Deep brain stimulation of the mesencephalic locomotor centre induces stimulation-dependent behavioural states beyond locomotion

Deep brain stimulation (DBS) targeting the mesencephalic locomotor region (MLR) has the potential to trigger a range of behavioral states beyond mere locomotion, according to a recent study. Previous clinical trials have shown limited success with this approach, often resulting in modest improvements and occasional side effects such as anxiety. However, preclinical research in various species suggests that MLR-DBS can enhance locomotor and gait difficulties, albeit with the emergence of defensive behaviors in some cases.

In this study, researchers investigated the impact of different frequencies and amplitudes of DBS on healthy rats. They discovered that high-frequency, high-amplitude DBS (80-130 Hz) induced hyperlocomotion accompanied by acute defensive-like behaviors, while low-frequency stimulation (20-60 Hz) promoted periods of immobility. Furthermore, only the high-frequency stimulation led to increased c-fos expression in the MLR, indicating heightened neuronal activity in this region.

The researchers also found that the position of the DBS electrode tip within the MLR significantly influenced the types of complex behaviors observed. When the electrode was localized to the cuneiform nucleus (CnF) of the MLR, animals exhibited behaviors such as hyperlocomotion, rearing, tail rattling, and immobility. Using AAV tracer constructs, the team mapped out the ascending projections from the CnF to various brain regions, including the thalamus, substantia nigra pars compacta, zona incerta, hypothalamus, subthalamic nucleus, and central amygdala (CeA).

Retrograde tracing confirmed the presence of a specific CnF-to-CeA projection, further supporting the anatomical connectivity between the MLR and higher-order brain centers that link motor and defensive networks. These findings demonstrate that the choice of DBS frequency and amplitude can significantly influence the behavioral outcomes beyond locomotion, highlighting the importance of precise stimulation parameters in achieving desired treatment effects.