Prefrontal cortex executive processes affected by stress in health and disease

The review addresses how stress—acute and chronic—modulates executive functions mediated by the prefrontal cortex, including working memory, attention, response inhibition, and cognitive flexibility. It situates executive functions as top-down processes essential for adaptive behavior, which can be compromised by stress and are commonly impaired across psychiatric disorders (depression, GAD, OCD, ADHD, PTSD, addiction). The PFC, within distributed networks (e.g., hippocampus, amygdala, striatum, parietal cortex) and large-scale systems (central executive network), underpins these functions. Acute stress transiently reallocates cognitive resources toward salience and hypervigilance at the expense of higher-order executive processing, whereas chronic stress leads to persistent deficits and structural alterations in PFC circuitry. The purpose is to synthesize evidence from human and animal studies on behavioral impacts, neurochemical and molecular mechanisms, and therapeutic strategies to ameliorate stress-related executive impairments.

The review consolidates evidence that acute stress enhances salience network activity (amygdala, cingulate, insula, striatum, locus coeruleus) and sensory vigilance while impairing working memory, problem-solving, and cognitive flexibility; genomic glucocorticoid actions later improve executive performance as acute stress resolves. Chronic stress in humans correlates with attentional shifting and working memory deficits, habitual decision-making biases, and executive impairments across stress-related psychopathologies. In animals, chronic stress impairs working memory and cognitive flexibility, accompanied by dendritic retraction and spine loss in mPFC and hypertrophy in OFC, amygdala, and putamen, mirroring structural-functional changes observed in clinical populations. Detailed sections synthesize domain-specific evidence: Working memory—assessment paradigms (T-maze, object recognition; n-back) and stress effects follow an inverted-U, with neurochemical roles for glutamate (AMPA/NMDA), GABA, dopamine, norepinephrine, serotonin; pharmacotherapies include stimulants, modafinil, guanfacine/clonidine, vortioxetine. Attention—assessed via 5-CSRTT and human tasks (Stroop, selective/sustained attention); stress impairs selective and sustained attention, with mechanistic insights into glutamate (NMDA, mGluR2/3), dopamine D1/D2, norepinephrine (NET inhibitors, alpha receptors), and serotonin (5-HT1A/5-HT2A/2C). Response inhibition—measured by 5-CSRTT and stop-signal tasks; chronic stress reduces inhibitory control; mechanisms include glutamate (NMDA interactions, 5-HT modulation), striatal dopamine D2, norepinephrine (atomoxetine), serotonin (SSRIs, 5-HT2A antagonism), and multi-system agents (methylphenidate, atypical antipsychotics). Cognitive flexibility—reversal learning and set-shifting; chronic stress impairs both; reversal learning relies on OFC with modulatory roles for glutamate (LTD, AMPA/NMDA; JAK2/STAT3; ketamine/HNK), dopamine (striatal D2), norepinephrine (alpha-mediated), serotonin (tone and receptor subtype actions including 5-HT1A/1B/2C; vortioxetine). Set-shifting depends on mPFC glutamate (NMDA/AMPA) and catecholamines, improved by ketamine and noradrenergic agents (atomoxetine, desipramine; alpha1/alpha2 interactions), serotonin receptor modulation (5-HT7/5-HT6 antagonism), and dopamine receptor balance (D1, D2/D3, D4). Non-pharmacological treatments across domains include cognitive training (working memory), mindfulness/MBSR, CBT (ADHD, OCD), transcranial magnetic stimulation, vagal nerve stimulation, exposure therapy, and ECT.

As a narrative review, two complementary searches were conducted for each executive function domain: preclinical animal studies and human populations (non-clinical cohorts and clinical disorders where stress is etiological or exacerbating: Depression, PTSD, OCD, ADHD). For neurochemical mechanisms and pharmacological targets, combinatorial search terms included “stress” with each executive domain plus neurotransmitter systems (dopamine, glutamate, GABA, norepinephrine, serotonin) and non-pharmacological interventions (e.g., transcranial magnetic stimulation). Searches used Google Scholar and PubMed/Medline (MeSH), limited to English-language publications from 1960–2017. Exclusions included confounds from neurological conditions or physical trauma. Citations within reviews were cross-referenced.

Highlights: (1) Executive functions such as working memory, attention, behavioral inhibition, and cognitive flexibility are mediated in the prefrontal cortex. (2) Stress impairs executive function, compromising adaptive behavior and contributing to psychiatric pathology. (3) Chronic stress alters multiple neurotransmitter systems (glutamate, GABA, dopamine, norepinephrine, serotonin) and molecular signaling pathways required for optimal executive function. (4) Understanding chronic stress effects on executive function may yield therapeutic targets. Additional findings: Acute stress rapidly enhances salience processing and hypervigilance via catecholamines and glucocorticoids, while impairing working memory and flexibility; post-stress genomic glucocorticoid effects can transiently improve executive function. Chronic stress consistently impairs working memory, attention, response inhibition, and cognitive flexibility in humans and animals, and is associated with mPFC dendritic spine loss and atrophy, with hypertrophy in OFC/putamen, paralleling clinical structural-functional abnormalities in mood disorders. Mechanistic insights include inverted-U relationships for catecholamines and glucocorticoids in working memory; glutamatergic receptor regulation (AMPA/NMDA) underlies stress effects; norepinephrine via alpha receptors supports attention, response inhibition, and flexibility; striatal dopamine D2 signaling impacts reversal learning and impulsivity; serotonergic tone and receptor-specific actions (5-HT1A/1B/2A/2C/5-HT6/5-HT7) differentially modulate domains. Therapeutic evidence spans pharmacological agents (atomoxetine, desipramine, duloxetine, clonidine/guanfacine, stimulants, modafinil, SSRIs, vortioxetine, ketamine/HNK, atypical antipsychotics) and non-pharmacological interventions (CBT, mindfulness/MBSR, exposure therapy, TMS, VNS, ECT), with domain-specific improvements.

The synthesis indicates that stress engages neurobiological mechanisms that reallocate cognitive resources toward rapid, salience-driven processing while disrupting higher-order executive functions reliant on PFC network integrity. Chronic stress induces structural remodeling (dendritic retraction and spine loss in mPFC) and functional dysregulation across glutamatergic and monoaminergic systems, aligning with executive deficits observed in stress-related psychiatric disorders. These convergent data clarify how stress exposure contributes to the executive dysfunction central to clinical symptoms and suggest that targeting PFC network plasticity, glutamatergic synaptic mechanisms (including LTD and AMPA/NMDA balance), and catecholaminergic/serotonergic modulation can remediate domain-specific impairments. The review underscores translational relevance: pharmacologic agents (e.g., atomoxetine, desipramine/duloxetine, ketamine/vortioxetine) and neuromodulatory/non-pharmacological interventions (CBT, mindfulness, TMS, VNS, ECT) show promise across executive domains, although efficacy is context- and receptor-subtype dependent.

Stress exerts robust, multi-level effects on executive functions mediated by the prefrontal cortex, with acute stress temporarily impairing working memory and flexibility and chronic stress producing persistent deficits and PFC structural changes. Mechanistic insights implicate glutamate (AMPA/NMDA signaling, LTD, JAK2/STAT3), GABA, dopamine (striatal and PFC receptor-specific actions), norepinephrine (alpha receptor-mediated), and serotonin (receptor subtype-specific modulation) in stress-induced executive dysfunction. The review highlights existing pharmacologic and non-pharmacologic strategies that improve executive domains and emphasizes the need for more detailed circuit- and receptor-level understanding to develop targeted interventions. Future research should: (1) delineate stress dose–duration interactions across executive domains; (2) map circuit-specific plasticity in PFC–striatal–limbic networks; (3) resolve receptor-subtype and region-specific roles within neurotransmitter systems; (4) refine translational models to bridge preclinical findings to clinical outcomes; and (5) systematically evaluate combined pharmacological and behavioral/neuromodulatory treatments for domain-specific restoration.

As a literature review, conclusions are constrained by heterogeneity in stress paradigms (acute vs. chronic, intensity, timing), behavioral tasks across species, and methodological differences that produce mixed findings (e.g., NMDA antagonist effects on reversal learning). Many mechanistic inferences are indirect or correlative, with limited causal evidence in humans. Pharmacological agents frequently act on multiple neurotransmitter systems, complicating attribution of effects to specific receptors. Human data on norepinephrine-specific modulation of set-shifting and attention are limited due to non-selective medications. Overall, despite characterization of some circuitry and neurochemical processes, substantial gaps remain in understanding how stress modifies executive-related networks and synaptic mechanisms, warranting further targeted studies.