Faculty Bibliography

Purpose Pre-operative three-dimensional (3D) printed renal malignancy models are tools with potential benefits in surgical training and patient education [1,2]. Most importantly, 3D models may facilitate surgical planning by allowing surgeons to assess tumor complexity as well as the relationship of the tumor to major anatomic structures [3]. The objective of this study was to evaluate this impact. Methods Imaging was obtained from an IRB approved, prospectively collected database of multiparametric magnetic resonance imaging (MRI) of renal masses. Ten cases eligible for elective partial nephrectomy were retrospectively selected. High-fidelity models were 3D printed in multiple colors based on T1 images (Fig. 1). Cases were reviewed by three attending surgeons and six senior residents with imaging alone and in addition to the 3D model. A standardized questionnaire was developed to capture the planned surgical approach and intraoperative technique in both sessions. Results Surgical approach was changed in 20 % of decisions, intraoperative considerations were changed in 40 % (Fig. 2). Thirty percent and 23 % of decisions in the attending and resident groups, respectively, were altered by the 3D model. Overall, every case was modified with this additional information. All participants reported that the models helped plan the surgical approach for partial nephrectomy. Most reported improved comprehension of anatomy and confidence in surgical plan. Half reported that the 3D printed model altered their surgical plan significantly. Due to use of T1 images, reconstruction of calyces and tertiary blood vessels were limited: 8 of the 9 participants desired more information regarding these structures. (Figure presented) Conclusion Utilization of 3D modeling may aid in pre-operative and intra-operative planning for both attending and resident surgeons. While 3D models with MR imaging is feasible, computed tomography (CT) imaging may provide additional anatomical information. Future study is required to prospectively assess the utility of models and pre-operative planning and intra-operative guidance

Interindividual differences play a crucial role in research on mental imagery. The inherently private nature of imagery does not allow for the same experimental control that is possible in perception research. Even when there are precise instructions subjects will differ in their particular imagery strategy and, hence, show different brain activations. Here, we show results of a time-resolved searchlight analysis for 12 individual subjects who perform a visual motion imagery task. The data show the spatial and temporal extent of brain areas and time windows that allow for a successful decoding of the direction of imagined motion out of four options. Accuracy maps for six different time windows are shown for every individual subject and are made freely available on NeuroVault. These data accompany the findings in the publication "Decoding the direction of imagined visual motion using 7 T ultra-high field fMRI" (Emmerling et al., 2016) [1].

Our aim was to characterize the nature and extent of pathological changes in the normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS) using novel diffusion kurtosis imaging-derived white matter tract integrity (WMTI) metrics and to investigate the association between these WMTI metrics and clinical parameters. Thirty-two patients with relapsing-remitting MS and 19 age- and gender-matched healthy controls underwent MRI and neurological examination. Maps of mean diffusivity, fractional anisotropy and WMTI metrics (intra-axonal diffusivity, axonal water fraction, tortuosity and axial and radial extra-axonal diffusivity) were created. Tract-based spatial statistics analysis was performed to assess for differences in the NAWM between patients and controls. A region of interest analysis of the corpus callosum was also performed to assess for group differences and to evaluate correlations between WMTI metrics and measures of disease severity. Mean diffusivity and radial extra-axonal diffusivity were significantly increased while fractional anisotropy, axonal water fraction, intra-axonal diffusivity and tortuosity were decreased in MS patients compared with controls (p values ranging from <0.001 to <0.05). Axonal water fraction in the corpus callosum was significantly associated with the expanded disability status scale score (rho = -0.39, p = 0.035). With the exception of the axial extra-axonal diffusivity, all metrics were correlated with the symbol digits modality test score (p values ranging from 0.001 to <0.05). WMTI metrics are thus sensitive to changes in the NAWM of MS patients and might provide a more pathologically specific, clinically meaningful and practical complement to standard diffusion tensor imaging-derived metrics.

Interactions between the hippocampus and the cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but the mechanisms by which they interact with physiological patterns of network activity are mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation, and that they are precisely coordinated with spindle oscillations in the prefrontal cortex during nonrapid-eye-movement (NREM) sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during rapid-eye movement (REM) sleep and wakefulness-behavioral states that do not naturally express these oscillations-by generating a cortical 'down' state. In a pilot clinical examination of four subjects with focal epilepsy, we confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions. These findings imply that IEDs may impair memory via the misappropriation of physiological mechanisms for hippocampal-cortical coupling, which suggests a target for the treatment of memory impairment in epilepsy.

Tinbergen proposed that instinctive behaviors can be divided into appetitive and consummatory phases. During mating and aggression, the appetitive phase contains various actions to bring an animal to a social target and the consummatory phase allows stereotyped actions to take place. Here, we summarize recent advances in elucidating the neural circuits underlying the appetitive and consummatory phases of sexual and aggressive behaviors with a focus on male mice. We outline the role of the main olfactory inputs in the initiation of social approach; the engagement of the accessory olfactory system during social investigation, and the role of the hypothalamus and its downstream pathways in orchestrating social behaviors through a suite of motor actions.

Conformational phosphorylation and cleavage events drive the tau protein from a soluble, monomeric state to a relatively insoluble, polymeric state that precipitates the formation of neurofibrillary tangles (NFTs) in projection neurons in Alzheimer's disease (AD), including the magnocellular perikarya located in the nucleus basalis of Meynert (NBM) complex of the basal forebrain. Whether these structural changes in the tau protein are associated with pathogenic changes at the molecular and cellular level remains undetermined during the onset of AD. Here, we examined alterations in gene expression within individual NBM neurons immunostained for pS422, an early tau phosphorylation event, or dual labeled for pS422 and TauC3, a later stage tau neoepitope, from tissue obtained postmortem from subjects who died with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild/moderate AD. Specifically, pS422-positive pretangles displayed an upregulation of select gene transcripts subserving protein quality control. On the other hand, late-stage TauC3-positive NFTs exhibited upregulation of messenger RNAs involved in protein degradation but also cell survival. Taken together, these results suggest that molecular pathways regulating protein homeostasis are altered during the evolution of NFT pathology in the NBM. These changes likely contribute to the disruption of protein turnover and neuronal survival of these vulnerable NBM neurons during the progression of AD.

As information propagates along the ventral visual hierarchy, neuronal responses become both more specific for particular image features and more tolerant of image transformations that preserve those features. Here, we present evidence that neurons in area V2 are selective for local statistics that occur in natural visual textures, and tolerant of manipulations that preserve these statistics. Texture stimuli were generated by sampling from a statistical model, with parameters chosen to match the parameters of a set of visually distinct natural texture images. Stimuli generated with the same statistics are perceptually similar to each other despite differences, arising from the sampling process, in the precise spatial location of features. We assessed the accuracy with which these textures could be classified based on the responses of V1 and V2 neurons recorded individually in anesthetized macaque monkeys. We also assessed the accuracy with which particular samples could be identified, relative to other statistically matched samples. For populations of up to 100 cells, V1 neurons supported better performance in the sample identification task, whereas V2 neurons exhibited better performance in texture classification. Relative to V1, the responses of V2 show greater selectivity and tolerance for the representation of texture statistics.

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes, and coupling depends on Cx43 expression.

Alzheimer's disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (qRT-PCR). We found similar protein and mRNA levels of the major cholinergic "tailed"-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic "readthrough" AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine.

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.