Lynn K. Paul

Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity.

Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.

Lesion mapping of cognitive control and value-based decision making in the prefrontal cortex.

A considerable body of previous research on the prefrontal cortex (PFC) has helped characterize the regional specificity of various cognitive functions, such as cognitive control and decision making. Here we provide definitive findings on this topic, using a neuropsychological approach that takes advantage of a unique dataset accrued over several decades. We applied voxel-based lesion-symptom mapping in 344 individuals with focal lesions (165 involving the PFC) who had been tested on a comprehensive battery of neuropsychological tasks. Two distinct functional-anatomical networks were revealed within the PFC: one associated with cognitive control (response inhibition, conflict monitoring, and switching), which included the dorsolateral prefrontal cortex and anterior cingulate cortex and a second associated with value-based decision-making, which included the orbitofrontal, ventromedial, and frontopolar cortex. Furthermore, cognitive control tasks shared a common performance factor related to set shifting that was linked to the rostral anterior cingulate cortex. By contrast, regions in the ventral PFC were required for decision-making. These findings provide detailed causal evidence for a remarkable functional-anatomical specificity in the human PFC.

Distributed neural system for general intelligence revealed by lesion mapping

General intelligence (g) captures the performance variance shared across cognitive tasks and correlates with real-world success. Yet it remains debated whether g reflects the combined performance of brain systems involved in these tasks or draws on specialized systems mediating their interactions. Here we investigated the neural substrates of g in 241 patients with focal brain damage using voxel-based lesion–symptom mapping. A hierarchical factor analysis across multiple cognitive tasks was used to derive a robust measure of g. Statistically significant associations were found between g and damage to a remarkably circumscribed albeit distributed network in frontal and parietal cortex, critically including white matter association tracts and frontopolar cortex. We suggest that general intelligence draws on connections between regions that integrate verbal, visuospatial, working memory, and executive processes.

Lesion Mapping of Cognitive Abilities Linked to Intelligence

The Wechsler Adult Intelligence Scale (WAIS) assesses a wide range of cognitive abilities and impairments. Factor analyses have documented four underlying indices that jointly comprise intelligence as assessed with the WAIS: verbal comprehension (VCI), perceptual organization (POI), working memory (WMI), and processing speed (PSI). We used nonparametric voxel-based lesion-symptom mapping in 241 patients with focal brain damage to investigate their neural underpinnings. Statistically significant lesion-deficit relationships were found in left inferior frontal cortex for VCI, in left frontal and parietal cortex for WMI, and in right parietal cortex for POI. There was no reliable single localization for PSI. Statistical power maps and cross-validation analyses quantified specificity and sensitivity of the index scores in predicting lesion locations. Our findings provide comprehensive lesion maps of intelligence factors, and make specific recommendations for interpretation and application of the WAIS to the study of intelligence in health and disease.

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome).

Largely Typical Patterns of Resting-State Functional Connectivity in High-Functioning Adults with Autism

A leading hypothesis for the neural basis of autism postulates globally abnormal brain connectivity, yet the majority of studies report effects that are either very weak, inconsistent across studies, or explain results incompletely. Here we apply multiple analytical approaches to resting-state BOLD-fMRI data at the whole-brain level. Neurotypical and high-functioning adults with autism displayed very similar patterns and strengths of resting-state connectivity. We found only limited evidence in autism for abnormal resting-state connectivity at the regional level and no evidence for altered connectivity at the whole-brain level. Regional abnormalities in functional connectivity in autism spectrum disorder were primarily in the frontal and temporal cortices. Within these regions, functional connectivity with other brain regions was almost exclusively lower in the autism group. Further examination showed that even small amounts of head motion during scanning have large effects on functional connectivity measures and must be controlled carefully. Consequently, we suggest caution in the interpretation of apparent positive findings until all possible confounding effects can be ruled out. Additionally, we do not rule out the possibility that abnormal connectivity in autism is evident at the microstructural synaptic level, which may not be reflected sensitively in hemodynamic changes measured with BOLD-fMRI.

Communicative deficits in agenesis of the corpus callosum: nonliteral language and affective prosody.

While some individuals with agenesis of the corpus callosum can perform normally on standardized intelligence tests, clinical observations suggest that they nevertheless have deficits in the domains of fluid and social intelligence. Particularly important for social competence is adequate understanding and use of paralinguistic information. This study examined the impact of callosal absence on the processing of pragmatic and paralinguistic information. Young adult males with agenesis of the corpus callosum (ACC) were evaluated in the areas of nonliteral language comprehension, proverb recognition and interpretation, and perception of affective prosody. Ten ACC individuals with normal Wechsler IQ were compared to 14 sex, age, and IQ matched normal controls. The Formulaic and Novel Language Comprehension Test (FANL-C), Gorham Proverbs Test, and LA Prosody Test were administered. ACC subjects exhibited significant impairment on the nonliteral items of the FANL-C, but no significant difference from controls in comprehension of literal items. ACC subjects also exhibited significant deficits in both self-generated interpretation and recognition of proverb meaning, and in recognition of affective prosody. These results demonstrate that normally intelligent individuals with ACC are impaired in the understanding of nonliteral language and emotional-prosodic cues that are important in social communication. In all three tests, the performance of individuals with ACC was similar to patients with right hemisphere brain damage. Thus, persons with ACC appear to lack interhemispheric integration of critical aspects of language processed by the right hemisphere.

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.

Cognitive and psychosocial deficits in agenesis of the corpus callosum with normal intelligence

Cognitive disabilities in agenesis of the corpus callosum (ACC) have been described in scattered reports, but few complete case descriptions are available. Consequent psychosocial disabilities in ACC have received little attention. We expected that ACC would be manifest in deficits specific to complex reasoning, concept formation, and problem solving. We also expected that these cognitive problems would be particularly evident in difficulties interpreting and understanding social situations, and in abnormal self-perception. Methods. Cognitive and psychosocial deficits were studied in two adolescents with ACC and normal IQ using a battery of cognitive and psychological tests. Results. Test results indicated poor interhemispheric integration of complex material. Performance on tests of reasoning, and concept formation were clearly below expectations based on IQ. Significantly poor performance was also found on tests of social insight, proverb interpretation, social logic, self-perception, and interpretation of ambiguous stimuli. Gross behavioural disorder or psychopathology were not found. Conclusions. ACC results in disabilities in social cognition that appear to be secondary to deficits in complex cognitive operations such as reasoning, concept formation, and problem solving. It is suggested that these cognitive deficits may be related to diminished interhemispheric transfer of complex information.

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.