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, 36 (19), 5362-72

The Cerebral Network of Parkinson's Tremor: An Effective Connectivity fMRI Study

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The Cerebral Network of Parkinson's Tremor: An Effective Connectivity fMRI Study

Michiel F Dirkx et al. J Neurosci.

Abstract

Parkinson's resting tremor has been linked to pathophysiological changes both in the basal ganglia and in a cerebello-thalamo-cortical motor loop, but the role of those circuits in initiating and maintaining tremor remains unclear. Here, we test whether and how the cerebello-thalamo-cortical loop is driven into a tremor-related state by virtue of its connectivity with the basal ganglia. An internal replication design on two independent cohorts of tremor-dominant Parkinson patients sampled brain activity and tremor with concurrent EMG-fMRI. Using dynamic causal modeling, we tested: (1) whether activity at the onset of tremor episodes drives tremulous network activity through the basal ganglia or the cerebello-thalamo-cortical loop and (2) whether the basal ganglia influence the cerebello-thalamo-cortical loop through connectivity with the cerebellum or motor cortex. We compared five physiologically plausible circuits, model families in which transient activity at the onset of tremor episodes (assessed using EMG) drove network activity through the internal globus pallidus (GPi), external globus pallidus, motor cortex, thalamus, or cerebellum. In each family, we compared two models in which the basal ganglia and cerebello-thalamo-cortical loop were connected through the cerebellum or motor cortex. In both cohorts, cerebral activity associated with changes in tremor amplitude (using peripheral EMG measures as a proxy for tremor-related neuronal activity) drove network activity through the GPi, which effectively influenced the cerebello-thalamo-cortical loop through the motor cortex. We conclude that cerebral activity related to Parkinson's tremor first arises in the GPi and is then propagated to the cerebello-thalamo-cortical circuit.

Significance statement: Parkinson's resting tremor has been linked to pathophysiological changes both in the basal ganglia and in a cerebello-thalamo-cortical motor loop, but the role of those circuits in initiating and maintaining tremor remains unclear. Using dynamic causal modeling of concurrently collected EMG-fMRI data in two cohorts of Parkinson's patients, we showed that cerebral activity associated with changes in tremor amplitude drives network activity through the basal ganglia. Furthermore, the basal ganglia effectively influenced the cerebello-thalamo-cortical circuit through the motor cortex (but not the cerebellum). Out findings suggest that Parkinson's tremor-related activity first arises in the basal ganglia and is then propagated to the cerebello-thalamo-cortical circuit.

Keywords: Parkinson's; cerebellum; effective connectivity; frontostriatal circuits; functional magnetic resonance imaging.

Figures

Figure 1.
Figure 1.
Schematic illustration of model space. A, Left, Illustration of the anatomical connections between the cerebello-thalamo-cortical loop and basal ganglia. Middle, Our DCM implementation of this anatomical model, which includes only the GPi, GPe, STN, MC, CBLM, and VIM. The dashed lines indicate variable connections representing our competing hypotheses. Right, Two-state implementation of these nodes, with blue indicating the inhibitory and red the excitatory part of each node. Inhibitory and excitatory connections are indicated by blue and red lines, respectively. B, All 12 competing models. Every model indicates a unique combination of an input to one of four measured nodes (GPe, GPe, MC, VIM, CBLM) and either a connection from GPi→MC or STN→CBLM. In addition, the last two models have no input to test whether our tremor regressor positively contributes to the model evidence. VLa, Anterior part of venterolateral nucleus of thalamus; VLp, posterior part of venterolateral nucleus of thalamus; ILN, interlaminar nuclei.
Figure 2.
Figure 2.
Tremor-related activity in the cerebello-thalamo-cortical loop. All images of patients with a left-sided affected arm were flipped so that the lateralization of the involved brain regions was the same among all subjects (i.e., corresponding to the most affected hand). A, ROIs used for extraction of the time series of the contralateral motor cortex, contralateral thalamus (VIM), and ipsilateral cerebellum. These ROIs are based on second-level tremor-amplitude-related activity in C1 (Helmich et al., 2011). B, Illustration of tremor-amplitude related activity of the cerebello-thalamo-cortical circuit in C2. Significant activation was found in all three ROI's, thus replicating the results of C1.
Figure 3.
Figure 3.
Tremor dynamics. This figure shows spontaneous tremor dynamics during scanning for one patient and the relationship between tremor variability and cerebral activity in the motor cortex and GPi. A, EMG power spectrum during scanning with the individual tremor frequency marked for this subject. B, Spontaneous fluctuations in tremor amplitude (at the individual tremor frequency) during the scanning period (in black) plotted together with changes in tremor amplitude (in blue). C, Correlation between the convolved tremor amplitude regressor (in black) and the BOLD response of the MC (in red). D, Correlation between the convolved tremor amplitude-change regressor (in blue) and the BOLD response of the GPi (in red). All regressors are high-pass filtered (cutoff 128 s), z-normalized, and log-transformed. Effects across the whole group are shown in Figure 2 and Table 2.
Figure 4.
Figure 4.
Observed versus predicted BOLD response. Representative example of observed versus predicted BOLD response (model 3; subject 2 of C1) in all of our measured ROIs.
Figure 5.
Figure 5.
Results of BMS for C1 (top) and C2 (bottom). For both cohorts, model 3 (which specifies an input to the GPi and a connection from MC→GPi) is the clear winner, as indicated by a protected exceedance probability of >99%.

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