Deep Brain Stimulation Induced Normalization of the Human Functional Connectome in Parkinson's Disease

Andreas Horn; Gregor Wenzel; Friederike Irmen; Julius Huebl; Ningfei Li; Wolf-Julian Neumann; Patricia Krause; Georg Bohner; Michael Scheel; Andrea A. Kühn

Disclosures

Brain. 2019;142(10):3129-3143. 

In This Article

Abstract and Introduction

Abstract

Neuroimaging has seen a paradigm shift away from a formal description of local activity patterns towards studying distributed brain networks. The recently defined framework of the 'human connectome' enables global analysis of parts of the brain and their interconnections. Deep brain stimulation (DBS) is an invasive therapy for patients with severe movement disorders aiming to retune abnormal brain network activity by local high frequency stimulation of the basal ganglia. Beyond clinical utility, DBS represents a powerful research platform to study functional connectomics and the modulation of distributed brain networks in the human brain. We acquired resting-state functional MRI in 20 patients with Parkinson's disease with subthalamic DBS switched on and off. An age-matched control cohort of 15 subjects was acquired from an open data repository. DBS lead placement in the subthalamic nucleus was localized using a state-of-the art pipeline that involved brain shift correction, multispectral image registration and use of a precise subcortical atlas. Based on a realistic 3D model of the electrode and surrounding anatomy, the amount of local impact of DBS was estimated using a finite element method approach. On a global level, average connectivity increases and decreases throughout the brain were estimated by contrasting on and off DBS scans on a voxel-wise graph comprising eight thousand nodes. Local impact of DBS on the motor subthalamic nucleus explained half the variance in global connectivity increases within the motor network (R = 0.711, P < 0.001). Moreover, local impact of DBS on the motor subthalamic nucleus could explain the degree to how much voxel-wise average brain connectivity normalized towards healthy controls (R = 0.713, P < 0.001). Finally, a network-based statistics analysis revealed that DBS attenuated specific couplings known to be pathological in Parkinson's disease. Namely, coupling between motor thalamus and motor cortex was increased while striatal coupling with cerebellum, external pallidum and subthalamic nucleus was decreased by DBS. Our results show that resting state functional MRI may be acquired in DBS on and off conditions on clinical MRI hardware and that data are useful to gain additional insight into how DBS modulates the functional connectome of the human brain. We demonstrate that effective DBS increases overall connectivity in the motor network, normalizes the network profile towards healthy controls and specifically strengthens thalamo-cortical connectivity while reducing striatal control over basal ganglia and cerebellar structures.

Introduction

Deep brain stimulation (DBS) is a highly efficacious and established treatment option for Parkinson's disease (Deuschl et al., 2006) and a multitude of mechanisms of action have been proposed over the years (Lozano and Lipsman, 2013). Increasingly, these undergo a paradigm shift away from localized stimulation of specific areas towards global modulation of distributed brain networks (McIntyre and Hahn, 2010; Litvak et al., 2011; Vanegas Arroyave et al., 2016; Akram et al., 2017; Horn et al., 2017). To elucidate such network effects of DBS, modern-day neuroimaging methods become more and more useful (Horn, 2019). In addition, DBS could reversely be a powerful tool to study network changes as a function of precisely targeted stimuli.

One of the few neuroimaging options to study the functional organization of the brain is functional MRI (fMRI). Intrinsic associations between subparts of the brain may be estimated using resting-state (rs-) fMRI and in this way, the 'functional connectome' of the brain can be explored (Biswal et al., 2010). When blood oxygenated level-dependent (BOLD) signals of two brain regions are correlated over time, these have been called functionally 'connected' in the literature (Fox et al., 2005; Friston, 2011), although this measure includes highly indirect connections (Varoquaux and Craddock, 2013). Until recently, it was not straightforward to acquire rs-fMRI data in patients with DBS implants, let alone with the stimulator switched on in the scanner. The reason was that no official certificate of device manufacturers allowed this practice and only limited pioneering work by a few specialized centres—the Jech and Foltynie groups should be mentioned among others—investigated changes of fMRI data under DBS in a so far limited fashion (Jech et al., 2001; Kahan et al., 2014) (Supplementary Table 1). In a first study of four patients, Jech et al. (2001) showed that the BOLD signals increase in ipsilateral subcortical structures under DBS. In a case report, Stefurak et al. (2003) then showed more distributed signal increases in (pre-) motor cortices, ventrolateral thalamus, putamen and cerebellum under effective DBS. Seminal work by Kahan et al. in 2014 described changes of direct, indirect and hyperdirect pathways of the basal ganglia—cortical loops under DBS using dynamic causal modelling. The same data were used to fit a computational mean-field model that was able to identify additional potential DBS targets beyond the classical subthalamic nucleus (STN) target used to treat Parkinson's disease (Saenger et al., 2017). In a formal literature analysis, we identified further studies that used fMRI under active DBS in humans and animal models so far (Supplementary Table 1). In summary, STN-DBS in Parkinson's disease may lead to increased overall functional connectivity in the premotor cortex (Mueller et al., 2013) and strengthened cortico-striatal and thalamo-cortical pathways in fMRI (Kahan et al., 2014).

In sum, even though there was no official allowance for active DBS in fMRI until recently (see below), the concept was explored in small case numbers. One issue that has been neglected in prior studies is that slight changes of millimetres in lead placement may result in large differences in clinical improvement (Horn et al., 2019) and similarly, slight differences in connectivity profiles of DBS electrodes may be used to predict clinical improvement across patients, cohorts and DBS centres (Horn et al., 2017). Finally, small variations in lead placement can even explain changes of behaviour in motor (Neumann et al., 2018) and cognitive (Irmen et al., 2018) domains. Thus, we argue that it is crucial to incorporate DBS lead placement into an analysis of how they impact distributed brain networks. Instead, prior studies characterized fMRI changes in DBS on versus off contrasts and, by doing so, implicitly assumed that the DBS effect was equal in each patient. In reality, the impact of each DBS electrode on the target structure largely varies across patients and may be used as a regressor to better explain network changes.

In the present study, we investigated a cohort of 20 patients with Parkinson's disease at rest under DBS on and off conditions. We characterized changes in average connectivity (i.e. centrality) of brain regions and laid special focus on network changes as a function of the degree of motor STN-DBS modulation. Based on minor differences in DBS electrode placement, different amounts of motor STN volume were stimulated in each patient. As a result, we expected correspondingly differing changes in motor cortical activation that should be stronger or weaker as a function of electrode placement. Moreover, because differences in therapeutic effects are equally dependent on lead placement (Horn et al., 2017, 2019), we expected network properties to normalize towards healthy controls to a degree that is dependent on lead placement. We expected that an optimally placed lead would result in strong modulations in the motor network, normalizing towards the network properties found in healthy controls. In contrast, poorly placed leads would not result in strong motor network changes.

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