Frequency-dependent effects of electrical stimulation in the globus pallidus of dystonia patients

Abstract

Deep brain stimulation (DBS) in the globus pallidus internus (GPi) has been shown to improve dystonia, a movement disorder of repetitive twisting movements and postures. DBS at frequencies above 60 Hz improves dystonia, but the mechanisms underlying this frequency dependence are unclear. In patients undergoing dual-microelectrode mapping of the GPi, microstimulation has been shown to reduce neuronal firing, presumably due to synaptic GABA release. This study examined the effects of different microstimulation frequencies (1-100 Hz) and train length (0.5-20 s), with and without prior high-frequency stimulation (HFS) on neuronal firing and evoked field potentials (fEPs) in 13 dystonia patients. Pre-HFS, the average firing decreased as stimulation frequency increased and was silenced above 50 Hz. The average fEP amplitudes increased up to frequencies of 20-30 Hz but then declined and at 50 Hz, were only at 75% of baseline. In some cases, short latency fiber volleys and antidromic-like spikes were observed and followed high frequencies. Post-HFS, overall firing was reduced compared with pre-HFS, and the fEP amplitudes were enhanced at low frequencies, providing evidence of inhibitory synaptic plasticity in the GPi. In a patient with DBS electrodes already implanted in the GPi, recordings from four neurons in the subthalamic nucleus showed almost complete inhibition of firing with clinically effective but not clinically ineffective stimulation parameters. These data provide additional support for the hypothesis of stimulation-evoked GABA release from afferent synaptic terminals and reduction of neuronal firing during DBS and additionally, implicate excitation of GPi axon fibers and neurons and enhancement of inhibitory synaptic transmission by high-frequency GPi DBS as additional putative mechanisms underlying the clinical benefits of DBS in dystonia.

Response of Human Thalamic Neurons to High-Frequency Stimulation

“…The manner in which DBS alleviates symptoms bears close parallels with lesions in the same target nuclei, which led to early hypotheses that the therapeutic effects of DBS were due to inhibition of the target nucleus, although it was also proposed that DBS may reduce tremor by masking the low frequency neuronal oscillatory activity by generating high frequency continuous firing - termed “jamming” [32] or “informational lesion” [33]. The inhibitory hypothesis was supported by recordings of human thalamic, pallidal and subthalamic neurons in response to HFS, in which post-stimulus inhibition was demonstrated in the period immediately after the high frequency trains [15], [34], [35], as also seen in the present work and in recent results demonstrating frequency-dependent inhibition of neuronal firing during the stimulation train [36]. However, in apparent conflict with these results, animal studies indicated that the neuronal activity of at least some of the neurons in globus pallidus increased during high frequency stimulation of STN [37] and decreased in thalamus following pallidal stimulation (consistent with exciting the inhibitory GABAergic pallidal neurons) [38], and that the levels of glutamate and GABA were increased in SNr following STN stimulation [39].…”

Research Priorities in Limb and Task-Specific Dystonias

“…Direct measurement of GPi activity during DBS implantation has also provided evidence that short-term plasticity is abnormal in dystonia patients, with impaired paired-pulse depression seen (96). This and other studies suggest that the impaired inhibition seen cortically in associative plasticity studies is also reflected at the basal ganglia level in direct recordings (96–98). …”

Deep Brain Stimulation Imposes Complex Informational Lesions

“…However, in contrast to globus pallidus, more than twice as many cells in the VLo were able to retain their original tuning during GP-DBS (60% in motor thalamus versus 25% in globus pallidus), suggesting that the partial loss of tuning observed in GP did not proportionally transfer to the VLo thalamus. While it is possible that GP-DBS attenuated the synaptic strength of pallidal projections within thalamus, as it was found to induce inhibitory synaptic plasticity within the GP [55], such decreased responsiveness would be expected to occur at longer time scales of stimulation than those investigated in this study. It is also possible that given the stable condition of the pathophysiology in both non-human primates, motor thalamus may already have been in a state that is less responsive to basal ganglia input.…”