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TREATMENTS
 

Beth Israel Deaconess Medical Center, Boston, MA
2014

Principal Investigator(s): Cliff Saper, MD, PhD, and Mouhsin Shafi, MD

Transcranial Magnetic Stimulation: Giving Epilepsy and Autistic Patients Increased Access to Pioneering Treatments

This grant will be used to purchase a transcranial magnetic stimulation (TMS) device for inpatient use. This device would be used therapeutically for patients with epilepsy, including those with autism and other brain disorders whose symptoms may include seizures. The device would also be used in research studies to benefit patients with these profiles. Currently, Beth Israel is limited to TMS devices for outpatient use and this additional device, for inpatient use, would expand its ability to provide treatment and to conduct research studies for the benefit of these patients.

TMS is a non-invasive technique that uses the principle of electromagnetic induction to focus currents in the brain and modulate the function of the cortex. TMS helps to treat a wide range of patients with neurological diseases and disorders. This tool is also helpful in treating epilepsy patients who are diagnosed with autism spectrum disorders (ASD). As many as 40 percent of individuals with ASD and intellectual disability have epilepsy. The treatment for this subpopulation is challenging because of difficulties with medication side effects. TMS is unique in that it can deliver targeted, non-pharmacologic therapy that works via a different mechanism than all known medications, and may be effective when conventional medications fail. Because it is targeted to a specific brain region, it also does not produce any systemic side effects. TMS can also be used in a variety of diagnostic and therapeutic research studies to benefit patients with neurologic diseases, including epilepsy and autism. For example, conventional electroencephalography (EEG), the test typically used to help diagnose epilepsy, is an imperfect tool that tries to capture brain activity as it occurs spontaneously. Since seizures are intermittent, EEG rarely captures them, and we rely on finding interictal "spikes" to help diagnose epilepsy. However, these spikes may not always be present in individuals with epilepsy, and can also be present in individuals with other neurologic disorders. For example, studies have suggested that up to 60 percent of individuals with ASD but without known epilepsy had interictal spikes. Consequently, better tools are needed, including a better biomarker for epilepsy. Because TMS enables us to stimulate the brain and assess how it responds, this technique may be a useful tool in this regard. TMS can be used in research studies of new treatments. For example, many individuals with ASD but without known epilepsy have interictal spikes on their EEG. In some cases these spikes are frequent, clearly associated with intellectual regression. Treatment with conventional seizure medications can significantly improve cognitive function. In the majority of cases, however, there is no such clear improvement. This may in part be because the seizure medications do not completely suppress the spikes, and because the seizure medications often themselves have cognitive side effects. Since TMS can be used to deliver treatment specifically to the spike focus, and without general cognitive side effects, TMS treatment could be helpful in improving cognitive function in individuals with ASD with interictal spikes.

A new TMS machine will enable BIDMC to expand services to inpatients with epilepsy, including those with autism, by giving physicians increased access to this pioneering treatment and expanding the ability to conduct related research.

Clifford Saper Laboratory

Mouhsin Shafi



Children’s Hospital, Boston, MA
2012- 2015

Principal Investigator: Sarah Spence, MD, Ph.D.

Treatment of Children with ASD and Epileptiform EEG with Divalproex Sodium (Co-funded with the Simons Foundation)

Epilepsy or seizure disorders happen relatively frequently in individuals with autism spectrum disorders (ASD) and seizures are always treated with medication.  However, abnormalities on the electroencephalogram (EEG) can also be present in ASD even when there are no seizures. The need for treatment of these EEG abnormalities is unclear.  Dr. Spence’s research group believes that these EEG epileptiform discharges may represent an important biomarker in some individuals with ASD and wants to explore them as a target for treatment.  Studies suggest that epileptiform discharges contribute to problems in attention, language and behavior.  Dr. Spence will test whether there is a positive effect of treating children with ASD and epileptiform EEGs using an anti-seizure medication that is known to help normalize the EEG (Depakote).  Thirty subjects ages 4-8 will be recruited from two large autism centers (Children’s Hospital Boston and Vanderbilt University).  Subjects will be in the study for 26 weeks receiving active drug for 12 weeks and placebo (inactive substance) for 12 weeks.  EEGs and behavioral assessments will be done at the beginning, middle, and the end.  The hope is to show that administration of Depakote will reduce the number of epileptiform EEG discharges.  Dr. Spence’s group also wants to show that Depakote improves a wide range of behavioral measures including: language, mood, irritability, attention, motor, sensory, adaptive function and core ASD behaviors.  Because there is a known relationship between Depakote, EEG discharges and sleep, they will look at changes in sleep and how these measures relate as well.   Finally they will test a special EEG to see if brain connectivity measures change and are related to behavioral improvements.

Sarah Spence



MGH/HST Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA
2015 - 2016

Principal Investigator(s): Bruce Rosen, MD, PhD and Kristin Ciesielski, PhD

Real-Time Modulation of Brain Oscillatory Activity as a Novel Treatment/Preventive Toll for Children with ASD and OCD.

Clinical, neuroimaging and genetic studies suggest that children with autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD) share a common pattern of heritability and obsessive/compulsive symptoms, and thus may be considered jointly as obsessive-compulsive (O-C) spectrum disorders. Current conceptual frameworks for both disorders emphasize deficits in attentional inhibitory control and connectivity in inhibitory brain networks. Magnetoencephalography (MEG) studies demonstrate in ASD and OCD a significantly reduced power and task-related flexibility of brain oscillations in the alpha range (8-13Hz), an indicator of top-down inhibitory control.

The objective of this study is to examine whether training of real-time enhancement of alpha power and task-related brain alpha modulation using a Brain-MEG Interface system, will be associated with improvement in children’s attentional capacity and with an increase in top-down inhibitory control of behavior.

The potential contribution of this study is to enhance our understanding of the neural developmental bases of brain top-down attentional inhibitory control in children with ASD and OCD. The ultimate goal is to contribute to development of a novel, neuroimaging-inspired, non-invasive and child-friendly treatment and preventive approach for children with ASD and OCD.

MGH/HST Martinos Center for Biomedical Imaging



State University of New York at Buffalo, Buffalo, NY
2016-2019

Principal Investigator: Zhen Yan, Ph.D.

Novel Therapeutic Strategies for Autism

The goal of this study is to understand the causal mechanism underlying synaptic and behavioral deficits in autism, and develop mechanism-based therapeutic strategies for this complex brain disorder. In previous studies. Dr. Yan and colleagues discovered how to reverse certain disruptions of neuronal communication stemming from the deletion of the Shank3 gene, which results in autism-like behaviors in an animal model. They found that the disruption of this neuronal communication results from the dysregulation of actin filaments, a kind of cellular “highway” in the brain’s prefrontal cortex, the command center for high level executive functions and a key region implicated in ASD. Dr. Yan and colleagues found that once the expression or activity of certain actin regulators was returned to normal, which allowed for the normal trafficking and functioning of important neuronal receptors, they were able to restore social behaviors in these mice. Dr. Yan and colleagues hope to extend their research on novel therapeutic strategies for autism by finding an effective treatment for patients with ASD who have genetic deletion or loss-of-function mutations of Shank3. They also will study how these findings might be applied to treating ASD when other genetic mutations are implicated.

Zhen Yan



 
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