Faculty Bibliography

This paper reviews our recent work addressing the role of both synaptic-input and connectivity-architecture fluctuations in coarse-grained descriptions of integrate-and-fire (I&F) point-neuron network models. Beginning with the most basic coarse-grained description, the all-to-all coupled, mean-field model, which ignores all fluctuations, we add the effects of the two types of fluctuations one at a time. To study the effects of synaptic-input fluctuations, we derive a kinetic-theoretic description, first in the form of a Boltzmann equation in (2+1) dimensions, simplifying that to an advection-diffusion equation, and finally reducing the dimension to a system of two (1+1)-dimensional kinetic equations via the maximum entropy principle. In the limit of an infinitely-fast conductance relaxation time, we derive a Fokker-Planck equation which captures the bifurcation between a bistable, hysteretic operating regime of the network when the amount of synaptic-input fluctuations is small, and a stable regime when the amount of fluctuations increases. To study the effects of complex neuronal-network architecture, we incorporate the network connectivity statistics in the mean-field description, and investigate the dependence of these statistics on the statistical properties of the neuronal firing rates for three network examples with increasingly complex connectivity architecture

Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. Methods: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease. Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued. Muscle Nerve, 2012.

In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO(2)), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P<0.0001) and decreased CMRO(2) (P=0.003) in MS patients (mean+/-s.d.: 65.9%+/-5.1% and 138.8+/-35.4 mumol per 100 g per minute) as compared with healthy control subjects (60.2%+/-4.0% and 180.2+/-24.8 mumol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n=30); on the contrary, there was a significant negative correlation between CMRO(2) and EDSS and between CMRO(2) and lesion load (n=12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease.

To survive in a dynamic environment, an organism must be able to effectively learn, store, and recall the expected benefits and costs of potential actions. The nature of the valuation and decision processes is thus of fundamental interest to researchers at the intersection of psychology, neuroscience, and economics. Although normative theories of choice have outlined the theoretical structure of these valuations, recent experiments have begun to reveal how value is instantiated in the activity of neurons and neural circuits. Here, we review the various forms of value coding that have been observed in different brain systems and examine the implications of these value representations for both neural circuits and behavior. In particular, we focus on emerging evidence that value coding in a number of brain areas is context dependent, varying as a function of both the current choice set and previously experienced values. Similar contextual modulation occurs widely in the sensory system, and efficient coding principles derived in the sensory domain suggest a new framework for understanding the neural coding of value.

Idiopathic generalized epilepsy (IGE) is associated with widespread cortical network abnormalities on electroencephalography. Resting state functional connectivity (RSFC), based on fMRI, can assess the brain's global functional organization and its disruption in clinical conditions. We compared RSFC associated with the 'default mode network' (DMN) between people with IGE and healthy controls. Strength of functional connectivity within the DMN associated with seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortices (MPFC) was compared between people with IGE and healthy controls and was correlated with seizure duration, age of seizure onset and age at scan. Those with IGE showed markedly reduced functional network connectivity between anterior and posterior cortical seed regions. Seizure duration positively correlates with RSFC between parahippocampal gyri and the PCC but negatively correlates with connectivity between the PCC and frontal lobe. The observed pattern of disruption provides evidence for integration- and segregation-type network abnormalities and supports aberrant network organization among people with IGE.

Abstract Objective. Brain iron deficiency has been supposed to be involved in the pathophysiology of ADHD. Available studies assessing iron in ADHD are based on serum ferritin, a peripheral marker of iron status. To what extent serum ferritin correlates with brain iron (BI) is unclear. The main aim of this study was to compare BI, estimated with magnetic resonance imaging (MRI) in the putamen, pallidum, caudate, and thalamus, between children with and without ADHD. The secondary aim was to assess the correlation between serum ferritin and BI levels. Methods. Thirty-six children (18 with and 18 without ADHD, the latter including nine healthy controls and nine psychiatric controls) completed MRI and blood sampling. Brain iron levels were estimated by imaging T2*. Results. Children with ADHD showed significantly lower estimated BI in right and left thalamus compared to healthy controls. Estimated BI did not differ significantly between children with ADHD and psychiatric controls. Children with ADHD had significantly lower levels of serum ferritin than healthy as well as psychiatric controls. Serum ferritin and T2* values did not correlate significantly in most regions. Conclusions. Low iron in the thalamus may contribute to ADHD pathophysiology.

Respiratory sinus arrhythmia (RSA) is largely mediated by the autonomic nervous system through its modulating influence on the heart beats. We propose a robust algorithm for quantifying instantaneous RSA as applied to heart beat intervals and respiratory recordings under dynamic breathing patterns. The blood volume pressure-derived heart beat series (pulse intervals, PIs) are modeled as an inverse Gaussian point process, with the instantaneous mean PI modeled as a bivariate regression incorporating both past PIs and respiration values observed at the beats. A point process maximum likelihood algorithm is used to estimate the model parameters, and instantaneous RSA is estimated via a frequency domain transfer function evaluated at instantaneous respiratory frequency where high coherence between respiration and PIs is observed. The model is statistically validated using Kolmogorov-Smirnov goodness-of-fit analysis, as well as independence tests. The algorithm is applied to subjects engaged in meditative practice, with distinctive dynamics in the respiration patterns elicited as a result. The presented analysis confirms the ability of the algorithm to track important changes in cardiorespiratory interactions elicited during meditation, otherwise not evidenced in control resting states, reporting statistically significant increase in RSA gain as measured by our paradigm.

Genetics plays an important role in establishing susceptibility to nephrolithiasis, although diet and other environmental factors make major contributions. In a small number of patients, the genetic causes of stones are more clearly established. Four of these hereditary diseases include primary hyperoxaluria, Dent disease, cystinuria, and adenine phosphoribosyltransferase deficiency, which results in 2,8-dihydroxyadenine stones. Patients with these disorders often experience recurring stones from early childhood, requiring frequent hospitalizations and procedures. They are at risk of kidney damage and chronic kidney disease. Because of their rarity, these four disorders are difficult to study and recognize. This in turn slows progress toward effective therapies and increases the risk of misdiagnosis or diagnosis late in the course of the disease. Therefore, patients may experience unnecessary and harmful treatments and accelerated loss of kidney function. In this article, we will review the pathogenesis, clinical presentation, diagnosis of and treatments for these four disorders. 2011 Springer Science+Business Media, LLC

After extinction, the reappearance of a conditioned response induced by an unconditioned stimulus which is weaker than that used during the conditioning training indicates that the extinction procedure does not eliminate the original conditioned memory. Recent studies on fear conditioning have shown that rats exhibited little or no recovery of conditioned responding if the time interval between fear acquisition and extinction was short, suggesting that the extinction process may erase the original conditioning trace in this situation. In the present study, a saving experiment was conducted in rats to investigate whether an aversive response could be recovered following extinction training with different time intervals after acquisition of conditioned taste aversion (CTA). Male Long-Evans rats developed CTA by associating a 0.2% sucrose solution with malaise induced by intraperitoneal injection of 4 ml/kg 0.15 M LiCl and were subjected to extinction training with an interval of 5 h (5H group) or 24 h (24H group) after acquisition of CTA. Rats in the 5H group, but not in the 24H group, exhibited no aversive responding to the sucrose solution followed by the injection of a lower dose of LiCl (1 ml/kg). These findings indicate that the extinction procedure administered at different time points following the acquisition of CTA affects recovery of extinguished aversive memory and suggest that an unlearning process may be involved in the mechanisms of CTA extinction with short intervals between acquisition and extinction.

Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K(ATP) channel, but many of the techniques described are also used to study other ion channels.