Encoding of Cerebellar-Olivary Neuronal Ensemble Activity for Tremor Frequency in Mice and Patients with Essential Tremor

Research Background

Essential Tremor (ET) is a common movement disorder characterized primarily by action tremor, affecting about 20% of the elderly population. The frequency and intensity of tremor are core features of ET. However, the neurological mechanisms encoding tremor frequency are still poorly understood, making current treatment methods largely ineffective for many patients. Approximately half of the patients do not respond to current pharmacological treatments, and although surgical interventions like deep brain stimulation (DBS) initially show good results, they often lead to treatment tolerance.

Recent studies suggest that defects in synaptic pruning in the cerebellum and overgrowth of climbing fibers lead to increased cerebellar oscillations and ET tremor. However, the exact neural encoding mechanisms determining tremor frequency remain unclear. This gap in research hinders the development of more effective treatments for ET.

Source of Paper

The primary author of this paper is Yi-Mei Wang, with the research team mainly from National Taiwan University and Columbia University. This study was published in the journal “Science Translational Medicine” on May 15, 2024.

Research Process

The study utilized a grid2dupe3 mouse model and human experiments, combining in vivo electrophysiological techniques, optogenetics, and motion tracking to explore whether and how tremor frequencies are encoded in olivo-cerebellar (inferior olivary-cerebellar) neural activity.

Research Steps

Step 1: Detecting Neuronal Ensemble Activity

The study first used in vivo electrophysiological techniques by implanting deep or surface electrodes combined with simultaneous motion tracking. This detected 20 Hz tremor and associated oscillatory activities in the motor cortex, inferior olive, cerebellar cortex, deep cerebellar nuclei, and thalamus.

Step 2: Study of Oscillation Propagation Pathways

By injecting the anesthetic lidocaine into the mouse thalamus, it was found that although the tremor and motor cortex oscillations were suppressed, the cerebellar oscillations persisted, indicating that the cerebellar oscillations might not directly participate in tremor generation. Moreover, injecting lidocaine into the cerebellar cortex, deep cerebellar nuclei, or inferior olive eliminated activity in these areas, stopping brain-cerebellar oscillations and tremors, suggesting that the olivo-cerebellar circuit is the source of tremor frequency-related oscillations.

Step 3: Study of Neuronal Frequency Encoding

By recording single-neuron activities, local field potentials, and kinematic data from grid2dupe3 mice, the study found that the firing frequency of individual neurons did not match the tremor frequency. However, spectral analysis using vector strength showed that when all neuronal activities were linearly summed, the spectral peak of vector strength gradually concentrated at 20 Hz, corresponding to the cerebellar oscillation and tremor frequencies.

Step 4: Optogenetic Verification

Using optogenetic stimulation in mice expressing humanized Channelrhodopsin-2 (ChR2), stimulation of DCN (deep cerebellar nuclei) at 20 Hz frequency immediately induced 20 Hz circuit oscillations and tremors. Similarly, 13 Hz stimulation also precisely regulated cerebellar and tremor frequencies, validating that tremor frequencies are generated by neurally ensemble activity regulated forcibly by optogenetics.

Step 5: Frequency Tremor Limbs and Human Patients Study

DBS experiments in ET patients also demonstrated that although DBS effectively suppressed tremor symptoms, it did not eliminate cerebellar oscillations. Transcranial alternating current stimulation (tACS) of the cerebellum at fixed frequencies near individual tremor frequencies could stabilize or destabilize tremor, validating the cerebellum’s role in tremor frequency encoding.

Main Results

• Detection of Oscillatory Activities: Oscillatory activities related to tremor were detected in the cerebellum, brain, and thalamus.
• Oscillation Propagation Pathways: Cerebellar oscillations persisted after thalamic inhibition, suggesting the inferior olivary-cerebellar circuit is the main source of tremor frequencies.
• Study of Neuronal Frequency Encoding: Individual neurons had difficulty encoding tremor frequency, but synchronous activity in neuronal ensembles played a crucial role in frequency encoding.
• Optogenetic Verification: Specific frequencies of cerebellar oscillations generated through optogenetics could precisely produce corresponding tremor frequencies.
• Human Experiments: DBS suppressed tremor symptoms but did not eliminate cerebellar oscillations. tACS modulation of the cerebellum could effectively control tremor frequencies.

Research Conclusion

This study confirms that tremor frequency is encoded through the synchronization of neuronal activity in the inferior olivary-cerebellar circuit. This mechanism exists not only in mouse models but also in ET patients. DBS and tACS further confirm that cerebellar oscillations play a central role in the generation and regulation of tremor frequencies.

Research Significance and Application

This study not only reveals the neural encoding mechanism of tremor frequency but also opens new treatment avenues. By regulating neuronal ensemble activity, it holds the potential to develop more precise and effective treatments, improving existing issues like treatment tolerance. Additionally, it provides a significant theoretical basis and experimental methods for the study of other movement disorders.