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  • Deep brain stimulation boosts neurons and memory in Rett animals.

    Deep brain stimulation boosts neurons and memory in Rett animals.

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    Newswise — A recent study from the lab of Dr. Jianrong Tang, associate professor at Baylor College of Medicine and principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital shows that deep brain stimulation (DBS) of a specific brain region results in a significant and sustained improvement of memory in Rett mice. Moreover, they found that this treatment promotes the generation of new healthy neurons in these mice.

    The study, published in the journal Brain Stimulation, provides crucial preclinical evidence that supports the development of DBS as a feasible treatment for Rett syndrome patients.

    Rett syndrome (RTT) is a rare but devastating neurodevelopmental disorder that causes regression of motor, social, cognitive, and language skills along with the development of autistic behaviors and seizures. It is caused by mutations in the X-linked gene that encodes the methyl-CpG-binding protein 2 (MeCP2) protein and thus, primarily affects young girls. Since the loss of cognitive skills is one of the tragic aspects of this condition, there has been intense interest in developing therapeutic approaches to mitigate this loss.

    Forniceal DBS induces significant and sustained improvements in learning and memory among RTT mice

    DBS is a neurosurgical procedure that involves the placement of a medical device called a neurostimulator to send electrical signals through the electrodes that have been implanted in targeted brain regions to treat various neurological conditions such as movement disorders (e.g. Parkinson’s, tremors, dystonia),  neuropsychiatric disorders (e.g. obsessive-compulsive disorders, depression), and epilepsy.

    “Inspired by a study which showed that stimulation of the fornix region of the hippocampus improved memory in Alzheimer’s disease, a few years ago we performed forniceal DBS in a mouse model of RTT and found that two weeks of a specific regimen of this treatment improved learning and memory in female RTT mice,” Dr. Jianrong Tang said. “While those findings demonstrated the potential of DBS to mitigate learning and memory deficits in RTT, it was not clear how long the benefits of this treatment would last.”

    Their goal in this study was to address that question. Using well-established behavioral assays, they discovered that DBS improved contextual fear memory in RTT mice and these beneficial effects persisted for 6 to 9 weeks after the treatment. Further, repeated DBS – specifically in the fornix, not other brain regions – maintained the contextual memory improvement in RTT mice.

    Forniceal DBS induces the production of new hippocampal neurons in adult RTT mice

    Adult hippocampal neurogenesis – the process of forming new neurons in specialized regions of the hippocampus of adult animals – is critical for the neurons to ‘learn and remember’.

    Previous studies from the Tang lab revealed that right after the DBS treatment, there was a significant formation of new neurons in specialized regions of the hippocampus. Since it takes anywhere between 2-5 weeks for newborn neurons to be mature and functionally integrate into the neural networks, this correlated with improved contextual memory in these mice three weeks later. Here, they found this close correspondence between the DBS-induced birth of new neurons and improvements in contextual memory persisted several weeks after the treatment as well.

    Forniceal DBS promotes a neuroprotective environment with healthy neurons

    In female mice that carry one copy of defective MECP2, the expression of this gene is switched off/inactivated in some neurons. This means some newborn neurons in RTT mice will be healthy and have MeCP2 while others may not express MeCP2. Interestingly, the Duncan NRI team found that forniceal DBS preferentially induced the birth of more healthy neurons with MeCP2 in Rett mutants.

    Moreover, DBS treatment also induced the production of a key neurotrophin -brain-derived neurotrophic factor(BDNF) – which is a neuroprotective molecule essential for the survival and growth of neurons as well as for their plasticity i.e., their ability to learn and remember.

    “The findings from this study are very promising. We found forniceal DBS not only results in a significant and long-lasting improvement to memory in Rett animals, but that it also promotes a favorable neuroprotective environment in the brain and leads to the production of more healthy neurons – which together suggests DBS could be an excellent therapy to treat Rett patients,” Dr. Tang said.

    Others involved in the study were Qi Wang, Bin Tang, Shuang Hao, Zhenyu Wu and Tingting Yang. They are affiliated with the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and Baylor College of Medicine. The study was funded by the National Institute of Neurological Disorders and Stroke, a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (IDDRC), Neuroconnectivity Core, Circuit Modulation Core, Neurovisualization Core, In Situ Hybridization Core, the In Vivo Neurophysiology Core of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, the Chao Family Foundation, and the Cockrell Family Foundation.

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  • Imaging brain connections can predict improvements in obsessive-compulsive disorder patients after deep brain stimulation

    Imaging brain connections can predict improvements in obsessive-compulsive disorder patients after deep brain stimulation

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    Newswise — Deep brain stimulation (DBS) is a promising therapy for treatment-resistant obsessive-compulsive disorder (OCD). A first-of-its-kind collaborative study led by researchers at Texas Children’s Hospital, Baylor College of Medicine, and Brigham & Women’s Hospital has found that mapping neural connections in the brains of OCD patients offers key insights that explain the observed improvements in their clinical outcomes after DBS. The study was published in Biological Psychiatry.

    Neuropsychiatric disorders such as obsessive-compulsive disorder are a result of dysfunction across broad neural networks and typically involve brain domains responsible for cognitive and higher-order decision-making such as the prefrontal cortex.

    “The goal of neuromodulatory therapies like DBS is to restore the functional balance within these networks. Since the extent of functional dysfunction in these networks varies between individuals, it is important to customize DBS surgery for each patient. To do that reliably, we first need to precisely map the neural connections involved in the specific condition and then understand how these connections are affected by DBS,” said co-corresponding author Dr. Sameer Sheth, professor in the department of neurosurgery at Baylor College of Medicine, director of the Cain Foundation Labs, and principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital.

    In 2020, a seminal study by Dr. Andreas Horn and his team at Brigham & Women’s Hospital identified an ‘OCD response tract’ – a white matter circuit that precisely mapped the specific fiber bundles and brain regions whose modulation by DBS could improve clinical outcomes in OCD patients. The present study is the first one to conduct blind testing of the OCD response tract model with the goal of developing a predictive ‘connectomic’ model.

    Connectomic imaging strategies such as white matter tractography – a three-dimensional magnetic resonance imaging (MRI) technique that maps the location and direction of white matter bundles and their constituent fibers within the brain – are becoming increasingly reliable methods to identify these networks that inform surgeons where to implant DBS electrodes in the brain of the patient during surgery. Here, Sheth and colleagues used this approach to rank and conduct ‘blind’ comparison of clinical outcomes in ten OCD patients who had undergone a specific DBS procedure six months prior to the study.

    DBS programming was performed by Dr. Wayne Goodman, Chair of the department of psychiatry at Baylor College, and patient outcomes were periodically assessed by Dr. Eric Storch, Vice Chair of psychology, for changes in the severity of their OCD and mood symptoms.

    Then the Brigham & Women’s Hospital (BWH) team led by Dr. Andreas Horn analyzed the imaging data and provided rank predictions based solely on the neuroimaging data and stimulation parameters. This team was not involved in DBS planning or programming and did not have prior knowledge of clinical outcomes. The outcomes predicted by the BWH team closely matched the actual clinical outcomes that the Baylor team observed in these patients.

    “To our knowledge, this is the first example of such a collaborative ‘blinded’ team effort by two research centers to validate DBS therapy for a brain tract proposed on the basis of retrospective data,” co-corresponding author, Dr. Horn added. “This is also a big step in the continued optimization and improving the efficacy of DBS procedures that target this brain tract to treat OCD, even as efforts are underway to make this therapy more widely available to patients. Finally, this two-center ‘blinded’ approach could serve as a model for validating and optimizing DBS therapies for other neurological conditions in the future.”

    Others involved in the study were Ron Gadot, Ningfei Li, Ben Shofty, Michelle Avendano-Ortega, Sarah McKay, Kelly Bijanki, Megan Robinson, Garrett Banks, and Nicole Provenza. They are affiliated with one or more of the following institutions: Baylor College of Medicine, Charité – Universitätsmedizin Berlin, Germany; University of Utah, and Brigham and Women’s Hospital. This research was funded by the National Institutes for Health and the McNair Foundation.

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