Neural signatures of hyperdirect pathway activity in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with ‘hyperdirect pathway’ fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD.

Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit

“…Furthermore, we found that the HD pathway shifts beta rhythms to higher frequencies in line with the hypothesis that β 2 activity is a signature of cortico-subthalamic drive, following the finding a correlation between β 2 power and HD tract density in PD patients [40]. Whether β 1 or β 2 bands reflect functionally distinct rhythms is not well understood-lower frequency activity is more readily suppressed by Levodopa [18] and DBS [38], and STN activity in the two sub-bands synchronize with different cortical regions [38,39].…”

“…Nonetheless, model fits did not well reproduce the broadband high frequency activity present in the data (Fig 1B ; inset spectra). The model also produced activity at two subpeaks at lower (β 1 : 14-21 Hz) and upper (β 2 : 21-30 Hz) beta frequencies, reflecting the bimodal structure of directed functional connectivity (see analysis of multiple Gaussian fits to features from individual animals; S2 Fig) , and in line with experimental reports of a functionally related subdivision of the beta band [39,40].…”

“…Similarly, cortico-subthalamic coherence followed increases in M2 power (Fig 2I) with β 2 synchrony most predominant in the HD-Up state. A similar differential response of beta sub-bands in Parkinsonism has been reported experimentally [40] and will be used as the main spectral discriminator between HD-Down and HD-Up states in this model.…”

Decoding Dynamically Shifting States of Parkinson’s Disease: Tremor, Bradykinesia, and Effective Motor Control

“…Our anatomical results suggest that this propagation may be specific to dorsal STN. Slowness decoding models alternatively relied upon β activity in macroelectrode recordings, perhaps reflecting anti-kinetic β bursts relayed to ventral STN from inferior frontal or supplementary motor cortex (31, 32) . But while prior work did not directly compare the neuroanatomical substrate of distinct PD features within or across subjects, this work directly demonstrates how alternating motor features of PD manifest along these anatomical subdivisions.…”

“…3D). Power in γ low frequencies (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48) in particular was found to be significantly increased during effective motor control relative to both tremor and slowness decoding models ( p<0.006, permutation test) (Fig. 3E-F, right).…”