic structure, topographic organization, function, and clinical relevance of the CC. Methods: To achieve this, we reviewed the literature for pertinent histological, anatomical, and advanced neuroimaging studies, and the findings were synthesized to provide the basis for the creation of novel color-coded schematic diagrams. Results: A standard midline sagittal magnetic resonance image was used to illustrate schematics of the CC partitioned into seven anatomic segments and the vascular supply of the CC from the anterior and posterior cerebral circulation. We further highlighted the microstructural features across each segment of the CC as well as the topographical organization of callosal fibers in connection with cortical regions of the brain. Finally, we applied these visual summaries as a guide for the discussion of the clinical relevance of the CC. Summary: Understanding the microstructural properties and related functional capacities of the CC is critical to understanding its clinical relevance. Consequently, having a clear and concise visual representation of complex callosal microstructural and anatomical features may be useful to the rehabilitation clinician in understanding overall clinical patterns seen in healthy populations across all ages and patients with neurologic injuries and pathologies with possible callosal involvement.

Keywords: Callosal anatomy, callosal function, corpus callosum, diffusion tensor imaging, interhemispheric connection, topography of the human corpus callosum, white matter tracts


How to cite this article:
Ughwanogho UO, Taber KH, Chiou-Tan FY. Special anatomy series: Updates in structural, functional, and clinical relevance of the corpus callosum: What new imaging techniques have revealed. J Int Soc Phys Rehabil Med 2022;5:81-9

How to cite this URL:
Ughwanogho UO, Taber KH, Chiou-Tan FY. Special anatomy series: Updates in structural, functional, and clinical relevance of the corpus callosum: What new imaging techniques have revealed. J Int Soc Phys Rehabil Med [serial online] 2022 [cited 2022 Dec 1];5:81-9. Available from: https://www.jisprm.org/text.asp?2022/5/3/81/354192




  Introduction Top


White matter tracts serve as the major pathways of communication between areas of the central nervous system. The corpus callosum (CC) is the largest white matter tract in the brain, comprised 200–250 million myelinated axonal fibers.[1] CC comes from the Latin term for “tough body” with its thick band of myelinated fibers. It is considered the primary commissural tract in the brain. Through the study of postcallosotomy or “split-brain” patients, much has been gleaned about its structural organization and interhemispheric functional connectivity.[2] The CC serves as the major communication pathway between the cerebral hemispheres, supporting the integration, processing, and transfer of complex sensory, motor, and cognitive signals. Given its uniquely central location, it is prone to various neurologic insults such as strokes, trauma, and age-related changes.[3] Furthermore, these neurologic injuries may not be fully captured by conventional neuroimaging techniques but have significant clinical implications in the rehabilitation setting. Consequently, it is important to understand the structural architecture and topography of the human CC as it relates to its functional specialization. This investigation is designed to further enhance our understanding of the anatomic structure, function, and clinical relevance of the CC.


  Methods Top


A detailed search of peer-reviewed literature was conducted in multiple electronic databases, including MEDLINE and PubMed, using the key phrases “corpus callosum, callosal anatomy, callosal function, white matter tracts, interhemispheric connection, diffusion tensor imaging, topography of the human CC.” Except for earlier histological and anatomical studies (i.e., Witelson)[4], which were used to provide a foundational overview of the CC, search results were filtered to include more up-to-date data published within the past two decades. Specific focus was placed on high-yield advanced neuroimaging studies of the CC, which were then synthesized to provide the basis for the creation of color-coded schematic diagrams outlining key anatomic and functional features of the CC. We further highlighted the topographical organization of callosal fibers in connection with the cortical regions of the brain. These visual summaries serve as guides for the discussion of the clinical relevance of the CC in the context of development, acquired brain injury, and normal aging.


  Results Top


Corpus callosum: Anatomic review

Anatomic nomenclature

The most recognized approach to classifying the CC anatomically is the Witelson criteria, which uses a geometric partitioning of the human CC into seven regions in the midsagittal cross-sectional plane [Figure 1].[4] This division was generated from measurements of human cadaveric brains using a linear axis drawn from the anterior-most to the posterior-most region of the CC, followed by perpendicular lines to the axis dividing the CC into seven callosal segments: rostrum, genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. Commonly, the rostrum, genu, rostral, and anterior midbody are considered anterior callosal regions, while the posterior midbody, isthmus, and splenium are considered posterior callosal regions.[6],[7] While this parcellation of the CC is useful for standardizing comparisons across individuals and studies, the Witelson criteria do not relate to either functional specialization or microscopic architecture.[4],[8]
Figure 1: The Witelson criteria, which use a geometric partitioning of the human CC into seven regions in the midsagittal cross-sectional plane, are illustrated on a midsagittal MRI.[4],[5] A linear axis is drawn from the anterior-most to the posterior-most CC. Lines perpendicular to this axis divide the CC into seven segments: rostrum, genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. CC: Corpus callosum, MRI: Magnetic resonance image

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Embryologic development and myelination

Commissures are white matter tracts that connect homologous structures across the two hemispheres. There are three major interhemispheric commissures in the brain. The anterior commissure is located within the anterior wall of the third ventricle, posterior to the rostrum of the CC. It interconnects the olfactory bulb, amygdala, septal nuclei, and parts of the orbitofrontal and temporal lobes. The hippocampal commissure, as its name suggests, interconnects the hippocampi across the hemispheres.[9],[10] The CC is the largest of the three interhemispheric commissures. The CC originates from the lamina terminalis and lies in the roof of the lateral ventricles just below the cerebral cortex. Development begins at approximately 8 weeks of gestation and continues at various rates throughout fetal life.[11],[12] In the initial stages of callosal development, axons arising from the cingulate cortex serve as a guide as they traverse the midline and create a pathway for callosal fibers. The formation and elongation of the callosal fibers occur anterior to posterior (from genu to splenium) except for the rostrum, which is the last to appear. While the structure of the CC is fully formed by 20 weeks of gestation, studies have shown that the volume, maturation, and organization of its nerve fibers increase with age up to the mid-twenties.[12],[13],[14]

CC thickening is due to myelination. Myelination begins at approximately 4 months of age and continues well into adolescence.[12],[15] Myelin not only serves as an insulator for nerve fibers but it also allows fibers to transfer information more quickly. Interestingly, there is not a direct correlation between the total number of neocortical neurons and the number of myelinated callosal fibers. After the development of the initial callosal projection fibers, a vast number may undergo further activity or sensory-dependent refinement in the postnatal stages with the capacity to form future diverse local connections.[15] Thus, myelination of the CC fibers also corresponds with the functional development of neuronal pathways critical to higher cognitive processes.[4],[6],[16] This is further testament to the degree of plasticity of the CC, given the intricate and complex processes involved in the development of its mature myelinated fibers. This is important to note because the disruption of myelinated fibers is implicated in numerous neurologic diseases and injuries. Understanding the process and regulation of myelination is critical in developing diagnostic approaches and therapeutic interventions when these pathologies arise.[17]

Vascular supply

The CC receives blood supply from both the anterior and posterior circulation [Figure 2].[18],[19] In about 80% of the population, the most anterior region (including the rostrum and genu) is supplied by a branch arising from the anterior communicating artery. The CC anterior to the splenium is supplied by arteries which branch off the pericallosal trunk of the anterior cerebral artery. The splenium is supplied by arteries which branch off the posterior pericallosal artery, a branch of the posterior cerebral artery.[18] Vessels arising from the anterior and posterior circulation typically anastomose within the splenium. The splenium has been reported to be the most commonly affected callosal region in ischemic injuries and is often associated with bilateral hemispheric involvement.[19]
Figure 2: The CC receives blood supply from both the anterior (pink) and posterior (blue) circulation. In about 80% of individuals, the most anterior region (including the rostrum and genu) is supplied by a branch (dark pink) arising from the anterior communicating artery. The CC anterior to the splenium is supplied by arteries, which branch off the pericallosal trunk (dark pink) of the anterior cerebral artery (light pink). The splenium is supplied by arteries which branch off the posterior pericallosal artery (dark blue), a branch off the posterior cerebral artery (light blue). Vessels arising from the anterior and posterior circulation typically anastomose within the splenium.[18],[19] Ischemic injuries more commonly involve the splenium (63%, yellow) than the rostrum and genu (27%, yellow) or the body (26%, yellow). In 15% of cases, more than one CC area is affected. CC: Corpus callosum

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Neuroimaging techniques

Two commonly used methods for visualizing aspects of the CC are microscopy and magnetic resonance image (MRI). Microscopy-based imaging clearly delineates anatomy at a finely detailed level (micrometer scale), allowing visualization and accurate measurement of small structures such as individual axons. It is also very labor intensive and requires tissue to be excised and sectioned, limiting its usefulness in the clinical setting. In the research setting, microscopy provides a robust basis for quantitative analyses of microstructural differences between areas and accurate tracing of axonal connections. In contrast, MRI delineation of anatomy is relatively coarser (millimeter scale), and the signals from a large number and wide variety of cells and processes are averaged together.[20] However, MRI-based techniques are noninvasive and safe, with the potential to monitor clinically relevant changes across time in individual patients.

Most MRI techniques are based on influencing the small magnetic field surrounding hydrogen atoms, a major component of water in soft tissue. Different types of MRI provide information about different aspects of tissue microstructure because the physical environment of the water greatly affects how the hydrogen atoms behave. Speed of acquisition and processing is important for the versions of MRI techniques utilized in clinical work, while greater sensitivity to specific aspects of tissue structure or composition is emphasized in versions utilized in research. For example, several MRI techniques are sensitive to microscopic movement (diffusion) of water.[21] Diffusion-weighted MRI provides a rough approximation of the speed of water diffusion and is useful for visualizing areas of acute ischemia. In contrast, DTI requires considerably more time to acquire and process but is sensitive to both the speed and directionality of diffusion. One of the most common metrics derived from DTI is fractional anisotropy (FA), the proportion of diffusion that is moving in the major direction. FA is influenced by axon density, size, and myelination, and so provides a useful indication of the integrity of white matter. The greater the number of intact, mature axons in parallel bundles, the greater the FA. The more disruption or disorganization there is within axonal fibers (i.e., white matter injury), the lower the FA.[22] DTI also provides a basis for the approximate reconstruction of white matter bundles (diffusion tensor tractography [DTT]).[15] Recent advances in diffusion MRI provide an approximation of other factors, such as average axon diameter and density.[23] There are also MRI techniques that are sensitive to the presence of anything that alters the magnetic field, such as calcium deposition or the presence of deoxygenated blood (deoxyhemoglobin is paramagnetic). Susceptibility-weighted imaging is used clinically to visualize tiny areas of extravasated blood (e.g., petechial hemorrhage).[20] Functional MRI (fMRI), also called blood-oxygen-level-dependent MRI, is based on measuring the very small changes in the oxygenation state of intravascular blood induced by neuronal activity.[24] Like DTI, fMRI is a robust neuroimaging research tool that allows in vivo study of the human brain.

Functional area review

Topographical arrangements of corpus callosum fibers and interconnections to cortical regions

In recent years, there have been numerous studies utilizing noninvasive advanced MRI techniques such as DTT and fMRI to shed further light on the topographical organization of the callosal fibers. These fibers connect both heterotopic and homotopic cortical regions between the two cerebral hemispheres. De Benedictis et al. identified several heterotopic fronto-callosal fibers connecting frontal regions with various parts of the human brain.[25] There have also been studies in primates that have identified heterotopic callosal projections between the premotor cortical areas and other regions of the brain, including the parietal, temporal, and prefrontal areas.[26] The vast majority of callosal fibers are homotopic, interconnecting homologous cortical regions. These fibers are topographically arranged such that frontal lobes, which contain the primary motor, premotor, and prefrontal higher order processing cortical regions, are interconnected by the more anterior callosal areas: the rostrum, genu, rostral body, and anterior midbody [Figure 3].[27],[28],[29],[30],[31] The fibers radiating laterally into both hemispheres from the genu of the CC form the forceps minor. The parietal and temporal lobes, which contain the primary somatosensory, and auditory cortical regions, are interconnected by more posterior callosal areas: the posterior midbody and isthmus. Finally, the occipital lobes, which contain the primary visual cortex, are interconnected by the most posterior callosal area: the splenium. The radiating fibers of the splenium form the forceps major.[4],[6],[7]
Figure 3: A simplified summary of the functional topography of the CC is color-coded onto a midline sagittal MRI.[27],[28],[29],[30],[31] The majority of callosal fibers are homotopic, meaning that they connect mirror cortical regions of each hemisphere. Illustrated here are the approximate locations of fibers interconnecting areas of the frontal (pink), parietal (green), temporal (orange), and occipital (blue) lobes. The areas are drawn as overlapping because the detailed functional topography varies across studies. MRI: Magnetic resonance image

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Functional classification: Axonal fiber characteristics and composition

Histologic studies have quantified how the composition of the CC varies by area through microscopic measurements of features such as axonal diameter, myelin density, and axon density [Figure 4].[7],[32],[33] The anterior callosal regions contain greater proportions of smaller diameter fibers, while the mid-and posterior callosal regions contain the majority of the larger diameter fibers. Fiber density is much higher in anterior areas, supporting the presence of an inverse relationship between an area's average callosal fiber diameter and fiber density. Although the thinnest fibers (<1.1 um) are most prevalent in the anterior regions, they are found in high proportions throughout the entire length of the CC. Intermediate-sized fibers (1.1–2.2 μm) and larger diameter fibers (>2.2 μm) increase in concentration from the anterior to posterior regions. This regional distribution likely reflects the temporal requirements for the interhemispheric transfer of different types of information. Larger diameter, heavily myelinated fibers have greater conduction velocities. They are more characteristic of callosal regions interconnecting primary and secondary sensory and motor areas for which high-speed transfer of information is essential. In contrast, smaller diameter, less heavily myelinated fibers are concentrated in the more anterior callosal regions interconnecting prefrontal and temporoparietal areas supporting cognitive or higher-order functions more tolerant of longer transfer times.[4],[32],[33]
Figure 4: Studies utilizing microscopy have quantified how microstructural features vary across the CC.[5],[33] Graphed here are results from one study showing that the proportion of smaller fibers (blue) is highest in the anterior regions (rostrum, genu, rostral body), whereas the proportion of large fibers (orange) is highest in the posterior regions (posterior midbody, isthmus, splenium).[5] Fiber density (white circles) is much higher in anterior areas

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As noted earlier, there are several types of advanced MRI that have metrics that correlate with aspects of tissue microstructure. These can be used for mapping how microstructure varies across the CC [Figure 5].[7],[23] One study used a high gradient version of diffusion MRI that provides a basis for calculating estimates of average axon diameter and axon density.[23] They reported that larger diameter axons were clustered in mid-and posterior regions of the CC and that areas of lower diameter axons had higher axon density as predicted by microscopy [Figure 5]a. Another study that used high-resolution T1 relaxation time MRI to estimate average myelinated axon diameter reported a generally similar pattern of results.[7] Larger diameter axons (indicated by higher T1 values) were clustered in the posterior midbody and the inferior splenium and smaller diameter axons in the more anterior CC regions and the anterior midbody [Figure 5]b. Both studies replicated the average regional differences reported in microscopy-based studies. These rough visualizations greatly facilitate understanding how microscopic anatomy varies across the CC.
Figure 5: There are several types of MRI that provide qualitative visualizations of metrics that correlate with aspects of tissue microstructure. Illustrated here are simplified diagrams color-coded as in [Figure 4] of the results from two studies using different advanced MRI techniques. (a). The first study used a high gradient version of diffusion MRI to calculate and visualize rough approximations of average axon diameter (upper panel) and axon density (lower panel).[23] Illustrated here are the results from a young (age 27 years) healthy female. Larger diameter axons (upper panel, orange and red) were clustered in the mid and posterior regions of the CC, and areas of lower diameter axons (upper panel, blue and green) had higher axon density (lower panel, orange and red) as predicted by microscopy. As noted by the authors, the model they utilized is known to inflate axon diameters considerably, so results should be considered qualitative rather than quantitative. (b). The second study, which used high-resolution T1 relaxation time MRI to estimate average myelinated axon diameter, reported a generally similar pattern of results.[7] Illustrated here are the average results from a group (n = 16) of young (mean age 29.2) healthy individuals (11 males, 5 females). Larger diameter axons (as indicated by higher T1 values, orange and red) were clustered in the posterior midbody and the inferior splenium and smaller diameter axons (as indicated by lower T1 values, blue and green) in the more anterior CC regions and the anterior midbody. Both studies replicated the average regional differences reported in microscopy-based studies. These rough visualizations greatly facilitate an understanding of how microscopic anatomy varies across the CC. CC: Corpus callosum, MRI: Magnetic resonance image

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Clinical/rehabilitation implications

Traumatic brain injuries

Midline structures such as the CC are particularly vulnerable to the shear-strain mechanical forces that result in traumatic axonal injury (TAI), the most common pathophysiologic finding resulting from traumatic brain injuries (TBI).[34] Advanced MRI techniques aid in the detection of microstructural white matter changes in the postacute or chronic phases following TBI.[35] Specifically, DTI is thought to be more sensitive than conventional neuroimaging modalities. Consequently, it may serve as a useful prognostic tool in identifying long-term outcomes postinjury in the clinical setting. In Strauss et al., several cases were described of subjects who sustained TBIs in whom initially computed tomography or MRI revealed no significant abnormalities.[36] Many years later, the subjects continued to demonstrate significant neurocognitive deficits, with subsequent quantitative analysis of DTI demonstrating abnormally low FA at sites consistent with the mechanism of injury.[36] A study of subjects with persistent cognitive, emotional and somatic symptoms at 12 months' postmild TBI reported a significant correlation between greater symptom burden and lower FA, presumably resulting from disruption of myelinated fibers.[34] Furthermore, the strongest association between DTI parameters reflecting white matter injury and symptoms were noted in the frontal regions of the brain, including the forceps minor and the genu of the CC.[34] Other studies have also demonstrated a positive correlation between the severity of somatic, neurocognitive, and neurobehavioral symptoms post-TBI and a reduction in FA.[35],[37] With its major role centered on the transfer of information across the hemispheres, the CC plays a vital role in memory functions. Disruptions of callosal fibers have been implicated in deficits in verbal and working memory.[35] Several studies have shown that the splenium may be involved with declarative memory, while the genu plays a role in working memory.[38] However, in examining the effects of TBI on specific callosal regions, there are significant discrepancies highlighted in the literature. A systematic review including 16 articles and 701 subjects with mild-to-severe TBI found a moderately positive correlation between FA in the CC as a whole and level of consciousness.[39] More specifically, the body and the splenium were more strongly associated with lower FA values than the genu, thus identifying the more posterior segments as most vulnerable to TAI. In other studies, looking at the long-term impact of TBI on social processing speeds, the posterior callosal segments, including the isthmus and splenium, were the most significantly affected regions following a severe injury.[37] A possible explanation for this pattern is that while the anterior callosal regions reach adult size in early childhood, the posterior regions continue to mature, with continued myelination well into adulthood. Thus, callosal maturation in the posterior segments may be stunted by traumatic injuries occurring in the early years.[37] On the contrary, Rutgers et al. looked at the effects of injury severity on DTI indices throughout all segments of the CC.[3] They found that subjects with mild TBI had notably decreased FA in the genu but not the body or the splenium, while those with moderate and severe TBI had reduced FA in both the genu and splenium. This is in contrast to the notion that TBI preferentially affects the splenium. There are many other DTI studies that have demonstrated a reduction in FA in both the genu and the splenium following all severities of TBI.[40],[41]

In addition to its utility as a powerful diagnostic tool for identifying traumatic injuries to the CC, advanced neuroimaging shows potential for monitoring neuroplastic changes underlying recovery in the postacute phases following a TBI. In a case study, a 50-year-old man who sustained a TBI manifested as brain contusions and CC rupture who had ceased to improve after 4 months of standard inpatient rehabilitation showed appreciable response to 1 month of comprehensive intensive inpatient rehabilitation including improved language and cognition, and improved motor function.[42] Increases in DTT metrics of the CC postrehabilitation, including average length and total visible number of fiber, mirrored clinical improvement in symptoms. Most affected were fibers interconnecting the hemispheres. Thus, there is evidence suggesting some degree of activity-dependent remyelination with neural regeneration and reorganization within the CC following intensive inpatient rehabilitation reflected by improvement in symptoms over time.[42]

Stroke

Stroke remains one of the leading causes of morbidity and disability in the United States. Infarcts to the CC, especially isolated callosal infarcts, are rare and account for <1% of ischemic stroke.[43] Li et al. proposed several possible explanations for this low prevalence.[44] The CC has a rich vascular supply from both the anterior and posterior cerebral arteries with a tremendous number of collaterals. Furthermore, callosal arteries branch off the main cerebral arteries in a perpendicular direction, thus making embolic events less likely. Finally, the CC is comprised of a dense collection of white matter fibers, which are generally less susceptible to hypoxic or ischemic insults than gray matter.[44] As noted earlier, the splenium is the most commonly affected callosal region [Figure 2] and is often associated with bilateral hemispheric involvement. This is likely a reflection of the higher incidence of posterior artery infarctions compared to anterior infarctions.[18],[37],[44] Infarcts affecting the CC body generally have a worse prognosis. One possible explanation for this is that the anterior and posterior regions of the CC receive 80% of the vascular supply. It has been proposed that the body of the CC may not have sufficient collaterals to facilitate neurologic recovery over time.[45] Furthermore, it may also be that the greater proportion of larger fibers with higher myelination (thus faster or more efficient interhemispheric communication) within the posterior midbody in this region may lead to more catastrophic clinical presentations.

The clinical presentation of a CC infarct is often nonspecific and challenging to characterize, as it encompasses a wide range of symptoms that are often seen in infarcts in other regions of the brain. This may be due to infarcts in adjacent noncallosal regions that frequently accompany CC infarcts.[46],[47],[48] In a study by Giroud and Dumas, most of the subjects with callosal infarcts also had infarcts in other brain regions (52/59, 88%).[49] Only 7 (12%) presented with isolated callosal infarction. Yang et al. examined 25 subjects with acute callosal injury and found the most common clinical manifestations included limb dyskinesias (80%), language deficits (48%), and cognitive and psychiatric impairments (40%).[46] Other commonly noted clinical features of CC infarcts include neuropsychiatric symptoms and gait disorders. In addition, in what is classically termed callosal disconnection syndrome, there may be apraxia, agraphia, tactile anomia, and alien hand syndrome.[45],[46]

The CC is known to be involved with skilled motor movements and plays a vital role in interhemispheric connections between the sensorimotor cortices. Consequently, stroke lesions affecting the CC directly or indirectly through its cortical connecting tracts may correlate with motor impairments. Stewart et al. compared chronic stroke patients with a wide spectrum of motor impairments to healthy individuals to measure the impact of stroke on white matter integrity in various regions of the CC.[50] As expected, there was an overall positive correlation between the FA in the motor regions of the CC and motor function in the healthy group, while FA in both motor and sensory callosal segments was significantly reduced in the stroke group. In addition, there was a stronger correlation between the structural integrity of the motor and sensory regions of the CC and motor function in subjects with milder motor impairments.[50] Another study using DTI and transcranial magnetic stimulation (TMS) demonstrated a strong association between white matter integrity (FA) in the genu of the CC and transcallosal inhibition (ipsilateral decrease in muscle activity following TMS of nonlesioned hemisphere) with a degree of motor impairment in the chronic poststroke population.[51] A possible explanation for this is a compensatory role of enhanced cognitive functions such as improved attention, working memory, motor learning, and sensory processing (all features of the premotor cortex) on impaired motor function.[51] This highlights the role of the premotor callosal region in motor recovery following a stroke. The CC also plays an essential role in language processing. In a case study of a young male who sustained a left-brain stroke resulting in chronic aphasia, DTT fiber tracking before and following 5-month speech therapy that resulted in substantial improvements in language functioning revealed increased fiber connections between the splenium and the left superior temporal gyrus (Wernicke's region) and the genu and the right inferior frontal gyrus (Broca's region).[52] Thus, these specific callosal regions may serve as targets for intensive intervention measures such as noninvasive brain stimulation, advanced cognitive therapies, or motor task retraining in poststroke rehabilitation.

Aging

Age-related development and degradation of white matter result in quantifiable changes to the callosal microarchitecture. Histological studies have identified the anterior callosal fibers (genu) to be more vulnerable to age-related degeneration than the more heavily myelinated fibers of the posterior region (splenium). Several studies using advanced MRI techniques (multi T2 mapping or quantitative synthetic MRI) have reported linear increases with age in surrogate measures of myelin content (e.g., shortest T2 component, which is presumed to be immobile water within myelin sheaths and so termed myelin water fraction, MWF) in the CC reflecting significant myelination from childhood to middle adulthood.[53],[54],[55] Studies differed on whether myelin content leveled off or declined significantly in older adults. Peak values occurred earlier in the anterior regions (47–49 years in the genu) than in the posterior regions (60 years in the splenium).[53] These studies also reported decreases in surrogate measures of fiber density (e.g., the higher geometric mean of intracellular and extracellular water T2, geomT2iew) with age in all CC regions. The combination of increasing myelin content and decreasing fiber density until middle age is likely due to the age-related increase in larger, more heavily myelinated axons with greater interaxon distances, thus lower packing density.[53] The increased prominence of larger diameter fibers versus smaller fibers with increasing age may denote a compensatory functional advantage. Larger, more heavily myelinated and faster-conducting fibers could facilitate more efficient interhemispheric communication, especially in regions associated with higher-order, cognitive tasks (e.g., genu).[12],[47] The transition at later ages to a stable or decreasing myelin content with continuing decreasing fiber density suggests the presence of degenerative changes. This interpretation is supported by studies using advanced diffusion MRI (DTT or high-gradient diffusion MRI) metrics that reported decreasing fibers per voxel (fiber density approximation) and increasing axonal diameter with age in all CC regions.[23],[56] One study also reported a statistically significant increase in axonal diameter in the genu with associated decrease in packing density noted in the genu and the posterior body with advancing age.[23] In contrast, no significant age-associated change in axon diameter index or packing density was noted in the splenium, supporting an anterior to the posterior gradient of axonal degeneration. This is the most prominent in the anterior regions which likely reflects a greater susceptibility of association regions of the prefrontal areas tasked with higher-order cognitive skills to age-related degenerative changes and disruption of myelin sheaths. Clinically, this is reflected by the decline in cognition seen with aging. Most importantly, studies have shown increased FA values in the genu of the CC induced by cognitive training across all ages, indicating potential for age-related white matter decline to be attenuated by experience or activity-dependent plasticity of myelinated fibers.[53]


  Conclusions Top


The CC is a commonly affected region of the brain following neurologic insults. It also undergoes numerous age-related degenerative changes. Understanding its microstructural properties and related functional capacities is critical to understanding its clinical relevance. This is especially important in the rehabilitation setting, where the management is provided for patients with various neurologic injuries, including callosal injuries that may not be fully captured by conventional neuroimaging techniques. As highlighted above and utilized in many of the references credited in this article, advances in neuroimaging techniques have allowed a more in-depth study of the CC. Currently, most of these advanced MRI techniques are mainly used in the realm of research and are not available in routine clinical practice. Furthermore, given the CC's prominence as the largest white matter tract and its primary role in facilitating interhemispheric cognitive, perceptual, and learned information, research about its anatomic characteristics, functional relevance, and rehabilitation implication are rapidly evolving. Consequently, having a clear and concise visual representation of complex callosal microstructural and its functional features may be useful to the rehabilitation clinician in understanding overall clinical patterns seen in healthy populations across all ages and patients with confirmed or suspected callosal injuries. By integrating information provided by previous histological and advanced neuroimaging studies, we gain a better understanding of the microstructural composition of the CC and its functional and clinical relevance.

Summary

Functional anatomy imaging has allowed science to update the gross anatomic organization of the CC that was originally described by Witelson [Figure 1]. The highly vascular posterior region of the CC is often affected in ischemic injuries [Figure 2]. These posterior regions connect to the parietal, temporal, and occipital region thereby affecting function in these areas clinically after ischemia [Figure 3]. In contrast, the anterior portions are connected to the frontal lobes and may be less affected after ischemic insults. In addition, fiber density and fiber size are inversely correlated [Figure 4] with the larger fibers more predominant in the posterior regions. These larger, more myelinated fibers allow for faster transit time in the temporal, parietal, and occipital regions which are necessary for sensory and motor function [Figure 4] and [Figure 5].

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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