Faculty Bibliography

Forming valid predictions about the environment is crucial to survival. However, whether humans are able to form valid predictions about natural stimuli based on their temporal statistical regularities remains unknown. Here we presented subjects with tone sequences whose pitch fluctuation over time capture long-range temporal dependence structures prevalent in natural stimuli. We found that subjects were able to exploit such naturalistic statistical regularities to make valid predictions about upcoming items in a sequence. Magnetoencephalography (MEG) recordings revealed that slow, arrhythmic cortical dynamics tracked the evolving pitch sequence over time such that neural activity at a given moment was influenced by the pitch of up to seven previous tones. Importantly, such history integration contained in neural activity predicted the expected pitch of the upcoming tone, providing a concrete computational mechanism for prediction. These results establish humans' ability to make valid predictions based on temporal regularities inherent in naturalistic stimuli and further reveal the neural mechanisms underlying such predictive computation.SIGNIFICANCE STATEMENTA fundamental question in neuroscience is how the brain predicts upcoming events in the environment. To date, this question has primarily been addressed in experiments using relatively simple stimulus sequences. Here, we study predictive processing in the human brain using auditory tone sequences that exhibit temporal statistical regularities similar to those found in natural stimuli. We observed that humans are able to form valid predictions based on such complex temporal statistical regularities. We further show that neural response to a given tone in the sequence reflects integration over the preceding tone sequence, and that this history dependence forms the foundation for prediction. These findings deepen our understanding of how humans form predictions in an ecologically valid environment.

Inhibitory interneurons represent 10-15% of the neurons in the somatosensory cortex, and their activity powerfully shapes sensory processing. Three major groups of GABAergic interneurons have been defined according to developmental, molecular, morphological, electrophysiological, and synaptic features. Dendritic-targeting somatostatin-expressing interneurons (SST-INs) have been shown to display diverse morphological, electrophysiological and molecular properties and activity patterns in vivo. However, the correlation between these properties and SST-IN subtype is unclear. In this study we aimed to correlate the morphological diversity of layer 5 (L5) SST-INs with their electrophysiological and molecular diversity in mice of either sex. Our morphological analysis demonstrated the existence of three subtypes of L5 SST-INs with distinct electrophysiological properties: T-shaped Martinotti cells innervate L1, and are low-threshold spiking; fanning-out Martinotti cells innervate L2/3 and the lower half of L1, and show adapting firing patterns; non-Martinotti cells innervate L4, and show a quasi-fast spiking firing pattern. We estimated the proportion of each subtype in L5 and found that T-shaped Martinotti, fanning-out Martinotti and Non-Martinotti cells represent ∼10, ∼50 and ∼40% of L5 SST-INs, respectively. Lastly we examined the connectivity between the three SST-IN subtypes and L5 pyramidal cells (PCs). We found that L5 T-shapped Martinotti cells inhibit the L1 apical tuft of nearby PCs; L5 fanning-out Martinotti cells also inhibit nearby PCs but they target the dendrite mainly in L2/3. On the other hand non-Martinotti cells inhibit the dendrites of L4 neurons while avoiding L5 PCs. Our data suggest that morphologically distinct SST-INs gate different excitatory inputs in the barrel cortex.SIGNIFICANCE STATEMENTMorphologically diverse layer 5 SST-INs show different patterns of activity in behaving animals. However, little is known about the abundance and connectivity of each morphological type and the correlation between morphological subtype and spiking properties. We demonstrate a correlation between the morphological and electrophysiological diversity of layer 5 SST-INs. Based on these findings we built a classifier to infer the abundance of each morphological subtype. Lastly, using paired recordings combined with morphological analysis, we investigated the connectivity of each morphological subtype. Our data suggest that, by targeting different cell types and cellular compartments, morphologically diverse SST-INs might gate different excitatory inputs in the mouse barrel cortex.

Temperature and relative humidity have opposing effects on evaporative water loss, the likely mediator of the temperature-dependence of nephrolithiasis. However, prior studies considered only dry-bulb temperatures when estimating the temperature-dependence of nephrolithiasis. We used distributed lag non-linear models and repeated 10-fold cross-validation to determine the daily temperature metric and corresponding adjustment for relative humidity that most accurately predicted kidney stone presentations during hot and cold periods in South Carolina from 1997 to 2015. We examined three metrics for wet-bulb temperatures and heat index, both of which measure the combination of temperature and humidity, and for dry-bulb temperatures: (1) daytime mean temperature; (2) 24-h mean temperature; and (3) most extreme 24-h temperature. For models using dry-bulb temperatures, we considered four treatments of relative humidity. Among 188,531 patients who presented with kidney stones, 24-h wet bulb temperature best predicted kidney stone presentation during summer. Mean cross-validated residuals were generally lower in summer for wet-bulb temperatures and heat index than the corresponding dry-bulb temperature metric, regardless of type of adjustment for relative humidity. Those dry-bulb models that additionally adjusted for relative humidity had higher mean residuals than other temperature metrics. The relative risk of kidney stone presentations at the 99th percentile of each temperature metric compared to the respective median temperature in summer months differed by temperature metric and relative humidity adjustment, and ranged from an excess risk of 8-14%. All metrics performed similarly in winter. The combination of temperature and relative humidity determine the risk of kidney stone presentations, particularly during periods of high heat and humidity. These results suggest that metrics that measure moist heat stress should be used to estimate the temperature-dependence of kidney stone presentations, but that the particular metric is relatively unimportant.

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the build up of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMPK activation and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant negative and knockout of NR4A1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally-active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions constituting a pathological feature across disorders.SIGNIFICANCE STATEMENTThe bioenergetics cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust responses of mitochondria and synapses to the build up of chronic stress. NR4A1 plays such role by controlling mitochondria energetic competence with respect to synapse number. As an immediate-early gene, NR4A1 promotes neuronal plasticity but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the build up of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.

Because salicylism is a clinical diagnosis, the serum concentration should be interpreted in conjunction with the clinical presentation. A 26-year-old man presented to the Emergency Department with abdominal painand had extremely elevated serum triglycerides (>7000 mg/dL). Ethanol, acetaminophen, and salicylate concentrations were checked because of concern of self-injurious behavior, which returned at 13.1 mg/dL, undetectable, and >100 mg/dL, respectively. His basic metabolic panel revealed a bicarbonate of 23 mEq/L and an anion gap of 11. An arterial blood gas showed a pH 7.39 and a PCO2 of 36.6 mmHg. On physical examination, he was awake and alert, and had a respiratory rate of 12–14/min. The possible effect of hyperlipidemia to falsely elevate the salicylate concentration was recognized. He was treated for severe hypertriglyceridemia and as his triglyceride level dropped, his repeat salicylate concentration was <1 mg/dL. Since dfferent sized lipoproteins contribute variably to serum sample turbiditythey have the potential to interfere with the absorption of light thereby producing erroneous laboratory results . Clinicians need to be aware of the implications of severe hyperlipidemia and interference to prevent clinical errors based on false positive laboratory results

The multielectrode technique described here was developed for simultaneously recording complex spike activity from arrays of Purkinje cells in anesthetized rodents. The technique involves placing a platform on the surface of the brain and implanting microelectrodes through this platform, which then serves to hold the individual electrodes in place and to protect the brain surface. With this technique, stable recordings of complex spike activity for over 24 h have been achieved. Typical arrays consist of ~40 electrodes that are arranged as a 4 x 10 matrix with electrodes spaced by ~250 mum; however, denser and larger arrays are possible. The technique was designed for recording complex spike activity in anesthetized animals. However, it has also been successfully used to record Purkinje cell simple spikes and activity from other neurons. Moreover, it is possible to use this approach with awake, head-fixed animals performing behavioral tasks.

OBJECTIVE:To test the hypothesis that localization-related epilepsy is associated with widespread neuronal dysfunction beyond the ictal focus, reflected by a decrease in patients' global concentration of their proton MR spectroscopy (1H-MRS) observed marker, N-acetyl-aspartate (NAA). METHODS:Thirteen patients with localization-related epilepsy (7 men, 6 women) 40±13 (mean±standard-deviation)years old, 8.3±13.4years of disease duration; and 14 matched controls, were scanned at 3 T with MRI and whole-brain (WB) 1H MRS. Intracranial fractions of brain volume, gray and white matter (fBV, fGM, fWM) were segmented from the MRI, and global absolute NAA creatine (Cr) and choline (Cho) concentrations were estimated from their WB 1H MRS. These metrics were compared between patients and controls using an unequal variance t test. RESULTS:Patients' fBV, fGM and fWM: 0.81±0.07, 0.47±0.04, 0.31±0.04 were not different from controls' 0.79±0.05, 0.48±0.04, 0.32±0.02; nor were their Cr and Cho concentrations: 7.1±1.1 and 1.3±0.2 millimolar (mM) versus 7.7±0.7 and 1.4±0.1mM (p>0.05 all). Patients' global NAA concentration: 11.5±1.5 mM, however, was 12% lower than controls' 13.0±0.8mM (p=0.004). CONCLUSIONS:These findings indicate that neuronal dysfunction in localization-related epilepsy extends globally, beyond the ictal zone, but without atrophy or spectroscopic evidence of other pathology. This suggests a diffuse decline in the neurons' health, rather than their number, early in the disease course. WB 1H-MRS assessment, therefore, may be a useful tool for quantification of global neuronal dysfunction load in epilepsy.

INTRODUCTION/BACKGROUND:Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. MATERIALS AND METHODS/METHODS:Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. RESULTS:Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036). CONCLUSION/CONCLUSIONS:Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.

BACKGROUND:Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS:We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS:A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION/CONCLUSIONS:Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

Hilar mossy cells (MCs) of the dentate gyrus (DG) distinguish the DG from other hippocampal subfields (CA1-3) because there are two glutamatergic cell types in the DG rather than one. Thus, in the DG, the main cell types include glutamatergic granule cells (GCs) and MCs, whereas in CA1-3, the only glutamatergic cell type is the pyramidal cell. In contrast to GCs, MCs are different in morphology, intrinsic electrophysiological properties, afferent input and axonal projections, so their function is likely to be very different from GCs. Why are MCs necessary to the DG? In past studies, the answer has been unclear because MCs not only excite GCs directly but also inhibit them disynaptically, by exciting GABAergic neurons that project to GCs. Results of new studies are discussed that shed light on this issue. These studies take advantage of recently available transgenic mice with Cre recombinase expression mostly in MCs and techniques such as optogenetics and DREADDs (designer receptors exclusively activated by designer drugs). The recent studies also address in vivo behavioral functions of MCs. Some of the results support past hypotheses whereas others suggest new conceptualizations of how the MCs contribute to DG circuitry and function. While substantial progess has been made, additional research is still needed to clarify the characteristics and functions of these unique cells.