Striato-pallidal oscillatory connectivity correlates with symptom severity in dystonia patients

Abstract

Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes that allow for parallel recordings of several basal ganglia nuclei, namely the striatum, external and internal pallidum, that all displayed activity in the low frequency band (3-12 Hz). In addition to a correlation with low-frequency activity in the internal pallidum (R = 0.88, P = 0.001), we demonstrate that dystonic symptoms correlate specifically with low-frequency coupling between striatum and internal pallidum (R = 0.75, P = 0.009). This points towards a pathophysiological role of the direct striato-pallidal pathway in dystonia that is conveyed via coupling in the enhanced low-frequency band. Our study provides a mechanistic insight into the pathophysiology of dystonia by revealing a link between symptom severity and frequency-specific coupling of distinct basal ganglia pathways.

Fig. 1. Methodological set-up and recording sites across basal ganglia nuclei of all patients.

A In this study, the DBS-electrode Boston Scientific Vercise was implanted in all patients. Note that this DBS-electrode model is composed of eight circular contacts that span over 15.5 mm. B Shown is an exemplary recording in the post-operative period. In all patients, we performed bipolar recordings from adjacent contacts resulting in 7 parallel recordings per hemisphere. After DBS-electrode localization, recordings were assigned to either striatum, GPi or GPe if two recording contacts were localized in the respective structure. In the shown example, this would fit to the recording between contact 1 and 2, which are both localized in the GPi (green); contact 5 and 6, both localized within the GPe (blue) and contact 7 and 8, both localized within the striatum (purple). Thus, these recordings were retained for further analysis. In contrast, all other parallel recordings (namely bipolar recordings from contact 2 and 3, contact 3 and 4 as well as contact 6 and 7 as colored in black) are removed from further analysis steps. Thereby, only three parallel recordings per hemisphere (striatum, GPe and GPi) are kept from the original seven. C Shown are the exact localization within striatum (purple), GPe (blue) and GPi (green) of these retained recording sites from all hemispheres across all patients (red dots). For visualization purposes all recording sites have been flipped to the respective nuclei of the right hemisphere.

Fig. 2. Spectral patterns are similar across basal ganglia nuclei in dystonia patients.

A When averaged across hemispheres of all subjects, similar spectral patterns are observed with spectral peaks in the low-frequency (upper row) and beta band (lower row) in the striatum (STR, left column), GPi (mid column) and GPe (right column). Averaged power spectra across hemispheres and patients are colored (STR=purple, GPi=green, GPe=blue), while individual power spectra of each hemisphere are plotted in grey. For visualization purposes, power spectra are flattened and aligned to the individual peak frequency. No significant difference in power spectral density at peak frequency is seen across basal ganglia nuclei. B Similarly, peak frequencies in the respective frequency bands (low frequency and beta band) in the 19 hemispheres per structure did not significantly differ across basal ganglia nuclei and were distributed across the low frequency (upper row) and beta band (lower row) as validated by permutation tests and FDR-corrected for multiple comparisons. n.s. not significant. In box plots, the whiskers indicate minimal and maximal values per hemisphere, the central marks indicate the median and edges the 25th and 75th percentiles of the distribution. A.u. arbitrary units.

Fig. 3. Connectivity patterns across basal ganglia structures and their correlation to symptom severity.

A Shown are averaged coherence spectra (iCOH= imaginary part of coherence) between striatum and GPe (purple), striatum and GPe (blue), GPe and GPi (green) and averaged shuffled coherence (grey) across hemispheres. Shaded areas indicate standard deviation of the mean. B All recorded basal ganglia structures are functionally coupled in the low-frequency band as shown by significantly higher coherence values (colored box plots) when compared to shuffled data (grey box plots); STR-GPi: P = 0.002; STR-GPe: P = 0.003; GPi-GPe: P = 0.003 as validated by permutation tests and FDR-corrected for multiple comparisons. Black dots indicate mean value of coherence per hemisphere (n = 19 per basal ganglia structure). In box plots, the whiskers indicate minimal and maximal values per hemisphere, the central marks indicate the median and edges the 25th and 75th percentiles of the distribution. C Shown are averaged spectra of Granger causality with GPi (blue) or striatum (purple) as source. Shaded areas indicated standard deviation of the mean. D When each frequency bin is considered separately, the majority of the low-frequency band is led by the striatum in 63% and by the GPi in 37% of cases. E Dystonic symptom severity correlates with averaged low-frequency power in the GPi, but not the striatum. F Moreover, the significant coupling strength of low-frequency activity between the striatum and the GPi, but not between striatum and GPe hints towards an involvement of the direct but not the indirect pathway. E, F show Pearson’s correlation coefficients. **p < 0.01.