Publications by authors named "Paul R Carney"

79 Publications

Seizure frequency, quality of life, behavior, cognition, and sleep in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

Epilepsy Behav 2021 Sep 21;124:108325. Epub 2021 Sep 21.

Department of Child Health, University of Missouri, Columbia, MO 65201, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA.

Objective: To evaluate the effects of oral pharmacological cannabidiol (CBD) on seizures, side effects, quality of life, behavior, mood, and sleep in children with drug-resistant epilepsy (DRE) during a phase II, prospective, open-label clinical study.

Methods: During a phase II expanded access program (EAP) study to evaluate the safety and efficacy of using cannabidiol (CBD) for the long-term treatment of children with drug-resistant epilepsy, secondary outcome measures were also performed, including quality of life (QOLCE), behavior (aberrant behavior checklist ABC), and sleep (children's sleep habit questionnaire, CSHQ). Participants between the ages of 2 and 16 years of age with drug-resistant epilepsy (n = 35) were included in this EAP. Primary outcomes included change in parent-recorded seizure frequency relative to baseline, as well as the safety and tolerability over the course of 24 months of CBD treatment. Secondary outcomes observed in the first 12 months included changes in child behavior, and cognitive function, and sleep quality.

Results: The median change in overall seizure frequency decreased from baseline (n = 33) by -61.3% ([n = 33], Inter Quartile Range (IQR): 43-88%) at month 3, -62.9% at month 6 ([n = 29], IQR: 48-92%), -74.7% at month 12 ([n = 29], IQR: 64-96%), and finally -83.7% ([n = 28], IQR: 68-100%) at the conclusion of 24 months of treatment. Seven (20%) of the 35 patients enrolled withdrew from treatment and observation by month 24: 2 failed inclusion criteria at baseline, 4 due to lack of treatment efficacy, and 1 was lost to follow-up. The 12-month recording of secondary measures revealed a significant improvement in Irritability (-39.4%, [n = 28], ABC), Hyperactivity (-45.4%, [n = 28], ABC), Cognition in Quality of Life (+14.2%, [n = 28], QOLCE), Behavioral function (+14.7%, [n = 28], QOLCE), General Health (+14.7%, [n = 28], QOLCE), Sleep duration (-33.9%, [n = 28], CSHQ), Daytime sleepiness (-23.8%, [n = 28], CSHQ), and nocturnal arousals (-36.2%, [n = 28], CSHQ).

Significance: The results of this phase II open-label study demonstrate that pharmacological CBD significantly reduces seizure frequency, and improves QOL, behavior deficits, and sleep disruption, in children with drug-resistant epilepsy. The results also suggest that CBD is efficacious in controlled seizures over a 2-year period in childhood DRE.
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http://dx.doi.org/10.1016/j.yebeh.2021.108325DOI Listing
September 2021

Psychoactive Drugs Like Cannabis -Induce Hypodopaminergic Anhedonia and Neuropsychological Dysfunction in Humans: Putative Induction of Dopamine Homeostasis via Coupling of Genetic Addiction Risk Severity (GARS) testing and Precision Pro-dopamine Regulation (KB220).

Neurology (ECronicon) 2021 Apr 31;13(4):86-92. Epub 2021 Mar 31.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction and intoxication. The major active ingredient of (marijuana), Δ-tetrahydrocannabinol (THC) and it powerfully stimulates the type-1 cannabinoid (CB) receptor. When used in the form of the plant marijuana, because of the many compounds that exist in the plant form they could inhibit the activity of the CB receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee., . incorrectly suggest that blocking CB receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. We caution the scientific community that, other CB receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB receptor blockers were rejected by the FDA due to mood changes including suicide ideation. We argue that one issue facing the scientific community, has to do with the increasing legalization of Cannabis products in many states across America. We are in favor of some reform in terms of either decriminalization or restrictive legalization especially in control of legal limits of THC. Like other psychoactive compounds at high doses, it is our hypothesis that chronic use of these drugs including high THC content in its various forms (wax, smoke or vapor) resulting in brain reward dysfunction induces an imbalance of neurotransmission and subsequent hypodopaminergia and lead to aberrant substance and non-substance (behavioral) addictions. It is further proposed that in order to overcome THC and even other psychoactive drugs of abuse induced anhedonia the coupling of genetic risk testing and pro dopamine regulation is warranted.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171216PMC
April 2021

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.

J Clin Invest 2019 12;129(12):5462-5467

Department of Cell Biology and Physiology.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in individuals with AS are common, debilitating, and often drug resistant. Thus, there is an unmet need for better treatment options. Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has shown antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here, we show that acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS. However, neither acute CBD nor a 2-week-long course of CBD administered immediately after a kindling protocol could halt the proepileptogenic plasticity observed in AS model mice. CBD had a dose-dependent sedative effect but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including the delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. We believe our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS and will thus help guide the rational development of CBD as a treatment for AS.
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http://dx.doi.org/10.1172/JCI130419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877312PMC
December 2019

Sustained somatostatin gene expression reverses kindling-induced increases in the number of dividing Type-1 neural stem cells in the hippocampi of behaviorally responsive rats.

Epilepsy Res 2019 02 11;150:78-94. Epub 2019 Jan 11.

J. Crayton Pruitt Family Department of Biomedical Engineering, USA; Department of Neuroscience, USA; McKnight Brain Institute, USA. Electronic address:

Neurogenesis persists throughout life in the hippocampi of all mammals, including humans. In the healthy hippocampus, relatively quiescent Type-1 neural stem cells (NSCs) can give rise to more proliferative Type-2a neural progenitor cells (NPCs), which generate neuronal-committed Type-2b NPCs that mature into Type-3 neuroblasts. Many Type-3 neuroblasts survive and mature into functionally integrated granule neurons over several weeks. In kindling models of epilepsy, neurogenesis is drastically upregulated and many new neurons form aberrant connections that could support epileptogenesis and/or seizures. We have shown that sustained vector-mediated hippocampal somatostatin (SST) expression can both block epileptogenesis and reverse seizure susceptibility in fully kindled rats. Here we test whether adeno-associated virus (AAV) vector-mediated sustained SST expression modulates hippocampal neurogenesis and microglial activation in fully kindled rats. We found significantly more dividing Type-1 NSCs and a corresponding increased number of surviving new neurons in the hippocampi of kindled versus sham-kindled rats. Increased numbers of activated microglia were found in the granule cell layer and hilus of kindled rats at both time points. After intrahippocampal injection with either eGFP or SST-eGFP vector, we found similar numbers of dividing Type-1 NSCs and -2 NPCs and surviving BrdU neurons and glia in the hippocampi of kindled rats. Upon observed variability in responses to SST-eGFP (2/4 rats exhibited Grade 0 seizures in the test session), we conducted an additional experiment. We found significantly fewer dividing Type-1 NSCs in the hippocampi of SST-eGFP vector-treated responder rats (5/13 rats) relative to SST-eGFP vector-treated non-responders and eGFP vector-treated controls that exhibited high-grade seizures on the test session. The number of activated microglia was upregulated in the GCL and hilus of kindled rats, regardless of vector treatment. These data support the hypothesis that sustained SST expression exerts antiepileptic effects potentially through normalization of neurogenesis and suggests that abnormally high proliferating Type-1 NSC numbers may be a cellular mechanism of epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.01.005DOI Listing
February 2019

Longitudinal evaluation of tumor microenvironment in rat focal brainstem glioma using diffusion and perfusion MRI.

J Magn Reson Imaging 2019 05 14;49(5):1322-1332. Epub 2018 Oct 14.

Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, Florida, USA.

Background: Brainstem gliomas are aggressive and difficult to treat. Growth of these tumors may be characterized with MRI methods.

Purpose: To visualize longitudinal changes in tumor volume, vascular leakiness, and tissue microstructure in an animal model of brainstem glioma.

Study Type: Prospective animal model.

Animal Model: Male Sprague-Dawley rats (n = 9) were imaged with 9L gliosarcoma cells infused into the pontine reticular formation of the brainstem. The MRI tumor microenvironment was studied at 3 and 10 days postimplantation of tumor cells.

Field Strength/sequence: Diffusion tensor imaging (DTI) and dynamic contrast-enhanced (DCE)-MRI were performed at 4.7T using spin-echo multislice echo planar imaging and gradient echo multislice imaging, respectively.

Assessment: Tumor leakiness was assessed by the forward volumetric transfer constant, K , estimated from DCE-MRI data. Tumor structure was evaluated with fractional anisotropy (FA) obtained from DTI. Tumor volumes, delineated by a T map, T -weighted image, FA, and DCE signal enhancement were compared.

Statistical Tests: Changes in the assessed parameters within and across the groups (ie, rats 3 and 10 days post tumor cell implantation) were evaluated with Wilcoxon rank-sum tests.

Results: Day 3 tumors were visible mainly on contrast-enhanced images, while day 10 tumors were visible in both contrast-enhanced and diffusion-weighted images. Mean K at day 10 was 41% lower than at day 3 (P =  0.23). In day 10 tumors, FA was regionally lower in the tumor compared to normal tissue (P =  0.0004), and tumor volume, segmented based on FA map, was significantly smaller (P ≤ 0.05) than that obtained from other contrasts.

Data Conclusion: Contrast-enhanced MRI was found to be more sensitive in detecting early-stage tumor boundaries than other contrasts. Areas of the tumor outlined by DCE-MRI and DTI were significantly different. Over the observed period of tumor growth, average vessel leakiness decreased with tumor progression.

Level Of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1322-1332.
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http://dx.doi.org/10.1002/jmri.26315DOI Listing
May 2019

Temporal lobe epilepsy affects spatial organization of entorhinal cortex connectivity.

Epilepsy Behav 2018 11 20;88:87-95. Epub 2018 Sep 20.

Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, United States of America; Department of VA Brain Rehabilitation Research Center, Malcolm Randall VA Center Gainesville, FL, United States of America.

Evidence for structural connectivity patterns within the medial temporal lobe derives primarily from postmortem histological studies. In humans and nonhuman primates, the parahippocampal gyrus (PHg) is subdivided into parahippocampal (PHc) and perirhinal (PRc) cortices, which receive input from distinct cortical networks. Likewise, their efferent projections to the entorhinal cortex (ERc) are distinct. The PHc projects primarily to the medial ERc (M-ERc). The PRc projects primarily to the lateral portion of the ERc (L-ERc). Both M-ERc and L-ERc, via the perforant pathway, project to the dentate gyrus and hippocampal (HC) subfields. Until recently, these neural circuits could not be visualized in vivo. Diffusion tensor imaging algorithms have been developed to segment gray matter structures based on probabilistic connectivity patterns. However, these algorithms have not yet been applied to investigate connectivity in the temporal lobe or changes in connectivity architecture related to disease processes. In this study, this segmentation procedure was used to classify ERc gray matter based on PRc, ERc, and HC connectivity patterns in 7 patients with temporal lobe epilepsy (TLE) without hippocampal sclerosis (mean age, 14.86 ± 3.34 years) and 7 healthy controls (mean age, 23.86 ± 2.97 years). Within samples paired t-tests allowed for comparison of ERc connectivity between epileptogenic and contralateral hemispheres. In healthy controls, there were no significant within-group differences in surface area, volume, or cluster number of ERc connectivity-defined regions (CDR). Likewise, in line with histology results, ERc CDR in the control group were well-organized, uniform, and segregated via PRc/PHc afferent and HC efferent connections. Conversely, in TLE, there were significantly more PRc and HC CDR clusters in the epileptogenic than the contralateral hemisphere. The surface area of the PRc CDR was greater, and that of the HC CDRs was smaller, in the epileptogenic hemisphere as well. Further, there was no clear delineation between M-ERc and L-ERc connectivity with PRc, PHc or HC in TLE. These results suggest a breakdown of the spatial organization of PHg-ERc-HC connectivity in TLE. Whether this breakdown is the cause or result of epileptic activity remains an exciting research question.
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http://dx.doi.org/10.1016/j.yebeh.2018.06.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294293PMC
November 2018

Stimulants Do Not Increase the Risk of Seizure-Related Hospitalizations in Children with Epilepsy.

J Child Adolesc Psychopharmacol 2018 03 13;28(2):111-116. Epub 2017 Oct 13.

1 Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida , Gainesville, Florida.

Objective: To evaluate the safety of stimulants in children with epilepsy.

Methods: In a retrospective cohort study based on Medicaid Analytic eXtract billing records from 26 U.S. states from 1999 to 2010, we identified incident stimulant use among children with epilepsy through outpatient encounter claims and pharmacy claims. We established a control group of nonusers and used frequency matching to generate index dates. We followed both cohorts for 12 months and calculated hazard ratios [HRs] of current and former use of stimulants versus no use on the outcome of seizure-related hospitalization using multivariate Cox proportional hazard models.

Results: We identified 18,166 stimulant users and 54,197 nonusers in children with epilepsy. The incidence of seizure-related hospitalization in current stimulant users, former users, and nonusers was 3.6, 3.5, and 4.3 per 100 patient-years. After adjustment for confounders, we found current and former use of stimulants did not increase seizure-related hospitalizations (HR 0.95, 95% confidence interval [CI]: 0.83, 1.09 and HR 0.99, 95% CI: 0.85, 1.15). Children with cerebral palsy, congenital nervous system anomalies, or intellectual disability did not have significantly higher HRs than those without the already mentioned comorbidities.

Conclusion: This study has not identified any overall increase in the rate of seizure-related hospitalizations with the use of stimulants in children with epilepsy.
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http://dx.doi.org/10.1089/cap.2017.0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911707PMC
March 2018

Fast noninvasive functional diffuse optical tomography for brain imaging.

J Biophotonics 2018 03 25;11(3). Epub 2017 Sep 25.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida.

Advances in epilepsy studies have shown that specific changes in hemodynamics precede and accompany seizure onset and propagation. However, it has been challenging to noninvasively detect these changes in real time and in humans, due to the lack of fast functional neuroimaging tools. In this study, we present a functional diffuse optical tomography (DOT) method with the guidance of an anatomical human head atlas for 3-dimensionally mapping the brain in real time. Central to our DOT system is a human head interface coupled with a technique that can incorporate topological information of the brain surface into the DOT image reconstruction. The performance of the DOT system was tested by imaging motor tasks-involved brain activities on N = 6 subjects (3 epilepsy patients and 3 healthy controls). We observed diffuse areas of activations from the reconstructed [HbT] images of patients, relative to more focal activations for healthy subjects. Moreover, significant pretask hemodynamic activations were also seen in the motor cortex of patients, which indicated abnormal activities persistent in the brain of an epilepsy patient. This work demonstrates that fast functional DOT is a valuable tool for noninvasive 3-dimensional mapping of brain hemodynamics.
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http://dx.doi.org/10.1002/jbio.201600267DOI Listing
March 2018

Trends in Antiepileptic Drug Use in Children and Adolescents With Epilepsy.

Pediatr Neurol 2017 Sep 29;74:32-40. Epub 2017 May 29.

Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida; Epidemiology, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, Florida.

Objective: We describe the trends in antiepileptic drug (AED) use in children and adolescents with epilepsy in the United States.

Methods: We undertook a cross-sectional study based on Medicaid Analytic eXtract data set from 26 US states. Children and adolescents aged three to 18 years with at least one year continuous Medicaid fee-for-service coverage after the second outpatient or the first inpatient diagnosis of epilepsy in each calendar year during 1999 to 2009 were included in the study; therefore, 11 cohorts were established. A patient was defined as being exposed to a specific AED if he or she had at least one-day supply of the AED during the 1-year follow-up period. The annual prevalence of AEDs was reported, stratified by gender and age. The trends in AED use were evaluated through linear regression.

Results: The sample sizes of the 11 cohorts ranged between 17,304 and 22,672. The annual prevalence of valproic acid use declined from 42.4% in 1999 to 26.5% in 2009, and the prevalence of carbamazepine use declined from 37.1% to 10.2%. Meanwhile, the prevalence of levetiracetam use increased from 5.1% to about 32.0% in 2009, and the prevalence of oxcarbazepine use increased from 1.3% to 19.1%. Since 2008, levetiracetam (29.6%) has replaced valproic acid (27.8%) as the most commonly used AED in children and adolescents with epilepsy. The prevalence of diazepam use increased from 11.6% to 28.1%.

Significance: Compared with first- and second-generation antiepileptic drugs, third-generation AEDs have fewer adverse side effects, resulting in increased patient treatment adherence. Equally important is the economic impact of these newer AEDs. This first-of-its-kind study underscores the need for large database studies that objectively assess the cost-effectiveness of third-generation AEDs versus first- and second-generation AEDs in the treatment of childhood epilepsy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.05.016DOI Listing
September 2017

The hippocampus: detailed assessment of normative two-dimensional measurements, signal intensity, and subfield conspicuity on routine 3T T2-weighted sequences.

Surg Radiol Anat 2017 Oct 12;39(10):1149-1159. Epub 2017 Mar 12.

Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.

Purpose: The hippocampus has a critical role in many common disease processes. Currently, routine 3 Tesla structural MRI is a mainstay of clinical diagnosis. The goal of our study is to evaluate the normal variability in size and/or conspicuity of the hippocampal subcomponents in routine clinical 3 Tesla high-resolution T2-weighted images to provide a basis for better defining pathological derangements. Additionally, we utilize diffusion data acquired from a 17.6 Tesla MRI of the hippocampus as a benchmark to better illustrate these subcomponents.

Methods: The hippocampus was retrospectively assessed on 104 clinically normal patients undergoing coronal T2-weighted imaging. The conspicuity of the majority of hippocampal subcomponents was assessed in each portion of the hippocampus. Additionally, easily applicable cross-sectional measurements and signal intensities were obtained to evaluate the range of normal, as well as inter- and intra-subject variability.

Results: The normal range of cross-sectional measurements of the hippocampal subcomponents was calculated. There was minimal side-to-side variability in cross-sectional measurements of hippocampal subcomponents (< 5%) with the exception of the subiculum (R>L by 8.3%) and the CA4/DG (R>L by 5.8%). The internal architecture showed high variability in visibility of subcomponents between different segments of the hippocampus.

Conclusions: Confident clinical assessment of the hippocampus requires a thorough knowledge of hippocampal size and signal, but also the internal architecture expected to be seen. The data provided in this study will provide the reader with vital information necessary for distinguishing a normal from abnormal exam.
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http://dx.doi.org/10.1007/s00276-017-1843-xDOI Listing
October 2017

Detecting and characterizing high-frequency oscillations in epilepsy: a case study of big data analysis.

R Soc Open Sci 2017 Jan 18;4(1):160741. Epub 2017 Jan 18.

School of Electrical, Computer and Energy Engineering, Arizona State University, Tempe, AZ 85287, USA; Department of Physics, Arizona State University, Tempe, AZ 85287, USA.

We develop a framework to uncover and analyse dynamical anomalies from massive, nonlinear and non-stationary time series data. The framework consists of three steps: preprocessing of massive datasets to eliminate erroneous data segments, application of the empirical mode decomposition and Hilbert transform paradigm to obtain the fundamental components embedded in the time series at distinct time scales, and statistical/scaling analysis of the components. As a case study, we apply our framework to detecting and characterizing high-frequency oscillations (HFOs) from a big database of rat electroencephalogram recordings. We find a striking phenomenon: HFOs exhibit on-off intermittency that can be quantified by algebraic scaling laws. Our framework can be generalized to big data-related problems in other fields such as large-scale sensor data and seismic data analysis.
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http://dx.doi.org/10.1098/rsos.160741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319343PMC
January 2017

Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats.

Epilepsy Res 2017 02 7;130:81-92. Epub 2017 Jan 7.

Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA; Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA. Electronic address:

Somatostatin is expressed widely in the hippocampus and notably in hilar GABAergic neurons that are vulnerable to seizure neuropathology in chronic temporal lobe epilepsy. We previously demonstrated that sustained bilateral preprosomatostatin (preproSST) expression in the hippocampus prevents the development of generalized seizures in the amygdala kindling model of temporal lobe epilepsy. Here we tested whether sustained preproSST expression is anticonvulsant in rats already kindled to high-grade seizures. Rats were kindled until they exhibited 3 consecutive Racine Grade 5 seizures before adeno-associated virus serotype 5 (AAV5) vector driving either eGFP (AAV5-CBa-eGFP) or preproSST and eGFP (AAV5-CBa-preproSST-eGFP) expression was injected bilaterally into the hippocampal dentate gyrus and CA1 region. Retested 3 weeks later, rats that received control vector (AAV5-CBa-eGFP) continued to exhibit high-grade seizures whereas 6/13 rats that received preproSST vector (AAV5-CBa-preproSST-eGFP) were seizure-free. Of these rats, 5/6 remained seizure-free after repeated stimulation sessions and when the stimulation current was increased. These results suggest that vector-mediated expression of preproSST may be a viable therapeutic strategy for temporal lobe epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.01.002DOI Listing
February 2017

Epilepsy and restless legs syndrome.

Epilepsy Behav 2017 03 19;68:41-44. Epub 2017 Jan 19.

Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Objective: Restless legs syndrome (RLS) is a common neurological movement disorder occurring in approximately 10% of the general population. The prevalence of moderately severe RLS is 2.7% overall (3.7% for women and 1.7% for men). Epilepsy is also a common neurological disorder with significant associated morbidity and impact on quality of life. We evaluated the severity and frequency of primary RLS in patients with localization-related temporal lobe epilepsy (TLE) and investigated the role of prodromal RLS symptoms as a warning sign and lateralizing indicator.

Methods: All epilepsy patients seen in the outpatient clinic were screened for movement disorders from 2005 to 2015. Ninety-eight consecutive patients with localization-related TLE (50 right TLE and 48 left TLE) who met inclusion criteria were seen in the outpatient clinic. The control group consisted of 50 individuals with no history or immediate family history of epilepsy. Each patient was evaluated with the International Restless Legs Study Group (IRLSSG) questionnaire, NIH RLS diagnostic criteria, ferritin level, and comprehensive sleep screening including polysomnography. Furthermore, patients with obstructive sleep apnea or a definite cause of secondary restless legs syndrome such as low serum ferritin or serum iron levels were also excluded from the study.

Results: There was a significant association between the type of epilepsy and whether or not patients had RLS χ (1)=10.17, p<.01, using the χ Goodness of Fit Test. Based on the odds ratio, the odds of patients having RLS were 4.60 times higher if they had right temporal epilepsy than if they had left temporal epilepsy, serving as a potential lateralizing indicator. A prodromal sensation of worsening RLS occurred in some patients providing the opportunity to intervene at an earlier stage in this subgroup.

Significance: We identified frequent moderate to severe RLS in patients with epilepsy. The frequency of RLS was much more common than would typically be seen in patients of similar age. The restlessness was typically described as moderately severe. The RLS symptoms were more common and somewhat more severe in the right TLE group than the left TLE group.
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http://dx.doi.org/10.1016/j.yebeh.2016.12.010DOI Listing
March 2017

Animal Models of Posttraumatic Seizures and Epilepsy.

Methods Mol Biol 2016 ;1462:481-519

Banyan Biomarkers, Inc, Alachua, FL, USA.

Posttraumatic epilepsy (PTE) is one of the most common and devastating complications of traumatic brain injury (TBI). Currently, the etiopathology and mechanisms of PTE are poorly understood and as a result, there is no effective treatment or means to prevent it. Antiepileptic drugs remain common preventive strategies in the management of TBI to control acute posttraumatic seizures and to prevent the development of PTE, although their efficacy in the latter case is disputed. Different strategies of PTE prophylaxis have been showing promise in preclinical models, but their translation to the clinic still remains elusive due in part to the variability of these models and the fact they do not recapitulate all complex pathologies associated with human TBI. TBI is a multifaceted disorder reflected in several potentially epileptogenic alterations in the brain, including mechanical neuronal and vascular damage, parenchymal and subarachnoid hemorrhage, subsequent toxicity caused by iron-rich hemoglobin breakdown products, and energy disruption resulting in secondary injuries, including excitotoxicity, gliosis, and neuroinflammation, often coexisting to a different degree. Several in vivo models have been developed to reproduce the acute TBI cascade of events, to reflect its anatomical pathologies, and to replicate neurological deficits. Although acute and chronic recurrent posttraumatic seizures are well-recognized phenomena in these models, there is only a limited number of studies focused on PTE. The most used mechanical TBI models with documented electroencephalographic and behavioral seizures with remote epileptogenesis include fluid percussion, controlled cortical impact, and weight-drop. This chapter describes the most popular models of PTE-induced TBI models, focusing on the controlled cortical impact and the fluid percussion injury models, the methods of behavioral and electroencephalogram seizure assessments, and other approaches to detect epileptogenic properties, and discusses their potential application for translational research.
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http://dx.doi.org/10.1007/978-1-4939-3816-2_27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036905PMC
January 2018

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies.

J Biomech Eng 2016 May;138(5):051007

Convection enhanced delivery (CED) is a promising novel technology to treat neural diseases, as it can transport macromolecular therapeutic agents greater distances through tissue by direct infusion. To minimize off-target delivery, our group has developed 3D computational transport models to predict infusion flow fields and tracer distributions based on magnetic resonance (MR) diffusion tensor imaging data sets. To improve the accuracy of our voxelized models, generalized anisotropy (GA), a scalar measure of a higher order diffusion tensor obtained from high angular resolution diffusion imaging (HARDI) was used to improve tissue segmentation within complex tissue regions of the hippocampus by capturing small feature fissures. Simulations were conducted to reveal the effect of these fissures and cerebrospinal fluid (CSF) boundaries on CED tracer diversion and mistargeting. Sensitivity analysis was also conducted to determine the effect of dorsal and ventral hippocampal infusion sites and tissue transport properties on drug delivery. Predicted CED tissue concentrations from this model are then compared with experimentally measured MR concentration profiles. This allowed for more quantitative comparison between model predictions and MR measurement. Simulations were able to capture infusate diversion into fissures and other CSF spaces which is a major source of CED mistargeting. Such knowledge is important for proper surgical planning.
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http://dx.doi.org/10.1115/1.4032626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101044PMC
May 2016

High-field magnetic resonance imaging of the human temporal lobe.

Neuroimage Clin 2015 1;9:58-68. Epub 2015 Aug 1.

Department of Neurology, University of Florida, Gainesville, FL, USA ; Department of Pediatrics, University of Florida, Gainesville, FL, USA ; Department of Neuroscience, University of Florida, Gainesville, FL, USA ; J. Crayton Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.

Background: Emerging high-field diffusion weighted MR imaging protocols, along with tractography, can elucidate microstructural changes associated with brain disease at the sub-millimeter image resolution. Epilepsy and other neurological disorders are accompanied by structural changes in the hippocampal formation and associated regions; however, these changes can be subtle and on a much smaller scale than the spatial resolution commonly obtained by current clinical magnetic resonance (MR) protocols in vivo.

Methods: We explored the possibility of studying the organization of fresh tissue with a 17.6 Tesla magnet using diffusion MR imaging and tractography. The mesoscale organization of the temporal lobe was estimated using a fresh unfixed specimen obtained from a subject who underwent anterior temporal lobectomy for medically refractory temporal lobe epilepsy (TLE). Following ex vivo imaging, the tissue was fixed, serial-sectioned, and stained for correlation with imaging.

Findings: We resolved tissue microstructural organizational features in the temporal lobe from diffusion MR imaging and tractography in fresh tissue.

Conclusions: Fresh ex vivo MR imaging, along with tractography, revealed complex intra-temporal structural variation corresponding to neuronal cell body layers, dendritic fields, and axonal projection systems evident histologically. This is the first study to describe in detail the human temporal lobe structural organization using high-field MR imaging and tractography. By preserving the 3-dimensional structures of the hippocampus and surrounding structures, specific changes in anatomy may inform us about the changes that occur in TLE in relation to the disease process and structural underpinnings in epilepsy-related memory dysfunction.
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http://dx.doi.org/10.1016/j.nicl.2015.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543219PMC
April 2016

Dimensionless, Scale Invariant, Edge Weight Metric for the Study of Complex Structural Networks.

PLoS One 2015 14;10(7):e0131493. Epub 2015 Jul 14.

Department of Biochemistry and Molecular Biology University of Florida, Gainesville, Florida, United States of America.

High spatial and angular resolution diffusion weighted imaging (DWI) with network analysis provides a unique framework for the study of brain structure in vivo. DWI-derived brain connectivity patterns are best characterized with graph theory using an edge weight to quantify the strength of white matter connections between gray matter nodes. Here a dimensionless, scale-invariant edge weight is introduced to measure node connectivity. This edge weight metric provides reasonable and consistent values over any size scale (e.g. rodents to humans) used to quantify the strength of connection. Firstly, simulations were used to assess the effects of tractography seed point density and random errors in the estimated fiber orientations; with sufficient signal-to-noise ratio (SNR), edge weight estimates improve as the seed density increases. Secondly to evaluate the application of the edge weight in the human brain, ten repeated measures of DWI in the same healthy human subject were analyzed. Mean edge weight values within the cingulum and corpus callosum were consistent and showed low variability. Thirdly, using excised rat brains to study the effects of spatial resolution, the weight of edges connecting major structures in the temporal lobe were used to characterize connectivity in this local network. The results indicate that with adequate resolution and SNR, connections between network nodes are characterized well by this edge weight metric. Therefore this new dimensionless, scale-invariant edge weight metric provides a robust measure of network connectivity that can be applied in any size regime.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501757PMC
April 2016

Noninvasive high-speed photoacoustic tomography of cerebral hemodynamics in awake-moving rats.

J Cereb Blood Flow Metab 2015 Aug 17;35(8):1224-32. Epub 2015 Jun 17.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA.

We present a noninvasive method of photoacoustic tomography (PAT) for imaging cerebral hemodynamics in awake-moving rats. The wearable PAT (wPAT) system has a size of 15 mm in height and 33 mm in diameter, and a weight of ~8 g (excluding cabling). The wPAT achieved an imaging rate of 3.33 frames/s with a lateral resolution of 243 μm. Animal experiments were designed to show wPAT feasibility for imaging cerebral hemodynamics on awake-moving animals. Results showed that the cerebral oxy-hemoglobin and deoxy-hemoglobin changed significantly in response to hyperoxia; and, after the injection of pentylenetetrazol (PTZ), cerebral blood volume changed faster over time and larger in amplitude for rats in awake-moving state compared with rats under anesthesia. By providing a light-weight, high-resolution technology for in vivo monitoring of cerebral hemodynamics in awake-behaving animals, it will be possible to develop a comprehensive understanding on how activity alters hemodynamics in normal and diseased states.
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http://dx.doi.org/10.1038/jcbfm.2015.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527999PMC
August 2015

Diagnosis and management of childhood epilepsy.

Curr Probl Pediatr Adolesc Health Care 2015 Jan;45(1):3-17

Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL; Department of Neurology, University of Florida College of Medicine, Gainesville, FL.

Epilepsy is a relatively common neurologic disorder in children that has important implications for development, parents, and society. Making the correct diagnosis starts with an accurate and complete history that consequently leads to a directed diagnostic workup. This article outlines a diagnostic and management approach to pediatric seizures and epilepsy syndromes. Making the correct diagnosis of epilepsy or nonepileptic imitators allows the practitioner to prescribe appropriate therapy. Initial management for typical epileptic syndromes and seizures and potential adverse effects are discussed. Alternative treatment options for pharmacologically resistant patients such as ketogenic diet, vagal nerve stimulation, and surgery are also discussed. While most children favorably respond to antiepileptic medications, early identification of medication failure is important to ensure optimal neurodevelopment.
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http://dx.doi.org/10.1016/j.cppeds.2014.12.002DOI Listing
January 2015

In vivo imaging of epileptic foci in rats using a miniature probe integrating diffuse optical tomography and electroencephalographic source localization.

Epilepsia 2015 Jan 19;56(1):94-100. Epub 2014 Dec 19.

Department of Biomedical Engineering, University of Florida, Gainesville, Florida, U.S.A.

Objective: The goal of this work is to establish a new dual-modal brain-mapping technique based on diffuse optical tomography (DOT) and electroencephalographic source localization (ESL) that can chronically/intracranially record optical/electroencephalography (EEG) data to precisely map seizures and localize the seizure-onset zone and associated epileptic brain network.

Methods: The dual-modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths.

Results: This novel imaging technique successfully localized the seizure-onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view (FOV) of the DOT/ESL interface, ESL gave false-positive detection of the focus, while DOT showed negative detection.

Significance: This study represents the first to identify seizure-onset zone using implantable DOT. In addition, the combination of DOT/ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels.
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http://dx.doi.org/10.1111/epi.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308439PMC
January 2015

Towards real-time detection of seizures in awake rats with GPU-accelerated diffuse optical tomography.

J Neurosci Methods 2015 Jan 1;240:28-36. Epub 2014 Nov 1.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA. Electronic address:

Background: Advancement in clinically relevant studies like seizure interruption using functional neuro imaging tools has shown that specific changes in hemodynamics precede and accompany seizure onset and propagation. However, preclinical seizure experiments need to be conducted in awake animals with images reconstructed and displayed in real-time.

Methods: This article describes an approach that can be utilized to tackle these challenges. A subject specific head interface and restraining method was designed to allow for DOT to imaging of hemodynamic changes in unanesthetized rats during evoked acute seizures. Using CUDA programming model, the finite-element based nonlinear iterative algorithm for image reconstruction was parallelized.

Results: Early hemodynamic changes were monitored in real time and observed tens of seconds prior to seizure onset. Utilizing the massive parallelization offered by graphic processing units (GPU), DOT was extended to online image reconstruction within 1s.

Comparison With Existing Methods: Pre-seizure state related hemodynamic changes were detected in awake rats. 3D monitoring of hemodynamic changes was performed in real time with our parallelized image reconstruction procedure.

Conclusion: Diffuse optical tomography (DOT) is a promising neuroimaging tool for the investigation of seizures in awake animals.
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http://dx.doi.org/10.1016/j.jneumeth.2014.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284948PMC
January 2015

Augmentation of cognitive function in epilepsy.

Front Syst Neurosci 2014 14;8:147. Epub 2014 Aug 14.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida Gainesville, FL, USA ; Department of Pediatrics, University of Florida Gainesville, FL, USA.

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http://dx.doi.org/10.3389/fnsys.2014.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132293PMC
September 2014

In vivo evaluation of needle force and friction stress during insertion at varying insertion speed into the brain.

J Neurosci Methods 2014 Nov 20;237:79-89. Epub 2014 Aug 20.

Department of Mechanical & Aerospace Engineering, University of Florida, Gainesville, FL, USA. Electronic address:

Background: Convection enhanced delivery (CED) infuses drugs directly into brain tissue. Needle insertion is required and results in tissue damage which can promote flowback along the needle track and improper targeting. The goal of this study was to evaluate friction stress (calculated from needle insertion force) as a measure of tissue contact and damage during needle insertion for varying insertion speeds.

New Method: Forces and surface dimpling during needle insertion were measured in rat brain in vivo. Needle retraction forces were used to calculate friction stresses. These measures were compared to track damage from a previous study. Differences between brain tissues and soft hydrogels were evaluated for varying insertion speeds: 0.2, 2, and 10mm/s.

Results: In brain tissue, average insertion force and surface dimpling increased with increasing insertion speed. Average friction stress along the needle-tissue interface decreased with insertion speed (from 0.58 ± 0.27 to 0.16 ± 0.08 kPa). Friction stress varied between brain regions: cortex (0.227 ± 0.27 kPa), external capsule (0.222 ± 0.19 kPa), and CPu (0.383 ± 0.30 kPa). Hydrogels exhibited opposite trends for dimpling and friction stress with insertion speed.

Comparison With Existing Methods: Previously, increasing needle damage with insertion speed has been measured with histological methods. Friction stress appears to decrease with increasing tissue damage and decreasing tissue contact, providing the potential for in vivo and real time evaluation along the needle track.

Conclusion: Force derived friction stress decreased with increasing insertion speed and was smaller within white matter regions. Hydrogels exhibited opposite trends to brain tissue.
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http://dx.doi.org/10.1016/j.jneumeth.2014.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011429PMC
November 2014

Effect of needle insertion speed on tissue injury, stress, and backflow distribution for convection-enhanced delivery in the rat brain.

PLoS One 2014 28;9(4):e94919. Epub 2014 Apr 28.

Department of Mechanical & Aerospace Engineering, University of Florida, Gainesville, Florida, United States of America.

Flow back along a needle track (backflow) can be a problem during direct infusion, e.g. convection-enhanced delivery (CED), of drugs into soft tissues such as brain. In this study, the effect of needle insertion speed on local tissue injury and backflow was evaluated in vivo in the rat brain. Needles were introduced at three insertion speeds (0.2, 2, and 10 mm/s) followed by CED of Evans blue albumin (EBA) tracer. Holes left in tissue slices were used to reconstruct penetration damage. These measurements were also input into a hyperelastic model to estimate radial stress at the needle-tissue interface (pre-stress) before infusion. Fast insertion speeds were found to produce more tissue bleeding and disruption; average hole area at 10 mm/s was 1.87-fold the area at 0.2 mm/s. Hole measurements also differed at two fixation time points after needle retraction, 10 and 25 min, indicating that pre-stresses are influenced by time-dependent tissue swelling. Calculated pre-stresses were compressive (0 to 485 Pa) and varied along the length of the needle with smaller average values within white matter (116 Pa) than gray matter (301 Pa) regions. Average pre-stress at 0.2 mm/s (351.7 Pa) was calculated to be 1.46-fold the value at 10 mm/s. For CED backflow experiments (0.5, 1, and 2 µL/min), measured EBA backflow increased as much as 2.46-fold between 10 and 0.2 mm/s insertion speeds. Thus, insertion rate-dependent damage and changes in pre-stress were found to directly contribute to the extent of backflow, with slower insertion resulting in less damage and improved targeting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094919PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002424PMC
June 2015

Genesis of interictal spikes in the CA1: a computational investigation.

Front Neural Circuits 2014 27;8. Epub 2014 Jan 27.

J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida Gainesville, FL, USA ; Department of Pediatrics, University of Florida Gainesville, FL, USA ; Qualcomm Corp R&D San Diego, CA, USA.

Interictal spikes (IISs) are spontaneous high amplitude, short time duration <400 ms events often observed in electroencephalographs (EEG) of epileptic patients. In vitro analysis of resected mesial temporal lobe tissue from patients with refractory temporal lobe epilepsy has revealed the presence of IIS in the CA1 subfield. In this paper, we develop a biophysically relevant network model of the CA1 subfield and investigate how changes in the network properties influence the susceptibility of CA1 to exhibit an IIS. We present a novel template based approach to identify conditions under which synchronization of paroxysmal depolarization shift (PDS) events evoked in CA1 pyramidal (Py) cells can trigger an IIS. The results from this analysis are used to identify the synaptic parameters of a minimal network model that is capable of generating PDS in response to afferent synaptic input. The minimal network model parameters are then incorporated into a detailed network model of the CA1 subfield in order to address the following questions: (1) How does the formation of an IIS in the CA1 depend on the degree of sprouting (recurrent connections) between the CA1 Py cells and the fraction of CA3 Shaffer collateral (SC) connections onto the CA1 Py cells? and (2) Is synchronous afferent input from the SC essential for the CA1 to exhibit IIS? Our results suggest that the CA1 subfield with low recurrent connectivity (absence of sprouting), mimicking the topology of a normal brain, has a very low probability of producing an IIS except when a large fraction of CA1 neurons (>80%) receives a barrage of quasi-synchronous afferent input (input occurring within a temporal window of ≤24 ms) via the SC. However, as we increase the recurrent connectivity of the CA1 (P sprout > 40); mimicking sprouting in a pathological CA1 network, the CA1 can exhibit IIS even in the absence of a barrage of quasi-synchronous afferents from the SC (input occurring within temporal window >80 ms) and a low fraction of CA1 Py cells (≈30%) receiving SC input. Furthermore, we find that in the presence of Poisson distributed random input via SC, the CA1 network is able to generate spontaneous periodic IISs (≈3 Hz) for high degrees of recurrent Py connectivity (P sprout > 70). We investigate the conditions necessary for this phenomenon and find that spontaneous IISs closely depend on the degree of the network's intrinsic excitability.
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http://dx.doi.org/10.3389/fncir.2014.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902301PMC
September 2014

Pre-seizure state identified by diffuse optical tomography.

Sci Rep 2014 Jan 21;4:3798. Epub 2014 Jan 21.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida Gainesville, FL 32611, USA.

In epilepsy it has been challenging to detect early changes in brain activity that occurs prior to seizure onset and to map their origin and evolution for possible intervention. Here we demonstrate using a rat model of generalized epilepsy that diffuse optical tomography (DOT) provides a unique functional neuroimaging modality for noninvasively and continuously tracking such brain activities with high spatiotemporal resolution. We detected early hemodynamic responses with heterogeneous patterns, along with intracranial electroencephalogram gamma power changes, several minutes preceding the electroencephalographic seizure onset, supporting the presence of a "pre-seizure" state. We also observed the decoupling between local hemodynamic and neural activities. We found widespread hemodynamic changes evolving from local regions of the bilateral cortex and thalamus to the entire brain, indicating that the onset of generalized seizures may originate locally rather than diffusely. Together, these findings suggest DOT represents a powerful tool for mapping early seizure onset and propagation pathways.
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http://dx.doi.org/10.1038/srep03798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896905PMC
January 2014

Influence of neuropathology on convection-enhanced delivery in the rat hippocampus.

PLoS One 2013 8;8(11):e80606. Epub 2013 Nov 8.

Department of Neuroscience, University of Florida, Gainesville, Florida, United States of America ; Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, Florida, United States of America ; Department of Pediatrics, Division of Pediatric Neurology, University of Florida, Gainesville, Florida, United States of America.

Local drug delivery techniques, such as convention-enhanced delivery (CED), are promising novel strategies for delivering therapeutic agents otherwise limited by systemic toxicity and blood-brain-barrier restrictions. CED uses positive pressure to deliver infusate homogeneously into interstitial space, but its distribution is dependent upon appropriate tissue targeting and underlying neuroarchitecture. To investigate effects of local tissue pathology and associated edema on infusate distribution, CED was applied to the hippocampi of rats that underwent electrically-induced, self-sustaining status epilepticus (SE), a prolonged seizure. Infusion occurred 24 hours post-SE, using a macromolecular tracer, the magnetic resonance (MR) contrast agent gadolinium chelated with diethylene triamine penta-acetic acid and covalently attached to albumin (Gd-albumin). High-resolution T1- and T2-relaxation-weighted MR images were acquired at 11.1 Tesla in vivo prior to infusion to generate baseline contrast enhancement images and visualize morphological changes, respectively. T1-weighted imaging was repeated post-infusion to visualize final contrast-agent distribution profiles. Histological analysis was performed following imaging to characterize injury. Infusions of Gd-albumin into injured hippocampi resulted in larger distribution volumes that correlated with increased injury severity, as measured by hyperintense regions seen in T2-weighted images and corresponding histological assessments of neuronal degeneration, myelin degradation, astrocytosis, and microglial activation. Edematous regions included the CA3 hippocampal subfield, ventral subiculum, piriform and entorhinal cortex, amygdalar nuclei, middle and laterodorsal/lateroposterior thalamic nuclei. This study demonstrates MR-visualized injury processes are reflective of cellular alterations that influence local distribution volume, and provides a quantitative basis for the planning of local therapeutic delivery strategies in pathological brain regions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080606PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832660PMC
August 2014

MR measurement of alloy magnetic susceptibility: towards developing tissue-susceptibility matched metals.

J Magn Reson 2013 Aug 13;233:49-55. Epub 2013 May 13.

J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States.

Magnetic resonance imaging (MRI) can be used to relate structure to function mapped with high-temporal resolution electrophysiological recordings using metal electrodes. Additionally, MRI may be used to guide the placement of electrodes or conductive cannula in the brain. However, the magnetic susceptibility mismatch between implanted metals and surrounding brain tissue can severely distort MR images and spectra, particularly in high magnetic fields. In this study, we present a modified MR method of characterizing the magnetic susceptibility of materials that can be used to develop biocompatible, metal alloys that match the susceptibility of host tissue in order to eliminate MR distortions proximal to the implant. This method was applied at 4.7T and 11.1T to measure the susceptibility of a model solid-solution alloy of Cu and Sn, which is inexpensive but not biocompatible. MR-derived relative susceptibility values of four different compositions of Cu-Sn alloy deviated by less than 3.1% from SQUID magnetometry absolute susceptibility measurements performed up to 7T. These results demonstrate that the magnetic susceptibility varies linearly with atomic percentage in these solid-solution alloys, but are not simply the weighted average of Cu and Sn magnetic susceptibilities. Therefore susceptibility measurements are necessary when developing susceptibility-matched, solid-solution alloys for the elimination of susceptibility artifacts in MR. This MR method does not require any specialized equipment and is free of geometrical constraints, such as sample shape requirements associated with SQUID magnetometry, so the method can be used at all stages of fabrication to guide the development of a susceptibility matched, biocompatible device.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774001PMC
http://dx.doi.org/10.1016/j.jmr.2013.05.002DOI Listing
August 2013

Phase shift in the 24-hour rhythm of hippocampal EEG spiking activity in a rat model of temporal lobe epilepsy.

J Neurophysiol 2013 Sep 15;110(5):1070-86. Epub 2013 May 15.

Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA.

For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of ∼12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction.
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http://dx.doi.org/10.1152/jn.00911.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763091PMC
September 2013

Special issue on epilepsy.

Authors:
Paul R Carney

Exp Neurol 2013 Jun;244:1-3

Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.

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http://dx.doi.org/10.1016/j.expneurol.2013.04.006DOI Listing
June 2013
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