Tuberous sclerosis complex is associated with a wide range of nervous system symptoms, including language and communication difficulties and delays, autism, neurocognitive abnormalities, brain malformations and tumors and epilepsy. Epilepsy in TSC begins in early childhood and is often severe and resistant to drug treatment, leading to developmental delays and regression. Because of these observations, our clinical epilepsy group strives to treat childhood epilepsy in TSC aggressively, especially given the developmental regression often reported in TSC following increased seizures. Given the drug resistance of epilepsy in these patients, we often pursue surgical options. Currently, implanting multiple stereo-EEG electrodes is the state-of the-art method for identifying seizure-generating areas in the brain of TSC patients. The goal is to target these regions surgically with resection or stereotactic laser ablation or neural modulation with an implanted device.

The goal of epilepsy surgery in TSC is to reduce or eliminate seizures while avoiding any adverse side effects, including difficulties with language and movement. However, because TSC is associated with changes in brain structure, including benign tumors (called tubers), it is not known whether these tubers change or remodel brain regions required for speech and language, or whether they contain functional responses to speech. It can be difficult for children with TSC to perform the tasks required for clinical language mapping due to language and cognitive delays, so clinicians may need to act on limited information. Knowing the location of language in the brain is important for avoiding any unwanted post-surgical issues with communication. If tubers do not contain functional tissue or responses to language and are involved in causing seizures, it may be safe to remove them, even if they appear to be in a region that would normally respond to language in people without TSC. On the other hand, if we can identify areas that respond to language in children undergoing surgical epilepsy treatment who would not otherwise be able to complete clinical language mapping, we may help to avoid unwanted adverse outcomes from epilepsy surgery that could reduce the child's communication ability.

Our research investigates how speech and language are represented in the brain in pediatric patients with tuberous sclerosis complex and drug-resistant epilepsy undergoing surgical treatment, with the goal of improving surgical outcomes. These patients already have electrodes placed in language areas of the brain for mapping seizures, so there is no additional risk, and we can study activity from these areas in parallel with clinical management. Our project addresses two FY23 TSCRP focus areas: (1) Understanding, preventing, and treating the features of TSC-Associated Neuropsychiatric Disorders (TAND) and reducing their impact, including pharmacological, behavioral, and surgical interventions; and (2) Preventing epilepsy, improving treatment, and mitigating neurodevelopmental and adverse outcomes associated with TSC-related seizures.

Our project has three parts. First, we are developing a new way to assess brain responses to language in children with TSC undergoing epilepsy surgery. We use movie clips that we annotate with the words and phonemes present in each clip and play them to children with implanted intracranial electrodes that record brain activity. The task is easy and engaging, as it involves children watching movies they are already familiar with from studios like Pixar and Disney. We will compare brain activity during movie watching to brain areas that are active during standard clinical testing using functional magnetic resonance imaging and electrocortical stimulation mapping. Second, we will determine if tubers or surrounding tissue identified in MRI behave differently in response to speech and language. Third, we will use caregiver reports of speech and language ability before and after epilepsy surgery to test how the location of language responses in the brain, the number of tubers and their location, and type of epilepsy surgery impact communication ability. We will use a measure that includes multiple aspects of communication ability, including verbal and nonverbal, to fully capture the diversity of communication strengths and needs in TSC.

This addresses an important unmet need in TSC research. By determining changes to the language network in TSC, safer and more effective surgical procedures may be pursued, and we may gain better insights into abnormal circuitry associated with seizures in language areas that contribute to further regression in communication and language with severe, drug resistant epilepsy. The timeline for clinical benefit could be as short as 5 to 10 years, since this proposal could catalyze future clinical trials and potentially provide additional data to assess the impact of seizures and surgical removal of brain tissue on communication. Additionally, this study will enhance our understanding of speech and language representations in TSC compared to epilepsy without TSC and shed light on the influence of tubers on brain function, informing future surgical approaches.