Faculty Bibliography

Is covert visuospatial attention-selective processing of information in the absence of eye movements-preserved in adults with attention-deficit/hyperactivity disorder (ADHD)? Previous findings are inconclusive due to inconsistent terminology and suboptimal methodology. To settle this question, we used well-established spatial cueing protocols to investigate the perceptual effects of voluntary and involuntary attention on an orientation discrimination task for a group of adults with ADHD and their neurotypical age-matched and gender-matched controls. In both groups, voluntary attention significantly improved accuracy and decreased reaction times at the relevant location, but impaired accuracy and slowed reaction times at irrelevant locations, relative to a distributed attention condition. Likewise, involuntary attention improved accuracy and speeded responses. Critically, the magnitudes of all these orienting and reorienting attention effects were indistinguishable between groups. Thus, these counterintuitive findings indicate that spatial covert attention remains functionally intact in adults with ADHD.

PURPOSE: To develop and evaluate a novel dynamic contrast-enhanced imaging technique called RACER-GRASP (Respiratory-weighted, Aortic Contrast Enhancement-guided and coil-unstReaking Golden-angle RAdial Sparse Parallel) MRI that extends GRASP to include automatic contrast bolus timing, respiratory motion compensation, and coil-weighted unstreaking for improved imaging performance in liver MRI. METHODS: In RACER-GRASP, aortic contrast enhancement (ACE) guided k-space sorting and respiratory-weighted sparse reconstruction are performed using aortic contrast enhancement and respiratory motion signals extracted directly from the acquired data. Coil unstreaking aims to weight multicoil k-space according to streaking artifact level calculated for each individual coil during image reconstruction, so that coil elements containing a high level of streaking artifacts contribute less to the final results. Self-calibrating GRAPPA operator gridding was applied as a pre-reconstruction step to reduce computational burden in the subsequent iterative reconstruction. The RACER-GRASP technique was compared with standard GRASP reconstruction in a group of healthy volunteers and patients referred for clinical liver MR examination. RESULTS: Compared with standard GRASP, RACER-GRASP significantly improved overall image quality (average score: 3.25 versus 3.85) and hepatic vessel sharpness/clarity (average score: 3.58 versus 4.0), and reduced residual streaking artifact level (average score: 3.23 versus 3.94) in different contrast phases. RACER-GRASP also enabled automatic timing of the arterial phases. CONCLUSIONS: The aortic contrast enhancement-guided sorting, respiratory motion suppression and coil unstreaking introduced by RACER-GRASP improve upon the imaging performance of standard GRASP for free-breathing dynamic contrast-enhanced MRI of the liver. Magn Reson Med, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine.

PURPOSE: The aim of this study was to evaluate the effect of integrated high-permittivity materials (HPMs) on excitation homogeneity and global specific absorption rate (SAR) for transmit arrays at 7T. METHODS: A rapid electrodynamic simulation framework was used to calculate L-curves associated with excitation of a uniform 2D profile in a dielectric sphere. We used ultimate intrinsic SAR as an absolute performance reference to compare different transmit arrays in the presence and absence of a layer of HPM. We investigated the optimal permittivity for the HPM as a function of its thickness, the sample size, and the number of array elements. RESULTS: Adding a layer of HPM can improve the performance of a 24-element array to match that of a 48-element array without HPM, whereas a 48-element array with HPM can perform as well as a 64-element array without HPM. Optimal relative permittivity values changed based on sample and coil geometry, but were always within a range obtainable with readily available materials (epsilonr = 100-200). CONCLUSION: Integration of HPMs could be a practical method to improve RF shimming performance, alternative to increasing the number of coils. The proposed simulation framework could be used to explore the design of novel transmit arrays for head imaging at ultra-high field strength. Magn Reson Med, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine.

Developmental ethanol exposure is a well-known cause of lifelong cognitive deficits, behavioral hyperactivity, emotional dysregulation, and more. In healthy adults, sleep is thought to have a critical involvement in each of these processes. Our previous work has demonstrated that some aspects of cognitive impairment in adult mice exposed at postnatal day 7 (P7) to ethanol (EtOH) correlate with slow-wave sleep (SWS) fragmentation (Wilson et al., 2016). We and others have also previously demonstrated that co-treatment with LiCl on the day of EtOH exposure prevents many of the anatomical and physiological impairments observed in adults. Here we explored cognitive function, diurnal rhythms (activity, temperature), SWS, and parvalbumin (PV) and perineuronal net (PNN)-positive cell densities in adult mice that had received a single day of EtOH exposure on P7 and saline-treated littermate controls. Half of the animals also received a LiCl injection on P7. The results suggest that developmental EtOH resulted in adult behavioral hyperactivity, cognitive impairment, and reduced SWS compared to saline controls. Both of these effects were reduced by LiCl treatment on the day of EtOH exposure. Finally, developmental EtOH resulted in decreased PV/PNN-expressing cells in retrosplenial (RS) cortex and dorsal CA3 hippocampus at P90. As with sleep and behavioral activity, LiCl treatment reduced this decrease in PV expression. Together, these results further clarify the long-lasting effects of developmental EtOH on adult behavior, physiology, and anatomy. Furthermore, they demonstrate the neuroprotective effects of LiCl co-treatment on this wide range of developmental EtOH's long-lasting consequences.

OBJECTIVE: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities. METHODS: Morquio A patients aged >/=7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined). RESULTS: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO2), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO2/work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost. CONCLUSIONS: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.

Surface roughness is one of the most important qualities in haptic perception. Roughness is a major identifier for judgments of material composition, comfort and friction, and is tied closely to manual dexterity. Some attention has been given to the study of roughness perception in the past, but it has typically focused on non-controllable natural materials or on a narrow range of artificial materials. The advent of high-resolution 3D printing technology provides the ability to fabricate arbitrary 3D textures with precise surface geometry to be used in tactile studies. We used parametric modeling and 3D printing to manufacture a set of textured plates with defined element spacing, shape, and arrangement. Using active touch and two-alternative forced choice protocols, we investigated the contributions of these surface parameters to roughness perception in human subjects. Results indicate that large spatial periods produce higher estimations of roughness (with Weber fraction = 0.19), small texture elements are perceived as rougher than large texture elements of the same wavelength, perceptual differences exist between textures with the same spacing but different arrangements, and roughness equivalencies exist between textures differing along different parameters. We posit that papillary ridges serve as tactile processing units, and neural ensembles encode the spatial profiles of the texture contact area to produce roughness estimates. The stimuli and the manufacturing process may be used in further studies of tactile roughness perception and in related neurophysiological applications.

ATP-sensitive K+ (KATP) channels uniquely link cellular energy metabolism to membrane excitability and are expressed in diverse cell types that range from the endocrine pancreas to neurons and smooth, skeletal, and cardiac muscle. A decrease in the surface expression of KATP channels has been linked to various disorders, including dysregulated insulin secretion, abnormal blood pressure, and impaired resistance to cardiac injury. In contrast, up-regulation of KATP channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate KATP channel trafficking are poorly understood. Here, we used cellular assays with immunofluorescence, surface biotinylation, and patch clamping to demonstrate that Eps15 homology domain-containing protein 2 (EHD2) is a novel positive regulator of KATP channel trafficking to increase surface KATP channel density. EHD2 had no effect on cardiac Na+ channels (Nav1.5). The effect is specific to EHD2 as other members of the EHD family-EHD1, EHD3, and EHD4-had no effect on KATP channel surface expression. EHD2 did not directly affect KATP channel properties as unitary conductance and ATP sensitivity were unchanged. Instead, we observed that the mechanism by which EHD2 increases surface expression is by stabilizing KATP channel-containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated KATP channel trafficking in isolated cardiomyocytes, which validated the physiologic relevance of these observations. Pathophysiologically, EHD2 may be cardioprotective as a dominant-negative EHD2 mutant sensitized cardiomyocytes to ischemic damage. Our findings highlight EHD2 as a potential pharmacologic target in the treatment of diseases with KATP channel trafficking defects.-Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection.

RATIONALE: Recent evidence suggests that Obstructive Sleep Apnea (OSA) may be a risk factor for developing Mild Cognitive Impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood. OBJECTIVE: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. METHODS: Data was derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 to 90, were non-depressed and had a consensus clinical diagnosis of cognitively normal. CSF Amyloid beta was measured using ELISA. Subjects received Pittsburgh compound B Positron Emission Tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. MEASUREMENTS AND MAIN RESULTS: We found that severity of OSA indices (lnAHIall [F1,88=4.26, p<.05] and lnAHI4% [F1,87=4.36, p<.05]) were associated with annual rate of change of CSF Abeta42 using linear regression after adjusting for age, sex, BMI and ApoE4 status. LnAHIall and lnAHI4 were not associated with increases in ADPiB-mask most likely due to the small sample size although there was a trend for lnAHIall (F1,28=2.96, p=.09 and F1,28=2.32, n.s. respectively). CONCLUSION: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2 year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs.

OBJECTIVE: To use high-permittivity materials (HPM) positioned near radiofrequency (RF) surface coils to manipulate transmit/receive field patterns. MATERIALS AND METHODS: A large HPM pad was placed below the RF coil to extend the field of view (FOV). The resulting signal-to-noise ratio (SNR) was compared with that of other coil configurations covering the same FOV in simulations and experiments at 7 T. Transmit/receive efficiency was evaluated when HPM discs with or without a partial shield were positioned at a distance from the coil. Finally, we evaluated the increase in transmit homogeneity for a four-channel array with HPM discs interposed between adjacent coil elements. RESULTS: Various configurations of HPM increased SNR, transmit/receive efficiency, excitation/reception sensitivity overlap, and FOV when positioned near a surface coil. For a four-channel array driven in quadrature, shielded HPM discs enhanced the field below the discs as well as at the center of the sample as compared with other configurations with or without unshielded HPM discs. CONCLUSION: Strategically positioning HPM at a distance from a surface coil or array can increase the overlap between excitation/reception sensitivities, and extend the FOV of a single coil for reduction of the number of channels in an array while minimally affecting the SNR.