The ability to modulate neural activity in specific brain circuits remotely and systematically could revolutionize studies of brain function and treatments of brain disorders. Sound waves of high frequencies (ultrasound) have shown promise in this respect, combining the ability to modulate neuronal activity with sharp spatial focus. Here, we show that the approach can have potent effects on choice behavior. Brief, low-intensity ultrasound pulses delivered noninvasively into specific brain regions of macaque monkeys influenced their decisions regarding which target to choose. The effects were substantial, leading to around a 2:1 bias in choices compared to the default balanced proportion. The effect presence and polarity was controlled by the specific target region. These results represent a critical step towards the ability to influence choice behavior noninvasively, enabling systematic investigations and treatments of brain circuits underlying disorders of choice.

Noninvasive and reversible modulation of neuronal activity in specific brain circuits may allow us to diagnose and treat brain disorders in, targeted ways. Low-intensity ultrasound, applied to the brain noninvasively, can be used to modulate neural activity with spatial specificity superior to other noninvasive methods such as transcranial electrical or magnetic stimulation (1–5). The neuromodulatory potential of ultrasound has been highlighted in studies that targeted peri-motor regions of anesthetized rodents or rabbits. Brief, low-intensity stimuli lead to observable movements of the limbs or other body parts (6–13).

However, the enthusiasm about the neuromodulatory potential of ultrasound has recently been dampened by studies that called these effects into question (14, 15). In addition, such overt effects have not been observed in large mammals including humans. Only small changes in neural signals (16–23) or small changes in reaction time or other metrics (24–26) have been found. Yet, to make it truly useful, the approach would ideally provide neuromodulatory effects that are strong enough to manifest in behavior. For example, if clinicians are to determine which brain circuits drive a patient’s craving for an addictive drug, the neuromodulatory effects on a particular neural circuit should be potent enough to yield measurable changes in the subject’s choice behavior, i.e., whether the subject decides to use the drug or not.

Schizophrenia is a devastating psychiatric disorder characterized by positive, negative and cognitive symptoms. While aberrant dopamine system function is typically associated with the positive symptoms of the disease, it is thought that this is secondary to pathology in afferent regions. Indeed, schizophrenia patients show dysregulated activity in the hippocampus and prefrontal cortex, two regions known to regulate dopamine neuron activity. These deficits in hippocampal and prefrontal cortical function are thought to result, in part, from reductions in inhibitory interneuron function in these brain regions. Therefore, it has been hypothesized that restoring interneuron function in the hippocampus and/or prefrontal cortex may be an effective treatment strategy for schizophrenia. In this article, we will discuss the evidence for interneuron pathology in schizophrenia and review recent advances in our understanding of interneuron development. Finally, we will explore how these advances have allowed us to test the therapeutic value of interneuron transplants in multiple preclinical models of schizophrenia.

Schizophrenia is devastating psychiatric disorder that affects approximately 1% of the population¹. Positive symptoms, such as paranoia, grandiosity, delusions, and hallucinations, are often the most striking features of the disorder; however, schizophrenia patients also display characteristic negative and cognitive symptoms, which can be severely debilitating. Negative symptoms, such as blunted affect, emotional withdrawal, and social avoidance and cognitive symptoms, including disruptions in working memory, attentional deficits, disorganized thought, and cognitive inflexibility, can negatively influence social and occupational functioning and diminish quality of life^2–4. Currently prescribed antipsychotic medications, which act as antagonists at the dopamine D2 receptor⁵, have been somewhat effective in treating the positive symptoms of schizophrenia⁶.