Faculty Bibliography

Background: Alzheimer's disease (AD) has been shown to be associated with shrinkage of the corpus callosum mid-sagittal cross-sectional area (CCA). Objective: To study temporal rates of corpus callosum atrophy not previously reported for early AD. Methods: We used longitudinal MRI scans to study the rates of change of CCA and circularity (CIR), a measure of its shape, in normal controls (NC, n = 75), patients with very mild AD (AD-VM, n = 51), and mild AD (AD-M, n = 21). Results: There were significant reduction rates in CCA and CIR in all three groups. While CCA reduction rates were not statistically different between groups, the CIR declined faster in AD-VM (p < 0.03) and AD-M (p < 0.0001) relative to NC, and in AD-M relative to AD-VM (p < 0.0004). Conclusion: CIR declines at an accelerated rate with AD severity. Its rate of change is more closely associated with AD progression than CCA or any of its sub-regions. CIR may be a useful group biomarker for objective assessment of treatments that aim to slow AD progression.

Individuals exposed to traumatic stressors follow divergent patterns including resilience and chronic stress. However, researchers utilizing animal models that examine learned or instrumental threat responses thought to have translational relevance for Posttraumatic Stress Disorder (PTSD) and resilience typically use central tendency statistics that assume population homogeneity. This approach potentially overlooks fundamental differences that can explain human diversity in response to traumatic stressors. The current study tests this assumption by identifying and replicating common heterogeneous patterns of response to signaled active avoidance (AA) training. In this paradigm, rats are trained to prevent an aversive outcome (shock) by performing a learned instrumental behavior (shuttling between chambers) during the presentation of a conditioned threat cue (tone). We test the hypothesis that heterogeneous trajectories of threat avoidance provide more accurate model fit compared to a single mean trajectory in two separate studies. Study 1 conducted 3 days of signaled AA training (n = 81 animals) and study 2 conducted 5 days of training (n = 186 animals). We found that four trajectories in both samples provided the strongest model fit. Identified populations included animals that acquired and retained avoidance behavior on the first day (Rapid Avoiders: 22 and 25%); those who never successfully acquired avoidance (Non-Avoiders; 20 and 16%); a modal class who acquired avoidance over 3 days (Modal Avoiders; 37 and 50%); and a population who demonstrated a slow pattern of avoidance, failed to fully acquire avoidance in study 1 and did acquire avoidance on days 4 and 5 in study 2 (Slow Avoiders; 22.0 and 9%). With the exception of the Slow Avoiders in Study 1, populations that acquired demonstrated rapid step-like increases leading to asymptotic levels of avoidance. These findings indicate that avoidance responses are heterogeneous in a way that may be informative for understanding both resilience and PTSD as well as the nature of instrumental behavior acquisition. Characterizing heterogeneous populations based on their response to threat cues would increase the accuracy and translatability of such models and potentially lead to new discoveries that explain diversity in instrumental defensive responses.

Alzheimer's disease is a neurodegenerative disorder that is the most common cause of dementia in the elderly today. One of the earliest reported signs of Alzheimer's disease is olfactory dysfunction, which may manifest in a variety of ways. The present study sought to address this issue by investigating odor coding in the anterior piriform cortex, the primary cortical region involved in higher order olfactory function, and how it relates to performance on olfactory behavioral tasks. An olfactory habituation task was performed on cohorts of transgenic and age-matched wild-type mice at 3, 6 and 12 months of age. These animals were then anesthetized and acute, single-unit electrophysiology was performed in the anterior piriform cortex. In addition, in a separate group of animals, a longitudinal odor discrimination task was conducted from 3-12 months of age. Results showed that while odor habituation was impaired at all ages, Tg2576 performed comparably to age-matched wild-type mice on the olfactory discrimination task. The behavioral data mirrored intact anterior piriform cortex single-unit odor responses and receptive fields in Tg2576, which were comparable to wild-type at all age groups. The present results suggest that odor processing in the olfactory cortex and basic odor discrimination is especially robust in the face of amyloid beta precursor protein (AbetaPP) over-expression and advancing amyloid beta (Abeta) pathology. Odor identification deficits known to emerge early in Alzheimer's disease progression, therefore, may reflect impairments in linking the odor percept to associated labels in cortical regions upstream of the primary olfactory pathway, rather than in the basic odor processing itself.

Sharing drafts of scientific manuscripts on preprint hosting services for early exposure and pre-publication feedback is a well-accepted practice in fields such as physics, astronomy, or mathematics. The field of neuroscience, however, has yet to adopt the preprint model. A reason for this reluctance might partly be the lack of central preprint services for the field of neuroscience. To address this issue, we announce the launch of Preprints of the R-fMRI Network (PRN), a community funded preprint hosting service. PRN provides free-submission and free hosting of manuscripts for resting state functional magnetic resonance imaging (R-fMRI) and neuroscience related studies. Submissions will be peer viewed and receive feedback from readers and a panel of invited consultants of the R-fMRI Network. All manuscripts and feedback will be freely available online with citable permanent URL for open-access. The goal of PRN is to supplement the "peer reviewed" journal publication system - by more rapidly communicating the latest research achievements throughout the world. We hope PRN will help the field to embrace the preprint model and thus further accelerate R-fMRI and neuroscience related studies, eventually enhancing human mental health.

Much remains to be learned about typical and individual growth trajectories across treatment for adolescent panic disorder with and without agoraphobia and about critical treatment points associated with key changes. The present study examined the rate and shape of change across an 8-day intensive cognitive behavioral therapy for adolescent panic disorder with and without agoraphobia (N = 56). Participants ranged in age from 12 to 17 (M = 15.14, SD = 1.70; 58.9% female, 78.6% Caucasian). Multilevel modeling evaluated within-treatment linear and nonlinear changes across three treatment outcomes: panic severity, fear, and avoidance. Overall panic severity showed linear change, decreasing throughout treatment. In contrast, fear and avoidance ratings both showed cubic change, peaking slightly at the first session of treatment, starting to decrease at the second session of treatment, and with large gains continuing then plateauing at the fourth session. Findings are considered with regard to the extent to which they may elucidate critical treatment components and sessions for adolescents with panic disorder with and without agoraphobia.

Automated segmenting and labeling of individual brain anatomical regions, in MRI are challenging, due to the issue of individual structural variability. Although atlas-based segmentation has shown its potential for both tissue and structure segmentation, due to the inherent natural variability as well as disease-related changes in MR appearance, a single atlas image is often inappropriate to represent the full population of datasets processed in a given neuroimaging study. As an alternative for the case of single atlas segmentation, the use of multiple atlases alongside label fusion techniques has been introduced using a set of individual "atlases" that encompasses the expected variability in the studied population. In our study, we proposed a multi-atlas segmentation scheme with a novel graph-based atlas selection technique. We first paired and co-registered all atlases and the subject MR scans. A directed graph with edge weights based on intensity and shape similarity between all MR scans is then computed. The set of neighboring templates is selected via clustering of the graph. Finally, weighted majority voting is employed to create the final segmentation over the selected atlases. This multi-atlas segmentation scheme is used to extend a single-atlas-based segmentation toolkit entitled AutoSeg, which is an open-source, extensible C++ based software pipeline employing BatchMake for its pipeline scripting, developed at the Neuro Image Research and Analysis Laboratories of the University of North Carolina at Chapel Hill. AutoSeg performs N4 intensity inhomogeneity correction, rigid registration to a common template space, automated brain tissue classification based skull-stripping, and the multi-atlas segmentation. The multi-atlas-based AutoSeg has been evaluated on subcortical structure segmentation with a testing dataset of 20 adult brain MRI scans and 15 atlas MRI scans. The AutoSeg achieved mean Dice coefficients of 81.73% for the subcortical structures.

Reviews the book, Reading Anna Freud by Nick Midgley (see record 2012-32286-000). Reading Anna Freud is less a work of criticism than a work of orientation, and doubly valuable as such. First, because of the Freud family fame, one sometimes presumes one knows more about them than one really does (indeed, a misplaced presumption of familiarity is at the core of so much of the popular contempt hurled Sigmund's way). Second, orienting yourself to Anna Freud is a way of orienting yourself to child mental health: from how we speak to children and the role of schools in a child's psychological health to developmental psychopathology and the consultation-liaison service. What comes through in Reading Anna Freud is that the core of Freud's success was not just patient, compassionate intellectualism, genes, or an ability to get published, but advocacy. Moreover, you do not need a degree or an internal review board to be an advocate. In fact, it is in this regard that she is most inspiring. Although the book provides a historical and personal orientation, it is intended as an orientation to Freud's intellectual contributions, and Midgely does an excellent job translating her work, some of it nearly a century old, into a language that is still alive, relevant, and enriching.

The future of the textbook as we know it is in doubt. Knowledge is being shuttled into the virtual world, where it is collaborative, linked, multimedia, and transnational. The iterative nature of knowledge never fit comfortably with textbooks. They have always been notoriously out of date by the time they roll off the press. Nevertheless, there remains something comforting in the textbook's authoritative heft, which is lost not only in the vapor-thin flicker of Web pages but also in the suspicion with which we approach anything online, knowing full well that the provenance is dubious. Sock puppetry is not just a children's craft anymore; it's a modern form of authorship. Of course, textbooks have value as a corpus of knowledge that is not constantly changing; as a way of studying a topic without being distracted by the rabbit holes of the Internet; and as a backup: all knowledge will not be lost in a blackout. What the future of the textbook means for expert knowledge is unclear. How can hardcover and paperback textbooks carve out a place in tomorrow's society? One answer may be to look back.

In many systems, sleep plays a vital role in memory consolidation and synaptic homeostasis. These processes together help store information of biological significance and reset synaptic circuits to facilitate acquisition of information in the future. In this review, we describe recent evidence of sleep-dependent changes in olfactory system structure and function which contribute to odor memory and perception. During slow-wave sleep, the piriform cortex becomes hypo-responsive to odor stimulation and instead displays sharp-wave activity similar to that observed within the hippocampal formation. Furthermore, the functional connectivity between the piriform cortex and other cortical and limbic regions is enhanced during slow-wave sleep compared to waking. This combination of conditions may allow odor memory consolidation to occur during a state of reduced external interference and facilitate association of odor memories with stored hedonic and contextual cues. Evidence consistent with sleep-dependent odor replay within olfactory cortical circuits is presented. These data suggest that both the strength and precision of odor memories is sleep-dependent. The work further emphasizes the critical role of synaptic plasticity and memory in not only odor memory but also basic odor perception. The work also suggests a possible link between sleep disturbances that are frequently co-morbid with a wide range of pathologies including Alzheimer's disease, schizophrenia and depression and the known olfactory impairments associated with those disorders.

The International League Against Epilepsy (ILAE) defined a seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain." This definition has been used since the era of Hughlings Jackson, and does not take into account subsequent advances made in epilepsy and neuroscience research. The clinical diagnosis of a seizure is empirical, based upon constellations of certain signs and symptoms, while simultaneously ruling out a list of potential imitators of seizures. Seizures should be delimited in time, but the borders of ictal (during a seizure), interictal (between seizures) and postictal (after a seizure) often are indistinct. EEG recording is potentially very helpful for confirmation, classification and localization. About a half-dozen common EEG patterns are encountered during seizures. Clinicians rely on researchers to answer such questions as why seizures start, spread and stop, whether seizures involve increased synchrony, the extent to which extra-cortical structures are involved, and how to identify the seizure network and at what points interventions are likely to be helpful. Basic scientists have different challenges in use of the word 'seizure,' such as distinguishing seizures from normal behavior, which would seem easy but can be very difficult because some rodents have EEG activity during normal behavior that resembles spike-wave discharge or bursts of rhythmic spiking. It is also important to define when a seizure begins and stops so that seizures can be quantified accurately for pre-clinical studies. When asking what causes seizures, the transition to a seizure and differentiating the pre-ictal, ictal and post-ictal state is also important because what occurs before a seizure could be causal and may warrant further investigation for that reason. These and other issues are discussed by three epilepsy researchers with clinical and basic science expertise.