Circuit transitions from fear and anxiety to suicidal brain states

Neurosci Biobehav Rev. 2026 Jul 6;189:106848. doi: 10.1016/j.neubiorev.2026.106848. Online ahead of print.

ABSTRACT

Fear, anxiety, and suicidality are often conceptualized along a severity continuum; however, this view fails to capture critical mechanistic differences in how threat is processed and regulated in the brain. Here, we propose a circuit-based framework in which these states represent distinct modes of neural organization defined by their temporal dynamics, network configurations, and regulatory control. Fear is mediated by phasic, stimulus-bound processing within amygdala-centered microcircuits that enable rapid and precise responses to immediate threat. Anxiety emerges through temporal expansion of threat processing, involving recruitment of bed nucleus of the stria terminalis (BNST) circuits, interoceptive amplification via insula-anterior cingulate cortex (ACC) networks, and reduced prefrontal regulation, resulting in sustained anticipatory activation. Suicidal states reflect a further reconfiguration in which threat becomes internalized within self-referential systems. Altered interactions between default mode network (DMN) regions and salience-related systems may contribute to persistent negative self-referential processing, while dysfunction in frontostriatal circuits and reduced serotonergic regulation may contribute to impaired behavioral inhibition and increased behavioral vulnerability. Across these states, three partially overlapping processes temporal persistence, internalization of threat, and impaired action regulation are proposed to represent dynamic reconfigurations within shared neural systems rather than fixed sequential stages.

PMID:42407412 | DOI:10.1016/j.neubiorev.2026.106848