Faculty Bibliography

Abstract Conclusion: The human frequency-to-place map may be modified by experience, even in adult listeners. However, such plasticity has limitations. Knowledge of the extent and the limitations of human auditory plasticity can help optimize parameter settings in users of auditory prostheses. Objectives: To what extent can adults adapt to sharply different frequency-to-place maps across ears? This question was investigated in two bilateral cochlear implant users who had a full electrode insertion in one ear, a much shallower insertion in the other ear, and standard frequency-to-electrode maps in both ears. Methods: Three methods were used to assess adaptation to the frequency-to-electrode maps in each ear: (1) pitch matching of electrodes in opposite ears, (2) listener-driven selection of the most intelligible frequency-to-electrode map, and (3) speech perception tests. Based on these measurements, one subject was fitted with an alternative frequency-to-electrode map, which sought to compensate for her incomplete adaptation to the standard frequency-to-electrode map. Results: Both listeners showed remarkable ability to adapt, but such adaptation remained incomplete for the ear with the shallower electrode insertion, even after extended experience. The alternative frequency-to-electrode map that was tested resulted in substantial increases in speech perception for one subject in the short insertion ear.

Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca2+-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca2+-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.

Evolutionary modifications in nervous systems enabled organisms to adapt to their specific environments and underlie the remarkable diversity of behaviors expressed by animals. Resolving the pathways that shaped and modified neural circuits during evolution remains a significant challenge. Comparative studies have revealed a surprising conservation in the intrinsic signaling systems involved in early patterning of bilaterian nervous systems but also raise the question of how neural circuit compositions and architectures evolved within specific animal lineages. In this review, we argue that within the spinal cord a flexible system involving modulation of rostrocaudal positional information, acting in the context of a relatively uniform DV patterning system, can act to modify neuronal organization and connectivity within circuits governing a specific locomotor output.

Neural oscillations have been measured and interpreted in multitudinous ways, with a variety of hypothesized functions in physiology, information processing and cognition. Much attention has been paid in recent years to gamma-band (30-100 Hz) oscillations and synchrony, with an increasing interest in 'high gamma' (>100 Hz) signals as mesoscopic measures of inter-regional communication. The biophysical origins of the measured variables are often difficult to precisely identify, however, making their interpretation fraught with pitfalls. Here we discuss how measurements of inter-regional gamma coherence can be prone to misinterpretation and suggest strategies for deciphering the roles that synchronized oscillations across brain networks may play in neural function.

OBJECTIVE: Several distinctive clinical features of patients with familial dysautonomia (FD) including dysarthria and dysphagia suggest a developmental defect in brainstem reflexes. Our aim was to characterize the neurophysiological profile of brainstem reflexes in these patients. METHODS: We studied the function of sensory and motor trigeminal tracts in 28 patients with FD. All were homozygous for the common mutation in the IKAP gene. Each underwent a battery of electrophysiological tests including; blink reflexes, jaw jerk reflex, masseter silent periods and direct stimulation of the facial nerve. Responses were compared with 25 age-matched healthy controls. RESULTS: All patients had significantly prolonged latencies and decreased amplitudes of all examined brainstem reflexes. Similar abnormalities were seen in the early and late components. In contrast, direct stimulation of the facial nerve revealed relative preservation of motor responses. CONCLUSIONS: The brainstem reflex abnormalities in FD are best explained by impairment of the afferent and central pathways. A reduction in the number and/or excitability of trigeminal sensory axons is likely the main problem. SIGNIFICANCE: These findings add further evidence to the concept that congenital mutations of the elongator-1 protein (or IKAP) affect the development of afferent neurons including those carrying information for the brainstem reflex pathways.

Neuronal microcircuits in the superficial layers of the mammalian cortex provide the substrate for associative cortical computation. Inhibitory interneurons constitute an essential component of the circuitry and are fundamental to the integration of local and long-range information. Here we report that, during early development, superficially positioned Reelin-expressing neurogliaform interneurons in the mouse somatosensory cortex receive afferent innervation from both cortical and thalamic excitatory sources. Attenuation of ascending sensory, but not intracortical, excitation leads to axo-dendritic morphological defects in these interneurons. Moreover, abrogation of the NMDA receptors through which the thalamic inputs signal results in a similar phenotype, as well as in the selective loss of thalamic and a concomitant increase in intracortical connectivity. These results suggest that thalamic inputs are critical in determining the balance between local and long-range connectivity and are fundamental to the proper integration of Reelin-expressing interneurons into nascent cortical circuits.

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38alphaMAPK as a potential neurotherapeutic target, but isoform selective p38alphaMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38alphaMAPK in both neurons and glia, interacting cellular components of the pathophysiological axis to be modulated. We report a novel isoform selective p38alphaMAPK inhibitor, MW01-18-150SRM (= MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38alphaMAPK:MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.

OBJECTIVES: Fresh blood imaging (FBI) is a useful noncontrast magnetic resonance angiographic (MRA) method for the assessment of peripheral arterial disease, particularly for imaging patients with poor renal function. Compared with 1.5 T, 3 T enables higher signal-to-noise ratio and/or spatiotemporal resolution in FBI. Indeed, previous studies have reported successful FBI of the calf station at 3 T. However, FBI of the thigh station at 3 T has been reported to suffer from signal void in the common femoral artery of 1 thigh only because of the radial symmetry in transmit radiofrequency field (B1+) variation. We sought to increase the signal of femoral artery in FBI at 3 T using high-permittivity dielectric padding. MATERIALS AND METHODS: We performed FBI and B1+ mapping of the thigh station at 3 T in 13 human subjects to compare the following 3 dielectric padding settings: no padding, commercially available thick (approximately 5 cm) dielectric padding, and high-permittivity thin (approximately 2 cm) dielectric padding. We characterized the radial symmetry in B1+ variation as well as its impact on the FBI signal at baseline and how dielectric padding improves B1+ and FBI. We evaluated the quality of 3 FBI MRA acquisitions using quantitative (ie, contrast-to-noise ratio of femoral arteries) and qualitative (ie, conspicuity of femoral arteries) analyses. RESULTS: With the subjects positioned on the magnetic resonance table in feet-first, supine orientation, the radial symmetry in B1+ variation attenuates the signal in the right common femoral artery. The signal void can be improved partially with commercial padding and improved further with high-permittivity padding. Averaging the results over the 13 subjects, the mean B1+, contrast-to-noise ratio, and conspicuity scores for the right common femoral artery were significantly higher with high-permittivity padding than with commercial padding and baseline (P < 0.001). CONCLUSIONS: Our study shows that high-permittivity dielectric padding can be used to increase the signal of femoral artery in FBI at 3 T.

The present paper describes a new stochastic multisensory integration system capable of combining a number of co-registered inputs, integrating different aspects of the external world, into a common premotor coordinate metric. In the present solution, the model uses a Stochastic Gradient Descent (SGD) algorithm to blend different sensory inputs into a single premotor intensionality vector. This is done isochronally, as the convergence time is independent of the number and type of parallel sensory inputs. This intensionality vector, generated based on "the sum over histories" [1], makes this implementation ideal to govern noncontinuous control systems. The rapid convergence of the SGD [2-7] is also used to compare with its biological equivalent in vertebrates -the superior tectum- to evaluate limits of convergence, precision and variability. The overall findings indicate that mathematical modeling is effective in addressing multisensory transformations resembling biological systems. (C) 2014 Elsevier B.V. All rights reserved.