Neuronal activation sequences in lateral prefrontal cortex encode visuospatial working memory during virtual navigation.

Working memory (WM) is the ability to maintain and manipulate information 'in mind'. The neural codes underlying WM have been a matter of debate. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of male macaque monkeys during a visuospatial WM task that required navigation in a virtual 3D environment. Here, we demonstrate distinct neuronal activation sequences (NASs) that encode remembered target locations in the virtual environment. This NAS code outperformed the persistent firing code for remembered locations during the virtual reality task, but not during a classical WM task using stationary stimuli and constraining eye movements. Finally, blocking NMDA receptors using low doses of ketamine deteriorated the NAS code and behavioral performance selectively during the WM task. These results reveal the versatility and adaptability of neural codes supporting working memory function in the primate lateral prefrontal cortex.

A Systematic Review of Neurophysiology-Based Localization Techniques Used in Deep Brain Stimulation Surgery of the Subthalamic Nucleus.

OBJECTIVE: This systematic review is conducted to identify, compare, and analyze neurophysiological feature selection, extraction, and classification to provide a comprehensive reference on neurophysiology-based subthalamic nucleus (STN) localization. MATERIALS AND METHODS: The review was carried out using the methods and guidelines of the Kitchenham systematic review and provides an in-depth analysis on methods proposed on STN localization discussed in the literature between 2000 and 2021. Three research questions were formulated, and 115 publications were identified to answer the questions. RESULTS: The three research questions formulated are answered using the literature found on the respective topics. This review discussed the technologies used in past research, and the performance of the state-of-the-art techniques is also reviewed. CONCLUSION: This systematic review provides a comprehensive reference on neurophysiology-based STN localization by reviewing the research questions other new researchers may also have.

Intracortical brain-computer interfaces in primates: a review and outlook.

Brain-computer interfaces (BCI) translate brain signals into artificial output to restore or replace natural central nervous system (CNS) functions. Multiple processes, including sensorimotor integration, decision-making, motor planning, execution, and updating, are involved in any movement. For example, a BCI may be better able to restore naturalistic motor behaviors if it uses signals from multiple brain areas and decodes natural behaviors' cognitive and motor aspects. This review provides an overview of the preliminary information necessary to plan a BCI project focusing on intracortical implants in primates. Since the brain structure and areas of non-human primates (NHP) are similar to humans, exploring the result of NHP studies will eventually benefit human BCI studies. The different types of BCI systems based on the target cortical area, types of signals, and decoding methods will be discussed. In addition, various successful state-of-the-art cases will be reviewed in more detail, focusing on the general algorithm followed in the real-time system. Finally, an outlook for improving the current BCI research studies will be debated.

Volitional control of beta activities in Parkinson's disease patients.

Patients diagnosed with Parkinson's disease (PD) have difficulty initiating and executing movements due to an acquired imbalance of the basal ganglia thalamocortical circuit secondary to loss of dopaminergic input into the striatum. The unbalanced circuit is hyper-synchronized, presenting as larger and longer bursts of beta-band (13-30 Hz) oscillations in the subthalamic nucleus (STN). As a first step toward a novel PD therapy that aims to improve symptoms through beta desynchronization, we sought to determine if individuals with PD could acquire volitional control of STN beta power in a neurofeedback task. We found a significant difference in STN beta power between task conditions, and relevant brain signal features could be detected and decoded in real time. This demonstration of volitional control of STN beta motivates development of a neurofeedback therapy to modulate PD symptom severity.

Ensembles code for associative learning in the primate lateral prefrontal cortex.

The lateral prefrontal cortex (LPFC) of primates is thought to play a role in associative learning. However, it remains unclear how LPFC neuronal ensembles dynamically encode and store memories for arbitrary stimulus-response associations. We recorded the activity of neurons in LPFC of two macaques during an associative learning task using multielectrode arrays. During task trials, the color of a symbolic cue indicated the location of one of two possible targets for a saccade. During a trial block, multiple randomly chosen associations were learned by the subjects. A state-space analysis indicated that LPFC neuronal ensembles rapidly learn new stimulus-response associations mirroring the animals' learning. Multiple associations acquired during training are stored in a neuronal subspace and can be retrieved hours after learning. Finally, knowledge of old associations facilitates learning new, similar associations. These results indicate that neuronal ensembles in the primate LPFC provide a flexible and dynamic substrate for associative learning.

View cells in the hippocampus and prefrontal cortex of macaques during virtual navigation.

Cells selectively activated by a particular view of an environment have been found in the primate hippocampus (HPC). Whether view cells are present in other brain areas, and how view selectivity interacts with other variables such as object features and place remain unclear. Here, we explore these issues by recording the responses of neurons in the HPC and the lateral prefrontal cortex (LPFC) of rhesus macaques performing a task in which they learn new context-object associations while navigating a virtual environment using a joystick. We measured neuronal responses at different locations in a virtual maze where animals freely directed gaze to different regions of the visual scenes. We show that specific views containing task relevant objects selectively activated a proportion of HPC units, and an even higher proportion of LPFC units. Place selectivity was scarce and generally dependent on view. Many view cells were not affected by changing the object color or the context cue, two task relevant features. However, a small proportion of view cells showed selectivity for these two features. Our results show that during navigation in a virtual environment with complex and dynamic visual stimuli, view cells are found in both the HPC and the LPFC. View cells may have developed as a multiarea specialization in diurnal primates to encode the complexities and layouts of the environment through gaze exploration which ultimately enables building cognitive maps of space that guide navigation.

Decoding spatial locations from primate lateral prefrontal cortex neural activity during virtual navigation.

Objective. Decoding the intended trajectories from brain signals using a brain-computer interface system could be used to improve the mobility of patients with disabilities.Approach. Neuronal activity associated with spatial locations was examined while macaques performed a navigation task within a virtual environment.Main results.Here, we provide proof of principle that multi-unit spiking activity recorded from the lateral prefrontal cortex (LPFC) of non-human primates can be used to predict the location of a subject in a virtual maze during a navigation task. The spatial positions within the maze that require a choice or are associated with relevant task events can be better predicted than the locations where no relevant events occur. Importantly, within a task epoch of a single trial, multiple locations along the maze can be independently identified using a support vector machine model.Significance. Considering that the LPFC of macaques and humans share similar properties, our results suggest that this area could be a valuable implant location for an intracortical brain-computer interface system used for spatial navigation in patients with disabilities.

Stable Working Memory and Perceptual Representations in Macaque Lateral Prefrontal Cortex during Naturalistic Vision.

Primates use perceptual and mnemonic visuospatial representations to perform everyday functions. Neurons in the lateral prefrontal cortex (LPFC) have been shown to encode both of these representations during tasks where eye movements are strictly controlled and visual stimuli are reduced in complexity. This raises the question of whether perceptual and mnemonic representations encoded by LPFC neurons remain robust during naturalistic vision-in the presence of a rich visual scenery and during eye movements. Here we investigate this issue by training macaque monkeys to perform working memory and perception tasks in a visually complex virtual environment that requires navigation using a joystick and allows for free visual exploration of the scene. We recorded the activity of 3950 neurons in the LPFC (areas 8a and 9/46) of two male rhesus macaques using multielectrode arrays, and measured eye movements using video tracking. We found that navigation trajectories to target locations and eye movement behavior differed between the perception and working memory tasks, suggesting that animals used different behavioral strategies. Single neurons were tuned to target location during cue encoding and working memory delay, and neural ensemble activity was predictive of the behavior of the animals. Neural decoding of the target location was stable throughout the working memory delay epoch. However, neural representations of similar target locations differed between the working memory and perception tasks. These findings indicate that during naturalistic vision, LPFC neurons maintain robust and distinct neural codes for mnemonic and perceptual visuospatial representations.SIGNIFICANCE STATEMENT We show that lateral prefrontal cortex neurons encode working memory and perceptual representations during a naturalistic task set in a virtual environment. We show that despite eye movement and complex visual input, neurons maintain robust working memory representations of space, which are distinct from neuronal representations for perception. We further provide novel insight into the use of virtual environments to construct behavioral tasks for electrophysiological experiments.

Deep brain stimulation for Parkinson's Disease: A Review and Future Outlook.

Parkinson's Disease (PD) is a neurodegenerative disorder that manifests as an impairment of motor and non-motor abilities due to a loss of dopamine input to deep brain structures. While there is presently no cure for PD, a variety of pharmacological and surgical therapeutic interventions have been developed to manage PD symptoms. This review explores the past, present and future outlooks of PD treatment, with particular attention paid to deep brain stimulation (DBS), the surgical procedure to deliver DBS, and its limitations. Finally, our group's efforts with respect to brain mapping for DBS targeting will be discussed.

Distinct neural codes in primate hippocampus and lateral prefrontal cortex during associative learning in virtual environments.

The hippocampus (HPC) and the lateral prefrontal cortex (LPFC) are two cortical areas of the primate brain deemed essential to cognition. Here, we hypothesized that the codes mediating neuronal communication in the HPC and LPFC microcircuits have distinctively evolved to serve plasticity and memory function at different spatiotemporal scales. We used a virtual reality task in which animals selected one of the two targets in the arms of the maze, according to a learned context-color rule. Our results show that during associative learning, HPC principal cells concentrate spikes in bursts, enabling temporal summation and fast synaptic plasticity in small populations of neurons and ultimately facilitating rapid encoding of associative memories. On the other hand, layer II/III LPFC pyramidal cells fire spikes more sparsely distributed over time. The latter would facilitate broadcasting of signals loaded in short-term memory across neuronal populations without necessarily triggering fast synaptic plasticity.

Decoding Saccade Intention From Primate Prefrontal Cortical Local Field Potentials Using Spectral, Spatial, and Temporal Dimensionality Reduction.

Most invasive Brain Computer Interfaces (iBCIs) use spike and Local Field Potentials (LFPs) from the motor or parietal cortices to decode movement intentions. It has been debated whether harvesting signals from other brain areas that encode global cognitive variables, such as the allocation of attention and eye movement goals in a variety of spatial reference frames, may improve the outcome of iBCIs. Here, we explore the ability of LFP signals, sampled from the lateral prefrontal cortex (LPFC) of macaque monkeys, to encode eye-movement intention during the pre-movement fixation period of a delayed saccade task. We use spectral dimensionality reduction to examine the spatiotemporal properties of the extracted non-rhythmic broadband activity and explore its usefulness in decoding saccade goals. The dynamics of the broadband signal in low spatial dimensions across the pre-movement fixation period uncovered saccade target separation; its discriminative potential was confirmed using support vector machine classifications. These findings reveal that broadband LFP from the LPFC can be used to decode intended saccade target location during pre-movement periods. We further provide a general workflow that can be implemented in iBCIs and it is relatively robust to the loss of spikes in individual electrodes.

Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks.

Ketamine is a dissociative anesthetic drug, which has more recently emerged as a rapid-acting antidepressant. When acutely administered at subanesthetic doses, ketamine causes cognitive deficits like those observed in patients with schizophrenia, including impaired working memory. Although these effects have been linked to ketamine's action as an N-methyl-D-aspartate receptor antagonist, it is unclear how synaptic alterations translate into changes in brain microcircuit function that ultimately influence cognition. Here, we administered ketamine to rhesus monkeys during a spatial working memory task set in a naturalistic virtual environment. Ketamine induced transient working memory deficits while sparing perceptual and motor skills. Working memory deficits were accompanied by decreased responses of fast spiking inhibitory interneurons and increased responses of broad spiking excitatory neurons in the lateral prefrontal cortex. This translated into a decrease in neuronal tuning and information encoded by neuronal populations about remembered locations. Our results demonstrate that ketamine differentially affects neuronal types in the neocortex; thus, it perturbs the excitation inhibition balance within prefrontal microcircuits and ultimately leads to selective working memory deficits.

Scale-Free Analysis of Intraoperative ECoG During Awake Craniotomy for Glioma.

BACKGROUND: Electrocorticography (ECoG) has been utilized in many epilepsy cases however, the use of this technique for evaluating electrophysiological changes within tumoral zones is spare. Nonetheless, epileptic activities seem to arise from the neocortex surrounding the gliomas suggesting a link between epileptogenesis and glioma cell infiltration in the peritumoral area. The purpose of this study was to implement novel scale-free measures to assess how cortical physiology is altered by the presence of an invasive brain tumor. METHODS: Twelve patients undergoing an awake craniotomy for resection of a supratentorial glioma were included. ECoG data over the main tumor and the exposed surroundings was acquired intra-operatively just prior to tumor resection. Six of the patients presented with seizures and had data acquired both in the awake and anesthetic state. The corresponding anatomical location of each electrode in relation to the macroscopically-detectable tumor was recorded using the neuronavigation system based on structural anatomical images obtained pre-operatively. The electrodes were classified into tumoral, healthy or peritumoral based on the macroscopically detectable tumoral tissue from the pre-operative structural MRI. RESULTS: The electrodes overlying the tumoral tissue revealed higher power law exponent (PLE) values across tumoral area compared to the surrounding tissues. The difference between the awake and anesthetic states was significant in the tumoral and healthy tissue (p < 0.05) but not in the peritumoral tissue. The absence of a significant PLE reduction in the peritumoral tissue from the anesthetic to the awake state could be considered as an index of the presence or absence of infiltration of tumor cells into the peritumoral tissue. CONCLUSIONS: The current study portrays for the first time distinct power law exponent features in the tumoral tissue, which could provide a potential novel electrophysiological marker in the future. The distinct features seen in the peritumoral tissue of gliomas seem to indicate the area where both the onset of epileptiform activity and the tumor infiltration take place.

A Normalization Circuit Underlying Coding of Spatial Attention in Primate Lateral Prefrontal Cortex.

Lateral prefrontal cortex (LPFC) neurons signal the allocation of voluntary attention; however, the neural computations underlying this function remain unknown. To investigate this, we recorded from neuronal ensembles in the LPFC of two Macaca fascicularis performing a visuospatial attention task. LPFC neural responses to a single stimulus were normalized when additional stimuli/distracters appeared across the visual field and were well-characterized by an averaging computation. Deploying attention toward an individual stimulus surrounded by distracters shifted neural activity from an averaging regime toward a regime similar to that when the attended stimulus was presented in isolation (winner-take-all; WTA). However, attentional modulation is both qualitatively and quantitatively dependent on a neuron's visuospatial tuning. Our results show that during attentive vision, LPFC neuronal ensemble activity can be robustly read out by downstream areas to generate motor commands, and/or fed back into sensory areas to filter out distracter signals in favor of target signals.

The Effects of Methylphenidate (Ritalin) on the Neurophysiology of the Monkey Caudal Prefrontal Cortex.

Methylphenidate (MPH), commonly known as Ritalin, is the most widely prescribed drug worldwide to treat patients with attention deficit disorders. Although MPH is thought to modulate catecholamine neurotransmission in the brain, it remains unclear how these neurochemical effects influence neuronal activity and lead to attentional enhancements. Studies in rodents overwhelmingly point to the lateral prefrontal cortex (LPFC) as a main site of action of MPH. To understand the mechanism of action of MPH in a primate brain, we recorded the responses of neuronal populations using chronic multielectrode arrays implanted in the caudal LPFC of two macaque monkeys while the animals performed an attention task (N = 2811 neuronal recordings). Over different recording sessions (N = 55), we orally administered either various doses of MPH or a placebo to the animals. Behavioral analyses revealed positive effects of MPH on task performance at specific doses. However, analyses of individual neurons activity, noise correlations, and neuronal ensemble activity using machine learning algorithms revealed no effects of MPH. Our results suggest that the positive behavioral effects of MPH observed in primates (including humans) may not be mediated by changes in the activity of caudal LPFC neurons. MPH may enhance cognitive performance by modulating neuronal activity in other regions of the attentional network in the primate brain.

Realtime phase-amplitude coupling analysis of micro electrode recorded brain signals.

OBJECTIVE: To demonstrate a method to calculate phase amplitude coupling (PAC) quickly and robustly for realtime applications. METHODS: We designed and implemented a multirate PAC algorithm with efficient filter bank processing and efficient computation of PAC for many frequency-pair combinations. We tested the developed algorithm for computing PAC on simulated data and on intraoperative neural recording data obtained during deep brain stimulation (DBS) electrode implantation surgery. RESULTS: A combination of parallelized frequency-domain filtering and modulation index for PAC estimation provided robust results that could be calculated in real time on modest computing hardware. CONCLUSION: The standard methods for calculating PAC can be optimized for quick and robust performance. SIGNIFICANCE: These results demonstrated that PAC can be extracted in real time and is suitable for neurofeedback applications.

Use of 3D Navigation in Subaxial Cervical Spine Lateral Mass Screw Insertion.

Objective Cervical spine can be stabilized by different techniques. One of the common techniques used is the lateral mass screws (LMSs), which can be inserted either by freehand techniques or three-dimensional (3D) navigation system. The purpose of this study is to evaluate the difference between the 3D navigation system and the freehand technique for cervical spine LMS placement in terms of complications. Including intraoperative complications (vertebral artery injury [VAI], nerve root injury [NRI], spinal cord injury [SCI], lateral mass fracture [LMF]) and postoperative complications (screw malposition, screw complications). Methods Patients who had LMS fixation for their subaxial cervical spine from January 2014 to April 2015 at the Ottawa Hospital were included. A total of 284 subaxial cervical LMS were inserted in 40 consecutive patients. Surgical indications were cervical myelopathy and fractures. The screws' size was 3.5 mm in diameter and 8 to 16 mm in length. During the insertion of the subaxial cervical LMS, the 3D navigation system was used for 20 patients, and the freehand technique was used for the remaining 20 patients. We reviewed the charts, X-rays, computed tomography (CT) scans, and follow-up notes for all the patients pre- and postoperatively. Results Postoperative assessment showed that the incidence of VAI, SCI, and NRI were the same between the two groups. The CT scan analysis showed that the screw breakage, screw pull-outs, and screw loosening were the same between the two groups. LMF was less in the 3D navigation group but statistically insignificant. Screw malposition was less in the 3D navigation group compared with the freehand group and was statistically significant. The hospital stay, operative time, and blood loss were statistically insignificant between the two groups. Conclusions The use of CT-based navigation in LMS insertion decreased the rate of screw malpositions as compared with the freehand technique. Further investigations and trials will determine the effect of malpositions on the c-spine biomechanics. The use of navigation in LMS insertion did not show a significant difference in VAI, LMF, SCI, or NRI as compared with the freehand technique.

A Quadrantic Bias in Prefrontal Representation of Visual-Mnemonic Space.

Single neurons in primate dorsolateral prefrontal cortex (dLPFC) are known to encode working memory (WM) representations of visual space. Psychophysical studies have shown that the horizontal and vertical meridians of the visual field can bias spatial information maintained in WM. However, most studies and models have tacitly assumed that dLPFC neurons represent mnemonic space homogenously. The anatomical organization of these representations has also eluded clear parametric description. We investigated these issues by recording from neuronal ensembles in macaque dLPFC with microelectrode arrays while subjects performed an oculomotor delayed-response task. We found that spatial WM representations in macaque dLPFC are biased by the vertical and horizontal meridians of the visual field, dividing mnemonic space into quadrants. This bias is reflected in single neuron firing rates, neuronal ensemble representations, the spike count correlation structure, and eye movement patterns. We also found that dLPFC representations of mnemonic space cluster anatomically in a nonretinotopic manner that partially reflects the organization of visual space. These results provide an explanation for known WM biases, and reveal novel principles of WM representation in prefrontal neuronal ensembles and across the cortical surface, as well as the need to reconceptualize models of WM to accommodate the observed representational biases.