Faculty Bibliography

Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.Neuropsychopharmacology advance online publication, 23 October 2013; doi:10.1038/npp.2013.184.

OBJECTIVE: The objective of the study was to investigate the feasibility of 7-T shoulder magnetic resonance imaging by developing transmit and receive radiofrequency (RF) coil arrays and exploring RF shim methods. MATERIALS AND METHODS: A mechanically flexible 8-channel transmit array and an anatomically conformable 10-channel receive array were designed and implemented. The transmit performance of various RF shim methods was assessed through local flip angle measurements in the right and left shoulders of 6 subjects. The receive performance was assessed through signal-to-noise ratio measurements using the developed 7-T coil and a baseline commercial 3-T coil. RESULTS: The 7-T transmit array driven with phase-coherent RF shim weights provided adequate B1 efficiency and uniformity for turbo spin echo shoulder imaging. B1 twisting that is characteristic of high-field loop coils necessitates distinct RF shim weights in the right and left shoulders. The 7-T receive array provided a 2-fold signal-to-noise ratio improvement over the 3-T array in the deep articular shoulder cartilage. CONCLUSIONS: Shoulder imaging at 7-T is feasible with a custom transmit/receive array either in a single-channel transmit mode with a fixed RF shim or in a parallel transmit mode with a subject-specific RF shim.

PURPOSE: To develop a bilateral coil and fat suppressed T1-weighted sequence for 7 Tesla (T) breast MRI. MATERIALS AND METHODS: A dual-solenoid coil and three-dimensional (3D) T1w gradient echo sequence with B1 + insensitive fat suppression (FS) were developed. T1w FS image quality was characterized through image uniformity and fat-water contrast measurements in 11 subjects. Signal-to-noise ratio (SNR) and flip angle maps were acquired to assess the coil performance. Bilateral contrast-enhanced and unilateral high resolution (0.6 mm isotropic, 6.5 min acquisition time) imaging highlighted the 7T SNR advantage. RESULTS: Reliable and effective FS and high image quality was observed in all subjects at 7T, indicating that the custom coil and pulse sequence were insensitive to high-field obstacles such as variable tissue loading. 7T and 3T image uniformity was similar (P = 0.24), indicating adequate 7T B1 + uniformity. High 7T SNR and fat-water contrast enabled 0.6 mm isotropic imaging and visualization of a high level of fibroglandular tissue detail. CONCLUSION: 7T T1w FS bilateral breast imaging is feasible with a custom radiofrequency (RF) coil and pulse sequence. Similar image uniformity was achieved at 7T and 3T, despite different RF field behavior and variable coil-tissue interaction due to anatomic differences that might be expected to alter magnetic field patterns. J. Magn. Reson. Imaging 2013. (c) 2013 Wiley Periodicals, Inc.

PURPOSE: To demonstrate the feasibility of performing bone microarchitecture, high-resolution cartilage, and clinical imaging of the hip at 7T. MATERIALS AND METHODS: This study had Institutional Review Board approval. Using an 8-channel coil constructed in-house, we imaged the hips of 15 subjects on a 7T magnetic resonance imaging (MRI) scanner. We applied: 1) a T1-weighted 3D fast low angle shot (3D FLASH) sequence (0.23 x 0.23 x 1-1.5 mm3 ) for bone microarchitecture imaging; 2) T1-weighted 3D FLASH (water excitation) and volumetric interpolated breath-hold examination (VIBE) sequences (0.23 x 0.23 x 1.5 mm3 ) with saturation or inversion recovery-based fat suppression for cartilage imaging; 3) 2D intermediate-weighted fast spin-echo (FSE) sequences without and with fat saturation (0.27 x 0.27 x 2 mm) for clinical imaging. RESULTS: Bone microarchitecture images allowed visualization of individual trabeculae within the proximal femur. Cartilage was well visualized and fat was well suppressed on FLASH and VIBE sequences. FSE sequences allowed visualization of cartilage, the labrum (including cartilage and labral pathology), joint capsule, and tendons. CONCLUSION: This is the first study to demonstrate the feasibility of performing a clinically comprehensive hip MRI protocol at 7T, including high-resolution imaging of bone microarchitecture and cartilage, as well as clinical imaging. J. Magn. Reson. Imaging 2013;. (c) 2013 Wiley Periodicals, Inc.

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late-onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid-beta (Abeta) peptides occurs at residues 244-272 of apoE and residues 12-28 of Abeta. ApoE4 has been implicated in promoting Abeta deposition and impairing clearance of Abeta. We hypothesized that blocking the apoE/Abeta interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Abeta12-28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy (CAA). In the present study, we investigated whether the Abeta12-28P elicits a therapeutic effect on tau-related pathology in addition to amyloid pathology using old triple transgenic Alzheimer's disease mice (3xTg, with PS1M146V , APPS we and tauP30 IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Abeta12-28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice

Differential core symptoms and treatment responses are associated with the pure versus comorbid forms of attention-deficit/hyperactivity disorder (ADHD). However, comorbidity has largely been unaccounted for in neuroimaging studies of ADHD. We used diffusional kurtosis imaging to investigate gray matter (GM) and white matter (WM) microstructure of children and adolescents with ADHD (n = 22) compared to typically developing controls (TDC, n = 27) and examined whether differing developmental patterns are related to comorbidity. The ADHD group (ADHD-mixed) consisted of subgroups with and without comorbidity (ADHD-comorbid, n = 11; ADHD-pure, n = 11, respectively). Age-related changes and group differences in cerebral microstructure of the ADHD-mixed group and each ADHD subgroup were compared to TDC. Whole-brain voxel-based analyses with mean kurtosis (MK) and mean diffusivity (MD) metrics were conducted to probe GM and WM. Tract-based spatial statistics analyses of WM were performed with MK, MD, fractional anisotropy, and directional (axial, radial) kurtosis and diffusivity metrics. ADHD-pure patients lacked significant age-related changes in GM and WM microstructure that were observed globally in TDC and had significantly greater WM microstructural complexity than TDC in bilateral frontal and parietal lobes, insula, corpus callosum, and right external and internal capsules. Including ADHD patients with diverse comorbidities in analyses masked these findings. A distinct atypical age-related trajectory and aberrant regional differences in brain microstructure were detected in ADHD without comorbidity. Our results suggest that different phenotypic manifestations of ADHD, defined by the presence or absence of comorbidity, differ in cerebral microstructural markers. Hum Brain Mapp, 2013. (c) 2013 Wiley Periodicals, Inc.

The connectivity of neuronal systems is their most fundamental characteristic. Here, we focus on recent developments in understanding structural and functional connectivity at the macroscale, which is accessible with current imaging technology. Structural connectivity is examined via diffusion weighted imaging methods, of which diffusion tensor imaging is the most frequently used. Many cross-sectional and an increasing number of longitudinal studies using diffusion tensor imaging have been recently conducted over the period of development starting with newborns. Functional connectivity has been studied through task-based functional magnetic resonance imaging, and increasingly through studies on task-free functional imaging, also known as resting state functional imaging. The study of intrinsic functional connectivity beginning during fetal life reveals the developmental organization of intrinsic connectivity networks such as the default mode network, the dorsal attention network, the frontal-parietal executive control network, as well as primary cortical networks. As methods of examining both structural and functional connectivity mature, they increasingly inform our understanding of the development of connectivity in service of the long-term goal of delineating the substrates of much of developmental psychopathology.

In the Down syndrome (DS) population, there is an early incidence of dementia and neuropathology similar to that seen in sporadic Alzheimer's disease (AD), including dysfunction of the basal forebrain cholinergic neuron (BFCN) system. Using Ts65Dn mice, a model of DS and AD, we examined differences in the BFCN system between male and female segmentally trisomic (Ts65Dn) and disomic (2N) mice at ages 5-8 months. Quantitative stereology was applied to BFCN subfields immunolabeled for choline acetyltransferase (ChAT) within the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB) and nucleus basalis of Meynert/substantia innominata (NBM/SI). We found no sex differences in neuron number or subregion area measurement in the MS/VDB or HDB. However, 2N and Ts65Dn females showed an average 34% decrease in BFCN number and an average 20% smaller NBM/SI region area compared with genotype-matched males. Further, relative to genotype-matched males, female mice had smaller BFCNs in all subregions. These findings demonstrate that differences between the sexes in BFCNs of young adult Ts65Dn and 2N mice are region and genotype specific. In addition, changes in post-processing tissue thickness suggest altered parenchymal characteristics between male and female Ts65Dn mice.

Both mature BDNF and its precursor, proBDNF, play a crucial role in shaping neurons and contributing to the structural basis for neuronal connectivity. They do so in a largely opposing manner, and through differential engagement with their receptors. In this review, we will summarise the evidence that BDNF modulates neural circuit formation in vivo both within the central and peripheral nervous systems, through the control of neuronal morphology. The underlying intracellular mechanisms that translate BDNF signalling into changes of neuronal cell shape will be described. In addition, the signalling pathways that act either locally at the site of BDNF action, or over long distances to influence gene transcription will be discussed. These mechanisms begin to explain the diversity of actions that BDNF carries out on neuronal morphology. This article is part of a Special Issue entitled 'BDNF'.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.Molecular Psychiatry advance online publication, 18 June 2013; doi:10.1038/mp.2013.78.