Neuroscience and Neurobiology Commons^™

Neurobiology Of The Premonitory Urge In Tourette's Syndrome: Pathophysiology And Treatment Implications, Andrea E. Cavanna, Kevin J. Black, Mark Hallett, Valerie Voon

Kevin J. Black, MD

Minding The Aging Brain: Are We Ready For Personalized Medicine?, Jason Karlawish, Robert C. Green

Robert A. Green

No abstract provided.

Reward Enhances Tic Suppression In Children Within Months Of Tic Disorder Onset, Deanna J. Greene, Jonathan M. Koller, Amy Robichaux-Viehoever, Emily C. Bihun, Bradley L. Schlaggar, Kevin J. Black

Kevin J. Black, MD

Tic disorders are childhood onset neuropsychiatric disorders characterized by motor and/or vocal tics. Research has demonstrated that children with chronic tics (including Tourette syndrome and Chronic Tic Disorder: TS/CTD) can suppress tics, particularly when an immediate, contingent reward is given for successful tic suppression. As a diagnosis of TS/CTD requires tics to be present for at least one year, children in these tic suppression studies had been living with tics for quite some time. Thus, it is unclear whether the ability to inhibit tics is learned over time or present at tic onset. Resolving that issue would inform theories of …

The Capacity To Vote Of Persons With Alzheimer’S Disease, Paul S. Appelbaum, Richard S. Bonnie, Jason Karlawish

Jason Karlawish

OBJECTIVE: The right to vote can be abrogated when persons become incompetent to cast a ballot. This applies particularly to people with Alzheimer’s disease, who at some point will lose capacity. A 2001 federal court decision offered the first clear criteria (“Doe voting capacity standard”) for determining voting competence, focused on understanding the nature and effect of voting and on the ability to choose. This article explores how persons with Alzheimer’s disease perform on these criteria. METHOD: The Doe standard was operationalized in a brief questionnaire, along with measures of appreciation and reasoning about voting choices. Performance was assessed in …

Massively Parallel Nonparametric Regression, With An Application To Developmental Brain Mapping, Philip T. Reiss, Lei Huang, Yin-Hsiu Chen, Lan Huo, Thaddeus Tarpey, Maarten Mennes

Lei Huang

We propose a penalized spline approach to performing large numbers of parallel nonparametric analyses of either of two types: restricted likelihood ratio tests of a parametric regression model versus a general smooth alternative, and nonparametric regression. Compared with naively performing each analysis in turn, our techniques reduce computation time dramatically. Viewing the large collection of scatterplot smooths produced by our methods as functional data, we develop a clustering approach to summarize and visualize these results. Our approach is applicable to ultra-high-dimensional data, particularly data acquired by neuroimaging; we illustrate it with an analysis of developmental trajectories of functional connectivity at …

Prolactin And Fmri Response To Skf38393 In The Baboon, Brad D. Miller, Lauren A. Marks, Jonathan M. Koller, Blake J. Newman, G Larry Bretthorst, Kevin J. Black

Kevin J. Black, MD

Background: This study’s goal was to provide dose-response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select …

Welcome To The Journal Of Evolution And Health, Aaron Blaisdell, Paul Jaminet, David C. Pendergrass

Aaron P Blaisdell

Welcome to the first issue of the Journal of Evolution and Health! The Journal of Evolution and Health is the peer-reviewed, open-access journal of the Ancestral Health Society, a community of scientists, healthcare professionals, and laypersons who collaborate to understand health challenges from an evolutionary perspective.

The Intrinsic Severity Hypothesis Of Pharmacoresistance To Antiepileptic Drugs, Michael Rogawski

Michael A. Rogawski

Pharmacoresistance to antiepileptic drugs (AEDs) is a barrier to seizure freedom for many persons with epilepsy. For nearly two decades, pharmacoresistance has been framed in terms of factors affecting the access of AEDs to their molecular targets in the brain or the actions of the drugs on these targets. Shortcomings in this prevailing view led to the formulation of the intrinsic severity hypothesis of pharmacoresistance to AEDs, which is based on the recognition that there are neurobiologic factors that confer phenotypic variation among individuals with etiologically similar forms of epilepsy and postulates that more severe epilepsy is more difficult to …

Preclinical Pharmacology Of Perampanel, A Selective Non-Competitive Ampa Receptor Antagonist, Michael A. Rogawski, Takahisa Hanada

Michael A. Rogawski

Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile; E2007] is a potent, selective, orally active non-competitive AMPA receptor antagonist developed for the treatment of epilepsy. Perampanel has a 2,3′-bipyridin-6′-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes. Studies in various physiological systems indicate that perampanel selectively inhibits AMPA receptor-mediated synaptic excitation without affecting NMDA receptor responses. Blocking of AMPA receptors occurs at an allosteric site that is distinct from the glutamate recognition site. Radioligand-binding studies suggest that the blocking site coincides with that of the non-competitive antagonist GYKI 52466, believed to be on linker peptide segments of AMPA receptor subunits that transduce …

Glia And Epilepsy: Excitability And Inflammation, Orrin Devinsky, Annamaria Vezzani, Souhel Najjar, Nihal C. De Lanerolle, Michael A. Rogawski

Michael A. Rogawski

Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by nonneuronal cells, the glia – especially astrocytes and microglia – in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.

Ampa Receptors As A Molecular Target In Epilepsy Therapy, Michael A. Rogawski

Michael A. Rogawski

Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of nonconventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may …

Varying-Smoother Models For Functional Responses, Philip T. Reiss, Lei Huang, Huaihou Chen, Stan Colcombe

Philip T. Reiss

This paper studies estimation of a smooth function f(x,v) when we are given functional responses of the form f(x, ·) + error, but scientific interest centers on the collection of functions f(·,v) for different v. The motivation comes from studies of human brain development, in which x denotes age whereas v refers to brain locations. Analogously to varying-coefficient models, in which the mean response is linear in x, the “varying-smoother” models that we consider exhibit nonlinear dependence on x that varies smoothly with v. We discuss three approaches to estimating varying-smoother models: (a) methods that employ a tensor product penalty; …

How Theories Evolved Concerning The Mechanism Of Action Of Barbiturates, Wolfgang Löscher, Michael A. Rogawski

Michael A. Rogawski

The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ-aminobutyric acid (GABA) on GABA-A) receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABA-A) receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3 GABA-A)-receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent …

Paradoxical Results Of Adaptive False Discovery Rate Procedures In Neuroimaging Studies, Philip T. Reiss, Armin Schwartzman, Feihan Lu, Lei Huang, Erika Proal

Philip T. Reiss

Adaptive false discovery rate (FDR) procedures, which offer greater power than the original FDR procedure of Benjamini and Hochberg, are often applied to statistical maps of the brain. When a large proportion of the null hypotheses are false, as in the case of widespread effects such as cortical thinning throughout much of the brain, adaptive FDR methods can surprisingly reject more null hypotheses than not accounting for multiple testing at all—i.e., using uncorrected p-values. A straightforward mathematical argument is presented to explain why this can occur with the q-value method of Storey and colleagues, and a simulation study shows that …

Adjunctive Perampanel For Refractory Partial-Onset Seizures. Randomized Phase Iii Study 304, Jacqueline A. French, Gregory L. Krauss, Victor Biton, David Squillacote, Haichen Yang, Antonio Laurenza, Dinesh Kumar, Michael A. Rogawski

Michael A. Rogawski

Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures. Methods:This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (≥12 years, with ongoing seizures despite 1–3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder …

Function-On-Scalar Regression With The Refund Package, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Robust Dynamic Balance Of Ap-1 Transcription Factors In A Neuronal Gene Regulatory Network., Gregory M Miller, Babatunde A Ogunnaike, James S Schwaber, Rajanikanth Vadigepalli

Rajanikanth Vadigepalli

BACKGROUND: The octapeptide Angiotensin II is a key hormone that acts via its receptor AT1R in the brainstem to modulate the blood pressure control circuits and thus plays a central role in the cardiac and respiratory homeostasis. This modulation occurs via activation of a complex network of signaling proteins and transcription factors, leading to changes in levels of key genes and proteins. AT1R initiated activity in the nucleus tractus solitarius (NTS), which regulates blood pressure, has been the subject of extensive molecular analysis. But the adaptive network interactions in the NTS response to AT1R, plausibly related to the development of …

Characterization Of Seizures Induced By Acute And Repeated Exposure To Tetramethylenedisulfotetramine, Dorota Zolkowska, Christopher N. Banks, Ashish Dhir, Bora Inceoglu, James R. Sanborn, Mark R. Mccoy, Donald A. Bruun, Bruce D. Hammock, Pamela J. Lein, Michael A. Rogawski

Michael A. Rogawski

Tetramethylenedisulfotetramine (tetramine; TETS) is a potent convulsant poison that is considered to be a chemical threat agent. To provide a basis for the investigation of antidotes for TETS-induced seizures, we characterized the convulsant activity of TETS in mice and rats when administered by the intraperitoneal, intravenous, oral and intraventricular routes as a single acute dose and with repeated sublethal doses. In mice, parenteral and oral TETS caused immobility, myoclonic body jerks, clonic seizures of the forelimbs and/or hindlimbs, tonic seizures and death. The CD50 values for clonic and tonic seizures following oral administration were 0.11 and 0.22 mg/kg, respectively. Intraventricular …

Smoothness Selection For Penalized Quantile Regression Splines, Philip T. Reiss, Lei Huang

Philip T. Reiss

Modern data-rich analyses may call for fitting a large number of nonparametric quantile regressions. For example, growth charts may be constructed for each of a collection of variables, to identify those for which individuals with a disorder tend to fall in the tails of their age-specific distribution; such variables might serve as developmental biomarkers. When such analyses are carried out by penalized spline smoothing, reliable automatic selection of the smoothing parameter is particularly important. We show that two popular methods for smoothness selection may tend to overfit when estimating extreme quantiles as a smooth function of a predictor such as …

Semiparametric Methods For Mapping Brain Development, Philip T. Reiss, Yin-Hsiu Chen, Lan Huo

Philip T. Reiss

No abstract provided.

Role Of Neurosteroids In The Anticonvulsant Activity Of Midazolam, Ashish Dhir, Michael A. Rogawski

Michael A. Rogawski

BACKGROUND AND PURPOSE Midazolam is a short-acting benzodiazepine that is widely used as an intravenous sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA-A receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA-A receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. EXPERIMENTAL APPROACH Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the intravenous pentylenetetrazol (PTZ) threshold test. KEY …

Propofol Hemisuccinate Suppresses Cortical Spreading Depression, Ashish Dhir, Christoph Lossin, Michael A. Rogawski

Michael A. Rogawski

Propofol is a rapidly acting water-insoluble non-barbiturate anesthetic agent that is widely used as an intravenous sedative-hypnotic agent. Anecdotal evidence indicates that propofol may be effective at terminating intractable migraine headache. Cortical spreading depression (CSD) is believed to be the neural correlate of migraine aura and may be a trigger for migraine pain. Agents that block the induction or slow the spread of CSD may be of utility in treating migraine. Here we examined the ability of propofol hemisuccinate (PHS), a water-soluble prodrug of propofol, to affect CSD in mice. For comparison, we examinined dizocilpine, an NMDA receptor antagonist, that …

Migraine And Epilepsy—Shared Mechanisms Within The Family Of Episodic Disorders, Michael A. Rogawski

Michael A. Rogawski

Migraine and epilepsy are episodic disorders that share many clinical features and underlying pathophysiological mechanisms. Cortical spreading depression (CSD), a wave of profound cellular depolarization, is believed to underlie migraine aura and to be a trigger for the headache pain in migraine. However, the initial event preceding CSD is cellular hyperexcitability associated with localized epileptiform discharges. Glutamate is a critical mediator of the hyperexcitability in both focal seizures and migraine. In focal epilepsy, seizure generation and spread is mediated by synaptically released glutamate acting on AMPA receptors, whereas triggering of CSD depends on NMDA receptors and spread does not require …

Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski

Michael A. Rogawski

Certain steroid hormone metabolites that have activity as modulators of GABA-A receptors but lack conventional hormonal effects—including allopregnanolone and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly in principle (excitatory) neurons, and also in peripheral tissues. At low concentrations, such neurosteroids potentiate GABA-A receptor currents, whereas at higher concentrations they directly activate the receptor; large magnitude effects occur on nonsynaptic delta subunit-containing GABA-A receptors that mediate tonic currents. GABA-A receptor modulatory neurosteroids confer seizure protection in diverse animal models, without tolerance during chronic administration. Endogenous neurosteroids may play a role in catamenial epilepsy, stress-induced changes in seizure susceptibility, temporal lobe epilepsy, and …

Mechanisms Of Action Of Antiseizure Drugs (Chapter 39), Roger J. Porter, Ashish Dhir, Robert L. Macdonald, Michael A. Rogawski

Michael A. Rogawski

No abstract provided.

Map Kinases Couple Hindbrain-Derived Catecholamine Signals To Hypothalamic Adrenocortical Control Mechanisms During Glycemia-Related Challenges, Arshad M. Khan, Kimberly L. Kaminski, Graciela Sanchez-Watts, Todd A. Ponzio, J. Brent Kuzmiski, Jaideep S. Bains, Alan G. Watts

Arshad M. Khan, Ph.D.

No abstract provided.

Introducing Functional Data Analysis To Neuroimaging, And Vice Versa, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Disclosure Of Clinical Trial Results When Product Development Is Abandoned, Michael A. Rogawski, Howard J. Federoff

Michael A. Rogawski

Currently, sponsors are not required to report the outcomes of clinical research on drugs or devices that do not lead to an approved product. Consequently, the public cannot benefit from scientific information derived from all failed or abandoned drugs and devices. Provisions in the U.S. Food and Drug Administration Amendments Act of 2007 provide an opportunity for the Department of Health and Human Services to rectify this situation. By reporting the results of clinical trials of abandoned products in a publicly accessible database and in the peer-reviewed journal literature, sponsors would satisfy a core ethical obligation of clinical research and …

11beta-Hydroxylase Inhibitors Protect Against Seizures In Mice By Increasing Endogenous Neurosteroid Synthesis, Rafal Kaminski, Michael Rogawski

Michael A. Rogawski

Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABA-A receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but …

Massively Parallel Nonparametrics [Hds 2011 Slides], Philip T. Reiss, Lei Huang

Philip T. Reiss

No abstract provided.