Physiological mechanisms of thalamic ventral intermediate nucleus stimulation for tremor suppression

doi:10.1093/brain/awy139 BRAIN 2018: 141; 2142–2155 | 2142 Physiological mechanisms of thalamic ventral intermediate nucleus stimulation for tremor suppression Luka Milosevic,1,2 Suneil K. Kalia,3,4,5 Mojgan Hodaie,3,4,5 Andres M. Lozano,3,4,5 Milos R. Popovic1,2 and William D. Hutchison3,5,6 Ventral intermediate thalamic deep brain stimulation is a standard therapy for the treatment of medically refractory essential tremor and tremor-dominant Parkinson’s disease. Despite the therapeutic benefits, the mechanisms of action are varied and complex, and the pathophysiology and genesis of tremor remain unsubstantiated. This intraoperative study investigated the effects of high frequency microstimulation on both neuronal firing and tremor suppression simultaneously. In each of nine essential tremor and two Parkinson’s disease patients who underwent stereotactic neurosurgery, two closely spaced (600 mm) microelectrodes were advanced into the ventral intermediate nucleus. One microelectrode recorded action potential firing while the adjacent electrode delivered stimulation trains at 100 Hz and 200 Hz (2–5 s, 100 mA, 150 ms). A triaxial accelerometer was used to measure postural tremor of the contralateral hand. At 200 Hz, stimulation led to 68  8% (P 5 0.001) inhibition of neuronal firing and a 53  5% (P 5 0.001) reduction in tremor, while 100 Hz reduced firing by 26  12% (not significant) with a 17  6% (P 5 0.05) tremor reduction. The degree of cell inhibition and tremor suppression were significantly correlated (P 5 0.001). We also found that the most ventroposterior stimulation sites, closest to the border of the ventral caudal nucleus, had the best effect on tremor. Finally, prior to the inhibition of neuronal firing, microstimulation caused a transient driving of neuronal activity at stimulus onset (61% of sites), which gave rise to a tremor phase reset (73% of these sites). This was likely due to activation of the excitatory glutamatergic cortical and cerebellar afferents to the ventral intermediate nucleus. Temporal characteristics of the driving responses (duration, number of spikes, and onset latency) significantly differed between 100 Hz and 200 Hz stimulation trains. The subsequent inhibition of neuronal activity was likely due to synaptic fatigue. Thalamic neuronal inhibition seems necessary for tremor reduction and may function in effect as a thalamic filter to uncouple thalamo-cortical from cortico-spinal reflex loops. Additionally, our findings shed light on the gating properties of the ventral intermediate nucleus within the cerebello-thalamo-cortical tremor network, provide insight for the optimization of deep brain stimulation technologies, and may inform controlled clinical studies for assessing optimal target locations for the treatment of tremor. 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada 2 Rehabilitation Engineering Laboratory, Toronto Rehabilitation Institute – University Health Network, Toronto, Canada 3 Department of Surgery, University of Toronto, Toronto, Canada 4 Division of Neurosurgery, Toronto Western Hospital – University Health Network, Toronto, Canada 5 Krembil Research Institute, Toronto, Canada 6 Department of Physiology, University of Toronto, Toronto, Canada Correspondence to: William D. Hutchison Toronto Western Hospital, University Health Network MC12–417 – 399 Bathurst St, Toronto, Ontario, M5T 2S8, Canada E-mail: Received February 28, 2018. Revised April 4, 2018. Accepted April 5, 2018. Advance Access publication June 5, 2018 ß The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact Thalamic mechanisms in ET and PD tremor BRAIN 2018: 141; 2142–2155 | 2143 Keywords: clinical neurophysiology; deep brain stimulation; neurosurgery; tremor; Parkinson’s disease Abbreviations: DBS = deep brain stimulation; GPi = globus pallidus internus; HFS = high frequency stimulation; SNr = substantia nigra pars reticulata; STN = subthalamic nucleus; Vc = ventral caudal nucleus; Vim = ventral intermediate nucleus; Voa = ventral oral anterior nucleus; Vop = ventral oral posterior nucleus Introduction Tremor is characterized by involuntary rhythmic muscle contractions that can occur in one or more body parts. It can occur alone as in essential tremor, or with other motor symptoms as in Parkinson’s disease and occasionally dystonia. Essential tremor is currently the most prevalent movement disorder in man (Louis et al., 1998), and three of four patients with Parkinson’s disease develop tremor at some point during the disease process (Hughes et al., 1993). In Parkinson’s disease, tremor is typically present at rest, while essential tremor patients possess postural or kinetic tremor (Deuschl et al., 1998; Elble and Deuschl, 2009). Tremor is regarded as the most difficult to treat symptom of Parkinson’s disease as it may not respond well to dopamine replacement therapy, and essential tremor has also proven quite intractable to treat pharmaceutically in a subset of patients (Goldman et al., 1992; Koller et al., 1994; Ondo et al., 1998; Fishman, 2008). Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) is an efficacious and reversible standard of care that has largely replaced Vim thalamotomy for the amelioration of tremor (Benabid et al., 1991, 1993, 1996; Nguyen and Degos, 1993; Deiber et al., 1993). Numerous studies have supported the central origin of tremor by hypothesizing the presence of a single pathological oscillation frequency between 4 and 6 Hz (Rajput et al., 1991; Deuschl et al., 1998; Llinás et al., 2005). In Parkinson’s disease, an early thalamo-centric theory of tremor genesis stated that 12–15 Hz oscillations in pallidal output found in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys were converted into 4–6 Hz tremor oscillations by intrinsic thalamic membrane hysteresis (Llinás and Paré, 1995). A more recent pallido-centric theory (Helmich et al., 2011), termed the dimmer-switch hypothesis, suggests that Parkinson’s disease tremor is initiated by the basal ganglia (the switch) and its amplitude is modulated by the cerebello-thalamo-cortical network (the dimmer). Indeed, single neurons with 4–6 Hz tremor oscillations are present in the human globus pallidus internus (GPi; Hutchison et al., 1997). This theory suggests that the GPi sends tremorgenic output to the thalamus, which then ascends though the thalamo-cortical network. However, that would suggest a predominant role for the pallidal thalamic input nuclei, ventral oral anterior and posterior (Voa, Vop), in tremor-genesis, but th (...truncated)