Oscillatory Cortical Activity in an Animal Model of Dystonia Caused by Cerebellar Dysfunction

Abstract

The synchronization of neuronal activity in the sensorimotor cortices is crucial for motor control and learning. This synchrony can be modulated by upstream activity in the cerebello-cortical network. However, many questions remain over the details of how the cerebral cortex and the cerebellum communicate. Therefore, our aim is to study the contribution of the cerebellum to oscillatory brain activity, in particular in the case of dystonia, a severely disabling motor disease associated with altered sensorimotor coupling. We used a kainic-induced dystonia model to evaluate cerebral cortical oscillatory activity and connectivity during dystonic episodes. We performed microinjections of low doses of kainic acid into the cerebellar vermis in mice and examined activities in somatosensory, motor and parietal cortices. We showed that repeated applications of kainic acid into the cerebellar vermis, for five consecutive days, generate reproducible dystonic motor behavior. No epileptiform activity was recorded on electrocorticogram (ECoG) during the dystonic postures or movements. We investigated the ECoG power spectral density and coherence between motor cortex, somatosensory and parietal cortices before and during dystonic attacks. During the baseline condition, we found a phenomenon of permanent adaptation with a change of baseline locomotor activity coupled to an ECoG gamma band increase in all cortices. In addition, after kainate administration, we observed an increase in muscular activity, but less signs of dystonia together with modulations of the ECoG power spectra with an increase in gamma band in motor, parietal and somatosensory cortices. Moreover, we found reduced coherence in all measured frequency bands between the motor cortex and somatosensory or parietal cortices compared to baseline. In conclusion, examination of cortical oscillatory activities in this animal model of chronic dystonia caused by cerebellar dysfunction reveals a disruption in the coordination of neuronal activity across the cortical sensorimotor/parietal network, which may underlie motor skill deficits.

Reduced Interhemispheric Coherence in Cerebellar Kainic Acid-Induced Lateralized Dystonia

“…Similarly to previous studies, we showed that a limited region of cerebellar dysfunction could induce isolated abnormal movements such as limb prolonged contraction that resemble focal dystonia (24). The kainate microinjections into the left cerebellar cortex induced, especially ipsilateral dystonic contractions, whereas vermis microinjections induced generalized dystonia (21). After repeated kainic acid application on the left cerebellar hemisphere, we found a significant reduction of the interhemispheric coherence in low-frequency bands (delta, theta, beta).…”

“…Therapeutic modulation of the cerebellum or its outflow pathway was occasionally found to be effective in the treatment of dystonia (19,20). In animal models, dystonia can be triggered by kainic acid (a glutamate receptor agonist) injection into the cerebellum surface (21)(22)(23). Raike et al showed that focal and generalized dystonia may have similar physiopathology and can be treated with similar strategies (24).…”

Functional abnormalities in the cerebello-thalamic pathways in a mouse model of DYT25 dystonia

“…DN optogenetic θ-burst stimulations decreased the abnormal motor state in Gnal +/- mice following oxotremorine injection ( Figure 5H ). To confirm these observations, we also evaluated the activity of mice by measuring the percentage of time spent moving in an open field (‘active wakefulness’) ( Georgescu et al, 2018 ). In the saline-treated WT mice, DN optogenetic θ-burst stimulations had no significant effect on the active wake time.…”

Cerebellar Cortex 4–12 Hz Oscillations and Unit Phase Relation in the Awake Rat

“…Also, LFP oscillations could help in the coordination of spike timing even if cells are not rhythmic (Bush and Burgess, 2019 ), as we show here that a greater proportion of Golgi or Purkinje cell SSs are phase-locked than are outright rhythmic. Our study has focused on normal circuits, but oscillatory flow could also have implications in pathological circuits, influencing cerebellar and extra-cerebellar connectivity (Bares et al, 2010 ; Georgescu et al, 2018 ). As oscillations flowing through circuits can represent time (Buzsáki and Llinás, 2017 ), the understanding of oscillatory flow and the timing of unit activity through the cerebellar cortex, and outward, is of particular interest.…”