Metabolic dysregulation and neuropsychiatric burden in Long-COVID: linking fatigue, depression, and cerebral energy metabolism

Introduction

Neuropsychiatric symptoms such as fatigue, depression, and cognitive impairment are a leading cause of global disability and frequently co-occur across diagnostic categories, suggesting shared biological mechanisms. Converging evidence implicates immunometabolic processes - including insulin resistance, chronic low-grade inflammation, and altered energy metabolism - as contributors to brain dysfunction, particularly in circuits supporting motivation, reward processing, and affect regulation. Long-COVID, characterized by persistent symptoms following SARS-CoV-2 infection, provides a clinical model to investigate these mechanisms in a systemic, post-infectious context. Epidemiological studies indicate that metabolic vulnerability, particularly obesity and insulin resistance, increases both risk and persistence of Long-COVID symptoms. Together, this supports the hypothesis that immunometabolic dysregulation disrupts central energy homeostasis and contributes to sustained neuropsychiatric symptom burden.

Aims

This study aims to (i) characterize the neuropsychiatric and fatigue-related symptom burden in Long-COVID relative to healthy controls, (ii) provide objective evidence of physical fatigability, and (iii) examine immunometabolic and neuroimaging correlates of symptom severity, focusing on central insulin sensitivity.

Methods

In an ongoing randomized, double-blind, placebo-controlled crossover study, Long-COVID patients (COV; n=14) and healthy controls (HC; n=20) undergo multimodal MRI, including reward-related fMRI and ¹H/³¹P magnetic resonance spectroscopy. Central insulin sensitivity is modulated via intranasal insulin. Assessments include neuropsychiatric scales, metabolic parameters (e.g., HOMA-IR), and inflammatory markers. Physical fatigability is quantified using a repeated handgrip paradigm (10 trials). Group differences are analyzed using Mann–Whitney U tests and mixed-model ANOVA (Greenhouse–Geisser corrected).

Results

Long-COVID participants showed a broad neuropsychiatric symptom burden, with fatigue (MFIS: 50.2 vs. 6.3, p < .001) emerging as the dominant disabling feature alongside increased depressive symptoms (BDI: 14.6 vs. 1.7, p < .001) and cognitive complaints.

Consistent with fatigue as a central symptom, repeated handgrip trials revealed a significant decline in grip strength across repetitions in both groups (F(9, 279) = 12.24, p < .001, η²p = .283), indicative of physical fatigability. Importantly, the COV group showed lower grip strength overall compared to HC across all ten trials (F(1, 31) = 9.10, p = .005, η²p = .227), with a significant Group × Trial interaction (F(9, 279) = 1.97, p = .043, η²p = .060), indicating a distinct fatigability trajectory.

This pattern was mirrored in subjective state ratings assessed prior to the task. COV participants reported markedly lower perceived energy (M = 23.0, SD = 16.7) and vigor (M = 18.1, SD = 14.4) compared to HC (energy: M = 54.7, SD = 14.2; vigor: M = not shown; both p ≤ .001), alongside substantially higher exhaustion (COV: M = 71.8, SD = 24.3; HC: M = 31.3, SD = 23.5; p = .002).

Conclusions

These findings support a transdiagnostic model linking immunometabolic dysregulation to neuropsychiatric symptoms in Long-COVID, characterized by a prominent energetic-vital deficit. Ongoing neuroimaging analyses will determine whether altered cerebral energy metabolism and impaired insulin-mediated modulation of reward circuits underlie these symptoms. Elucidating these mechanisms may inform targeted, metabolism-based interventions for post-viral neuropsychiatric syndromes and related disorders.

References

No references