Setbacks in Alzheimer research demand new strategies, not surrender.

In this month's editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry.

Input clustering in the normal and learned circuits of adult barn owls.

Experience-dependent formation of synaptic input clusters can occur in juvenile brains. Whether this also occurs in adults is largely unknown. We previously reconstructed the normal and learned circuits of prism-adapted barn owls and found that changes in clustering of axo-dendritic contacts (putative synapses) predicted functional circuit strength. Here we asked whether comparable changes occurred in normal and prism-removed adults. Across all anatomical zones, no systematic differences in the primary metrics for within-branch or between-branch clustering were observed: 95-99% of contacts resided within clusters (<10-20 µm from nearest neighbor) regardless of circuit strength. Bouton volumes, a proxy measure of synaptic strength, were on average larger in the functionally strong zones, indicating that changes in synaptic efficacy contributed to the differences in circuit strength. Bootstrap analysis showed that the distribution of inter-contact distances strongly deviated from random not in the functionally strong zones but in those that had been strong during the sensitive period (60-250 d), indicating that clusters formed early in life were preserved regardless of current value. While cluster formation in juveniles appeared to require the production of new synapses, cluster formation in adults did not. In total, these results support a model in which high cluster dynamics in juveniles sculpt a potential connectivity map that is refined in adulthood. We propose that preservation of clusters in functionally weak adult circuits provides a storage mechanism for disused but potentially useful pathways.

Neuropsychological scores and WeeFIM cognitive ratings of children with traumatic brain injury: A brief report.

UNLABELLED: PRIMARY OBJECTIVE AND HYPOTHESIS: To test the hypothesis that there is a significant relationship between WeeFIM ratings of cognitive functioning and performance on neuropsychological tests of children with traumatic brain injury (TBI). DESIGN: Retrospective analysis of archival data. PARTICIPANTS: Data from 52 children with severe TBI collected during inpatient rehabilitation. MAIN OUTCOME MEASURES: Multiple regression analysis with Neuropsychological test scores from Wechsler Abbreviated Scale of Intelligence (WASI) and Children's Memory Scale (CMS) entered as predictor variables and WeeFIM cognitive ratings as criteria variables. RESULTS: Analyses revealed significant relationships between WeeFIM cognitive rating and neuropsychological test scores. Delayed verbal memory was most highly associated with WeeFIM cognitive ratings. CONCLUSIONS: Results support the hypothesis of significant relationships between neuropsychological performance and WeeFIM ratings of children with TBI and support generalizability of neuropsychological performance to daily cognitive functioning.

Epiploic Appendagitis Mimicking Acute Appendicitis: An Osteopathic Case Report.

Acute epiploic appendagitis is a rare cause of abdominal pain, often misdiagnosed as acute appendicitis or diverticulitis given similar clinical presentation and findings. The treatment is supportive care and is typically self-limited. The osteopathic structural exam can give insight into pathology and in this case, was suggestive of a non-appendiceal origin of her pain, in which emergent surgery could be avoided. Requiring computerized tomography to identify, acute epiploic appendagitis is a rare cause of abdominal pain and should be considered in the differential diagnosis.

Learning drives differential clustering of axodendritic contacts in the barn owl auditory system.

Computational models predict that experience-driven clustering of coactive synapses is a mechanism for information storage. This prediction has remained untested, because it is difficult to approach through time-lapse analysis. Here, we exploit a unique feature of the barn owl auditory localization pathway that permits retrospective analysis of prelearned and postlearned circuitry: owls reared wearing prismatic spectacles develop an adaptive microcircuit that coexists with the native one but can be analyzed independently based on topographic location. To visualize the clustering of axodendritic contacts (potential synapses) within these zones, coactive axons were labeled by focal injection of fluorescent tracer and their target dendrites labeled with an antibody directed against CaMKII (calcium/calmodulin-dependent protein kinase type II, alpha subunit). Using high-resolution confocal imaging, we measured the distance from each contact to its nearest neighbor on the same branch of dendrite. We found that the distribution of intercontact distances for the adaptive zone was shifted dramatically toward smaller values compared with distributions for either the maladaptive zone of the same animals or the adaptive zone of normal juveniles, which indicates that a dynamic clustering of contacts had occurred. Moreover, clustering in the normal zone was greater in normal juveniles than in prism-adapted owls, indicative of declustering. These data demonstrate that clustering is bidirectionally adjustable and tuned by behaviorally relevant experience. The microanatomical configurations in all zones of both experimental groups matched the functional circuit strengths that were assessed by in vivo electrophysiological mapping. Thus, the observed changes in clustering are appropriately positioned to contribute to the adaptive strengthening and weakening of auditory-driven responses.

Neuropsychological functioning in elderly patients with schizophrenia and Alzheimer's disease.

Cognitive functioning was compared in elderly patients with schizophrenia, elderly patients with probable Alzheimer's disease (AD), and matched healthy controls using a brief neuropsychological battery. Both schizophrenia and AD patients demonstrated marked impairment as compared to controls, with the profile of neuropsychological deficits in both disorders appearing remarkably similar. Only visual confrontation naming, verbal delayed recall, and rate of forgetting (i.e. savings score) significantly differentiated between the two patient groups, with AD patients showing poorer overall recall and more rapid forgetting of verbal information over delay. In addition, schizophrenia subjects showed a significantly greater deficit in visual confrontation naming than the AD group. The relationship of neuropsychological function and clinical symptoms of schizophrenia subjects was also examined. Results showed that word list learning, delayed recall, and rate of forgetting correlated most strongly with positive and negative symptoms. Recent neuropathological studies have indicated abnormalities in specific subfields of the hippocampal formation in schizophrenia that are also severely affected in AD. Though the specific histopathology of the two disorders differs, abnormalities in the common sites may underlie the common neuropsychological profile.

Input clustering and the microscale structure of local circuits.

The recent development of powerful tools for high-throughput mapping of synaptic networks promises major advances in understanding brain function. One open question is how circuits integrate and store information. Competing models based on random vs. structured connectivity make distinct predictions regarding the dendritic addressing of synaptic inputs. In this article we review recent experimental tests of one of these models, the input clustering hypothesis. Across circuits, brain regions and species, there is growing evidence of a link between synaptic co-activation and dendritic location, although this finding is not universal. The functional implications of input clustering and future challenges are discussed.

Heart rate and respiration in reptiles: contrasts between a sit-and-wait predator and an intensive forager.

The current study investigated respiration and heart rate in two species of reptiles with distinct behavioral strategies: (1) the Sudan plated lizard (Gerrhosaurus major), a sit-and-wait predator; and (2) the Savanna monitor (Varanus exanthematicus), an intensive forager. It was hypothesized that (a) the plated lizard would not express respiratory sinus arrhythmia, and (b) the monitor, a reptile with behavioral and physiological characteristics similar to mammals, might express respiratory sinus arrhythmia, a pattern previously observed only in mammals. The data demonstrated that although there were strong vagal influences on the heart, respiratory activity was not manifested in the heart rate pattern of the plated lizards. In contrast, the monitor exhibited a reliable ventilatory influence on the heart rate pattern, although the pattern differed from the respiratory sinus arrhythmia observed in mammals. Consistent with the Polyvagal Theory (), the vagal control of the reptilian heart in both species appears to be mediated through the phylogenetically older unmyelinated system, a system that evolved to support metabolic conservation and not social behavior.