Integration of valence and conflict processing through cellular-field interactions in human subgenual cingulate during emotional face processing in treatment-resistant depression.

The subgenual anterior cingulate cortex (sgACC) has been identified as a key brain area involved in various cognitive and emotional processes. While the sgACC has been implicated in both emotional valuation and emotional conflict monitoring, it is still unclear how this area integrates multiple functions. We characterized both single neuron and local field oscillatory activity in 14 patients undergoing sgACC deep brain stimulation for treatment-resistant depression. During recording, patients were presented with a modified Stroop task containing emotional face images that varied in valence and congruence. We further analyzed spike-field interactions to understand how network dynamics influence single neuron activity in this area. Most single neurons responded to both valence and congruence, revealing that sgACC neuronal activity can encode multiple processes within the same task, indicative of multifunctionality. During peak neuronal response, we observed increased spectral power in low frequency oscillations, including theta-band synchronization (4-8 Hz), as well as desynchronization in beta-band frequencies (13-30 Hz). Theta activity was modulated by current trial congruency with greater increases in spectral power following non-congruent stimuli, while beta desynchronizations occurred regardless of emotional valence. Spike-field interactions revealed that local sgACC spiking was phase-locked most prominently to the beta band, whereas phase-locking to the theta band occurred in fewer neurons overall but was modulated more strongly for neurons that were responsive to task. Our findings provide the first direct evidence of spike-field interactions relating to emotional cognitive processing in the human sgACC. Furthermore, we directly related theta oscillatory dynamics in human sgACC to current trial congruency, demonstrating it as an important regulator during conflict detection. Our data endorse the sgACC as an integrative hub for cognitive emotional processing through modulation of beta and theta network activity.

Optimization of an anatomically and electrically detailed rodent subthalamic nucleus neuron model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease, but its mechanisms of action remain unclear. Detailed multicompartment computational models of STN neurons are often used to study how DBS electric fields modulate the neurons. However, currently available STN neuron models have some limitations in their biophysical realism. In turn, the goal of this study was to update a detailed rodent STN neuron model originally developed by Gillies and Willshaw in 2006. Our design requirements consisted of explicitly representing an axon connected to the neuron and updating the ion channel distributions based on the experimental literature to match established electrophysiological features of rodent STN neurons. We found that adding an axon to the STN neuron model substantially altered its firing characteristics. We then used a genetic algorithm to optimize biophysical parameters of the model. The updated model exhibited spontaneous firing, action potential shape, hyperpolarization response, and frequency-current curve that aligned well with experimental recordings from STN neurons. Subsequently, we evaluated the general compatibility of the updated biophysics by applying them to 26 different STN neuron morphologies derived from three-dimensional anatomical reconstructions. The different morphologies affected the firing behavior of the model, but the updated biophysics were robustly capable of maintaining the desired electrophysiological features. The new STN neuron model developed in this work offers a valuable tool for studying STN neuron firing properties and may find application in simulating STN local field potentials and analyzing the effects of STN DBS.NEW & NOTEWORTHY This study presents an anatomically and biophysically realistic rodent STN neuron model. The work showcases the use of a genetic algorithm to optimize the model parameters. We noted a substantial influence of the axon on the electrophysiological characteristics of STN neurons. The updated model offers a valuable tool to investigate the firing of STN neurons and their modulation by intrinsic and/or extrinsic factors.

Dissecting deep brain stimulation evoked neural activity in the basal ganglia.

Deep brain stimulation (DBS) is an established therapeutic tool for the treatment of Parkinson's disease (PD). The mechanisms of DBS for PD are likely rooted in modulation of the subthalamo-pallidal network. However, it can be difficult to electrophysiologically interrogate that network in human patients. The recent identification of large amplitude evoked potential (EP) oscillations from DBS in the subthalamic nucleus (STN) or globus pallidus internus (GPi) are providing new scientific opportunities to expand understanding of human basal ganglia network activity. In turn, the goal of this review is to provide a summary of DBS-induced EPs in the basal ganglia and attempt to explain various components of the EP waveforms from their likely network origins. Our analyses suggest that DBS-induced antidromic activation of globus pallidus externus (GPe) is a key driver of these oscillatory EPs, independent of stimulation location (i.e. STN or GPi). This suggests a potentially more important role for GPe in the mechanisms of DBS for PD than typically assumed. And from a practical perspective, DBS EPs are poised to become clinically useful electrophysiological biomarker signals for verification of DBS target engagement.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Role of the volume conductor on simulations of local field potential recordings from deep brain stimulation electrodes.

OBJECTIVE: Local field potential (LFP) recordings from deep brain stimulation (DBS) electrodes are commonly used in research analyses, and are beginning to be used in clinical practice. Computational models of DBS LFPs provide tools for investigating the biophysics and neural synchronization that underlie LFP signals. However, technical standards for DBS LFP model parameterization remain to be established. Therefore, the goal of this study was to evaluate the role of the volume conductor (VC) model complexity on simulated LFP signals in the subthalamic nucleus (STN). APPROACH: We created a detailed human head VC model that explicitly represented the inhomogeneity and anisotropy associated with 12 different tissue structures. This VC model represented our "gold standard" for technical detail and electrical realism. We then incrementally decreased the complexity of the VC model and quantified the impact on the simulated LFP recordings. Identical STN neural source activity was used when comparing the different VC model variants. Results Ignoring tissue anisotropy reduced the simulated LFP amplitude by ~12%, while eliminating soft tissue heterogeneity had a negligible effect on the recordings. Simplification of the VC model to consist of a single homogenous isotropic tissue medium with a conductivity of 0.215 S/m contributed an additional ~3% to the error. SIGNIFICANCE: Highly detailed VC models do generate different results than simplified VC models. However, with errors in the range of ~15%, the use of a well-parameterized simple VC model is likely to be acceptable in most contexts for DBS LFP modeling.

Aperiodic subthalamic activity predicts motor severity and stimulation response in Parkinson disease.

INTRODUCTION: Rhythmic beta activity in the subthalamic nucleus (STN) local field potential (LFP) is associated with Parkinson disease (PD) severity, though not all studies have found this relationship. We investigated whether aperiodic 'noise' elements of LFP, specifically slope of the 1/f broadband, predict PD motor symptoms and outcomes of STN-DBS. METHODS: We studied micro-LFP from 19 PD patients undergoing STN-DBS, relating the aperiodic 1/f slope and the periodic beta oscillation components to motor severity using the UPDRS-III and improvement with DBS at 1 year. RESULTS: Beta power, not 1/f slope, independently predicted baseline UPDRS-III (r = 0.425, p = 0.020; r = -0.434, p = 0.032, respectively), but multiple regression using both predicted better (F (2, 16) = 6.621, p = 0.008, R2 = 0.453). Only multiple regression using both slope and beta power predicted improvement in UPDRS-III at 1 year post-operatively (F (2, 15) = 6.049, R2 = 0.446, p = 0.012). CONCLUSIONS: Both beta synchronization and slope of the 1/f broadband are informative of motor symptoms in PD and predict response to STN-DBS.

Monitoring stimulus-evoked hemodynamic response during deep brain stimulation with single fiber spectroscopy.

Deep brain stimulation (DBS) is a revolutionary treatment for movement disorders. Measuring DBS-induced hemodynamic responses may be useful for surgical guidance of DBS electrode implantation as well as to study the mechanism and assess therapeutic effects of DBS. In this study, we evaluated the performance of a single fiber spectroscopic (SFS) system for measuring hemodynamic response in different cortical layers in a DBS animal model. We showed that SFS is capable of measuring minute relative changes in oxygen saturation and blood volume fraction in-vivo at a sampling rate of 22-33 Hz. During stimulation, blood volume fraction increased, while oxygen saturation showed both increases and decreases at different cortical depths across animals. In addition, we showed the potential of using SFS for measuring other physiological parameters, for example, heart rate, and respiratory rate.

Biophysical characterization of local field potential recordings from directional deep brain stimulation electrodes.

OBJECTIVE: Two major advances in clinical deep brain stimulation (DBS) technology have been the introduction of local field potential (LFP) recording capabilities, and the deployment of directional DBS electrodes. However, these two technologies are not operationally integrated within current clinical DBS devices. Therefore, we evaluated the theoretical advantages of using directional DBS electrodes for LFP recordings, with a focus on measuring beta-band activity in the subthalamic nucleus (STN). METHODS: We used a computational model of human STN neural activity to simulate LFP recordings. The model consisted of 235,280 anatomically and electrically detailed STN neurons surrounding the DBS electrode, which was previously optimized to mimic beta-band synchrony in the dorsolateral STN. We then used that model system to compare LFP recordings from cylindrical and directional DBS contacts, and evaluate how the selection of different contacts for bipolar recording affected the LFP measurements. RESULTS: The model predicted two advantages of directional DBS electrodes over cylindrical DBS electrodes for STN LFP recording. First, recording from directional contacts could provide additional insight on the location of a synchronous volume of neurons within the STN. Second, directional contacts could detect a smaller volume of synchronous neurons than cylindrical contacts, which our simulations predicted to be a ~0.5 mm minimum radius. CONCLUSIONS: STN LFP recordings from 8-contact directional DBS electrodes (28 possible bipolar pairs) can provide more information than 4-contact cylindrical DBS electrodes (6 possible bipolar pairs), but they also introduce additional complexity in analyzing the signals. SIGNIFICANCE: Integration of directional electrodes with DBS systems that are capable of LFP recordings could improve localization of targeted volumes of synchronous neurons in PD patients.

Neurovascular coupling during deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders, yet its mechanisms of action remain unclear. One method used to study its circuit-wide neuromodulatory effects is functional magnetic resonance imaging (fMRI) which measures hemodynamics as a proxy of neural activity. To interpret functional imaging data, we must understand the relationship between neural and vascular responses, which has never been studied with the high frequencies used for DBS. OBJECTIVE: To measure neurovascular coupling in the rat motor cortex during thalamic DBS. METHOD: Simultaneous intrinsic optical imaging and extracellular electrophysiology was performed in the motor cortex of urethane-anesthetized rats during thalamic DBS at 7 different frequencies. We related Maximum Change in Reflectance (MCR) from the imaging data to Integrated Evoked Potential (IEP) and change in broadband power of multi-unit (MU) activity, computing Spearman's correlation to determine the strength of these relationships. To determine the source of these effects, we studied the contributions of antidromic versus orthodromic activation in motor cortex perfusion using synaptic blockers. RESULTS: MCR, IEP and change in MU power increased linearly to 60 Hz and saturated at higher frequencies of stimulation. Blocking orthodromic transmission only reduced the DBS-induced change in optical signal by ∼25%, suggesting that activation of corticofugal fibers have a major contribution in thalamic-induced cortical activation. CONCLUSION: DBS-evoked vascular response is related to both evoked field potentials as well as multi-unit activity.

Long-Lasting Electrophysiological After-Effects of High-Frequency Stimulation in the Globus Pallidus: Human and Rodent Slice Studies.

Deep-brain stimulation (DBS) of the globus pallidus pars interna (GPi) is a highly effective therapy for movement disorders, yet its mechanism of action remains controversial. Inhibition of local neurons because of release of GABA from afferents to the GPi is a proposed mechanism in patients. Yet, high-frequency stimulation (HFS) produces prolonged membrane depolarization mediated by cholinergic neurotransmission in endopeduncular nucleus (EP, GPi equivalent in rodent) neurons. We applied HFS while recording neuronal firing from an adjacent electrode during microelectrode mapping of GPi in awake patients (both male and female) with Parkinson disease (PD) and dystonia. Aside from after-suppression and no change in neuronal firing, high-frequency microstimulation induced after-facilitation in 38% (26/69) of GPi neurons. In neurons displaying after-facilitation, 10 s HFS led to an immediate decrease of bursting in PD, but not dystonia patients. Moreover, the changes of bursting patterns in neurons with after-suppression or no change after HFS, were similar in both patient groups. To explore the mechanisms responsible, we applied HFS in EP brain slices from rats of either sex. As in humans, HFS in EP induced two subtypes of after-excitation: excitation or excitation with late inhibition. Pharmacological experiments determined that the excitation subtype, induced by lower charge density, was dependent on glutamatergic transmission. HFS with higher charge density induced excitation with late inhibition, which involved cholinergic modulation. Therefore HFS with different charge density may affect the local neurons through multiple synaptic mechanisms. The cholinergic system plays a role in mediating the after-facilitatory effects in GPi neurons, and because of their modulatory nature, may provide a basis for both the immediate and delayed effects of GPi-DBS. We propose a new model to explain the mechanisms of DBS in GPi.SIGNIFICANCE STATEMENT Deep-brain stimulation (DBS) in the globus pallidus pars interna (GPi) improves Parkinson disease (PD) and dystonia, yet its mechanisms in GPi remain controversial. Inhibition has been previously described and thought to indicate activation of GABAergic synaptic terminals, which dominate in GPi. Here we report that 10 s high-frequency microstimulation induced after-facilitation of neural firing in a substantial proportion of GPi neurons in humans. The neurons with after-facilitation, also immediately reduced their bursting activities after high-frequency stimulation in PD, but not dystonia patients. Based on these data and further animal experiments, a mechanistic hypothesis involving glutamatergic, GABAergic, and cholinergic synaptic transmission is proposed to explain both short- and longer-term therapeutic effects of DBS in GPi.

Spatiotemporal dynamics of cortical perfusion in response to thalamic deep brain stimulation.

Deep brain stimulation (DBS) has revolutionized the treatment of movement disorders. The parameters of electrical stimulation are important to its therapeutic effect and remain a source of clinical controversy. DBS exerts its actions not only locally at the site of stimulation but also remotely through afferent and efferent connections, which are vital to its clinical effects. Yet, only a few studies have examined how cortical activity changes in response to various electrical parameters. Here, we investigated how the parameters of thalamic DBS alter cortical perfusion in rats using intrinsic optical imaging. We hypothesized that thalamic DBS will increase perfusion in primary motor cortex (M1), proportional to amplitude, pulse width, or frequency of the stimulation applied. We applied 45 different combinations of amplitude, pulse width and frequency in the ventro-lateral (VL) nucleus of the thalamus in anesthetized rats while measuring perfusion in M1. VL thalamic DBS reduced cortical reflectance, which corresponds to an increase in cortical perfusion. We computed the maximum change in reflectance (MCR) as well as the spatial spread of MCR in each trial. Both MCR and spatial spread increased linearly with increases in current amplitude or pulse width of stimulation; however, the effect of frequency was non-linear. Stimulation at 20 Hz was significantly different from that at higher frequencies while stimulation at higher frequencies did not differ significantly from each other. Moreover, the effect of pulse width on MCR was larger than the effect of amplitude. The proportional increase in M1 perfusion due to increase in amplitude or pulse width suggests that both activate more neural elements and increase the volume of tissue activated. These results should help clinicians set parameters of DBS. The use of optical imaging to monitor effects of DBS on M1 may not only help understand DBS mechanisms, but may also provide feedback for closed loop DBS devices.