Molecular biomarkers associated with cognitive gains from virtual reality rehabilitation in patients with schizophrenia and bipolar disorder

INTRODUCTION: Neurocognitive impairments have been recognized as a core feature of Schizophrenia Spectrum Disorders (SSD) since their earliest clinical descriptions. Key domains such as executive function, attention, memory, and verbal and visual learning are consistently affected in schizophrenia. Cognitive deficits can also be observed in bipolar disorder (BD). The profile of nonspecific cognitive deficits in BD is similar to the profile of cognitive dysfunction observed in SSD, although generally less pronounced. Cognitive rehabilitation, particularly through immersive virtual reality (VR) applications, offers a promising and engaging intervention for both populations. Furthermore, neurotrophic and neurodevelopmental pathways, especially those involving Brain-Derived Neurotrophic Factor (BDNF) and epigenetic regulation, have been implicated in the pathophysiology of both SSD and BD and are linked to cognitive dysfunction.

OBJECTIVES: This study aimed to evaluate whether molecular biomarkers, such as serum BDNF levels, are related to the putative efficacy of a virtual reality cognitive rehabilitation (VRCR) program on cognitive and psychosocial outcomes in patients with SSD and BD.

METHODS: Eighty participants (40 SSD and 40 BD) will be randomized (1:1) to VRCR (CEREBRUM, IDEGO) or treatment-as-usual waitlist. The 12-week intervention includes twice-weekly 45-minute sessions. Cognitive, psychosocial and clinical outcomes will be assessed longitudinally. Peripheral blood samples were collected from all patients in anticoagulant-free tubes for serum preparation. Serum BDNF levels were quantitative measured in duplicate through an enzyme-linked immunosorbent assay method (Quantikine Total BDNF Immunoassay ELISA kit) following the manufacturer’s instructions. Brain-derived neurotrophic factor content was expressed as picograms of protein per milliliter of serum.

RESULTS: Biospecimens were available at the two timepoints for 52 patients. In the combined sample (SSD+BD), no significant correlations were found between changes in BDNF levels and cognitive outcomes. Within the SSD group (n=27), no significant effects were observed, though a trend emerged for visual learning. No effects were found in the BD group. However, among SSD participants who received VRCR (n=17), significant correlations were found with improvements in visual learning (r=0.583, p=0.001), overall neurocognition (r=0.353, p=0.048), and global cognition (r=0.485, p=0.007). No such correlations were observed in SSD controls (n=10). In BD participants receiving VRCR (n=16), only non-significant trends were noted for attention and global cognition. Across all VRCR participants (n=33), significant correlations were observed for attention, neurocognition, and global cognition. In the non-intervention group (n=19), a significant negative association was found for reasoning.

CONCLUSION: These preliminary findings suggest that BDNF level changes may be associated with cognitive gains following VRCR, with more consistent correlations observed. Overall, the results support the potential utility of BDNF as a biomarker for cognitive response to VR-based rehabilitation and underscore the value of integrating molecular measures in intervention research. Further investigations are needed to confirm these associations and elucidate their clinical relevance since this pilot study suffers of modest sample size and require cautious interpretation and replication in larger studies.

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