Microstimulation-induced inhibition of thalamic reticular nucleus in non-human primates.

The thalamic reticular nucleus (TRN) modulates activity in the thalamus and controls excitatory input from corticothalamic and thalamocortical glutamatergic projections. It is made up of GABAergic neurons which project topographically to the thalamus. The TRN also receives inhibitory projections from the globus pallidus and the substantia nigra pars reticulata. Photostimulation of the TRN results in local inhibition in rat slice preparations but the effects of local stimulation in vivo are not known. This study aimed to characterize stimulation-evoked responses in the TRN of non-human primates (NHPs). Microelectrodes were inserted into the TRN and neurons were stimulated at 5, 10, 15, and 20 µA using 0.5 s trains at 100 Hz and the subsequent response was recorded from the same electrode. Stimulation in surrounding nuclei and the internal capsule was used for mapping the anatomical borders of the TRN. Stimulation as low as 10 µA resulted in predominantly inhibition, recorded in both single units and background unit activity (BUA). The duration of inhibition (~ 1-3 s) increased with increasing stimulation amplitude and was significantly increased in BUA when single units were present. At 20 µA of current, 93% of the single units (41/44) and 92% of BUA sites (67/73) were inhibited. Therefore, microstimulation of the NHP TRN with low currents results in current-dependent inhibition of single units and BUA. This finding may be useful to further aid in localization of deep thalamic and subthalamic nuclei during brain surgery.

Bilateral pallidal stimulation for Wilson's disease.

BACKGROUND: To report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in a 29-year-old patient with severe generalized dystonia secondary to Wilson's disease. METHODS: The primary outcome measure was the Burke-Fahn-Marsden Dystonia Scale motor severity score (blinded assessment) and the secondary outcome measures were the Abnormal Involuntary Movement Scale (blinded assessment) and the Zaritt Caregiver Burden Interview score, at 20-week postoperative follow up. RESULTS: There was a 14% improvement in the Burke-Fahn-Marsden Dystonia Scale motor severity score. Abnormal Involuntary Movement Scale score remained unchanged while the Zaritt Caregiver Burden Interview score improved by 44.4%. CONCLUSIONS: Bilateral globus pallidus deep brain stimulation can be effective in ameliorating dystonia and caregiver burden in Wilson's disease. Outcomes may depend on the stage of the disease at which the surgical procedure is completed. © 2013 Movement Disorder Society.

Pallidal deep brain stimulation for a case of hemidystonia secondary to a striatal stroke.

BACKGROUND: The efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for medically refractory idiopathic generalized dystonia has been demonstrated repeatedly. More variable outcomes have been reported in the treatment of secondary dystonia with GPi DBS. OBJECTIVES: The present study seeks to examine the pallidal physiology and clinical outcome of GPi DBS in a case of secondary dystonia. METHODS: We report on a 43-year-old man who at the age of 9 suffered a left basal ganglia stroke and at the age of 21 developed severe disabling hemidystonia. Following unsuccessful medical management for many years and an axial involvement of the dystonia, he underwent bilateral GPi DBS with dual microelectrode mapping of cell firing and evoked field potentials (fEP). RESULTS: On the intact side we found regular firing of pallidal neurons and normal fEP indicative of functioning striatopallidal pathways. The affected side was found to include a higher frequency of bursting pallidal neurons. fEP could not be evoked on the affected side, suggesting their origin to be striatal GABAergic afferents. CONCLUSIONS: The patient had marked benefit from bilateral GPi DBS, which suggests that the therapeutic effects of DBS were mediated by the intact pathways in this case of hemidystonia.

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

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.

Field evoked potentials in the globus pallidus of non-human primates.

Stimulation-induced field evoked potentials (fEPs) have been described in the basal ganglia output nuclei of patients with Parkinson's disease and dystonia. The aim of this study was to ascertain whether fEPs were inducible in the external (GPe) and internal (GPi) segments of the globus pallidus in normal non-human primates (NHPs). Microelectrode recording and stimulation was performed in the GPe and GPi of 2 healthy NHPs. Stimulus response curves of the fEP response to changing pulse width and amplitude examined strength-duration relationships and allowed for calculation of fEP chronaxie in the GPe and GPi. Traditional localization techniques were also used, including comparison of neuronal firing rates, optic tract activation, and internal capsule activation. Notable differences were seen in the fEPs found in GPe compared to the fEPs found in GPi. The GPe fEP had a smaller chronaxie time and larger positive deflection amplitude compared to GPi. In addition, an earlier negative deflection was identified in both nuclei and a late negative deflection was observed in the GPe in contrast to reported fEPs in patients with movement disorders. fEPs proved valuable as an ancillary method in localizing the GPe and GPi in NHPs and may be useful in the operating room during human GPi deep brain stimulation or pallidotomy procedures.

Low profile halo head fixation in non-human primates.

BACKGROUND: We present a new halo technique for head fixation of non-human primates during electrophysiological recording experiments. Our aim was to build on previous halo designs in order to create a simple low profile system that provided long-term stability. NEW METHOD: Our design incorporates sharp skull pins that are directly threaded through a low set halo frame and are seated into implanted titanium foot plates on the skull. The inwardly directed skull pins provide an easily calibrated force against the skull. RESULTS: This device allowed for head fixation within 1 week after implantation surgery. The low-profile design maximized the area of the skull available and potential implant orientations for electrophysiological experiments. It was easily maintained and was stable in 2 animals for the 6-8 months of testing. The quality of single unit neural recordings collected while using this device to head fix was indistinguishable from traditional head-post fixation. The foot plates used in this system did not result in significant MRI distortion in the location of deep brain targets (∼0.5mm) of a 3D printed phantom skull. COMPARISON WITH EXISTING METHOD(S): The low profile design of this halo design allows greater access to the majority of the frontal, parietal, and occipital skull. It has fewer parts and can hold larger animals than previous halo designs. CONCLUSIONS: Given the stability, simplicity, immediate usability, and low profile of our head fixation device, we propose that it is a practical and useful means for performing electrophysiological recording experiments on non-human primates.

Preliminary evidence for human globus pallidus pars interna neurons signaling reward and sensory stimuli.

The globus pallidus pars interna (GPi) is a component of the basal ganglia, a network of subcortical nuclei that process motor, associative, and limbic information. While non-human primate studies have suggested a role for the GPi in non-motor functions, there have been no single-unit studies of non-motor electrophysiological behavior of human GPi neurons. We therefore sought to extend these findings by collecting single-unit recordings from awake patients during functional stereotactic neurosurgery targeting the GPi for deep brain stimulation. To assess cellular responses to non-motor information, patients performed a reward task where virtual money could be won, lost, or neither, depending on their performance while cellular activity was monitored. Changes in the firing rates of isolated GPi neurons after the presentation of reward-related stimuli were compared between different reward contingencies (win, loss, null). We observed neurons that modulated their firing rate significantly to the presentation of reward-related stimuli. We furthermore found neurons that responded to visual-stimuli more broadly. This is the first single-unit evidence of human GPi neurons carrying non-motor information. These results are broadly consistent with previous findings in the animal literature and suggest non-motor information may be represented in the single-unit activity of human GPi neurons.