Cognitive control involves theta power within trials and beta power across trials in the prefrontal-subthalamic network.

There is increasing evidence that the medial prefrontal cortex participates in conflict and feedback monitoring while the subthalamic nucleus adjusts actions. Yet how these two structures coordinate their activity during cognitive control remains poorly understood. We recorded from the human prefrontal cortex and the subthalamic nucleus simultaneously while participants (n = 22) performed a novel task involving high conflict trials, complete response inhibition trials, and trial-to-trial behavioural adaptations to conflict and errors. Overall, we found that within-trial adaptions to both conflict and complete response inhibition involved changes in the theta band while across-trial behavioural adaptations to both conflict and errors involved changes in the beta band (P < 0.05). Yet the role each region's theta and beta oscillations played during the task differed significantly between the two sites. Trials that involved either within-trial conflict or complete response inhibition were associated with increased theta phase synchrony between the medial prefrontal cortex and the subthalamic nucleus (P < 0.05). Despite increased synchrony, however, increases in prefrontal theta power were associated with response inhibition, while increases in subthalamic theta power were associated with response execution (P < 0.05). In the beta band, post-response increases in prefrontal beta power were suppressed when the completed trial contained either conflict or an erroneous response (P < 0.05). Subthalamic beta power, on the other hand, was only modified during the subsequent trial that followed a conflict or error trial. Notably, these adaptation trials exhibited slower response times (P < 0.05), suggesting that both brain regions contribute to across-trial adaptations but do so at different stages of the adaptation process. Taken together, our data shed light on the mechanisms underlying within-trial and across-trial cognitive control and how disruption of this network can negatively impact cognition. More broadly, however, our data also demonstrate that the specific role of a brain region, rather than the frequency being utilized, governs the behavioural correlates of oscillatory activity.

Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict.

Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta- and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict.

Decisions Made with Less Evidence Involve Higher Levels of Corticosubthalamic Nucleus Theta Band Synchrony.

The switch between automatic action selection and more controlled forms of decision-making is a dynamic process thought to involve both cortical and subcortical structures. During sensory conflict, medial pFC oscillations in the theta band (<8 Hz) drive those of the subthalamic nucleus (STN), and this is thought to increase the threshold of evidence needed for one competing response to be selected over another. Here, we were interested in testing whether STN activity is also altered by the rate at which evidence is presented during a congruent dot motion task absent of any explicit sensory conflict. By having a series of randomly moving dots gradually transform to congruent motion at three different rates (slow, medium, fast), we were able to show that a slower rate increased the time it took participants to make a response but did not alter the total amount of evidence that was integrated before the response. Notably, this resulted in a decision being made with a lower amount of instantaneous evidence during the slow and medium trials. Consistent with the idea that medial pFC-STN activity is involved in executing cognitive control, the higher levels of ambiguity during these trials were associated with increased theta band synchrony between the cortex and the STN, with the cortical oscillations Granger-causal to those of the STN. These results further confirm the involvement of the STN in decision-making and suggest that the disruption of this network may underlie some of the unwanted cognitive deficits associated with STN deep brain stimulation.

Human subthalamic nucleus-medial frontal cortex theta phase coherence is involved in conflict and error related cortical monitoring.

The medial prefrontal cortex (mPFC) is thought to control the shift from automatic to controlled action selection when conflict is present or when mistakes have been recently committed. Growing evidence suggests that this process involves frequency specific communication in the theta (4-8Hz) band between the mPFC and the subthalamic nucleus (STN), which is the main target of deep brain stimulation (DBS) for Parkinson's disease. Key in this hypothesis is the finding that DBS can lead to impulsivity by disrupting the correlation between higher mPFC oscillations and slower reaction times during conflict. In order to test whether theta band coherence between the mPFC and the STN underlies adjustments to conflict and to errors, we simultaneously recorded mPFC and STN electrophysiological activity while DBS patients performed an arrowed flanker task. These recordings revealed higher theta phase coherence between the two sites during the high conflict trials relative to the low conflict trials. These differences were observed soon after conflicting arrows were displayed, but before a response was executed. Furthermore, trials that occurred after an error was committed showed higher phase coherence relative to trials that followed a correct trial, suggesting that mPFC-STN connectivity may also play a role in error related adjustments in behavior. Interestingly, the phase coherence we observed occurred before increases in theta power, implying that the theta phase and power may influence behavior at separate times during cortical monitoring. Finally, we showed that pre-stimulus differences in STN theta power were related to the reaction time on a given trial, which may help adjust behavior based on the probability of observing conflict during a task.

Human subthalamic nucleus in movement error detection and its evaluation during visuomotor adaptation.

Monitoring and evaluating movement errors to guide subsequent movements is a critical feature of normal motor control. Previously, we showed that the postmovement increase in electroencephalographic (EEG) beta power over the sensorimotor cortex reflects neural processes that evaluate motor errors consistent with Bayesian inference (Tan et al., 2014). Whether such neural processes are limited to this cortical region or involve the basal ganglia is unclear. Here, we recorded EEG over the cortex and local field potential (LFP) activity in the subthalamic nucleus (STN) from electrodes implanted in patients with Parkinson's disease, while they moved a joystick-controlled cursor to visual targets displayed on a computer screen. After movement offsets, we found increased beta activity in both local STN LFP and sensorimotor cortical EEG and in the coupling between the two, which was affected by both error magnitude and its contextual saliency. The postmovement increase in the coupling between STN and cortex was dominated by information flow from sensorimotor cortex to STN. However, an information drive appeared from STN to sensorimotor cortex in the first phase of the adaptation, when a constant rotation was applied between joystick inputs and cursor outputs. The strength of the STN to cortex drive correlated with the degree of adaption achieved across subjects. These results suggest that oscillatory activity in the beta band may dynamically couple the sensorimotor cortex and basal ganglia after movements. In particular, beta activity driven from the STN to cortex indicates task-relevant movement errors, information that may be important in modifying subsequent motor responses.

Midline frontal cortex low-frequency activity drives subthalamic nucleus oscillations during conflict.

Making the right decision from conflicting information takes time. Recent computational, electrophysiological, and clinical studies have implicated two brain areas as being crucial in assuring sufficient time is taken for decision-making under conditions of conflict: the medial prefrontal cortex and the subthalamic nucleus (STN). Both structures exhibit an elevation of activity at low frequencies (<10 Hz) during conflict that correlates with the amount of time taken to respond. This suggests that the two sites could become functionally coupled during conflict. To establish the nature of this interaction we recorded from deep-brain stimulation electrodes implanted bilaterally in the STN of 13 Parkinson's disease patients while they performed a sensory integration task involving randomly moving dots. By gradually increasing the number of dots moving coherently in one direction, we were able to determine changes in the STN associated with response execution. Furthermore, by occasionally having 10% of the dots move in the opposite direction as the majority, we were able to identify an independent increase in STN theta-delta activity triggered by conflict. Crucially, simultaneous midline frontal electroencephalographic recordings revealed an increase in the theta-delta band coherence between the two structures that was specific to high-conflict trials. Activity over the midline frontal cortex was Granger causal to that in STN. These results establish the cortico-subcortical circuit enabling successful choices to be made under conditions of conflict and provide support for the hypothesis that the brain uses frequency-specific channels of communication to convey behaviorally relevant information.

The subthalamic nucleus, oscillations, and conflict.

The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation (DBS) for Parkinson's disease (PD), has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article, we highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential among this evidence has been the reported effect of STN DBS in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patients' everyday lives remains uncertain.

Subthalamic nucleus local field potential activity during the Eriksen flanker task reveals a novel role for theta phase during conflict monitoring.

The subthalamic nucleus (STN) is thought to play a central role in modulating responses during conflict. Computational models have suggested that the location of the STN in the basal ganglia, as well as its numerous connections to conflict-related cortical structures, allows it to be ideally situated to act as a global inhibitor during conflict. Additionally, recent behavioral experiments have shown that deep brain stimulation to the STN results in impulsivity during high-conflict situations. However, the precise mechanisms that mediate the "hold-your-horses" function of the STN remain unclear. We recorded from deep brain stimulation electrodes implanted bilaterally in the STN of 13 human subjects with Parkinson's disease while they performed a flanker task. The incongruent trials with the shortest reaction times showed no behavioral or electrophysiological differences from congruent trials, suggesting that the distracter stimuli were successfully ignored. In these trials, cue-locked STN theta band activity demonstrated phase alignment across trials and was followed by a periresponse increase in theta power. In contrast, incongruent trials with longer reaction times demonstrated a relative reduction in theta phase alignment followed by higher theta power. Theta phase alignment negatively correlated with subject reaction time, and theta power positively correlated with trial reaction time. Thus, when conflicting stimuli are not properly ignored, disruption of STN theta phase alignment may help operationalize the hold-your-horses role of the nucleus, whereas later increases in the amplitude of theta oscillations may help overcome this function.

Adaptive deep brain stimulation in advanced Parkinson disease.

OBJECTIVE: Brain-computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof-of-principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS. METHODS: We tested BCI-controlled adaptive DBS (aDBS) of the subthalamic nucleus in 8 PD patients. Feedback was provided by processing of the local field potentials recorded directly from the stimulation electrodes. The results were compared to no stimulation, conventional continuous stimulation (cDBS), and random intermittent stimulation. Both unblinded and blinded clinical assessments of motor effect were performed using the Unified Parkinson's Disease Rating Scale. RESULTS: Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p = 0.03) and 27% (p = 0.005) better than cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time compared to cDBS, and a corresponding reduction in energy requirements (p < 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation. INTERPRETATION: BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD.

Electrophysiologic Mapping for Target Acquisition in Deep Brain Stimulation May Become Unnecessary in the Era of Intraoperative Imaging.

OBJECTIVE: Electrophysiologic mapping (EM) has been instrumental in advancing neuroscience and ensuring accurate lead placement for deep brain stimulation. However, EM is associated with increased operative time, expense, and potential risk. Intraoperative imaging to verify lead placement provides an opportunity to reassess the clinical role of EM. We investigated whether EM 1) provides new information that corrects suboptimal preoperative target selection by the physician or 2) simply corrects intraoperative stereotactic error, which can instead be quickly corrected with intraoperative imaging. METHODS: Deep brain stimulation lead location errors were evaluated by measuring whether repositioning leads based on EM directed the final lead placement 1) away from or 2) toward the original target. We retrospectively identified 50 patients with 61 leads that required repositioning directed by EM. The stereotactic coordinates of each lead were determined with intraoperative computed tomography. RESULTS: In 45 of 61 leads (74%), the electrophysiologically directed repositioning moved the lead toward the initial target. The mean radial errors between the preoperative plan and targeted contact coordinates before and after repositioning were 2.2 and 1.5 mm, respectively (P < 0.001). Microelectrode recording was more likely than test stimulation to direct leads toward the initial target (88% vs. 63%; P = 0.03). The nucleus targeted was associated with the likelihood of moving toward the initial target. CONCLUSIONS: Electrophysiologic mapping corrected primarily for errors in lead placement rather than providing new information regarding errors in target selection. Thus, intraoperative imaging and improvements in stereotactic techniques may reduce or even eliminate dependence on EM.

Doing More with Less: A Minimally Invasive, Cost-Conscious Approach to Stereoelectroencephalography.

BACKGROUND: Stereoelectroencephalography (SEEG) is a commonly used technique for mapping the epileptogenic zone before epilepsy surgery. Many SEEG depth electrode implantation techniques involve the use of extensive technological equipment and shaving of the patient's entire head before electrode implantation. Our goal was to evaluate an SEEG depth electrode implantation technique that used readily available cost-effective neurosurgical equipment, was minimally invasive in nature, and required negligible hair shaving. METHODS: Data on demographic characteristics, operative time, hemorrhagic complications, implantation complications, infection, morbidity, and mortality among patients who underwent this procedure were reviewed retrospectively. RESULTS: Between April 2016 and March 2018, 23 patients underwent implantation of 213 depth electrodes with use of this technique. Mean (SD) operative time was 123 (32) minutes (range, 66-181 minutes). A mean (SD) of 9.3 (1.4) electrodes were placed for each patient (range, 8-13 electrodes). Two of the 213 electrodes (0.9%) were associated with postimplantation asymptomatic hemorrhage. One of the 213 electrodes (0.5%) was placed extradurally or incorrectly. None of the 213 electrodes was associated with symptomatic complications. No patients experienced infectious complications at any point in the preoperative, perioperative, or postoperative stages. CONCLUSIONS: This minimally invasive, cost-effective technique for SEEG depth electrode implantation is a safe, efficient method that uses readily available basic neurosurgical equipment. This technique may be useful in neurosurgery centers with more limited resources. This study suggests that leaving the patient's hair largely intact throughout the procedure does not pose an additional infection risk.

Human subthalamic nucleus activity during non-motor decision making.

Recent studies have implicated the subthalamic nucleus (STN) in decisions that involve inhibiting movements. Many of the decisions that we make in our daily lives, however, do not involve any motor actions. We studied non-motor decision making by recording intraoperative STN and prefrontal cortex (PFC) electrophysiology as participants perform a novel task that required them to decide whether to encode items into working memory. During all encoding trials, beta band (15-30 Hz) activity decreased in the STN and PFC, and this decrease was progressively enhanced as more items were stored into working memory. Crucially, the STN and lateral PFC beta decrease was significantly attenuated during the trials in which participants were instructed not to encode the presented stimulus. These changes were associated with increase lateral PFC-STN coherence and altered STN neuronal spiking. Our results shed light on why states of altered basal ganglia activity disrupt both motor function and cognition.

Neural Correlates of Decision Thresholds in the Human Subthalamic Nucleus.

If humans are faced with difficult choices when making decisions, the ability to slow down responses becomes critical in order to avoid suboptimal choices. Current models of decision making assume that the subthalamic nucleus (STN) mediates this function by elevating decision thresholds, thereby requiring more evidence to be accumulated before responding [1-9]. However, direct electrophysiological evidence for the exact role of STN during adjustment of decision thresholds is lacking. Here, we show that trial-by-trial variations in STN low-frequency oscillatory activity predict adjustments of decision thresholds before subjects make a response. The relationship between STN activity and decision thresholds critically depends on the subjects' level of cautiousness. While increased oscillatory activity of the STN predicts elevated decision thresholds during high levels of cautiousness, it predicts decreased decision thresholds during low levels of cautiousness. This context-dependent relationship may be mediated by increased influence of the medial prefrontal cortex (mPFC)-STN pathway on decision thresholds during high cautiousness. Subjects who exhibit a stronger increase in phase alignment of low-frequency oscillatory activity in mPFC and STN before making a response have higher decision thresholds and commit fewer erroneous responses. Together, our results demonstrate that STN low-frequency oscillatory activity and corresponding mPFC-STN coupling are involved in determining how much evidence subjects accumulate before making a decision. This finding might explain why deep-brain stimulation of the STN can impair subjects' ability to slow down responses and can induce impulsive suboptimal decisions.

Activity-dependent long-term depression of electrical synapses.

Use-dependent forms of synaptic plasticity have been extensively characterized at chemical synapses, but a relationship between natural activity and strength at electrical synapses remains elusive. The thalamic reticular nucleus (TRN), a brain area rich in gap-junctional (electrical) synapses, regulates cortical attention to the sensory surround and participates in shifts between arousal states; plasticity of electrical synapses may be a key mechanism underlying these processes. We observed long-term depression resulting from coordinated burst firing in pairs of coupled TRN neurons. Changes in gap-junctional communication were asymmetrical, indicating that regulation of connectivity depends on the direction of use. Modification of electrical synapses resulting from activity in coupled neurons is likely to be a widespread and powerful mechanism for dynamic reorganization of electrically coupled neuronal networks.