NRI study: Deep brain stimulation restores learning, memory in Rett syndrome mice

Deep brain stimulation (DBS) is considered the best nonsurgical treatment available to reduce tremors in movement disorders such as Parkinson’s disease and dystonia. Electrodes are implanted within specific areas of the brain and external electrical stimulation is used to regulate abnormal neuronal activity. Based on the patient’s response, DBS can be regulated or removed and is safe for clinical use.

In a recent study led by Drs. Huda Zoghbi and Jianrong Tang, and published in the journal Nature, researchers from the Jan and Dan Duncan Neurological Research Institute at Texas Children’s and Baylor College of Medicine, demonstrated that DBS of a specific area of the brain reverts learning and memory deficits in a mouse model of Rett syndrome, a leading cause of intellectual disability in girls.

Although DBS has shown some promise in many movement disorders and neuropsychiatric disorders in children, this is the first experimental demonstration of the effectiveness of DBS in treating a childhood cognitive disorder.

Rett syndrome is caused by a mutation in MECP2 and manifests by the second year of life with loss in cognitive, motor and social skills. These children – most of whom are girls – lose their ability to talk, walk smoothly and are constantly wringing their hands. There is currently no treatment for this disorder.

The NRI team used female mice carrying a single copy of MECP2 to conduct their experiments because this model mimics the genetic defect observed in Rett patients and closely recapitulates the clinical features of this disease.

The researchers targeted fimbria-fornix, a large arch-like structure that contains millions of axons connecting the hippocampus to other parts of the limbic system, a group of interconnected structures that regulate emotions, learning and memory. Previously, DBS of this area has been shown to improve hippocampus-dependent memory defects in amnesiac rats and is showing promise in early stage studies of Alzheimer’s disease.

Researchers used a stimulation protocol that closely resembled currently used clinical treatment paradigms. Remarkably, they found that two weeks of forniceal stimulation in adult Rett syndrome mice significantly increased hippocampal learning and memory functions such as contextual fear and spatial memory.

They also found that forniceal DBS improved only hippocampal learning and memory tasks and did not affect amygdala-based memory. Other Rett Syndrome symptoms such as locomotion, anxiety, motor skills and social behavior, that do not have a forniceal origin, did not improve which demonstrates that the effects of DBS are specific to the targeted location.

Interestingly, the team found that forniceal DBS generated many new hippocampal neurons and strengthened the connections between neurons in both normal and RTT mice, which may contribute to the observed improvements in cognition.

This preclinical study lays the groundwork for exploring the use of DBS in other animal models of neurological disorders with defects in learning and memory and for investigating its potential as an intervention for Rett syndrome.

Texas Children’s Dr. Daniel Curry, director of Pediatric Surgical Epilepsy and Functional Neurosurgery, co-authored this study with Zoghbi and Tang.