Faculty Bibliography

Introduction: Slow wave sleep (SWS) is thought to benefit spatial memory consolidation. This study investigates whether disrupting SWS via sleep-stage specific OSA affects spatial memory consolidation and how sleep fragmentation and intermittent hypoxia differentially impact this effect. Methods: We recruited 5 subjects with severe OSA who are well treated and compliant with CPAP. Individual subjects spent 3 different nights in the lab and performed timed trials before and after sleep on unique but equally difficult 3D spatial mazes. The 3 conditions included: 1) consolidated sleep with treated OSA 2) CPAP withdrawn exclusively in SWS (SWS-OSA) and 3) CPAP withdrawn exclusively in SWS with simultaneous addition of supplemental oxygen (SWS-OSA+O2). Results: CPAP withdrawal in SWS both decreased %SWS (21% +/- 11% during consolidated sleep vs. 13% +/- 7% with SWS-OSA), and fragmented remaining SWS (SWS apnea hypopnea index with 3% oxygen desaturation or arousal (AHI3A) = 0.5/hour +/- 1 during consolidated sleep vs. 36/hour +/- 12 with SWS-OSA). During SWSOSA+ O2, SWS was also reduced (11% +/ 8%) and respiratory events continued (AHI3A 31/hour +/- 20), however indices of oxygen desaturation were minimized (%time below 90% in SWS = 4.3% +/- 1.7% during SWS-OSA vs 0.5% +/- 0.9% during SWS-OSA+O2; average oxygen saturation during respiratory event = 88.7% +/- 3.3% during SWS-OSA vs. 94% +/- 1.4% during SWS-OSA+O2). During consolidated sleep, median completion time improved from 180 sec pre-sleep (range 86 to 248 sec) to 111 sec post-sleep (range 87 to 412 sec) (38%). During SWS-OSA median completion time improved from 138 sec pre-sleep (range 116 to 272 sec) to 133 sec post-sleep (range 73 to 453 sec) (4%) and during SWS-OSA+O2 median completion time improved from 172 sec pre-sleep (range 61 to 339 sec) to 161 sec postsleep (range 51 to 306 sec) (6%). Conclusion: CPAP withdrawal during SWS in subjects with severe OSA reduces and fragments SWS. The addition of supplemental oxygen during CPAP withdrawal minimizes the associated intermittent hypoxia. Early evidence suggests a greater benefit of consolidated sleep on overnight change in spatial navigation performance than sleep with SWS disruption either with or without intermittent hypoxia

INTRODUCTION: Quantitative T2 mapping may provide an objective biomarker for occult nervous tissue pathology in relapsing-remitting multiple sclerosis (RRMS). We applied a novel echo modulation curve (EMC) algorithm to identify T2 changes in normal-appearing brain regions of subjects with RRMS (N = 27) compared to age-matched controls (N = 38). METHODS: The EMC algorithm uses Bloch simulations to model T2 decay curves in multi-spin-echo MRI sequences, independent of scanner, and scan-settings. T2 values were extracted from normal-appearing white and gray matter brain regions using both expert manual regions-of-interest and user-independent FreeSurfer segmentation. RESULTS: Compared to conventional exponential T2 modeling, EMC fitting provided more accurate estimations of T2 with less variance across scans, MRI systems, and healthy individuals. Thalamic T2 was increased 8.5% in RRMS subjects (p < 0.001) and could be used to discriminate RRMS from healthy controls well (AUC = 0.913). Manual segmentation detected both statistically significant increases (corpus callosum & temporal stem) and decreases (posterior limb internal capsule) in T2 associated with RRMS diagnosis (all p < 0.05). In healthy controls, we also observed statistically significant T2 differences for different white and gray matter structures. CONCLUSIONS: The EMC algorithm precisely characterizes T2 values, and is able to detect subtle T2 changes in normal-appearing brain regions of RRMS patients. These presumably capture both axon and myelin changes from inflammation and neurodegeneration. Further, T2 variations between different brain regions of healthy controls may correlate with distinct nervous tissue environments that differ from one another at a mesoscopic length-scale.

Weather, in particular the intensity and duration of sunshine (luminance), has been shown to significantly affect financial markets. Yet, because of the complexity of market interactions we do not know how human behavior is affected by luminance in a way that could inform theoretical choice models. In this paper, we use data from a field study using an incentive-compatible, decision task conducted daily over a period of two years and from the US Earth System Research Laboratory luminance sensor to investigate the impact of luminance on risk preferences, ambiguity preferences, choice consistency and dominance violations. We find that luminance levels affect all of these. Age and gender influence the strength of some of these effects.

Adaptation facilitates neural representation of a wide range of diverse inputs, including reward values. Adaptive value coding typically relies on contextual information either obtained from the environment or retrieved from and maintained in memory. However, it is unknown whether having to retrieve and maintain context information modulates the brain's capacity for value adaptation. To address this issue, we measured hemodynamic responses of the prefrontal cortex (PFC) in two studies on risky decision-making. In each trial, healthy human subjects chose between a risky and a safe alternative; half of the participants had to remember the risky alternatives, whereas for the other half they were presented visually. The value of safe alternatives varied across trials. PFC responses adapted to contextual risk information, with steeper coding of safe alternative value in lower-risk contexts. Importantly, this adaptation depended on working memory load, such that response functions relating PFC activity to safe values were steeper with presented versus remembered risk. An independent second study replicated the findings of the first study and showed that similar slope reductions also arose when memory maintenance demands were increased with a secondary working memory task. Formal model comparison showed that a divisive normalization model fitted effects of both risk context and working memory demands on PFC activity better than alternative models of value adaptation, and revealed that reduced suppression of background activity was the critical parameter impairing normalization with increased memory maintenance demand. Our findings suggest that mnemonic processes can constrain normalization of neural value representations.

Aims Acetylcholinesterase (AChE) exists as different splicing variants with particular regional, cellular, and subcellular locations that may reflect differential physiological roles. So we aimed to study the expression of AChE variants in Alzheimer's disease (AD) brain. Method We have analyzed protein levels of AChE variants in postmortem cerebral cortex from AD patients by Western blot using specific anti-AChE antibodies. Levels of AChE transcripts were also analysed by qRT-PCR. Further, we investigated expression levels of the anchoring AChE subunit proline-rich membrane anchor (PRiMA-1), limiting factor for correct localization of cholinergic AChE at plasma membrane. In addition we analysed expression levels of AChE variants in cell cultures after PRiMA overexpression. Changes in AChE promoter were also evaluated by Luciferase assays. Results We found similar protein and mRNA levels of the major cholinergic "tailed"-variant (AChE-T) and the anchorage subunit PRiMA-1 in cortex from AD patients and non-demented controls. Interestingly, we observed an increment in protein and transcript levels of the non-cholinergic "readthrought" AChE (AChE-R) subunits in cortex of AD patients compared to controls. Moreover an increase in N-extended variants of AChE, which were assigned to N-AChE-R variants, was detected in AD cortex. We further observed that PRiMA 1 could regulate the expression of AChE-T variants without effect in AChE-R forms. Conclusion Our findings reveal previously unknown expression patterns of AChE variants in AD cortex likely reflecting specific roles and/or differential regulation for each variant in AD, which may have strong implications for the re-evaluation of AChE inhibitors as therapeutic agents in dementia

Possession of the ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Although numerous hypotheses have been proposed, the precise cause of this increased AD risk is not yet known. In order to gain a more comprehensive understanding of APOE4's role in AD, we performed RNA-sequencing on an AD-vulnerable vs. an AD-resistant brain region from aged APOE targeted replacement mice. This transcriptomics analysis revealed a significant enrichment of genes involved in endosomal-lysosomal processing, suggesting an APOE4-specific endosomal-lysosomal pathway dysregulation in the brains of APOE4 mice. Further analysis revealed clear differences in the morphology of endosomal-lysosomal compartments, including an age-dependent increase in the number and size of early endosomes in APOE4 mice. These findings directly link the APOE4 genotype to endosomal-lysosomal dysregulation in an in vivo, AD pathology-free setting, which may play a causative role in the increased incidence of AD among APOE4 carriers.

Anti-PD-1 and anti-PD-L1 immunotherapy has provided a new therapeutic opportunity for treatment of advanced-stage non-small cell lung cancer (NSCLC). However, overall objective response rates are approximately 15%-25% in all NSCLC patients who receive anti-PD therapy. Therefore, strategies to overcome primary resistance to anti-PD immunotherapy are urgently needed. We hypothesized that the barrier to the success of anti-PD therapy in most NSCLC patients can be overcome by stimulating the lymphocyte infiltration at cancer sites through locoregional virotherapy. To this end, in this study, we determined combination effects of anti-PD immunotherapy and oncolytic adenoviral vector-mediated tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene therapy in syngeneic mice bearing subcutaneous tumors derived from M109 lung cancer cells. Both anti-PD-1 and anti-PD-L1 antibodies failed to elicit obvious therapeutic effects in the M109 tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed tumor growth in animals preexposed to an adenovector and bearing subcutaneous tumors derived from M109 cells. However, combining either anti-PD-1 or anti-PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice with existing immunity to adenoviral vectors. Dramatically enhanced intratumoral immune response was detected in this group of combination therapy based on infiltrations of CD4+ and CD8+ lymphocytes and macrophages in tumors. Our results demonstrate that resistance to anti-PD-1 immunotherapy in syngeneic mouse lung cancer can be overcome by locoregional virotherapy.

One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21-25years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non-users of cannabis. These participants have been followed longitudinally since age 7-9.9years as part of a large multi-site longitudinal study of ADHD, the Multimodal Treatment Study of Children with ADHD (MTA). We examined task-independent intrinsic functional connectivity (iFC) within 9 functional networks using a 2×2 design, which compared four groups of participants: (1) individuals with a childhood diagnosis of ADHD who currently use cannabis (n=23); (2) individuals with ADHD who do not currently use cannabis (n=22); (3) comparisons who currently use cannabis (n=15); and (4) comparisons who do not currently use cannabis (n=15). The main effects of childhood ADHD were primarily weakened iFC in networks supporting executive function and somatomotor control. Contrary to expectations, effects of cannabis use were distinct from those of diagnostic group and no interactions were observed. Exploratory brain-behavior analyses suggested that ADHD-related effects were primarily linked with poorer neurocognitive performance. Deficits in the integrity of functional networks supporting executive function and somatomotor control are consistent with the phenotypic and neurocognitive features of ADHD. Our data suggest that cannabis use does not exacerbate ADHD-related alterations, but this finding awaits replication in a larger sample. Longitudinal neuroimaging studies are urgently required to delineate the neurodevelopmental cascade that culminates in positive and negative outcomes for those diagnosed with ADHD in childhood.

1-octanol is a therapeutic candidate for disorders involving the abnormal activation of the T-type calcium current since it blocks this current specifically. Such disorders include essential tremor and a group of neurological and psychiatric disorders resulting from thalamocortical dysrhythmia (TCD). For example, clinically, the observable phenotype in essential tremor is the tremor itself. The differential diagnostic of TCD is not based only on clinical signs and symptoms. Rather, TCD incorporates an electromagnetic biomarker, the presence of abnormal thalamocortical low frequency brain oscillations. The effect of 1-octanol on brain activity has not been tested. As a preliminary step to such a TCD study, we examined the short-term effects of a single dose of 1-octanol on resting brain activity in 32 healthy adults using magnetoencephalograpy. Visual inspection of baseline power spectra revealed that the subjects fell into those with strong low frequency activity (set 2, n = 11) and those without such activity, but dominated by an alpha peak (set 1, n = 22). Cross-validated linear discriminant analysis, using mean spectral density (MSD) in nine frequency bands as predictors, found overall that 82.5% of the subjects were classified as determined by visual inspection. The effect of 1-octanol on the MSD in narrow frequency bands differed between the two subject groups. In set 1 subjects the MSD increased in the 4.5-6.5Hz and 6.5-8.5 Hz bands. This was consistent with a widening of the alpha peak toward lower frequencies. In the set two subjects the MSD decrease in the 2.5-4.5 Hz and 4.5-6.5 Hz bands. This decreased power is consistent with the blocking effect of 1-octanol on T-type calcium channels. The subjects reported no adverse effects of the 1-octanol. Since stronger low frequency activity is characteristic of patients with TCD, 1-octanol and other T-type calcium channel blockers are good candidates for treatment of this group of disorders following a placebo-controlled study.