Many individuals with autism spectrum disorder (ASD) experience persistent agitation or aggression, which has an enormous impact on their and their families’ quality of life. While treatment options are few, new therapeutic approaches such as non-invasive transcranial magnetic stimulation (TMS) have been used to great success in a number of neuropsychiatric conditions, including treatment-resistant depression and obsessive-compulsive disorder. However, we do not yet have enough information to suggest an appropriate neuroanatomical target for treating agitation and aggression in ASD.

In the current project, Alexander Li Cohen aims to address this limitation by using “lesion network mapping.” Such an approach involves leveraging highly detailed maps of brain connectivity to study the network effects of focal brain lesions or of developmental anomalies that generate consistent symptoms. This method has already successfully identified over 30 novel brain circuits, many of which also appear to be relevant for individuals without brain lesions. The overarching goal of this study is to identify a consistent brain circuit where injury or developmental alteration is consistently associated with increased agitation and aggression across age and clinical population, and thus, to localize a potential mechanism as well as a putative treatment target for non-invasive neuromodulation.

The project aims to test two hypotheses: (1) that a common critical brain network can be impacted by developmental lesions in children with tuberous sclerosis complex (TSC) who demonstrate increased agitation and aggression and (2) that this same network is affected by focal brain injury or TMS stimulation in adults and leads to new-onset agitation and aggression.

Data will be analyzed from more than 300 children and adolescents with TSC who have undergone extensive neuropsychological assessment to identify brain regions and networks where the presence of tubers is both sensitive and specific to agitation and aggression. Data will also be analyzed from nearly 1,000 adults who have suffered focal brain injury or have undergone focal neuromodulation and who have measures of subsequent changes in agitation and aggression as a measure of generalizability.

If successful, this project will identify a specific brain network that has a causal relationship with agitation and aggression and is consistent across age and clinical cohort. This will inform mechanistic studies of how specific genetic and biochemical alterations lead to increased agitation and aggression in ASD. The findings will also help facilitate neuromodulation studies aimed at altering brain activity in this network to reduce persistent agitation and aggression.