Music as medicine for traumatic brain injury: a perspective on future research directions

Traumatic brain injury (TBI) impacts 69 million individuals globally each year and is a leading cause of death and disability (Dewan et al., 2019). The majority of moderate-to-severe TBI survivors endure long-lasting disturbances in motor, cognitive, and affect that negatively impacts their life. Although a plethora of research on pharmacological interventions for TBI has been conducted, none has translated to the clinic, thus advocating for the evaluation of nonpharmacological therapeutic approaches that may increase translational success.

Music is well suited for facilitating recovery after TBI: Emerging evidence suggests that music-based interventions (MBIs) hold a relatively untapped potential for improving cognition and neurobehavior after TBI. In normal uninjured rats that received MBIs, there are reports of increased hippocampal brain-derived neurotrophic factor (BDNF) expression, reduced anxiety-like behavior, and improved cognitive benefit, which may be dependent on sex and age (Kim et al., 2006; Angelucci et al., 2007; Xiong et al., 2007; Xing et al., 2016; Papadakakis et al., 2019). Among human adults with neurological injury, MBIs improved physical and cognitive functioning, compared to those who listened to audiobooks or silence (Särkämö et al., 2008). Despite the encouraging findings, such studies are limited as many clinical centers do not utilize MBIs (i.e., music medicine) because of the paucity of pre-clinical data on dose, timing, behavioral effectiveness, and safety as well as the lack of mechanistic insights. Thus, given the potential of music to provide benefits after TBI plus the need to address current uncertainties held by clinicians, additional empirical research is warranted.

We recently reported the benefits of a MBI consisting of pieces from the classical baroque period that comprises fast and slow movements and repeated motifs between solo instruments and the orchestra and simultaneous harmonies with contrasting timbre, pitch, and rhythm. The music or ambient noise began 24 hours after TBI or sham surgery and was given for 3 hours per night during the rat’s natural active state (19:00 to 22:00) for 30 days, which is when the last behavioral assessment was done (Moschonas et al., 2023). To determine the behavioral benefits of our MBI, we utilized a well-established beam-walk tasks that measured the time to traverse the beam as well as the quality of ambulation, with the latter focusing on affected hind limb foot slips. A water maze test was used to determine the acquisition of spatial learning and memory retention, while the open field test was utilized to evaluate anxiety-like behavior. The shock probe defensive burying test was administered to assess passive avoidant coping vs. adaptive active coping strategies. The behavioral tests were conducted during the day so the findings could be comparable to previous intervention studies from our laboratory (Njoku et al., 2019; Gutova et al., 2021; Tapias et al., 2022).

The motor and cognitive data were acquired over multiple days and therefore were analyzed by repeated-measures analysis of variance, followed by the Newman-Keuls post-hoc test. Briefly, the results revealed that the TBI group exposed to the MBI traversed the beam significantly faster and was able to do so with significantly fewer foot slips than the TBI group that received only ambient noise (P < 0.05). Similar benefits were observed for cognition as the TBI group receiving the MBI located the hidden platform quicker over time vs. the no music group (P < 0.05). Additionally, analysis of the probe data, which is a measure of memory retention, revealed that the music-treated TBI group did not differ from the uninjured sham control, and both spent a greater percentage of the allotted time searching in the target zone relative to the no MBI TBI group (P < 0.05). Performance in the open field test was also better in the MBI-exposed TBI rats versus those exposed to only ambient room noise. Lastly, active coping response to a stressor was eliminated by TBI as revealed by a significant decrease in time spent burying in the no music TBI group. In marked contrast, the TBI MBI group did not differ from the sham controls, which suggests an active, adaptive coping response to the stressor.

Regarding the histological and Western blot data, the MBI reduced cortical lesion volume and activated microglia as well as increased resting microglia and hippocampal BDNF expression. Taking the behavioral and histological data together, the findings of our recently published study provide a strong rationale for additional preclinical studies utilizing MBIs as a potential efficacious rehabilitative therapy for TBI.

Future research directions: While our recent findings on music as a medicine for TBI are compelling, there is much more research needed. Specifically, our study was completed in adult male rats, but questions remain regarding whether the benefits of the current MBI protocol would also be effective in adult female rats; finding the answer is necessary as females make up over 40% of the TBI population and thus determining effective treatments for them cannot be ignored. Also important is whether MBIs can impart benefits to other age groups. Preliminary data from our laboratory has shown that brain-injured pediatric rats receiving the same MBI paradigm do show benefits in the acquisition of spatial learning and memory retention, but additional data are warranted before making definitive conclusions.

Determining other facets of MBIs is also important. For example, we utilized classical music for our study, but it is known that there are music preferences among patients and thus it is important to compare other genres of music to no music (ambient noise) for their ability to promote neurobehavioral and cognitive recovery after TBI in rats of both sexes and through the life span. We are currently evaluating different music types and comparing to classical. It is also important to determine the optimal amount of MBI to provide and at what times after TBI. We began the MBI early after TBI, as did all the other MBI studies cited (Table 1) but early times may not always be feasible due to life-saving measures taking precedence and thus the MBI will have to be delayed. Therefore, several crucial questions arise, such as will an MBI still work if presented a week or a month after TBI? Will new behavioral tests need to be utilized to evaluate the efficacy of music at later times as some behaviors may recover spontaneously? Also, important is determining potential mechanistic underpinnings. Based on the studies in non-injured rats and our recent TBI work (Table 1) there are several potential avenues to explore.

Table 1.

Summary of studies showing benefits from music-based interventions

Models	Music-based interventions	Assessments	Results	References
Developing rats (sex unclear)	Mozart’s sonata K.448, 12 h/d, PND 1 to 98	• Spatial learning, probe, PND 28, 56, and 98 • Immunohistochemistry, PND 28, 56, and 98	• MBI increased spatial learning and memory at each time point • MBI increased BDNF and TrkB in CA3 and DG at each time point • MBI increased spatial learning and memory	Xing et al., 2016
Adult male and female rats	L’amourEst Bleu composed by Richard Clayderman; 3 h, 2– daily, 15 days	• Spatial learning and probe, days 1–5 and 6–7, respectively	• No differences between males and females	Xiong et al., 2018
Young adult male BALB/c mice	New age music, 6 h/d for 21 consecutive days	• Hypothalamic concentrations of BDNF and NGF proteins	• MBI increased BDNF production • MBI decreasedNGF production	Angelucci et al., 2007
MS180 on PND 2–14 in male rats	Mozart’s Sonata K. 448, 12 h/d, PND 21 to 76.	• Social approach task, elevated plus maze, forced swim test • Golgi-Cox staining for dendritic spine density	• MBI reversed the decrease in sociability and the increase in anxiety- and depressive-like behaviors induced by MS180. • MBI increased mature dendritic spines in the CA1 region of hippocampus in adulthood.	Papadakakis et al., 2019
Adult female rats and pups	65 dB comfortable music or 95 dB supersonic machine sound for 1 h/d until delivery	• Radial-arm maze test, day 21 • BrdU and NeuN IHC, day 21.	• MBI increased hippocampal neurogenesis and enhanced spatial learning, which is in marked contrast to noise during pregnancy.	Kim et al., 2006
CCI adult male rats (moderate severity)	Music from the classical baroque period, 3 h/d, 30 days, 65 dB	• Beam-walk motor test, days 1–5 • Spatial learning and probe, days 14–19 and 20, respectively • Open field test, day 29 • Shock probe defensive burying test (SPDB), day 30 • Histology, IHC, and western blot assay	• MBI improved motor, cognitive, and anxiety-like behavior vs. no music (i.e., ambient room noise) • MBI reduced cortical lesion volume and activated microglia • MBI increased resting microglia and hippocampal BDNF expression	Moschonas et al., 2023

Except for the study by Moschonas et al. (2023), all other studies were non-TBI. BDNF: Brain-derived neurotrophic factor; BrdU: bromodeoxyuridine; CCI: controlled cortical impact; IHC: immunohistochemistry; MS180: maternal separation for 180 minutes; NeuN: neuronal nuclear protein; NGF: nerve growth factor; OVX: ovariectomized; PND: postnatal day; TBI: traumatic brain injury; TrkB: tropomyosin receptor kinase B.

Conclusion: The findings from our recently published manuscript evaluating the efficacy of a music-based therapy or medicine for TBI showed significant benefits in motor, cognitive, and affective outcomes as well as protection of cortical regions as evidenced by decreased lesion volumes. Increases in BDNF and resting microglia provide insight into potential mechanisms. In this perspective, we have provided additional avenues of research that could be useful in determining whether MBIs can indeed be a treatment for TBI that can successfully translate from the bench to the clinic. Future research delving deeper into MBIs after TBI will inform clinical practice in important ways. First, it will increase the understanding of how MBIs affect cognitive and neurobehavior after TBI at the biological level. Second, optimal dosing and timing schedules for improving cognitive and neurobehavioral function (i.e., will providing different durations or timing of initiation change the effect size) can be determined. Successful translation of MBIs may be cost-effective because it can be done in an outpatient setting and can overcome the risks and hindrances associated with drugs that often have various side effects. Lastly, MBIs can be provided across ages, genders, and cultures reflecting the diversity of TBI-survivors and importantly, signifying a widely applicable therapeutic strategy. A caveat to the previous statement is that sound sensitivity or hyperacusis does present after TBI. While the prevalence is not known, general population estimates range from 0.002% to 17% (Ren et al., 2021). As such, we acknowledge that music medicine may not be a “magic bullet” as those with extreme sound sensitivities may not be ideal candidates for treatment. However, determining the lowest decibel level that produces benefits might increase the likelihood of less extreme sound-sensitive patients also benefiting from MBIs.

This work was supported by NIH grants NS084967, NS121037 (to AEK) and NS110609 (to COB).