Faculty Bibliography

STUDY OBJECTIVES: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Abeta). We thus aimed to examine relationships between concentrations of Abeta42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. METHODS: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Abeta42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Abeta42 groups to compare SWS bout length using survival analyses. RESULTS: A significant inverse correlation was found between CSF Abeta42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Abeta42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Abeta42. CONCLUSIONS: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Abeta42, suggesting that disturbed sleep might drive an increase in soluble brain Abeta levels prior to amyloid deposition.

Understanding how the structure of cognition arises from the topographical organization of the cortex is a primary goal in neuroscience. Previous work has described local functional gradients extending from perceptual and motor regions to cortical areas representing more abstract functions, but an overarching framework for the association between structure and function is still lacking. Here, we show that the principal gradient revealed by the decomposition of connectivity data in humans and the macaque monkey is anchored by, at one end, regions serving primary sensory/motor functions and at the other end, transmodal regions that, in humans, are known as the default-mode network (DMN). These DMN regions exhibit the greatest geodesic distance along the cortical surface-and are precisely equidistant-from primary sensory/motor morphological landmarks. The principal gradient also provides an organizing spatial framework for multiple large-scale networks and characterizes a spectrum from unimodal to heteromodal activity in a functional metaanalysis. Together, these observations provide a characterization of the topographical organization of cortex and indicate that the role of the DMN in cognition might arise from its position at one extreme of a hierarchy, allowing it to process transmodal information that is unrelated to immediate sensory input.

BACKGROUND: Microtubules are dynamic polymers of alpha/beta tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either alpha- or beta-tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly. METHODS: This is a single case report or a patient with lissencephaly, developmental delay, nystagmus, persistent hyperplastic primary vitreous, and infantile spasms, and undertook a neurogenetic workup. We include studies of mutant function in Escherichia coli and HeLa cells. RESULTS: The patient was found to have a novel de novo mutation in kinesin family member 2A (KIF2A). This mutation results in a substitution of isoleucine at a highly conserved threonine residue within the ATP-binding domain. The KIF2A p.Thr320Ile mutant protein exhibited abnormal solubility, and KIF2A p.Thr320Ile overexpression in cultured cells led to the formation of aberrant microtubule networks. CONCLUSION: Findings support the pathogenic link between KIF2A mutation and lissencephaly, and expand the range of presentation to include infantile spasms and congenital anomalies.

Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data.

Delayed sleep and meal times promote metabolic dysregulation and obesity. Altered coordination of sleeping and eating times may impact food reward valuation and interoception in the brain, yet the independent and collective contributions of sleep and meal times are unknown. This randomized, inpatient crossover study experimentally manipulates sleep and meal times while preserving sleep duration (7.05+/-0.44 h for 5 nights). Resting-state functional MRI scans (2 x 5-minute runs) were obtained for 4 participants (3 males; 25.3+/-4.6 y), each completing all study phases (normal sleep/normal meal; late sleep/normal meal; normal sleep/late meal; late sleep/late meal). Normal mealtimes were 1, 5, 11, and 12.5 h after awakening; late mealtimes were 4.5, 8.5, 14.5 and 16 h after awakening. Seed-based resting-state functional connectivity (RSFC) was computed for a priori regions-of-interest (seeds) and contrasted across conditions. Statistically significant (P<0.05, whole-brain corrected) regionally-specific effects were found for multiple seeds. The strongest effects were linked to the amygdala: increased RSFC for late versus normal mealtimes (equivalent to skipping breakfast). A main effect of sleep and interaction with mealtime were also observed. Preliminary findings support the feasibility of examining the effects of sleep and meal time misalignment, independent of sleep duration, on RSFC in regions relevant to food reward and interoception.International Journal of Obesity accepted article preview online, 01 August 2016. doi:10.1038/ijo.2016.132.