Whether grocery shopping or choosing words to express a thought, selecting between options can be challenging, especially for people with anxiety. We investigate the neural mechanisms supporting selection during language processing and its breakdown in anxiety.Our neural network simulations demonstrate a critical role for competitive, inhibitory dynamics supported by GABAergic interneurons. As predicted by our model, we find that anxiety (associated with reduced neural inhibition) impairs selection among options and associated prefrontal cortical activity, even in a simple, nonaffective verb-generation task, and the GABA agonist midazolam (which increases neural inhibition) improves selection, whereas retrieval from semantic memory is unaffected when selection demands are low. Neural inhibition is key to choosing our words.P eople claim to love the freedom of unlimited choices, but in reality we are often stymied by too many options and disconcerted by not knowing what the outcomes of our choices will be. Selecting among multiple options is effortful and time consuming, whether choosing among fruit jams (1), retirement plans (2), or medical treatments (3). This problem is particularly pervasive during language production, when we must constantly choose words to express a thought (4-6). People with anxiety disorders find coping with too many options particularly difficult, and struggle with decision-making problems (7), indecisiveness (8), and intolerance of uncertainty (9). What mechanisms allow us to select among multiple options when speaking, and why does this process break down in people with anxiety? Current psychological theories of selection focus on the importance of cognitive control (5) and prefrontal cortical regions (4, 6, 10), but do not address questions at the level of specific neural mechanisms. We address these questions by implementing a unified, biologically plausible computational model of selection, and testing its predictions about both brain and behavior in humans making choices in a well-controlled language production task.Our model demonstrates how competitive, inhibitory dynamics among neurons in prefrontal cortical networks (11) support selection between alternatives. Specifically, these competitive dynamics serve to sharpen cognitive representations by amplifying activity in the most active, task-relevant, representations (e.g., the most appropriate word to complete a sentence) and suppressing competing representations (e.g., for the many other word possibilities). A tenet of the model is that these critical dynamics occur via inhibitory, GABAergic interneurons (12-14). Here we test the predictions of the model regarding selection processes that are supported by the left ventrolateral prefrontal cortex. We do so for the following reasons: (i) this region has been implicated in selecting among competing alternatives during language processing (6, 15-18); (ii) this region shows altered activity in individuals who suffer from anxiety (particularly anxious apprehension, characterized by w...

While structural abnormalities of the dorsolateral prefrontal cortex (DLPFC) may pre-date and predict psychosis onset, the relationships between functional deficits, cognitive and psychosocial impairments has yet to be explored in the at-risk period. An established measure of cognitive control (AXCPT) was administered to demographically matched clinical-high-risk (CHR; n=25), first-episode schizophrenia (FE; n=35), and healthy control (HC; n=35) participants during functional magnetic resonance imaging (fMRI) to investigate these relationships. CHR and FE individuals demonstrated impaired context processing and reduced DLPFC activation relative to HC individuals during increased cognitive control demands. FE and CHR individuals’ ability to increase DLPFC activity in response to cognitive control demands was associated with better task performance. Task performance was also associated with severity of disorganization and poverty symptoms in FE participants. These findings support more extensive studies using fMRI to examine the clinical significance of prefrontal cortical functioning in the earliest stages of psychosis.