Most research on insulin and its effects on mental health has focused on peripheral tissues as the brain was long considered an insulin-insensitive organ (Figlewicz, 2016, Unger et al., 1991). However, the brain is now known to be an insulin-sensitive organ with high expression of insulin receptors in many areas, including the hypothalamus, striatum, prefrontal cortex, amygdala and hippocampus. Importantly, decreased brain insulin levels and/or signaling has been linked to impaired cognitive functioning (Kullmann et al., 2016), neuronal atrophy (Willette et al., 2013), and altered cerebral blood perfusion (Hoscheidt et al., 2017). Consequently, brain insulin resistance (i.e., downregulation of brain insulin receptors or a decrease in the sensitivity of central pathways to insulin) is posited to be implicated in the pathophysiology of various neuropsychiatric diseases (such as, Alzheimer’s disease, major depressive disorder, and schizophrenia) and may represent a key therapeutic target for their related cognitive deficits (Frazier et al., 2019, Yang et al., 2018, Leonard and Wegener, 2020, Kullmann et al., 2016).

Intranasal insulin (INI) is a non-invasive approach that allows direct delivery of insulin to the brain (Kullmann et al., 2016). While circulating insulin enters the cerebrospinal fluid through saturable transport mechanisms, INI effectively bypasses the blood brain barrier and induces widespread insulin distribution in the brain via para-cellular transport into the cerebrospinal fluid, or via bulk flow along olfactory nerves and trigeminal perivascular channels (Lochhead et al., 2019). Employing this administration technique allows researchers to tease apart peripheral versus central insulin effects and investigate the effect of an insulin challenge on the brain. Previous reviews have explored the effect of an INI challenge on cerebral blood flow (Nijssen et al., 2023); however, the literature describing the effects of a pharmacological insulin challenge on various aspects of brain functioning, as assessed by multi-modal neuroimaging techniques, has yet to be synthesized comprehensively. Given the hypothesized pathophysiological role of central insulin dysregulation across various neuropsychiatric diseases and lack of a systematic review of existing evidence, this scoping review aims to 1) synthesize studies investigating brain insulin action in relation to functional connectivity, neuronal activity, cerebral blood flow, brain energetics, and dopaminergic signaling, and 2) highlight the implications of central insulin dysregulation in relation to cognitive, mental, and metabolic health.