Role of cortico-pallidal connectivity in the pathophysiology of dystonia Free

Sir,

We read with great interest the article by Neumann and associates (2015) regarding pallidal connectivity in dystonic patients. We commend the authors for the excellent findings they achieved with the novel technique of simultaneous magnetoencephalography-local field potentials (MEG-LFP) recording and we believe that their article is an important one with particular regard to the brain networks involved in the pathophysiology of dystonia (Neumann et al., 2015). The authors have demonstrated that internal globus pallidum (GPi) is connected with the cerebral cortex via three distinct functional oscillatory networks in patients with idiopathic dystonia. They showed in detail: (i) a pallido-temporal network oscillating in the theta frequency range; (ii) a sensorimotor cortico-pallidal beta network at rest; and (iii) a cerebello-pallidum alpha band network.

Although several studies in the last two decades have challenged our understanding of dystonia pathophysiology, an important gap at a network and system level still remains to be filled in order to understand the fundamental changes in high-order motor control underlying dystonic symptoms. It has been postulated that loss of inhibition, sensory abnormalities and abnormal plasticity could underlie the pathophysiological substrate of dystonia indicating that basal ganglia, cerebral cortex, cerebellum, thalamus and brainstem are key structures in the pathophysiology of dystonia (Quartarone and Hallet, 2013). In this new perspective, considering each structure as a single node of a wide network, dystonia may result from a single-node dysfunction, from an involvement of multiple nodes or from aberrant communication among the nodes (Quartarone and Hallet, 2013; Berman and Jinnah, 2015).

In the classical view, various tract-tracing methods combined with immunohistochemistry and in situ hybridization demonstrated that the cortical information flows through the basal ganglia via a dual-network model, based on the ‘direct’ and ‘indirect’ routes (Leblois et al., 2006). However, in addition to these two major projection systems, a ‘hyperdirect’ pathway, connecting the cerebral cortex with the subthalamic nucleus, has been proposed and demonstrated both in primates and humans (Nambu et al., 1996, 2002).

We have recently demonstrated the existence of a possible cortico-pallidal connectivity in humans by means of a High Angular Resolution Diffusion Imaging-Constrained Spherical Deconvolution-based technique (Milardi et al., 2015). Armed with this technique we identified a direct cortico-pallidal pathway running through the internal capsule and connecting both GPi and external globus pallidum (GPe) with Brodmann areas 12, 11, 46, 48, 6, 4, and 5. This is in line with monkey data that have shown a similar cortico-pallidal system by using vesicular glutamate transporter 1 (vGluT1) as a preferential marker of cortical terminals in the telencephalon (Smith et al., 2014; Smith and Wichmann, 2015).

We speculate that, as the hyperdirect pathway is a faster connection of cortex with STN, with respect to the direct and indirect pathways, similarly the cortico-pallidal fibres could represent a fast connection between cortex and globus pallidum. Interestingly since cortico-pallidal connections reach both segments of the globus pallidum, it is likely that this system is, hierarchically, a top level control on direct and indirect pathways. This hypothesis would meet the vision that the cortico-basal ganglia circuit is composed of several, parallel, segregated, and functionally distinct, but homologous loops.

Several authors suggested that the over-activation of the direct pathway and the under-activation of the indirect pathway should lead to excessive movement and a loss of surround inhibition (Hallett, 2006). As a direct consequence, changes in patterning and synchrony of discharge of the internal pallidum may enhance thalamo-cortical activation (Silberstein et al., 2003; Guo et al., 2013; Barow et al., 2014). In line with this abnormal oscillatory pallidal activity theory, Neumann and co-workers (Milardi et al., 2015; Neumann et al., 2015; Smith and Wichmann, 2015) have shown a robust band of beta coherence between cortex and GPi providing the functional framework for our direct cortico-pallidal connectivity revealed by the MRI tractography approach.

Altered movement-related beta band desynchronization over motor cortical areas (Toro et al., 2000), and abnormal beta band functional connectivity across premotor–motor areas during movement (Jin et al., 2011) in dystonia further suggest the role of beta oscillations in the pathophysiology of motor dysfunctions in this condition.

Despite no apparent correlation between the abnormal beta cortico-pallidal oscillations and clinical score, it is likely that a dysfunction of beta oscillation may contribute to abnormal sensory-motor plasticity and motor learning in dystonia (Quartarone and Hallett, 2013; Neumann et al., 2015).

In this framework the cortico-pallidal system may act as an important node involved in the functional interactions of beta signalling in the cortex-basal ganglia-cortex feedback loops for motor control.

Therefore we propose a new scenario where the existence of this abnormal cortico-pallidal connectivity should be explored at a functional and structural level to further understand the pathophysiology of basal ganglia disorders and to better design more efficient targets for deep brain stimulation.

Funding

This work was supported by the Italian Ministry of Health Project Number PE-2013-02357980 ‘Does intensive exercise induce plasticity-related changes in Parkinson's Disease?’

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