Faculty Bibliography

It is well-established that the feed-forward connected main hippocampal areas, CA3, CA2, and CA1 work cooperatively during spatial navigation and memory. These areas are similar in terms of the prevalent types of neurons; however, they display different spatial coding and oscillatory dynamics. Understanding the temporal dynamics of these operations requires simultaneous recordings from these regions. However, simultaneous recordings from multiple regions and subregions in behaving animals have become possible only recently. We performed large-scale silicon probe recordings simultaneously spanning across all layers of CA1, CA2, and CA3 regions in rats during spatial navigation and sleep and compared their behavior-dependent spiking, oscillatory dynamics and functional connectivity. The accuracy of place cell spatial coding increased progressively from distal to proximal CA1, suddenly dropped in CA2, and increased again from CA3a toward CA3c. These variations can be attributed in part to the different entorhinal inputs to each subregions, and the differences in theta modulation of CA1, CA2, and CA3 neurons. We also found that neurons in the subregions showed differences in theta modulation, phase precession, state-dependent changes in firing rates and functional connectivity among neurons of these regions. Our results indicate that a combination of intrinsic properties together with distinct intra- and extra-hippocampal inputs may account for the subregion-specific modulation of spiking dynamics and spatial tuning of neurons during behavior. (c) 2016 Wiley Periodicals, Inc.

Diverse translational and research applications could benefit from the noninvasive ability to reversibly modulate (excite or suppress) CNS activity using ultrasound pulses, however, without clarifying the underlying mechanism, advanced design-based ultrasonic neuromodulation remains elusive. Recently, intramembrane cavitation within the bilayer membrane was proposed to underlie both the biomechanics and the biophysics of acoustic bio-effects, potentially explaining cortical stimulation results through a neuronal intramembrane cavitation excitation (NICE) model. Here, NICE theory is shown to provide a detailed predictive explanation for the ability of ultrasonic (US) pulses to also suppress neural circuits through cell-type-selective mechanisms: according to the predicted mechanism T-type calcium channels boost charge accumulation between short US pulses selectively in low threshold spiking interneurons, promoting net cortical network inhibition. The theoretical results fit and clarify a wide array of earlier empirical observations in both the cortex and thalamus regarding the dependence of ultrasonic neuromodulation outcomes (excitation-suppression) on stimulation and network parameters. These results further support a unifying hypothesis for ultrasonic neuromodulation, highlighting the potential of advanced waveform design for obtaining cell-type-selective network control.

BACKGROUND: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. METHODS: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. RESULTS: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. CONCLUSIONS: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00957359.

BACKGROUND: Microtubules are dynamic polymers of alpha/beta tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either alpha- or beta-tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly. METHODS: This is a single case report or a patient with lissencephaly, developmental delay, nystagmus, persistent hyperplastic primary vitreous, and infantile spasms, and undertook a neurogenetic workup. We include studies of mutant function in Escherichia coli and HeLa cells. RESULTS: The patient was found to have a novel de novo mutation in kinesin family member 2A (KIF2A). This mutation results in a substitution of isoleucine at a highly conserved threonine residue within the ATP-binding domain. The KIF2A p.Thr320Ile mutant protein exhibited abnormal solubility, and KIF2A p.Thr320Ile overexpression in cultured cells led to the formation of aberrant microtubule networks. CONCLUSION: Findings support the pathogenic link between KIF2A mutation and lissencephaly, and expand the range of presentation to include infantile spasms and congenital anomalies.

Sharp-wave ripples (SPW-Rs) in the hippocampus are implied in memory consolidation, as shown by observational and interventional experiments. However, the mechanism of their generation remains unclear. Using two-dimensional silicon probe arrays, we investigated the propagation of SPW-Rs across the hippocampal CA1, CA2, and CA3 subregions. Synchronous activation of CA2 ensembles preceded SPW-R-related population activity in CA3 and CA1 regions. Deep CA2 neurons gradually increased their activity prior to ripples and were suppressed during the population bursts of CA3-CA1 neurons (ramping cells). Activity of superficial CA2 cells preceded the activity surge in CA3-CA1 (phasic cells). The trigger role of the CA2 region in SPW-R was more pronounced during waking than sleeping. These results point to the CA2 region as an initiation zone for SPW-Rs.

BACKGROUND: Arrhythmia can significantly alter the image quality of cardiovascular magnetic resonance (CMR); automatic detection and sorting of the most frequent types of arrhythmias during the CMR acquisition could potentially improve image quality. New CMR techniques, such as non-Cartesian CMR, can allow self-gating: from cardiac motion-related signal changes, we can detect cardiac cycles without an electrocardiogram. We can further use this data to obtain a surrogate for RR intervals (valley intervals: VV). Our purpose was to evaluate the feasibility of an automated method for classification of non-arrhythmic (NA) (regular cycles) and arrhythmic patients (A) (irregular cycles), and for sorting of common arrhythmia patterns between atrial fibrillation (AF) and premature ventricular contraction (PVC), using the cardiac motion-related signal obtained during self-gated free-breathing radial cardiac cine CMR with compressed sensing reconstruction (XD-GRASP). METHODS: One hundred eleven patients underwent cardiac XD-GRASP CMR between October 2015 and February 2016; 33 were included for retrospective analysis with the proposed method (6 AF, 8 PVC, 19 NA; by recent ECG). We analyzed the VV, using pooled statistics (histograms) and sequential analysis (Poincare plots), including the median (medVV), the weighted mean (meanVV), the total number of VV values (VVval), and the total range (VVTR) and half range (VVHR) of the cumulative frequency distribution of VV, including the median to half range (medVV/VVHR) and the half range to total range (VVHR/VVTR) ratios. We designed a simple algorithm for using the VV results to differentiate A from NA, and AF from PVC. RESULTS: Between NA and A, meanVV, VVval, VVTR, VVHR, medVV/VVHR and VVHR/VVTR ratios were significantly different (p values = 0.00014, 0.0027, 0.000028, 5x10-9, 0.002, respectively). Between AF and PVC, meanVV, VVval and medVV/VVHR ratio were significantly different (p values = 0.018, 0.007, 0.044, respectively). Using our algorithm, sensitivity, specificity, and accuracy were 93 %, 95 % and 94 % to discriminate between NA and A, and 83 %, 71 %, and 77 % to discriminate between AF and PVC, respectively; areas under the ROC curve were 0.93 and 0.89. CONCLUSIONS: Our study shows we can reliably detect arrhythmias and differentiate AF from PVC, using self-gated cardiac cine XD-GRASP CMR.

Nephrolithiasis is a complex disease of worldwide prevalence that is influenced by both genetic and environmental factors. About 75% of kidney stones are predominantly composed of calcium oxalate and urinary oxalate is considered a crucial risk factor. Microorganisms may have a role in the pathogenesis and prevention of kidney stones and the involvement of the intestinal microbiome in this renal disease has been a recent area of interest. Oxalobacter formigenes is a gram negative bacteria that degrades oxalate in the gut decreasing urinary oxalate excretion. In this review, we examine the data studying the role of Oxalobacter formigenes kidney stone disease in humans and animals, the effect of antibiotics on its colonization, and the potential role of probiotics and whole microbial communities as therapeutic interventions.