2007 — 2011 |
Rotenberg, Alexander |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Antiepileptogenesis by Transcranial Magnetic Stimulation @ Children's Hospital Boston
DESCRIPTION (provided by applicant): Status epilepticus (SE) is often the triggering event for epileptogenesis, a sequence of neuronal changes that lead to abnormal excitation and ultimately to epilepsy. Epileptogenesis is dependent in large part on lasting enhancement of excitatory synaptic strength that is similar to the long-term potentiation (LTP) seen with experimental high frequency repetitive neuronal stimulation. In this regard, we propose to investigate the anti-epileptogenic potential of transcranial magnetic stimulation (IMS), a noninvasive method for repetitive neuronal activation that is coming to attention as a new therapeutic tool in epilepsy. The attractive properties of TMS are its ability to 1) terminate seizures and to 2) produce a lasting decrease in synaptic strength. The latter effect may be similar to the long-term depression (LTD) that is LTP's inhibitory counterpart. Accordingly, our overall hypothesis is that the anticonvulsive and LTD-like effects of low frequency repetitive (rTMS) can interfere with SE-triggered epileptogenesis and prevent the expression of epilepsy. TMS is based on the principle of electromagnetic induction where intracranial stimulating currents are generated by a strong extracranial magnetic field. TMS is safe, painless and inexpensive. Its anticonvulsive capacity is demonstrated in a small number of human trials showing a reduction seizure frequency reduction in epileptic patients treated with rTMS. However, its mechanism of action is poorly understood. Therefore, this developing field would benefit from animal model research for elucidation of basic TMS physiology, and for evaluation of its therapeutic potential. We recently developed methods for simultaneous TMS and electroencephalography (EEG) in seizing rats, and identified new potent anti-convulsive effect. We now propose to use the rat kainate (KA) SE model to test the capacity of TMS to 1) stop SE and prevent the seizure-associate neuronal injury, and 2) prevent SE-triggered epileptogenesis. Further, to evaluate the TMS-related cellular and molecular mechanisms of action, we will test whether low frequency rTMS can induce LTD by extending our methods to in vitro hippocampal slice recording. To achieve these overall goals, we will extend our studies to include in vitro and ex vivo hippocampal slice recordings.
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2014 — 2018 |
Pascual-Leone, Alvaro [⬀] Rotenberg, Alexander |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Plasticity in Autism Spectrum Disorders @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): The clinical, social and financial burden of Autism Spectrum Disorders (ASD) is staggering. They are the most prevalent of the developmental disorders and their incidence is rising. However, the ASD phenotype variability is large, and ASD symptoms can manifest over a range of ages and to different degrees. In part for these reasons, the ASD clinical diagnosis is challenging and often is not made until 3-5 years of age. Thus, there remains an unmet need for a valid and reliable endophenotype which would facilitate ASD diagnosis early in life, enable efficient study of ASD risk factors, and eventually serve as a useful biomarker to inform the development of effective therapies and assess treatment response in future clinical trials. The overarching goal of this proposal is to explore te utility of transcranial magnetic stimulation (TMS) measures of brain plasticity as a novel neurophysiologic endophenotype in high- and low-functioning adults and children with ASD. Our work to date demonstrates the potential utility of these measures in higher-functioning adults with ASD, and pilot data support the feasibility and safety of applying the same measures to children and lower functioning individuals in whom the value of such an endophenotype would be particularly high. We thus propose to apply single-pulse TMS to evaluate the modulation in corticospinal reactivity induced by a specific repetitive TMS protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS is a unique noninvasive measure of brain plasticity in humans, and we have found that it shows a reliable abnormality in high-functioning adult individuals with ASD. Our hypothesis is that the alteration of TBS-induced modulation of TMS responses is a common neuropathophysiologic trait that is reliably linked to the ASD phenotype, and that will not be limited to high functioning adults but be also valid in children and low-functioning individuals. W thus anticipate that data from the proposed studies will address an important need for a rapid, noninvasive, reliable and safe endophenotype available to patients with ASD across ages and level of function.
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0.928 |
2015 — 2019 |
Rotenberg, Alexander |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mapping Progressive Loss of Intracortical Inhibition by Tms and Eeg in Posttraumatic Epileptogenesis @ Children's Hospital Corporation
? DESCRIPTION (provided by applicant): Cerebral injury often leads to epilepsy via epileptogenesis, the process by which the brain is transformed into an enduring state (epilepsy) characterized by repeated unprovoked seizures. Severe traumatic brain injury (TBI) is the most common example of epiletogenesis in young adults, and leads to epilepsy in 20-50% of instances. This epileptogenic period provides a window of opportunity where patients at risk for developing seizures may be identified, and where anti-epileptogenic therapy may be administered. Yet, there is no reliable clinical biomarker for epileptogenesis to identify whether epileptogenesis has started and how far it has advanced. Accordingly, the long-term goal of the proposed experiments is to use a rat epileptogenic TBI model to develop a safe, inexpensive and noninvasive electrophysiologic biomarker of epileptogenesis that is based on measures of cortical excitability by transcranial magnetic stimulation (TMS). As a secondary goal, we will test if similar measures can be obtained by cortical EEG. We recently developed methods for focal motor cortex TMS in rats, demonstrated that these reliably reflect the magnitude of GABA-mediated cortical inhibition, and showed that such inhibition is depressed in rat seizure models, including a model of posttraumatic epilepsy. Here we propose to use the rat lateral fluid percussion (LFP) possttraumatic epilepsy model to test (1) whether the loss of cortical inhibition is progressive in time during epileptogenesis, (2) whether loss of intracortical inhibition after injury can predict seizure onset, and (3) whether potentially reversible cellular changes such as loss of GABA-ergic interneurons underlie the TMS-derived measures of cortical inhibition loss. Although the proposed experiments are limited to a rat model of post-TBI epileptogenesis, we anticipate that the results will inform studies of TMS as a biomarker in other forms of epileptogenesis. Further, as we will record EEG in all animals, we will test whether gamma frequency EEG power, which also reflects the integrity of GABA-mediated cortical inhibition, can serve as an epileptogenesis biomarker. Since TMS and EEG are already in wide human use, we anticipate that favorable data from the proposed experiments will be rapidly translated to clinical trials in human TBI.
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2020 |
Rotenberg, Alexander |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Neurophysiologic Investigation of Somatosensory Dysfunction in Autism Spectrum Disorders @ Boston Children's Hospital
Project Summary Autism spectrum disorders (ASD) are the cause of large health-related and economical costs in the U.S. Thus, interventions that relieve symptoms for ASD patients are urgently needed. There are currently no treatments approved by the Food and Drug Administration for ASD. The development of novel therapeutic interventions will require early and reliable biomarkers and improved understanding of the underlying ASD pathophysiology. Most of the research on ASD so far has focused on mechanisms and circuits specific to the central nervous system with little attention to the contributions of abnormal signaling in the peripheral nervous system and spinal cord to the pathophysiology and core symptoms of ASD. Critically, most ASD patients exhibit enhanced responses to sensory stimuli, including tactile stimuli. Moreover, the degree of tactile hypersensitivity is strongly correlated with increased anxiety behaviors and social-behavior deficits observed in ASD. However, there are currently no neurophysiologic indices of tactile hypersensitivity and its contribution to dysfunction of brain networks. In cohorts of 40 ASD young adults, and 40 neurotypical young adults, we will compare the responses to paired associative stimulation (PAS) of the median nerve and the primary motor cortex between individuals with ASD and the control group ? this will serve as a primary measure of the lasting effects on cortical cuntion that aberrant (pathologically heightened) peripheral signaling may have in ASD. Second, we will examine the correlation between the extent of abnormal PAS response in the ASD group and the degree of tactile hypersensitivity as objectively quantified by tactile prepulse inhibition (PPI) and mechanical detection threshold with von Frey fibers. Third, we will test the contribution of the common Val66Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene to PAS measures. Each participant will undergo 4 visits, including two visits for quantitative tactile assessments and two visits for assessment of PAS-induced plasticity. All participants will undergo baseline assessment, including detailed screening, physical/neurological exam, neuropsychological assessment, and assessment of saliva samples for the BDNF SNP to explore predictors of PAS response. The proposed studies will be the first to validate well-formulated hypotheses from animal ASD research with PAS measures of tactile hypersensitivity. Favorable results from proposed experiments will validate standardized tools as biomarkers of tactile hypersensitivity in ASD and will provide measures of target engagement in future therapeutic trials aimed at improving tactile hypersensitivity and associated anxiety and social behavior deficits among ASD patients.
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2021 |
Rotenberg, Alexander |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Astrocytic Glutamate Transporter 1 (Glt-1) Enhancement For the Treatment of Seizures in Dravet Syndrome @ Boston Children's Hospital
Project Summary: Epilepsy is a common, multifactorial neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes, and heterozygous loss-of-function mutations in the SCN1A gene result in Dravet syndrome (DS), a severe infant- onset disease characterized by intractable seizures, developmental delays and increased mortality. While the DS phenotype, as in all monogenic epilepsies, expresses variably among individuals with the same mutation (suggesting that genetic or environmental modifiers may influence clinical severity), the resultant seizures are often resistant to conventional antiepileptic drugs (AEDs), some of which in fact exacerbate seizures in this disorder. Thus, a novel therapeutic AED target in DS is highly desirable. We and others have identified suboptimal removal of the excitatory neurotransmitter glutamate from synapses due to reduced expression of astrocytic glutamate transporter (GLT-1) as a contributor to acquired and congenital epilepsy, both in rodents and humans. Notably, GLT-1 (termed excitatory amino acid transporter 2, EAAT2 in humans) expression, when depressed, can be enhanced by common beta lactam antibiotics (unrelated to these compounds' antimicrobial properties), and we identified that treatment with ceftriaxone, a member of the ?-lactam class with good blood-brain barrier penetrance, suppresses seizures in a rat acquired epilepsy model. Relevant to DS, we documented a clinical observation where children with DS experience seizure suppression when exposed to beta lactam antibiotics. In parallel, in a DS SCN1A haploinsufficiency (Scn1a+/-) mouse model, we identified that GLT-1 protein is depressed in cortex and hippocampus, which raises prospects for GLT-1 deficiency as a plausible novel therapeutic target in DS. Accordingly, we propose a set of exploratory experiments aimed to (1) test the clinical utility of GLT-1 enhancement by ceftriaxone (or analogous compound) in DS treatment. (2) test whether GLT-1 reduction is an Scn1a+/- endophenotype, or the product of recurrent seizures, and (3) characterize the developmental regulation of GLT-1 expression in the Scn1a+/- mouse. Given that seizures in DS do not respond to conventional AEDs, our proposed experiments will be the first step toward a novel adjunctive antiepileptic treatment in this devasting syndrome. Beyond DS, the proposed experiments will provide insight into the role of astrocytic glutamate transport in milder variants of SCN1A haploinsufficiency, and in other epilepsies. As GLT-1 upregulation may be accomplished by safe and inexpensive drugs, we anticipate that favorable results from the proposed studies will translate rapidly to human trials in DS or in related disorders.
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