A widespread visually-sensitive functional network relates to symptoms in essential tremor

Abstract

Essential tremor is a neurological syndrome of heterogeneous pathology and aetiology that is characterized by tremor primarily in the upper extremities. This tremor is commonly hypothesized to be driven by a single or multiple neural oscillator(s) within the cerebello-thalamo-cortical pathway. Several studies have found an association of blood-oxygen level-dependent (BOLD) signal in the cerebello-thalamo-cortical pathway with essential tremor, but there is behavioural evidence that also points to the possibility that the severity of tremor could be influenced by visual feedback. Here, we directly manipulated visual feedback during a functional MRI grip force task in patients with essential tremor and control participants, and hypothesized that an increase in visual feedback would exacerbate tremor in the 4-12 Hz range in essential tremor patients. Further, we hypothesized that this exacerbation of tremor would be associated with dysfunctional changes in BOLD signal and entropy within, and beyond, the cerebello-thalamo-cortical pathway. We found that increases in visual feedback increased tremor in the 4-12 Hz range in essential tremor patients, and this increase in tremor was associated with abnormal changes in BOLD amplitude and entropy in regions within the cerebello-thalamo-motor cortical pathway, and extended to visual and parietal areas. To determine if the tremor severity was associated with single or multiple brain region(s), we conducted a birectional stepwise multiple regression analysis, and found that a widespread functional network extending beyond the cerebello-thalamo-motor cortical pathway was associated with changes in tremor severity measured during the imaging protocol. Further, this same network was associated with clinical tremor severity measured with the Fahn, Tolosa, Marin Tremor Rating Scale, suggesting this network is clinically relevant. Since increased visual feedback also reduced force error, this network was evaluated in relation to force error but the model was not significant, indicating it is associated with force tremor but not force error. This study therefore provides new evidence that a widespread functional network is associated with the severity of tremor in patients with essential tremor measured simultaneously at the hand during functional imaging, and is also associated with the clinical severity of tremor. These findings support the idea that the severity of tremor is exacerbated by increased visual feedback, suggesting that designers of new computing technologies should consider using lower visual feedback levels to reduce tremor in essential tremor.

Cortical dynamics within and between parietal and motor cortex in essential tremor

“…Using fMRI, studies have reported changes in activation within primary visual cortex, inferior/superior parietal cortex, primary motor cortex, dorsal premotor cortex, and supplementary motor area . In a recent fMRI study consisting of a cohort of ET subjects that overlapped with ET subjects examined in the current work, probabilistic tractography analyses revealed no structural changes within the cerebellum to motor cortex pathway and within the dorsal processing stream linking parietal and motor cortex of ET subjects when compared to controls. The current findings, showing altered connectivity between parietal cortex and motor cortex, complement another EEG study examining coherence between EMG and EEG signals between cerebellum and motor cortex .…”

“…We also found reduced bidirectional connectivity between the superior parietal cortex and contralateral motor cortex in ET. Using fMRI, studies have reported changes in activation within primary visual cortex, inferior/superior parietal cortex, primary motor cortex, dorsal premotor cortex, and supplementary motor area . In a recent fMRI study consisting of a cohort of ET subjects that overlapped with ET subjects examined in the current work, probabilistic tractography analyses revealed no structural changes within the cerebellum to motor cortex pathway and within the dorsal processing stream linking parietal and motor cortex of ET subjects when compared to controls.…”

“…Although our analysis approach revealed changes in the cortex, it is possible that our observations in the cortex may have been driven by ET‐related changes in subcortical circuits, including the thalamus and cerebellum. Nevertheless, the collective picture emerging from the current EEG study and previous EEG, MEG, fMRI, and postmortem studies is that tremor in ET is associated with a widespread network with multiple nodes, rather than one key region of the brain, and this perspective has important implications for pharmacological and other nonpharmacological treatments for ET because multiple targets may exist.…”

“…Three measures were examined: mean force noted as % maximum force, root mean square error (RMSE) with respect to the target force, and force tremor estimated as the sum of power of force between 4–12 Hz . All measures were computed over a 2.5‐second window after 1.5 seconds from force onset.…”

“…Multiple neurophysiological and neuroimaging studies examining ET subjects have reported changes in the motor cortex, thalamus, and cerebellum, which together form the cerebellar‐thalamo‐motor cortical pathway. More recently, ET has also been associated with changes in functional activity in regions beyond the cerebellar‐thalamo‐motor cortical pathway, including the parietal cortex . Despite our improved understanding of the key areas that are affected in ET, we know less about how cortical neuronal oscillations and connectivity within and between the parietal cortex and other cortical areas relate to the magnitude of tremor in ET.…”