When the inner ear’s balance organs fail on one side, the brain is thrown into chaos: vertigo, blurred vision, a tendency to fall, and a staggering gait all follow from a sudden asymmetry in the vestibular tone that normally keeps us upright. Recovery depends on a process called central vestibular compensation, in which the brain rewires itself around the lost signal. Now a research team at LMU Munich’s German Center for Vertigo and Balance Disorders has shown, in a rat model, that two familiar interventions, voluntary running and the standardized Ginkgo biloba extract EGb 761, act together to accelerate this rewiring, and that the behavioral benefit is visible in the living brain as preserved synaptic density. The findings, published in Frontiers in Neurology, offer one of the first whole-brain, longitudinal views of how multimodal therapy reshapes cerebral connectivity after acute vestibular loss.

The experiment was built around chemical unilateral labyrinthectomy, a surgical model in which the left inner ear is silenced by transtympanic injection. Under isoflurane anesthesia, the researchers perforated the tympanic membrane, instilled a 20 percent bupivacaine solution into the middle ear cavity three times, and then applied a 10 percent solution of p-arsanilic acid, which irreversibly desensitizes the primary sensory cells of the inner ear. All 32 male Sprague-Dawley rats developed clear signs of acute vestibular syndrome, including spontaneous nystagmus, postural asymmetry, and head roll tilt. Crucially, no animals met the exclusion criteria, which covered weight loss above 20 percent, corneal ulcers from facial nerve injury, tympanic bleeding, or abnormal behaviors such as convulsions or paresis, although two animals died during the study and their data were included up to the time of death.

The four-arm design allowed the team to disentangle the effects of exercise, drug, and their combination. Eight rats received control food alone, eight received control food plus access to a voluntary running wheel, eight received food supplemented with EGb 761 at 75 milligrams per day per kilogram body weight, and eight received both the Ginkgo extract and the running wheel. The drug feeding began six weeks before labyrinthectomy to allow habituation and established pharmacological action, and the extract was the quantified EGb 761 preparation, adjusted to 22 to 27 percent Ginkgo flavonoids, 5 to 7 percent terpene lactones including ginkgolides A, B, and C, and 2.6 to 3.2 percent bilobalide, with less than 5 parts per million ginkgolic acids. Running was genuinely voluntary: each wheel was monitored by computer through an implanted microchip, recording wheel turns at 360-second intervals for every animal.

Behavioral testing was rigorous and blinded. Two experienced veterinarians, unaware of treatment allocation, scored nystagmus, postural asymmetry, head roll tilt, and an elevation tail rotation test weekly until nine weeks after the lesion, using an established scoring system in which each component could reach ten points. Postural asymmetry, for example, ranged from spontaneous barrel rolling at ten points down to asymmetry noticeable only when the animal was picked up at one point. The team also tracked locomotion in an open field with automated video software, measuring mean velocity and the time spent in the center zone as proxies for mobility and spatial exploration. Nystagmus peaked on the first day after the lesion in all groups and followed a purely time-dependent rise-and-resolution course, unaffected by either treatment, consistent with its characteristically self-limiting nature.

The static vestibular deficits told a different story. Postural asymmetry peaked early, on day five in the control group and day three in the treated groups, owing to the delayed toxicity of p-arsanilic acid, and then declined at different rates. Only in the combined EGb 761 plus running wheel group were no clinical signs of postural asymmetry detected from day 35 onward, whereas all other groups retained mild residual asymmetry up to day 63. Head tilt persisted until the end of the study in every group except the combination group, which showed no head roll tilt between days 42 and 56 and significantly lower scores than controls from day 35 to 63. Locomotor velocity told the same tale: from day 28 the combination group moved fastest at around 14 centimeters per second, followed by the drug group at 12.5, the exercise group at 11, and controls at 9 centimeters per second.

The technical centerpiece was serial positron emission tomography with the radiotracer [18F]UCB-H, which binds to synaptic vesicle protein 2A, or SV2A, a validated surrogate measure of synaptic density in vivo. Rats were scanned at baseline and at weeks one, three, and nine after the lesion in a Siemens Inveon microPET scanner, receiving a bolus of roughly 40 megabecquerels of tracer followed by a 60-minute emission recording. Images were reconstructed with a three-dimensional ordered subsets expectation maximization algorithm, registered into a rat brain atlas space, normalized to whole-brain mean activity, and segmented into 57 brain regions, with additional regions of interest defined for the vestibular nuclei at the junction of pons and medulla. Voxel-wise analyses in SPM12 explored the spatial pattern of change across groups and time points.

The imaging results mapped the lesion’s footprint with striking regional specificity. By day 63, the control group showed the greatest synaptic loss in the vestibular nuclei, a reduction of 20.37 plus or minus 5.18 percent relative to baseline. The EGb 761 group showed the smallest loss, only 7.59 plus or minus 7.0 percent, a statistically significant difference from controls, while the exercise-only group fell in between at 10.32 plus or minus 7.41 percent. In the EGb 761 group, synaptic density in the vestibular nuclei had returned essentially to baseline level by day 63, indicating an almost complete recovery from the lesion-induced synaptic loss. In sharp contrast, the motor cortex displayed the highest relative gain of synaptic density in the control group, 6.60 plus or minus 3.13 percent, compared with just 0.19 plus or minus 2.82 percent in the drug group.

That inversion is biologically revealing. The authors propose that the synaptic gain in the motor cortex of untreated rats reflects a secondary adaptive remodeling, a structural coping mechanism for persistent vestibular asymmetry, which is reversed when behavioral recovery is faster and vestibular nuclear reoccupation more complete, as seen with EGb 761. All treatment groups showed increased synaptic density in the somatosensory cortices at weeks one to three relative to controls, which the team interprets as multisensory reweighting during successful compensation, echoing earlier findings that cutaneous receptive fields expand and somatotopic maps partially dedifferentiate after vestibular neurectomy. The combination of drug and exercise additionally increased synaptic density in the hippocampal formation, strongest on day seven, consistent with prior evidence that voluntary running promotes hippocampal plasticity and that EGb 761 enhances neuroprotective and plasticity-related pathways.

Mixed-effects modeling confirmed the additive effect statistically. Synaptic density in both the vestibular nuclei and the motor cortex showed a significant three-way interaction of time, drug, and exercise, indicating that the combination treatment’s behavioral benefit is accompanied by a corresponding structural correlate in vestibular and motor-related regions rather than symptom masking alone. EGb 761 alone most effectively reduced lesion-induced synaptic loss in the vestibular nuclei and vestibulocerebellum, with synaptic reoccupation visible after day seven. The authors note that EGb 761 alleviated vestibular nuclear synaptic loss by about two thirds compared with controls at nine weeks, and that comparable histological work in a cat neurectomy model found accelerated synaptic reoccupation to baseline at three months with the drug versus five months without, although a complete neurectomy produces more intense deafferentation than the chemical lesion used here.

The study has limits the authors acknowledge candidly. Synaptic density was assessed exclusively through longitudinal [18F]UCB-H PET without histological validation using markers such as SV2A, synaptophysin, or PSD95, so the findings should be read as imaging-based estimates rather than direct evidence of synaptic remodeling. Voxel-wise analyses used uncorrected statistical thresholds and are exploratory, with the principal conclusions resting on the predefined regional and behavioral analyses. EGb 761 was administered ad libitum through chow without quantification of individual intake, only male rats were studied, and the interaction between training intensity and pharmacological modulation, as well as the distinction between excitatory and inhibitory synaptic changes, remain open questions. Even so, the message is clear: combining the synaptogenic effects of EGb 761 with the activity-dependent plasticity of voluntary exercise targets complementary mechanisms, producing more efficient and robust recovery, and supporting the development of individualized rehabilitation protocols in neurotology that integrate pharmacological and behavioral components to maximize functional outcomes after acute vestibulopathy.

Subject of Research: Voluntary physical activity and pharmacological treatment with the Ginkgo biloba extract EGb 761 alleviate regional alterations in cerebral synaptic density and improve behavioral recovery after unilateral labyrinthectomy in the rat

Article Title: Voluntary physical activity and pharmacological treatment with the Ginkgo biloba extract EGb 761 alleviate regional alterations in cerebral synaptic density and improve behavioral recovery after unilateral labyrinthectomy in the rat

Article References: Fuxjäger, I. S., Lindner, M. J., Dietz, G. P. H., Oos, R., Palumbo, G., Krämer, A., Branner, C., Delker, A., Grosch, M., Lindner, S., Wind-Mark, K., Ziegler, S. I., Bartenstein, P., Brendel, M., Werner, R. A., Antons, M. J., & Zwergal, A. (2026). Voluntary physical activity and pharmacological treatment with the Ginkgo biloba extract EGb 761 alleviate regional alterations in cerebral synaptic density and improve behavioral recovery after unilateral labyrinthectomy in the rat. Frontiers in Neurology, 17, Article 1937612. https://doi.org/10.3389/fneur.2026.1937612

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1937612

Keywords: Voluntary, physical, activity, pharmacological, treatment, Ginkgo, biloba, extract, alleviate, regional, alterations, cerebral