Faculty Bibliography

Voltage-gated potassium channel subunit Kv3.3 is prominently expressed in cerebellar Purkinje cells and is known to be important for cerebellar function, as human and mouse movement disorders result from mutations in Kv3.3. To understand these behavioral deficits, it is necessary to know the role of Kv3.3 channels on the physiological responses of Purkinje cells. We studied the function of Kv3.3 channels in regulating the synaptically evoked Purkinje cell complex spike, the massive postsynaptic response to the activation of climbing fiber afferents, believed to be fundamental to cerebellar physiology. Acute slice recordings revealed that Kv3.3 channels are required for generation of the repetitive spikelets of the complex spike. We found that spikelet expression is regulated by somatic, and not by dendritic, Kv3 activity, which is consistent with dual somatic-dendritic recordings that demonstrate spikelet generation at axosomatic membranes. Simulations of Purkinje cell Na+ currents show that the unique electrical properties of Kv3 and resurgent Na+ channels are coordinated to limit accumulation of Na+ channel inactivation and enable rapid, repetitive firing. We additionally show that Kv3.3 knock-out mice produce altered complex spikes in vitro and in vivo, which is likely a cellular substrate of the cerebellar phenotypes observed in these mice. This characterization presents new tools to study complex spike function, cerebellar signaling, and Kv3.3-dependent human and mouse phenotypes

We present a simple and versatile technique of tailoring functionalized surface structures for protein enrichment and purification applications based on a superhydrophobic silicone nanofilament coating. Using amino and carboxyl group containing silanes, silicone nanofilament templates were chemically modified to mimic anionic and cationic exchange resins. Investigations on the selectivity of the functionalized surfaces toward adsorption of charged model proteins were carried out by means of fluorescence techniques. Due to a high contact area resulting from the nanoroughness of the coating, excellent protein retention characteristics under various conditions were found. The surfaces were shown to be highly stable and reusable over several retention-elution cycles. Especially the full optical transparency and the possibility to use glass substrates as support material open new opportunities for the development of optical biosensors, open geometry microfluidics, or lab-on-a-chip devices.

Although traditionally considered to be etiological factors in depression, corticosteroids have been shown to exert an acute antidepressant action under some conditions. To investigate the mechanism of this effect, the present experiment sought to develop an animal model of it in mice using the repeated forced swim procedure. Corticosterone or desmethylimipramine was administered in the drinking water before, during or after repeated daily forced swims or a tail suspension test. Glucocorticoid and mineralocorticoid receptor involvement were assessed by coadministration of RU486 or spironolactone. Plasma corticosterone and fos expression in the paraventricular nucleus of the hypothalamus and piriform cortex were also measured in the treated animals. Corticosterone, given either before/during or after repeated swim, was found to produce a rapid reduction of immobility that was greater than that produced by desmethylimipramine given by the same route and dose and for the same duration. There was a nonsignificant tendency toward this effect in the tail suspension test. RU486 failed to block the effect but results with spironolactone were ambiguous. Plasma corticosterone was elevated in an inverted U-shaped fashion by the hormone treatment. Fos expression in response to the last swim was blunted in the paraventricular hypothalamus but enhanced in the piriform cortex. It is concluded that short-term treatment with corticosterone has a marked antidepressant effect in the mouse repeated forced swim test and merits further consideration as a short-term therapeutic agent in low doses. The hormone may act by suppression of neural activity in central stress circuits leading to a disinhibition of regions involved in active behavioral coping

BACKGROUND: Pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) have focused on frontal-striatal circuitry with alternative hypotheses relatively unexplored. On the basis of evidence that negative interactions between frontal foci involved in cognitive control and the non-goal-directed 'default-mode' network prevent attentional lapses, we hypothesized abnormalities in functional connectivity of these circuits in ADHD. METHODS: Resting-state blood oxygen level-dependent functional magnetic resonance imaging (fMRI) scans were obtained at 3.0-Tesla in 20 adults with ADHD and 20 age- and sex-matched healthy volunteers. RESULTS: Examination of healthy control subjects verified presence of an antiphasic or negative relationship between activity in dorsal anterior cingulate cortex (centered at x = 8, y = 7, z = 38) and in default-mode network components. Group analyses revealed ADHD-related compromises in this relationship, with decreases in the functional connectivity between the anterior cingulate and precuneus/posterior cingulate cortex regions (p < .0004, corrected). Secondary analyses revealed an extensive pattern of ADHD-related decreases in connectivity between precuneus and other default-mode network components, including ventromedial prefrontal cortex (p < 3 x 10(-11), corrected) and portions of posterior cingulate (p < .02, corrected). CONCLUSIONS: Together with prior unbiased anatomic evidence of posterior volumetric abnormalities, our findings suggest that the long-range connections linking dorsal anterior cingulate to posterior cingulate and precuneus should be considered as a candidate locus of dysfunction in ADHD

PRIMARY OBJECTIVE: To explore whether baseline diffusion tensor imaging (DTI) metrics are predictive of cognitive functioning 6 months post-injury in patients with mild traumatic brain injury (MTBI). RESEARCH DESIGN: Seventeen patients with MTBI and 29 sex- and age-matched healthy controls were studied. METHODS AND PROCEDURES: Participants underwent an MRI protocol including DTI, at an average of 4.0 (range: 1-10) days post-injury. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in the following white matter (WM) regions: centra semiovale, the genu and the splenium of the corpus callosum and the posterior limb of the internal capsule. Participants underwent neuropsychological (NP) testing at baseline and at 6-month follow-up. Least squares regression analysis was used to evaluate the association of MD and FA with each NP test score at baseline and follow-up. MAIN OUTCOMES AND RESULTS: Compared to controls, average MD was significantly higher (p = 0.02) and average FA significantly lower (p = 0.0001) in MTBI patients. At the follow-up, there was a trend toward a significant association between baseline MD and response speed (r = -0.53, p = 0.087) and a positive correlation between baseline FA and Prioritization form B (r = 0.72, p = 0.003). CONCLUSIONS: DTI may provide short-term non-invasive predictive markers of cognitive functioning in patients with MTBI

The ultimate purpose of both dental industry and dental education is to improve the oral health of the public. This report provides background information on the different roles and objectives of the dental industry and dental education communities, the different operating environment of each sector and also areas of common interest where collaboration will be of mutual benefit. The report addresses five areas for potential collaboration between the dental industry and the dental education communities: 1. Contribution to joint activities. 2. Effectiveness and efficiency. 3. Workforce needs. 4. Middle- and low-income countries. 5. The future of International Federation of Dental Educators and Associations (IFDEA). The traditional areas of support and their limitations that have been provided by industry are outlined in the report and some new approaches for collaboration are considered. Industry-based research has been an important factor in developing new products and technologies and in promoting oral health. However there is a need to facilitate the introduction of these developments at an early stage in the education process. Industry has to operate in an efficient manner to remain competitive and maximise its returns and therefore survive. The academic sector operates in a different environment and under different governance structures; although some trends are noted towards adoption of greater efficiency and financial accountability similar to industry. Opportunities to jointly develop best business practices should be explored. Industry has responded well to the oral health needs of the public through the development of new products and technologies. The education community needs to respond in a similar way by examining different healthcare delivery models worldwide and developing programmes to train members of the dental team to cater for future needs and demands of communities in different regions of the world. The reputation of industry-based scientists and clinicians is high, and their role in contributing to the dental education process in practical ways needs to be explored and further developed. Closer relationships between industry scientists and faculty and students could assist industrys need and desire to develop new technologies for the broader dental care system. The corporate sector can play a key role in the future success of IFDEA by providing support and expertise in developing areas such as regional leadership institutes, a Global Faculty and Network and in collaborating in developing continuing education programmes as well as involvement in its governance. Thirteen recommendations are made in the report. These are considered to be important initial steps in developing the already strong relationship between the education and corporate sectors. Partnership and collaborating more effectively along the lines suggested should, almost certainly, generate mutually beneficial outcomes, whilst serving over the long term to elevate the publics oral health status on a global basis.

OBJECTIVE: To determine the source localization(s) of the midlatency auditory magnetic response M50, the equivalent of the P50 potential, a sleep state-dependent waveform known to habituate to repetitive stimulation. METHODS: We used a paired stimulus paradigm at interstimulus intervals of 250, 500 and 1000 ms, and magnetoencephalographic (MEG) recordings were subjected to computational methods for current density reconstruction, blind source separation, time-frequency analysis, and data visualization to characterize evoked dynamics. RESULTS: Each subject showed localization of a source for primary auditory evoked responses in the region of the auditory cortex, usually at a 20-30 ms latency. However, responses at 40-70 ms latency that also decreased following the second stimulus of a pair were not localizable to the auditory cortex, rather showing multiple sources usually including the frontal lobes. CONCLUSIONS: The M50 response, which shows habituation to repetitive stimulation, was not localized to the auditory cortex, but showed multiple sources including frontal lobes. SIGNIFICANCE: These MEG results suggest that sources for the M50 response may represent non-auditory, perhaps arousal-related, diffuse projections to the cortex

BACKGROUND AND PURPOSE: MR imaging can measure tissue perfusion and the integrity of the blood-brain barrier. We hypothesize that a combined measure of cerebral blood volume and vascular permeability using vascular-space occupancy (VASO) MR imaging, a recently developed imaging technique, is of diagnostic value for predicting tumor grade. MATERIALS AND METHODS: Thirty-nine patients (9 World Health Organization [WHO] grade II, 20 grade III, and 10 grade IV as determined by histopathologic assessment) were examined using VASO MR imaging, and regions-of-interest analysis was performed in tumoral regions, as well as in regions contralateral to the tumor. A Mann-Whitney test was conducted on the resulting VASO indices for a pairwise comparison across tumor grades. Nominal logistic regression was used to evaluate the use of VASO parameters for predicting group membership (by the percentage of correct classifications). RESULTS: The ratio between tumor side and contralateral side, VASO(Ratio), showed significant differences in all 3 of the pairwise comparisons (P < .01). VASO values in the tumoral regions, VASO(Tumor), showed significant difference between grade II and III and between II and IV but not between III and IV. Both VASO(Tumor) and VASO(Ratio) were found to be significant predictors of tumor grade, giving diagnostic accuracies of 66.7% and 71.8%, respectively. When testing to discriminate grade II tumors from higher grade tumors, the areas under the receiver operating characteristic curve were found to be 0.974 and 0.985 for VASO(Tumor) and VASO(Ratio), respectively. CONCLUSION: VASO MR imaging can be used for noninvasive tumor grade prediction based on cerebral blood volume and vascular permeability. VASO is more effective in separating WHO grade II from higher grades than in separating grade III from grade IV

The control of movement relies on the precision with which motor circuits are assembled during development. Spinal motor neurons (MNs) provide the trigger to signal the appropriate sequence of muscle contractions and initiate movement. This task is accommodated by the diversification of MNs into discrete subpopulations, each of which acquires precise axonal trajectories and central connectivity patterns. An upstream Hox factor-based regulatory network in MNs defines their competence to deploy downstream programs including the expression of Nkx and ETS transcription factors. These interactive transcriptional programs coordinate MN differentiation and connectivity, defining a sophisticated roadmap of motor circuit assembly in the spinal cord. Similar principles using modular interaction of transcriptional programs to control neuronal diversification and circuit connectivity are likely to act in other CNS circuits