Tag: neuropsychiatric syndromes

Proposed Mechanistic Axis of Infections and mTOR Hyperactivation: A Multidisciplinary Review of Immune, Rheumatologic, and Psychiatric Links

Abstract:

Early-life infections can produce durable changes in immune function and behavior. We propose a mechanistic hypothesis positioning the mechanistic target of rapamycin (mTOR) as the link between peripheral inflammation and central nervous system dysfunction in pediatric post-infectious syndromes. Based on clinical, translational, and experimental literature, we outline a stepwise pathway.

First, sustained mTOR activation skews T-cell and macrophage differentiation toward pro-inflammatory and autoimmune states. Second, endothelial mTOR signaling weakens tight junctions and increases vesicular transport, compromising blood-brain barrier integrity. Third, cytokines and sometimes autoreactive cells enter the brain and engage mTOR in microglia and neurons, driving neuroinflammation, impaired synaptic maintenance and plasticity, and neurotransmitter disruption.

This framework accounts for features observed in Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute neuropsychiatry syndrome (PANS/PANDAS) and yields testable predictions on pathway activity and barrier permeability. It also motivates targeted interventions that modulate mTOR-related processes in immune and endothelial compartments and within neural circuits in children. So, this article aims to outline a mechanistic framework linking infection-driven mTOR activation to post-infectious neuropsychiatric syndromes.

Source: Fronticelli Baldelli G, Buonsenso D. Proposed Mechanistic Axis of Infections and mTOR Hyperactivation: A Multidisciplinary Review of Immune, Rheumatologic, and Psychiatric Links. Children (Basel). 2025 Nov 25;12(12):1603. doi: 10.3390/children12121603. PMID: 41462744. https://www.mdpi.com/2227-9067/12/12/1603 (Full text)

Are cytokines associated with neuropsychiatric syndromes in humans?

Abstract:

Traditional aetiological models in neuropsychiatry have placed little emphasis on the abnormal behavioural responses (decreased psychomotor activity, anorexia, weight loss, decreased social exploration and sexual behaviour, impaired cognitive function and increased somnolence) that are common to both psychiatric syndromes, notably depression, and the illness behaviour of sick animals.

In recent years, the possible role of cytokines, as mediators of not only the immunological and metabolic responses to infection and inflammation but also a co-ordinated behavioural response, has been described. Further, a range of possible mechanisms for these effects has been postulated, notably involving corticotropin releasing factor (CRF) and prostaglandins of the E series (PgE) with the central nervous system (CNS).

Here we outline a series of human clinical conditions where neuropsychiatric syndromes co-occur with a host response to infection or inflammation. These may be characterized by cytokine production (e.g. acute, recurrent and chronic viral illness, systemic autoimmune diseases and chronic fatigue syndrome).

Other clinical situations characterized by exposure to or in vivo production of cytokines (e.g. treatment of chronic infections and malignancies, progression and/or recurrence of malignancies) are also discussed.

We postulate that the stereotyped behavioural repertoire observed is mediated by cytokine-dependent mechanisms within the CNS. Systematic studies of the behavioural responses of such patient groups are suggested, noting specifically correlations between the time course and severity of immune and neuroendocrine and behavioural responses and dose-response effects.

 

Source: Hickie I, Lloyd A. Are cytokines associated with neuropsychiatric syndromes in humans? Int J Immunopharmacol. 1995 Aug;17(8):677-83. http://www.ncbi.nlm.nih.gov/pubmed/8847162