Faculty Bibliography

In recent years, optogenetics has become a central tool in neuroscience research. Estimating the transmission of visible light through brain tissue is of crucial importance for controlling the activation levels of neurons in different depths, designing optical systems, and avoiding lesions from excessive power density. The Kubelka-Munk model and Monte Carlo simulations have previously been used to model light propagation through rodents' brain tissue, however, these prior attempts suffer from fundamental shortcomings. Here, we introduce and study two modified approaches for modeling the distributions of light emanating from a multimode fiber and scattering through tissue, using both realistic numerical Monte Carlo simulations and an analytical approach based on the beam-spread function approach. We demonstrate a good agreement of the new methods' predictions both with recently published data, and with new measurements in mouse brain cortical slices, where our results yield a new cortical scattering length estimate of approximately 47 microm at lambda = 473 nm, significantly shorter than ordinarily assumed in optogenetic applications.

In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-beta (Abeta) pathology, greater clinical efficacy may be achieved by clearing tau than Abeta aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.

Deficient cognitive top-down executive control has long been hypothesized to underlie inattention and impulsivity in attention-deficit/hyperactivity disorder (ADHD). However, top-down cognitive dysfunction explains a modest proportion of the ADHD phenotype whereas the salience of emotional dysregulation is being noted increasingly. Together, these two types of dysfunction have the potential to account for more of the phenotypic variance in patients diagnosed with ADHD. We develop this idea and suggest that top-down dysregulation constitutes a gradient extending from mostly non-emotional top-down control processes (i.e., "cool" executive functions) to mainly emotional regulatory processes (including "hot" executive functions). While ADHD has been classically linked primarily to the former, conditions involving emotional instability such as borderline and antisocial personality disorder are closer to the other. In this model, emotional subtypes of ADHD are located at intermediate levels of this gradient. Neuroanatomically, gradations in "cool" processing appear to be related to prefrontal dysfunction involving dorsolateral prefrontal cortex (dlPFC) and caudal anterior cingulate cortex (cACC), while "hot" processing entails orbitofrontal cortex and rostral anterior cingulate cortex (rACC). A similar distinction between systems related to non-emotional and emotional processing appears to hold for the basal ganglia (BG) and the neuromodulatory effects of the dopamine system. Overall we suggest that these two systems could be divided according to whether they process non-emotional information related to the exteroceptive environment (associated with "cool" regulatory circuits) or emotional information related to the interoceptive environment (associated with "hot" regulatory circuits). We propose that this framework can integrate ADHD, emotional traits in ADHD, borderline and antisocial personality disorder into a related cluster of mental conditions.

Introduction: Delayed sleep and meal timing promote metabolic dysregulation and obesity. Altered coordination of sleep and eating may impact food reward valuation in the brain; yet the independent and collective contribution of sleep and meal times remains unknown. This pilot, randomized crossover study manipulates both sleep and meal times while preserving normal sleep duration (8 h time in bed for 5 nights) to test how misalignment of sleeping and eating behaviors affects intrinsic functional connectivity (iFC) across reward and interoception-related brain circuitry. Methods: Resting state functional MRI scans (3T Siemens Skyra; TR = 2.5s; 2 x ~5-minute runs) were obtained for 4 participants (3 males; 25.3 +/- 4.6 years) who completed all 4 phases (normal sleep/normal meal; late sleep/normal meal; normal sleep/late meal; late sleep/late meal). Normal meal times were 1, 5, 11, and 12.5 h after awakening and late meal times were 4.5, 8.5, 14.5 and 16 h after awakening. For a priori selected regions-of-interest (seeds) relevant to food reward and interoception, each seed's iFC was calculated as the correlation between its time-series and that of every voxel, and then contrasted between conditions. Standard preprocessing and seed-based correlations used the Configurable Pipeline for the Analysis of Connectomes v0.3.9. Results: Statistically significant (p late) additionally significantly modulated iFC between left ventral striatum and precuneus. Other significant iFC modulations of components of reward and interoception circuitry will also be presented. Conclusion: These pilot findings provide support that misalignment of sleep and food timing alters iFC in regions relevant to food reward and interoception, motivating examination in a larger sample

This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (Abeta) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD.

PURPOSE: To design, construct and validate radiofrequency (RF) transmit and receive phased array coils for high-resolution visual cortex imaging at 7 Tesla. METHODS: A 4 channel transmit and 16 channel receive array was constructed on a conformal polycarbonate former. Transmit field efficiency and homogeneity were simulated and validated, along with the Specific Absorption Rate, using [Formula: see text] mapping techniques and electromagnetic simulations. Receiver signal-to-noise ratio (SNR), temporal SNR (tSNR) across EPI time series, g-factors for accelerated imaging and noise correlations were evaluated and compared with a commercial 32 channel whole head coil. The performance of the coil was further evaluated with human subjects through functional MRI (fMRI) studies at standard and submillimeter resolutions of upto 0.8mm isotropic. RESULTS: The transmit and receive sections were characterized using bench tests and showed good interelement decoupling, preamplifier decoupling and sample loading. SNR for the 16 channel coil was approximately 1.5 times that of the commercial coil in the human occipital lobe, and showed better g-factor values for accelerated imaging. fMRI tests conducted showed better response to Blood Oxygen Level Dependent (BOLD) activation, at resolutions of 1.2mm and 0.8mm isotropic. CONCLUSION: The 4 channel phased array transmit coil provides homogeneous excitation across the visual cortex, which, in combination with the dual row 16 channel receive array, makes for a valuable research tool for high resolution anatomical and functional imaging of the visual cortex at 7T.

The invention of new mouse molecular genetics techniques, initiated in the 1980s, has repeatedly expanded our ability to tackle exciting developmental biology problems. The brain is the most complex organ, and as such the more sophisticated the molecular genetics technique, the more impact they have on uncovering new insights into how our brain functions. I provide a general time line for the introduction of new techniques over the past 30 years and give examples of new discoveries in the neural development field that emanated from them. I include a look to what the future holds and argue that we are at the dawn of a very exciting age for young scientists interested in studying how the nervous system is constructed and functions with such precision.