Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal survival, synaptic plasticity, and cognitive resilience during aging. Declining BDNF levels are strongly associated with age-related cognitive impairment and neurodegenerative disorders. Music therapy, a non-invasive intervention, has shown promise in enhancing neuroplasticity and modulating neurochemical signaling. However, the mechanisms linking music therapy to BDNF signaling in the aging brain remain underexplored.

This systematic review aimed to examine the evidence on how music therapy influences BDNF signaling pathways and cognitive functions in older adults. 

Introduction | Background: BDNF and Aging | Mechanisms of Music and Neuroplasticity | Methods | Results | Preclinical Evidence | Clinical & Aging Evidence | Discussion | Limitations of Evidence | Clinical Implications | Conclusions & Future Directions | References

Introduction

Age-related cognitive decline poses an increasing global burden as populations age. Traditional pharmacological interventions show limited efficacy, prompting the exploration of lifestyle-based, non-pharmacological strategies. Music-based interventions (MBIs), including passive listening, active music-making, and rhythm-based therapies, have gained attention for their neurocognitive benefits. One proposed mechanism involves modulation of brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, neurogenesis, and resilience against neurodegeneration [1][3].

This systematic review aims to evaluate the efficacy of music-based interventions on BDNF signaling in the context of age-related changes, synthesizing evidence on BDNF levels, cognitive outcomes, and potential moderators. By elucidating mechanisms and efficacy, we provide insights for therapeutic applications in aging populations. 

Observational studies supported higher BDNF in lifelong musicians compared to non-musicians. Music-based interventions appear efficacious in enhancing BDNF signaling, potentially slowing age-related cognitive changes, though heterogeneity in intervention types and durations warrants further standardization. High-quality, long-term RCTs are needed to confirm causality and optimize protocols for clinical application.

Introduction

Background: BDNF and Aging

BDNF is a neurotrophin highly expressed in the hippocampus, prefrontal cortex, and striatum. It binds to tropomyosin receptor kinase B (TrkB), initiating cascades such as MAPK/ERK, PI3K/AKT, and PLCγ1/PKC pathways that regulate neuronal growth, survival, and long-term potentiation [6]. With aging, both peripheral and central BDNF levels decline, correlating with memory deficits, synaptic dysfunction, and increased vulnerability to Alzheimer's disease [9]. Strategies that enhance BDNF signaling could therefore mitigate age-related neuronal decline.

Mechanisms of Music and Neuroplasticity

Music engages widespread brain regions, including auditory, limbic, and prefrontal circuits. Neuroimaging studies demonstrate that musical training enhances cortical thickness and grey matter volume in regions implicated in cognition [0]. Animal studies reveal that musical stimulation increases hippocampal neurogenesis and upregulates BDNF expression [6]. The hypothesized mechanisms include:

• Neurotrophic modulation: Increased BDNF mRNA and protein in hippocampus and cortex.
• Stress regulation: Reduction in cortisol and inflammatory cytokines, indirectly sustaining BDNF levels.
• Dopaminergic reinforcement: Music-induced reward circuitry activation (ventral striatum) enhances plasticity.
• Multisensory integration: Rhythmic entrainment fosters cross-modal plasticity supporting cognition and motor learning.

Methods

Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science using keywords: "music intervention", "BDNF", "aging", "neuroplasticity", and "cognition". Inclusion criteria were:

• Peer-reviewed studies from 2000–2025
• Preclinical (animal) or clinical (human) studies
• Reported outcomes involving BDNF signaling, biomarkers, or cognitive measures in older adults

Data were extracted for sample characteristics, intervention type, BDNF-related outcomes, and cognitive effects.

Inclusion and Exclusion Criteria

Studies were included if they: (1) involved human participants aged ≥60 years with or without cognitive impairment (excluding severe dementia or acute neurological events); (2) evaluated music-based interventions (receptive or active); (3) measured BDNF levels (serum, plasma, or CSF) pre- and post-intervention; (4) assessed age-related outcomes like cognition, mood, or neuroplasticity; and (5) were RCTs, quasi-experimental, or observational designs. Exclusions: animal studies, case reports, interventions <4 weeks, or those lacking BDNF quantification

Results

Preclinical Evidence

Musical stimulation in rodents increased hippocampal BDNF and TrkB activation, enhancing long-term potentiation and memory performance [6]. In stroke models, music exposure promoted cortical BDNF accumulation and neurorepair, improving motor recovery [5]. These findings suggest that music engages molecular cascades critical for neuroprotection and regeneration.

Clinical & Aging Evidence

Cross-sectional studies indicate musicians show elevated plasma BDNF compared to non-musicians [1]. Neuroimaging studies report structural and functional plasticity after musical practice in older adults, although direct BDNF measures are limited [2]. In older adults with MCI, receptive music therapy improved memory and mood, suggesting indirect BDNF involvement [3]. Meta-analyses confirm cognitive benefits of MBIs, particularly in executive and episodic domains, though biomarker data remain sparse [4]. Ongoing longitudinal studies are explicitly measuring BDNF in aging cohorts undergoing choir-based interventions [7][8].

Discussion

The convergence of preclinical and human evidence supports the hypothesis that music enhances neuroplasticity through BDNF-dependent mechanisms. Animal studies provide mechanistic detail, while clinical work demonstrates cognitive and mood improvements consistent with BDNF-related pathways. However, gaps remain in direct biomarker evidence among aging humans.

Another consideration is the heterogeneity of interventions: active (instrumental training, choir singing) versus receptive (listening). Active participation may yield stronger BDNF-mediated effects due to motor, social, and cognitive engagement [4]. Personalized approaches accounting for age, baseline cognition, and genetic polymorphisms in BDNF (Val66Met) could optimize intervention efficacy.

Limitations of Evidence

Limitations: Heterogeneity in interventions and BDNF assays; few studies measured BDNF isoforms (e.g., pro- vs. mature-BDNF). Most focused on MCI/AD, limiting generalizability to healthy aging. Future research should incorporate neuroimaging to link BDNF changes to brain structure/function and explore personalized music selection.

Current limitations include:

• Few RCTs with direct BDNF measurements in elderly populations.
• Variability in intervention duration, frequency, and modality.
• Peripheral BDNF measures may not reflect central neurotrophic dynamics.
• Potential confounding effects of physical activity and social engagement.

Clinical Implications

MBIs may represent scalable, low-cost adjuncts for promoting cognitive health in aging populations. Integration into rehabilitation (post-stroke), dementia care, and preventive programs could leverage their neurotrophic potential. Monitoring BDNF as a biomarker may also provide objective evidence of efficacy, bridging behavioral outcomes and molecular mechanisms.

Conclusions & Future Directions

Music-based interventions appear to enhance BDNF signaling in preclinical models and improve cognition in aging humans. To validate translational efficacy, future research must include:

• Large-scale, multi-site RCTs with standardized MBI protocols.
• Simultaneous cognitive, neuroimaging, and biomarker assessments.
• Investigation of dose-response relationships in music exposure.
• Genetic and epigenetic moderators of BDNF response to music.

Such studies will clarify whether MBIs can serve as effective interventions to delay or mitigate age-associated cognitive decline. Music therapy may positively modulate BDNF signaling in the aging brain, supporting neuroplasticity and cognitive health.

While preliminary results are promising, heterogeneity in study design, intervention protocols, and biomarker assessment warrants further large-scale randomized controlled trials. Music-based interventions hold potential as cost-effective, accessible strategies for promoting healthy cognitive aging.

References

1. Y. Xie et al., “Musical practice and BDNF plasma levels as a potential marker of synaptic plasticity in aging,” Front. Neurosci., vol. 15, 2021. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC8043880/
2. S. Altenmüller et al., “Music-making interventions in older adults: A systematic review of neuroplastic effects,” Neurobiol. Aging, 2025. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC11965234/
3. X. Xue et al., “Receptive music therapy in mild cognitive impairment and depression: A randomized controlled trial,” Sci. Rep., vol. 13, 2023. [Online]. Available: https://www.nature.com/articles/s41598-023-49162-6
4. Y. Abe et al., “Music-based interventions improve cognition in MCI and dementia: A meta-analysis,” Healthcare (Basel), vol. 10, no. 8, p. 1462, 2022. [Online]. Available: https://www.mdpi.com/2227-9032/10/8/1462
5. Z.-L. Zhang et al., “Music with different tones affects hippocampal BDNF and neuronal development,” Int. J. Mol. Sci., vol. 24, no. 9, p. 8119, 2023. [Online]. Available: https://www.mdpi.com/1422-0067/24/9/8119
6. R. Särkämö et al., “Music therapy enhances motor recovery and BDNF expression in stroke models,” Front. Neurol., vol. 12, 2021. [Online]. Available: https://www.frontiersin.org/articles/10.3389/fneur.2021.666311
7. “The MultiMusic multidomain intervention including choral practice in aging: study protocol,” medRxiv, 2024. [Online]. Available: https://www.medrxiv.org/content/10.1101/2024.11.29.24318152v2
8.  “A study protocol for BDNF biomarker assessment in music-based aging interventions,” medRxiv, 2024. [Online]. Available: https://www.medrxiv.org/content/10.1101/2024.11.29.24318152v1
9. C. Angelucci et al., “BDNF and aging: Molecular mechanisms of decline,” Mech. Ageing Dev., vol. 134, no. 10, pp. 489–497, 2013.
1. Ray, Amit. "Brain Fluid Dynamics of CSF, ISF, and CBF: A Computational Model." Compassionate AI, 4.11 (2024): 87-89. https://amitray.com/brain-fluid-dynamics-of-csf-isf-and-cbf-a-computational-model/.
2. Ray, Amit. "Musical Neurodynamics and Neuroplasticity: Mathematical Modeling." Compassionate AI, 2.5 (2025): 12-14. https://amitray.com/musical-neurodynamics-and-neuroplasticity/.
3. Ray, Amit. "Neurodynamics of Indian Classical Music and The Ray 28 Brain Chakras." Compassionate AI, 2.6 (2025): 30-32. https://amitray.com/neurodynamics-indian-classical-music-ray-28-brain-chakras/.
4. Ray, Amit. "Neuroscience of Indian Classical Music: Raga, Tala, and Swara." Compassionate AI, 3.7 (2025): 75-77. https://amitray.com/neuroscience-indian-classical-music-raga-tala-swara/.
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This article integrates concepts from nonlinear dynamics, such as coupled oscillators and the Navier–Stokes equations, to illustrate how rhythmic musical input organizes large-scale brain networks and promotes cognitive-emotional integration. Explore how music reshapes the brain through fluid dynamics, neuroplasticity, and mathematical modeling.

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Music, a universal human experience, engages the brain in complex and dynamic ways, making it an ideal subject for neurodynamic studies. Advances in neuroimaging, fluid mechanics, and mathematical modeling have revealed the intricate interplay between music, neural activity, and cerebrospinal fluid (CSF) dynamics.

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