Faculty Bibliography

Increasing attention is being paid to the relationship between attention deficit/hyperactivity disorder (ADHD) and obesity. While most available research focused on determining the extent of the association between ADHD and obesity, a few studies have examined the clinical implications of diagnosing/treating ADHD in individuals with obesity. Here, we provide a narrative review of studies addressing the impact of ADHD, or its treatment, in individuals with obesity. Reviewed studies suggest that ADHD impedes the successful treatment of obesity in individuals with comorbid ADHD and obesity. Preliminary evidence also suggests that ADHD treatment might significantly increase the effectiveness of weight management strategies. We discuss the limitations of the reviewed studies and provide suggestions for future research in the field.

In the accompanying Annual Research Review, Horga and colleagues provide a comprehensive overview of the current limitations of magnetic resonance imaging (MRI) of developmental psychopathologies focusing particularly on experimental design. Horga et al. are unsparing in their assessment of the problems that plague current clinical neuroimaging studies. We will not reiterate the long list of deficiencies in the imaging literature, which persist despite its impressive volume (PubMed lists more than 135,000 papers with the terms 'magnetic resonance imaging' and 'brain'). Rather, in this Commentary, while we agree with Horga et al. that neuroimaging approaches merely represent one more types of tool, we look at where this leave us and the prospects (by attending to the lessons thoughtfully laid out by Horga and colleagues on how to place research design at the forefront in clinical neuroimaging) of better times ahead for our understanding of the pathophysiology of child- and adult-onset developmental psychiatric conditions.

One of the hallmarks of numerous life-threatening and debilitating brain diseases is cellular swelling that negatively impacts extracellular space (ECS) structure. The ECS structure is determined by two macroscopic parameters, namely tortuosity (lambda) and volume fraction (alpha). Tortuosity represents hindrance imposed on the diffusing molecules by the tissue in comparison with an obstacle-free medium. Volume fraction is the proportion of tissue volume occupied by the ECS. From a clinical perspective, it is essential to recognize which factors determine the ECS parameters and how these factors change in brain diseases. Previous studies demonstrated that dead-space (DS) microdomains increased lambda during ischemia and hypotonic stress, as these pocket-like structures transiently trapped diffusing molecules. We hypothesize that astrocytes play a key role in the formation of DS microdomains because their thin processes have concave shapes that may elongate as astrocytes swell in these pathologies. Here we selectively swelled astrocytes in the somatosensory neocortex of rat brain slices with a gliotoxin DL-alpha-Aminoadipic Acid (DL-AA), and we quantified the ECS parameters using Integrative Optical Imaging (IOI) and Real-Time Iontophoretic (RTI) diffusion methods. We found that alpha decreased and lambda increased during DL-AA application. During recovery, alpha was restored whereas lambda remained elevated. Increase in lambda during astrocytic swelling and recovery is consistent with the formation of DS microdomains. Our data attribute to the astrocytes an important role in determining the ECS parameters, and indicate that extracellular diffusion can be improved not only by reducing the swelling but also by disrupting the DS microdomains. GLIA 2014.

Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF.

An analytical representation of the leading non-Gaussian corrections for a class of diffusion orientation distribution functions (dODFs) is presented. This formula is constructed from the diffusion and diffusional kurtosis tensors, both of which may be estimated with diffusional kurtosis imaging (DKI). By incorporating model-independent non-Gaussian diffusion effects, it improves on the Gaussian approximation used in diffusion tensor imaging (DTI). This analytical representation therefore provides a natural foundation for DKI-based white matter fiber tractography, which has potential advantages over conventional DTI-based fiber tractography in generating more accurate predictions for the orientations of fiber bundles and in being able to directly resolve intra-voxel fiber crossings. The formula is illustrated with numerical simulations for a two-compartment model of fiber crossings and for human brain data. These results indicate that the inclusion of the leading non-Gaussian corrections can significantly affect fiber tractography in white matter regions, such as the centrum semiovale, where fiber crossings are common.