22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic condition caused by a microdeletion occurring on the 22nd chromosome. This microdeletion causes a variety of somatic abnormalities, but it is also one of the strongest genetic risk factors for developing schizophrenia, with up to 40% of adults in this population having a diagnosis of a schizophrenia spectrum disorder. While schizophrenia is typically diagnosed in adolescence or early adulthood with the emergence of positive symptoms, negative symptoms and cognitive deficits such as working memory (WM) deficits occur earlier in life. Addressing these symptoms earlier typically produces better long-term mental health outcomes, so a deletion carrier population with a known increased risk for schizophrenia is an ideal population for exploring early interventions before positive symptoms emerge. Symptoms of schizophrenia, depression, anxiety and attention deficit hyperactivity disorder (ADHD), which occur more frequently in populations of deletion carriers, are typically addressed with a variety of psychopharmaceutical medications. However, these medications struggle to target specific deficits of executive functions, such as working memory deficits, which often interfere with capacity for independence and occupational or educational success. In recent years, non-invasive brain stimulation interventions such as transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) have shown promise in modulating brain oscillations that underlie specific cognitive deficits. Theta-tuned tACS has been previously observed to successfully improve WM task performance in healthy adults, so we aimed to investigate the potential of such an intervention in a 22q11.2DS population.

This double-blind sham-controlled study explored the effects of repeated theta-tuned tACS targeting left prefrontal cortex and left temporal regions on WM deficits in 12 individuals with 22q11.2DS aged 12 to 25. The online effects of tACS were assessed based on WM task accuracy during 20 tACS sessions that took place over 4 weeks, the short-term offline effects were assessed based on task accuracy a few days following the final tACS session, and the long-term offline effects were assessed based on task accuracy one month following the final tACS session. We also assessed the safety and feasibility of repeated tACS and found it to be feasible with few side effects, primarily mild tingling.

We found that the active stimulation group performed statistically significantly better than the sham stimulation group during the tACS sessions, possibly reflecting the online effects of tACS. The active stimulation group also performed significantly better during the follow-up session a few days after the final tACS session compared to their own baseline, suggesting that the offline effects of tACS are able to induce improvements in accuracy on visual WM tasks in a 22q11.2DS population. However, the accuracy scores of the active stimulation group returned to near baseline at their third follow-up visit, suggesting that 20 tACS sessions over a