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The subthalamic nucleus (STN) is an important component of the basal ganglia (BG) and plays a major role in the pathogenesis of Parkinson’s disease (PD). Hyperactivity of STN as a consequence of the loss of dopaminergic inputs to the BG is believed to be a major factor in producing the motor symptoms of PD. High-frequency (HF) deep brain stimulation (DBS) of the STN has recently become an important treatment in PD patients where medications no longer provide satisfactory therapy. However, the mechanisms underlying DBS therapy are unknown, and there is seemingly conflicting data suggesting inhibition or excitation of STN neurons. This study directly examined the effects of stimulation in STN on the activity of STN neurons in PD patients during functional stereotactic mapping prior to insertion of DBS electrodes. Electrical stimulation in STN was investigated in twelve PD patients by recording the neural activity of a cell in STN with one electrode while applying current pulses through a second electrode located about 600 µm away. Stimulation at high frequencies (100–300 Hz) was found to produce inhibition following the stimulus train in 42% of the 60 cells tested. Inhibition during the train was seen in 13 of 15 neurons where it was possible to detect such activity. Furthermore, in 44% of the cases where HF stimulation produced inhibition there was an early inhibition followed by rebound excitation and a further inhibitory period, suggesting that the inhibitions observed are due to hyperpolarization. In eight of the 25 neurons inhibited by HF stimulation, the effects of single stimuli were determined and revealed that in seven of these there was an inhibitory period of 15–20 ms following each stimulus. Thus, the present findings suggest that local HF stimulation inhibits many STN neurons. However, these studies could not determine whether the stimulus also directly excited the cell and/or its axon, but other recent findings suggest that this is likely the case. Therefore, the overall effects of DBS stimulation in STN are likely to be inhibition of intrinsic and synaptically mediated activity, and its replacement by regular high-frequency firing. [ABSTRACT FROM AUTHOR]

High-frequency deep brain stimulation ( HFS- DBS) of the subcallosal cingulate ( SCC) region has been investigated as a treatment for refractory forms of depression with a ~50% remission rate in open label studies. However, the therapeutic mechanisms of DBS are still largely unknown. Using anaesthetized Sprague Dawley rats, we recorded neuronal spiking activity in 102 neurons of the dorsal raphe ( DR) before, during and after the induction of a 5-min HFS train in the infralimbic region ( IL) of the medial prefrontal cortex ( mPFC), the rodent homologue of the human SCC. The majority of DR cells (82%) significantly decreased firing rate during HFS ( P < 0.01, 55.7 ± 4.5% of baseline, 35 rats). To assess whether mPFC- HFS mediates inhibition of DR cellular firing by stimulating local GABAergic interneurons, the GABAA antagonist bicuculline ( Bic, 100 μ m) was injected directly into the DR during HFS. Neurons inhibited by HFS recovered their firing rate during Bic+ HFS ( P < 0.01, n = 15, seven rats) to levels not different from baseline. Cells that were not affected by HFS did not change firing rate during Bic+ HFS ( P = 0.968, n = 7, three rats). These results indicate that blocking GABAA reverses HFS-mediated inhibition of DR neurons. As the cells that were not inhibited by HFS were also unaffected by HFS+ Bic, they are probably not innervated by local GABA. Taken together, our results suggest that mPFC- HFS may exert a preferential effect on DR neurons with GABAA receptors. [ABSTRACT FROM AUTHOR]

External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13–30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD. • Single neurons in STN (72%) and GPi (52%) responded to auditory cued foot pedaling at rates from 1 to 3 Hz in awake PD persons OFF-drug • Accuracy of pedaling with respect to cues progressively decreased as cue frequencies increased, particularly above 1.5 Hz. • GPi showed decrease in tonic beta LFP power with fast auditory cues. STN showed tonic increases in beta power after onset of foot movement. • STN is involved in motor aspects of auditory cued pedaling while the GPi may play a role in sensory processing of the task. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus (PPN) lies within the brainstem reticular formation and is involved in the motor control of gait and posture. Interest has focused recently on the PPN as a target for implantation of chronic deep brain stimulation (DBS) electrodes for Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) therapy. The aim of this study was to examine the neurophysiology of the human PPN region and to identify neurophysiological landmarks that may aid the proper placement of DBS electrodes in the nucleus for the treatment of PD and PSP. Neuronal firing and local field potentials were recorded simultaneously from two independently driven microelectrodes during stereotactic neurosurgery for implantation of a unilateral DBS electrode in the PPN in five PD patients and two PSP patients. Within the PPN region, the majority (57%) of the neurons fired randomly while about 21% of the neurons exhibited ‘bursty’ firing. In addition, 21% of the neurons had a long action potential duration and significantly lower firing rate suggesting they were cholinergic neurons. A change in firing rate produced by passive and/or active contralateral limb movement was observed in 38% of the neurons that were tested in the PPN region. Interestingly, oscillatory local field potential activity in the beta frequency range (∼25 Hz) was also observed in the PPN region. These electrophysiological characteristics of the PPN region provide further support for the proposed role of this region in motor control. It remains to be seen to what extent the physiological characteristics of the neurons and the stimulation-evoked effects will permit reliable identification of PPN and determination of the optimal target for DBS therapy. [ABSTRACT FROM AUTHOR]

The cortical mechanisms and substrates of cognitive and emotional demands are poorly understood. Lesion studies and functional imaging implicate the anterior cingulate cortex (ACC). The caudal ACC (cACC) has been implicated in cognitive processes such as attention, salience, interference, and response competition, mostly on the basis of neuroimaging results. To test the hypothesis that individual cACC neurons subserve these functions, we monitored neuronal activity from single cells in the cACC while subjects were engaged in a mental arithmetic task, the cognitively demanding counting Stroop task, and/or the emotional Stroop interference task. We now report the first direct measures of single neurons in humans identifying a population of cACC neurons that respond differentially or in a graded manner to cognitively demanding high- and low-conflict Stroop tasks, including those with emotional valence. These data indicate that cACC neurons may be acting as salience detectors when faced with conflict and difficult or emotional stimuli, consistent with neuroimaging results of cACC responses to abrupt sensory, novel, task-relevant, or painful stimuli. [ABSTRACT FROM AUTHOR]

Dexmedetomidine (an alpha-2 adrenergic agonist) sedation is commonly used during subthalamic nucleus ( STN) deep-brain stimulation ( DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording ( MER) data from patients with Parkinson's disease who underwent STN DBS. A 'Dex bolus' group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a 'no sedation' group (29 cells from 11 patients). We also performed within-patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke-Vitek methodology and local field potential ( LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 ± 9.9 vs. 34.5 ± 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike-oscillations analysis(beta peak, P = 0.4; signal-to-noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high-dose dexmedetomidine should be avoided during DBS surgery. [ABSTRACT FROM AUTHOR]

Thalamic deep brain stimulation (DBS) is an effective treatment for tremor, but the mechanisms of action remain unclear. Previous studies of human thalamic neurons to noted transient rebound bursting activity followed by prolonged inhibition after cessation of high frequency extracellular stimulation, and the present study sought to identify the mechanisms underlying this response. Recordings from 13 thalamic neurons exhibiting low threshold spike (LTS) bursting to brief periods of extracellular stimulation were made during surgeries to implant DBS leads in 6 subjects with Parkinson's disease. The response immediately after cessation of stimulation included a short epoch of burst activity, followed by a prolonged period of silence before a return to LTS bursting. A computational model of a population of thalamocortical relay neurons and presynaptic axons terminating on the neurons was used to identify cellular mechanisms of the observed responses. The model included the actions of neuromodulators through inhibition of a non-pertussis toxin sensitive K+ current (IKL), activation of a pertussis toxin sensitive K+ current (IKG), and a shift in the activation curve of the hyperpolarization-activated cation current (Ih). The model replicated well the measured responses, and the prolonged inhibition was associated most strongly with changes in IKG while modulation of IKL or Ih had minimal effects on post-stimulus inhibition suggesting that neuromodulators released in response to high frequency stimulation are responsible for mediating the post-stimulation bursting and subsequent long duration silence of thalamic neurons. The modeling also indicated that the axons of the model neurons responded robustly to suprathreshold stimulation despite the inhibitory effects on the soma. The findings suggest that during DBS the axons of thalamocortical neurons are activated while the cell bodies are inhibited thus blocking the transmission of pathological signals through the network and replacing them with high frequency regular firing. [ABSTRACT FROM AUTHOR]

Intraoperative microelectrode single unit recordings are routinely made in the subthalamic nucleus (STN) of awake and alert Parkinson’s disease (PD) patients during surgery for implantation of deep brain stimulation (DBS) electrodes. These recordings not only assist in determining the optimal target for electrode implantation, but also offer the unique opportunity to study movement-evoked responses from the basal ganglia. We report on the responses of human STN neurons to eye movements from eight PD patients (five men and three women). Twenty percent (18/89) of tested STN neurons showed responses to eye movements. Patients made pro-saccades, voluntary saccades or smooth pursuit eye movements in four directions: up, down, left, right. The majority of STN neurons (72% or 13/18), that responded to eye movements were found in the ventral half of the nucleus, while 58% (22/38) of STN neurons that had somatic responses were found in the dorsal half of the nucleus. The firing rate for STN oculomotor neurons was 33±15 Hz ( n=18), which was not different from that reported previously for STN neurons. Most neurons only responded to eye movements in a single direction, but 17% (3/18) showed responses to more than one direction. The majority of responses (17/18) to eye movements were increases in firing rate although one neuron did show a pause in firing with eye movement onset. The phasic changes in firing rate in response to eye movement usually occurred up to 250 ms following eye movement onset. Neurons were found that showed task-specific responses to cued versus self-paced saccades, responded to both passive limb movement and voluntary eye movement, and appeared to show either visual or attentional responses. These human physiological data, in conjunction with previous anatomical studies, suggest that the STN might have an oculomotor role. Although there is no evidence that STN is responsible for driving eye movements, it may have a role in either sensory feedback, corollary discharge, or in focusing the substantia nigra pars reticulata to allow a saccade to occur through disinhibition of the superior colliculus. [ABSTRACT FROM AUTHOR]

Very fast oscillations (VFOs; 500-1,500 Hz) are associated with sensory-evoked potentials (SEPs), but their origin is unknown. To characterize the origins of VFOs, we studied 35 patients with deep brain stimulation (DBS) electrodes [15 with thalamic and 20 with the subthalamic nucleus (STN) electrodes]. We recorded median nerve stimulation-evoked SEPs from the thalamus and STN with microelectrodes during stereotactic surgery and from the contacts of the DBS electrodes postoperatively. We also examined the firing of individual neurons in thalamus in relation to the VFOs. In the thalamus, VFOs with frequencies around 1,000 Hz were superimposed on slow potentials. Both slow and fast SEP components showed phase reversals in the somatosensory thalamus [ventralis caudalis (Vc)]. Median nerve poststimulus time histograms showed that single thalamic neurons fired at preferred times at intervals between 0.8 to 1.2 ms that were synchronous with the VFOs, although the neurons fired only once or a few times per trial. In the STN, low-amplitude SEPs with VFOs were observed at a latency similar to the thalamic SEPs. The VFOs from STN probably represent volume conduction, possibly from the medial lemniscus. We conclude that the thalamic VFOs are generated within Vc and that they induce time-locked firing in a network of neurons. [ABSTRACT FROM AUTHOR]