Faculty Bibliography
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Department/Unit:Neuroscience Institute
Total Results:
13562
Modulating conscious movement intention by noninvasive brain stimulation and the underlying neural mechanisms
Conscious intention is a fundamental aspect of the human experience. Despite long-standing interest in the basis and implications of intention, its underlying neurobiological mechanisms remain poorly understood. Using high-definition transcranial DC stimulation (tDCS), we observed that enhancing spontaneous neuronal excitability in both the angular gyrus and the primary motor cortex caused the reported time of conscious movement intention to be approximately 60-70 ms earlier. Slow brain waves recorded approximately 2-3 s before movement onset, as well as hundreds of milliseconds after movement onset, independently correlated with the modulation of conscious intention by brain stimulation. These brain activities together accounted for 81% of interindividual variability in the modulation of movement intention by brain stimulation. A computational model using coupled leaky integrator units with biophysically plausible assumptions about the effect of tDCS captured the effects of stimulation on both neural activity and behavior. These results reveal a temporally extended brain process underlying conscious movement intention that spans seconds around movement commencement.
PMCID:4420786
PMID: 25948272
ISSN: 1529-2401
CID: 1781112
Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling
How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model's prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information.
PMCID:4552873
PMID: 26317432
ISSN: 1553-7358
CID: 1781102
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF
PMCID:4755714
PMID: 26367794
ISSN: 1476-4687
CID: 1779142
Measurement of Cochlear Implant Electrode Position From Intraoperative Post-insertion Skull Radiographs: A Validation Study
OBJECTIVE: To validate a method of measuring angular depth of insertion (aDOI) as well as positional depth of each electrode contact in a cochlear implant by using intraoperative postinsertion skull radiographs. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Intraoperative postinsertion radiographs obtained from 18 cochlear implant recipients were chosen for analysis. One high-resolution computer tomography scan of the head with the electrode in place was also analyzed. One cadaveric temporal bone with an inserted electrode provided additional data for analysis. INTERVENTION: aDOI and position of each electrode contact were measured from the radiographs using readily available software. High-resolution computer tomography imaging of the cochlea and electrode were reconstructed in three dimensions and used to simulate head rotation during intraoperative radiographs. The cadaveric temporal bone was imaged by x-ray at various acquisition angles. MAIN OUTCOME MEASURES: We evaluated the error introduced in measuring aDOI by assessing intra- and inter-rater variability. We also evaluated the error introduced by x-ray acquisition at nonstandardized angles by analyzing the three-dimensional construct and the cadaveric temporal bone. RESULTS: The concordance correlation coefficients for intrarater (0.991) and inter-rater (0.996) variability in aDOI measurement were excellent. The error introduced by nonstandardized x-ray acquisition angles was only -12.5 degrees to +15.8 degrees even at the limits of clinically relevant head rotation. CONCLUSIONS: The intraoperative postinsertion radiograph is sufficient for estimating positional depth of electrode contacts and the aDOI. This measure is robust in the face of nonstandardized x-ray acquisition angles, and shows good intra- and inter-rater variability.
PMCID:4574306
PMID: 26375970
ISSN: 1537-4505
CID: 1778232
Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons
Neurogliaform (RELN+) and bipolar (VIP+) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been elucidated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). Interestingly, Prox1 promotes the maturation of CGE-derived interneuron subtypes through intrinsic differentiation programs that operate in tandem with extrinsically driven neuronal activity-dependent pathways. Thus Prox1 represents the first identified transcription factor specifically required for the embryonic and postnatal acquisition of CGE-derived cortical interneuron properties. SIGNIFICANCE STATEMENT: Despite the recognition that 30% of GABAergic cortical interneurons originate from the caudal ganglionic eminence (CGE), to date, a specific transcriptional program that selectively regulates the development of these populations has not yet been identified. Moreover, while CGE-derived interneurons display unique patterns of tangential and radial migration and preferentially populate the superficial layers of the cortex, identification of a molecular program that controls these events is lacking.Here, we demonstrate that the homeodomain transcription factor Prox1 is expressed in postmitotic CGE-derived cortical interneuron precursors and is maintained into adulthood. We found that Prox1 function is differentially required during both embryonic and postnatal stages of development to direct the migration, differentiation, circuit integration, and maintenance programs within distinct subtypes of CGE-derived interneurons.
PMCID:4571608
PMID: 26377473
ISSN: 1529-2401
CID: 1778252
Hypothesis: Urbanization and exposure to urban heat islands contribute to increasing prevalence of kidney stones
The prevalence of kidney stones is increasing worldwide. Various etiologies may in part explain this observation including increased prevalence of diabetes, obesity and the metabolic syndrome, increased dietary protein and salt content, and decreased dietary dairy products. We hypothesize an additional and novel potential contributor to increasing kidney stone prevalence: migration to urban settings, or urbanization, and resultant exposure of the population to the higher temperatures of urban heat islands (UHIs). Both urbanization and exposure to UHIs are worldwide, continuous trends. Because the difference in temperature between rural and urban settings is greater than the increase in temperature caused by global warming, the potential effect of urbanization on stone prevalence may be of greater magnitude. However, demonstration of a convincing link between urbanization and kidney stones is confounded by many variables simultaneously affected by migration to cities, such as changes in occupation, income, and diet. No data have yet been published supporting this proposed association. We explore the plausibility and limitations of this possible etiology of increasing kidney stone prevalence.
PMCID:4648638
PMID: 26372336
ISSN: 1532-2777
CID: 1779222
Carbonic anhydrase generates a pH gradient in Bombyx mori silk glands
Silk is a protein of interest to both biological and industrial sciences. The silkworm, Bombyx mori, forms this protein into strong threads starting from soluble silk proteins using a number of biochemical and physical cues to allow the transition from liquid to fibrous silk. A pH gradient has been measured along the gland, but the methodology employed was not able to precisely determine the pH at specific regions of interest in the silk gland. Furthermore, the physiological mechanisms responsible for the generation of this pH gradient are unknown. In this study, concentric ion selective microelectrodes were used to determine the luminal pH of Bombyx mori silk glands. A gradient from pH 8.2 to 7.2 was measured in the posterior silk gland, with a pH 7 throughout the middle silk gland, and a gradient from pH 6.8 to 6.2 in the beginning of the anterior silk gland where silk processing into fibers occurs. The small diameter of the most anterior region of the anterior silk gland prevented microelectrode access in this region. Using a histochemical method, the presence of active carbonic anhydrase was identified in the funnel and anterior silk gland of fifth instar larvae. The observed pH gradient collapsed upon addition of the carbonic anhydrase inhibitor methazolamide, confirming an essential role for this enzyme in pH regulation in the Bombyx mori silk gland. Plastic embedding of whole silk glands allowed clear visualization of the morphology, including the identification of four distinct epithelial cell types in the gland and allowed correlations between silk gland morphology and silk stages of assembly related to the pH gradient. Bombyx mori silk glands have four different epithelial cell types, one of which produces carbonic anhydrase. Carbonic anhydrase is necessary for the mechanism that generates an intraluminal pH gradient, which likely regulates the assembly of silk proteins and then the formation of fibers from soluble silk proteins. These new insights into native silk formation may lead to a more efficient production of artificial or regenerated silkworm silk fibers.
PMCID:4628561
PMID: 26365738
ISSN: 1879-0240
CID: 1779092
Short-term test-retest reliability of resting state fMRI metrics in children with and without attention-deficit/hyperactivity disorder
To date, only one study has examined test-retest reliability of resting state fMRI (R-fMRI) in children, none in clinical developing groups. Here, we assessed short-term test-retest reliability in a sample of 46 children (11-17.9 years) with attention-deficit/hyperactivity disorder (ADHD) and 57 typically developing children (TDC). Our primary test-retest reliability measure was the intraclass correlation coefficient (ICC), quantified for a range of R-fMRI metrics. We aimed to (1) survey reliability within and across diagnostic groups, and (2) compare voxel-wise ICC between groups. We found moderate-to-high ICC across all children and within groups, with higher-order functional networks showing greater ICC. Nearly all R-fMRI metrics exhibited significantly higher ICC in TDC than in children with ADHD for one or more regions. In particular, posterior cingulate and ventral precuneus exhibited group differences in ICC across multiple measures. In the context of overall moderate-to-high test-retest reliability in children, regional differences in ICC related to diagnostic groups likely reflect the underlying pathophysiology for ADHD. Our currently limited understanding of the factors contributing to inter- and intra-subject variability in ADHD underscores the need for large initiatives aimed at examining their impact on test-retest reliability in both clinical and developing populations.
PMID: 26365788
ISSN: 1878-9307
CID: 1779102
Double-barreled and Concentric Microelectrodes for Measurement of Extracellular Ion Signals in Brain Tissue
Electrical activity in the brain is accompanied by significant ion fluxes across membranes, resulting in complex changes in the extracellular concentration of all major ions. As these ion shifts bear significant functional consequences, their quantitative determination is often required to understand the function and dysfunction of neural networks under physiological and pathophysiological conditions. In the present study, we demonstrate the fabrication and calibration of double-barreled ion-selective microelectrodes, which have proven to be excellent tools for such measurements in brain tissue. Moreover, so-called "concentric" ion-selective microelectrodes are also described, which, based on their different design, offer a far better temporal resolution of fast ion changes. We then show how these electrodes can be employed in acute brain slice preparations of the mouse hippocampus. Using double-barreled, potassium-selective microelectrodes, changes in the extracellular potassium concentration ([K(+)]o) in response to exogenous application of glutamate receptor agonists or during epileptiform activity are demonstrated. Furthermore, we illustrate the response characteristics of sodium-sensitive, double-barreled and concentric electrodes and compare their detection of changes in the extracellular sodium concentration ([Na(+)]o) evoked by bath or pressure application of drugs. These measurements show that while response amplitudes are similar, the concentric sodium microelectrodes display a superior signal-to-noise ratio and response time as compared to the double-barreled design. Generally, the demonstrated procedures will be easily transferable to measurement of other ions species, including pH or calcium, and will also be applicable to other preparations.
PMCID:4692589
PMID: 26381747
ISSN: 1940-087x
CID: 1779372
Urine proteomic analysis in cystinuric children with renal stones
INTRODUCTION: The gene mutations responsible for cystinuria do not fully explain kidney stone activity, suggesting that specific proteins may serve as promoters of cystine precipitation, aggregation or epithelial adherence. In this study we assessed (1) the differences in the urinary proteins between children with cystinuria and kidney stones (CYS) and healthy controls (HC), with particular attention to the fibrosis-related proteins, and (2) the presence of diagnostic biomarkers for CYS. MATERIAL AND METHODS: We conducted a pilot study comparing individual urinary proteomes of 2 newly diagnosed children with CYS and 2 age- and gender-matched HC, using liquid chromatography-mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest in both CYS and HC were selected using the following criteria: i) >/=5 spectral counts; ii) >/=2-fold difference in spectral counts; and iii)
PMCID:4540695
PMID: 26076823
ISSN: 1873-4898
CID: 1777152
