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

Processing Speed Delays Contribute to Executive Function Deficits in Individuals with Agenesis of the Corpus Callosum

Corpus callosum malformation and dysfunction are increasingly recognized causes of cognitive and behavioral disability. Individuals with agenesis of the corpus callosum (AgCC) offer unique insights regarding the cognitive skills that depend specifically upon callosal connectivity. We examined the impact of AgCC on cognitive inhibition, flexibility, and processing speed using the Color-Word Interference Test (CWIT) and Trail Making Test (TMT) from the Delis-Kaplan Executive Function System. We compared 36 individuals with AgCC and IQs within the normal range to 56 matched controls. The AgCC cohort was impaired on timed measures of inhibition and flexibility; however, group differences on CWIT Inhibition, CWIT Inhibition/Switching and TMT Number-Letter Switching appear to be largely explained by slow performance in basic operations such as color naming and letter sequencing. On CWIT Inhibition/Switching, the AgCC group was found to commit significantly more errors which suggests that slow performance is not secondary to a cautious strategy. Therefore, while individuals with agenesis of the corpus callosum show real deficits on tasks of executive function, this impairment appears to be primarily a consequence of slow cognitive processing. Additional studies are needed to investigate the impact of AgCC on other aspects of higher order cortical function

Microdissection of Shoot Meristem Functional Domains

The shoot apical meristem (SAM) maintains a pool of indeterminate cells within the SAM proper, while lateral organs are initiated from the SAM periphery. Laser microdissection–microarray technology was used to compare transcriptional profiles within these SAM domains to identify novel maize genes that function during leaf development. Nine hundred and sixty-two differentially expressed maize genes were detected; control genes known to be upregulated in the initiating leaf (P0/P1) or in the SAM proper verified the precision of the microdissections. Genes involved in cell division/growth, cell wall biosynthesis, chromatin remodeling, RNA binding, and translation are especially upregulated in initiating leaves, whereas genes functioning during protein fate and DNA repair are more abundant in the SAM proper. In situ hybridization analyses confirmed the expression patterns of six previously uncharacterized maize genes upregulated in the P0/P1. P0/P1-upregulated genes that were also shown to be downregulated in leaf-arrested shoots treated with an auxin transport inhibitor are especially implicated to function during early events in maize leaf initiation. Reverse genetic analyses of asceapen1 (asc1), a maize D4-cyclin gene upregulated in the P0/P1, revealed novel leaf phenotypes, less genetic redundancy, and expanded D4-CYCLIN function during maize shoot development as compared to Arabidopsis. These analyses generated a unique SAM domain-specific database that provides new insight into SAM function and a useful platform for reverse genetic analyses of shoot development in maize

Optimizing naloxone distribution to prevent opioid overdose fatalities: results from piloting the Systems Analysis and Improvement Approach within syringe service programs.

BACKGROUND: Opioid overdose fatalities are preventable with timely administration of naloxone, an opioid antagonist, during an opioid overdose event. Syringe service programs have pioneered naloxone distribution for potential bystanders of opioid overdose. The objective of this study was to pilot test a multi-component implementation strategy-the systems analysis and improvement approach for naloxone (SAIA-Naloxone)-with the goal of improving naloxone distribution by syringe service programs. METHODS: Two syringe service programs participated in a 6-month pilot of SAIA-Naloxone, which included (1) analyzing program data to identify gaps in the naloxone delivery cascade, (2) flow mapping to identify causes of attrition and brainstorm programmatic changes for improvement, and (3) conducting continuous quality improvement to test and assess whether modifications improve the cascade. We conducted an interrupted time series analysis using 52 weeks of data before and 26 weeks of data after initiating SAIA-Naloxone. Poisson regression was used to evaluate the association between SAIA-Naloxone and the weekly number of participants receiving naloxone and number of naloxone doses distributed. RESULTS: Over the course of the study, 11,107 doses of naloxone were distributed to 6,071 participants. Through SAIA-Naloxone, syringe service programs prioritized testing programmatic modifications to improve data collection procedures, proactively screen and identify naloxone-naïve participants, streamline naloxone refill systems, and allow for secondary naloxone distribution. SAIA-Naloxone was associated with statistically significant increases in the average number of people receiving naloxone per week (37% more SPP participants; 95% CI, 12% to 67%) and average number of naloxone doses distributed per week (105% more naloxone doses; 95% CI, 79% to 136%) beyond the underlying pre-SAIA-Naloxone levels. These initial increases were extended by ongoing positive changes over time (1.6% more SSP participants received naloxone and 0.3% more naloxone doses were distributed in each subsequent week compared to the weekly trend in the pre-SAIA Naloxone period). CONCLUSIONS: SAIA-Naloxone has strong potential for improving naloxone distribution from syringe service programs. These findings are encouraging in the face of the worsening opioid overdose crisis in the United States and support testing SAIA-Naloxone in a large-scale randomized trial within syringe service programs