On the role of the corpus callosum in interhemispheric functional connectivity in humans

Resting state functional connectivity is defined in terms of temporal correlations between physiologic signals, most commonly studied using functional magnetic resonance imaging. Major features of functional connectivity correspond to structural (axonal) connectivity. However, this relation is not one-to-one. Interhemispheric functional connectivity in relation to the corpus callosum presents a case in point. Specifically, several reports have documented nearly intact interhemispheric functional connectivity in individuals in whom the corpus callosum (the major commissure between the hemispheres) never develops. To investigate this question, we assessed functional connectivity before and after surgical section of the corpus callosum in 22 patients with medically refractory epilepsy. Section of the corpus callosum markedly reduced interhemispheric functional connectivity. This effect was more profound in multimodal associative areas in the frontal and parietal lobe than primary regions of sensorimotor and visual function. Moreover, no evidence of recovery was observed in a limited sample in which multiyear, longitudinal follow-up was obtained. Comparison of partial vs. complete callosotomy revealed several effects implying the existence of polysynaptic functional connectivity between remote brain regions. Thus, our results demonstrate that callosal as well as extracallosal anatomical connections play a role in the maintenance of interhemispheric functional connectivity

Multiscale Topological Properties Of Functional Brain Networks During Motor Imagery After Stroke

In recent years, network analyses have been used to evaluate brain reorganization following stroke. However, many studies have often focused on single topological scales, leading to an incomplete model of how focal brain lesions affect multiple network properties simultaneously and how changes on smaller scales influence those on larger scales. In an EEG-based experiment on the performance of hand motor imagery (MI) in 20 patients with unilateral stroke, we observed that the anatomic lesion affects the functional brain network on multiple levels. In the beta (13-30 Hz) frequency band, the MI of the affected hand (Ahand) elicited a significantly lower smallworldness and local efficiency (Eloc) versus the unaffected hand (Uhand). Notably, the abnormal reduction in Eloc significantly depended on the increase in interhemispheric connectivity, which was in turn determined primarily by the rise in regional connectivity in the parieto-occipital sites of the affected hemisphere. Further, in contrast to the Uhand MI, in which significantly high connectivity was observed for the contralateral sensorimotor regions of the unaffected hemisphere, the regions that increased in connection during the Ahand MI lay in the frontal and parietal regions of the contralaterally affected hemisphere. Finally, the overall sensorimotor function of our patients, as measured by Fugl-Meyer Assessment (FMA) index, was significantly predicted by the connectivity of their affected hemisphere. These results increase our understanding of stroke-induced alterations in functional brain networks.Comment: Neuroimage, accepted manuscript (unedited version) available online 19-June-201

Intact Bilateral Resting-State Networks in the Absence of the Corpus Callosum

Temporal correlations between different brain regions in the resting-state BOLD signal are thought to reflect intrinsic functional brain connectivity (Biswal et al., 1995; Greicius et al., 2003; Fox et al., 2007). The functional networks identified are typically bilaterally distributed across the cerebral hemispheres, show similarity to known white matter connections (Greicius et al., 2009), and are seen even in anesthetized monkeys (Vincent et al., 2007). Yet it remains unclear how they arise. Here we tested two distinct possibilities: (1) functional networks arise largely from structural connectivity constraints, and generally require direct interactions between functionally coupled regions mediated by white-matter tracts; and (2) functional networks emerge flexibly with the development of normal cognition and behavior and can be realized in multiple structural architectures. We conducted resting-state fMRI in eight adult humans with complete agenesis of the corpus callosum (AgCC) and normal intelligence, and compared their data to those from eight healthy matched controls. We performed three main analyses: anatomical region-of-interest-based correlations to test homotopic functional connectivity, independent component analysis (ICA) to reveal functional networks with a data-driven approach, and ICA-based interhemispheric correlation analysis. Both groups showed equivalently strong homotopic BOLD correlation. Surprisingly, almost all of the group-level independent components identified in controls were observed in AgCC and were predominantly bilaterally symmetric. The results argue that a normal complement of resting-state networks and intact functional coupling between the hemispheres can emerge in the absence of the corpus callosum, favoring the second over the first possibility listed above

The Role of Corpus Callosum Development in Functional Connectivity and Cognitive Processing

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified

Functional connectivity in relation to motor performance and recovery after stroke.

Plasticity after stroke has traditionally been studied by observing changes only in the spatial distribution and laterality of focal brain activation during affected limb movement. However, neural reorganization is multifaceted and our understanding may be enhanced by examining dynamics of activity within large-scale networks involved in sensorimotor control of the limbs. Here, we review functional connectivity as a promising means of assessing the consequences of a stroke lesion on the transfer of activity within large-scale neural networks. We first provide a brief overview of techniques used to assess functional connectivity in subjects with stroke. Next, we review task-related and resting-state functional connectivity studies that demonstrate a lesion-induced disruption of neural networks, the relationship of the extent of this disruption with motor performance, and the potential for network reorganization in the presence of a stroke lesion. We conclude with suggestions for future research and theories that may enhance the interpretation of changing functional connectivity. Overall findings suggest that a network level assessment provides a useful framework to examine brain reorganization and to potentially better predict behavioral outcomes following stroke

The case for a relationship between human memory, hippocampus and corpus callosum

Unilateral brain damage which includes the hippocampus leads to memory impairments consistent with hemispheric specialization on the same side. Damage to the corpus callosum, the major connecting pathway between the left and right hemispheres, also leads to memory impairments. This suggests both hemispheric specialization on the hippocampal level and a critical role for the corpus callosum in memory functions. A complete hippocampal formation is present on either side of the brain but traditionally only one is studied. However, a comparison between the neuronal populations in the hippocampus on both sides revealed asymmetry in connectivity among hippocampal subfields. The profile of memory impairments of commissurotomy (‘split-brain’) patients is described. The results are discussed in terms of a relationship between hippocampus and corpus callosum in humans. As hemispheric specialization evolved, inter-hippocampal connections became less important and the corpus callosum became prominent in memory functions

Asymmetry of parietal interhemispheric connections in humans

Visuospatial abilities are preferentially mediated by the right hemisphere. Although this asymmetry of function is thought to be due to an unbalanced interaction between cerebral hemispheres, the underlying neurophysiological substrate is still largely unknown. Here, using a method of trifocal transcranial magnetic stimulation, we show that the right, but not left, human posterior parietal cortex exerts a strong inhibitory activity over the contralateral homologous area by a short-latency connection. We also clarify, using diffusion-tensor magnetic resonance imaging, that such an interaction is mediated by direct transcallosal projections located in the posterior corpus callosum. We argue that this anatomo-functional network may represent a possible neurophysiological basis for the ongoing functional asymmetry between parietal cortices, and that its damage could contribute to the clinical manifestations of neglect

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker

The effects of hemodynamic lag on functional connectivity and behavior after stroke

Stroke disrupts the brain's vascular supply, not only within but also outside areas of infarction. We investigated temporal delays (lag) in resting state functional magnetic resonance imaging signals in 130 stroke patients scanned two weeks, three months and 12 months post stroke onset. Thirty controls were scanned twice at an interval of three months. Hemodynamic lag was determined using cross-correlation with the global gray matter signal. Behavioral performance in multiple domains was assessed in all patients. Regional cerebral blood flow and carotid patency were assessed in subsets of the cohort using arterial spin labeling and carotid Doppler ultrasonography. Significant hemodynamic lag was observed in 30% of stroke patients sub-acutely. Approximately 10% of patients showed lag at one-year post-stroke. Hemodynamic lag corresponded to gross aberrancy in functional connectivity measures, performance deficits in multiple domains and local and global perfusion deficits. Correcting for lag partially normalized abnormalities in measured functional connectivity. Yet post-stroke FC-behavior relationships in the motor and attention systems persisted even after hemodynamic delays were corrected. Resting state fMRI can reliably identify areas of hemodynamic delay following stroke. Our data reveal that hemodynamic delay is common sub-acutely, alters functional connectivity, and may be of clinical importance