New horizons in subdural haematoma.

Subdural haematoma (SDH) is a common injury sustained by older people living with frailty and multimorbidity, and typically following falls from a standing height. Anticoagulant and antiplatelet use are commonly indicated in older people with SDH, but few data inform decision-making surrounding these agents in the context of intracranial bleeding. Opposing risks of rebleeding and thrombosis must therefore be weighed judiciously. Decision-making can be complex and requires detailed awareness of the epidemiology to ensure the safest course of action is selected for each patient. Outcomes of surgical decompression in acute SDH are very poor in older people. However, burr hole drainage can be safe and effective in older adults with symptomatic chronic SDH (cSDH). Such patients need careful assessment to ensure symptoms arise from cSDH and not from coexisting medical pathology. Furthermore, the emerging treatment of middle meningeal artery embolisation offers a well-tolerated, minimally invasive intervention which may reduce the risks of rebleeding in older adults. Nonetheless, UK SDH management is heterogenous, and no accepted UK or European guidelines exist at present. Further randomised trial evidence is required to move away from clinical practice based on historic observational data.

Exploring options to strengthen rural health care: comparing the United States of America and United Kingdom.

INTRODUCTION: The USA has long wrestled with the challenges of delivering high quality care to rural areas and has developed an extensive set of policy interventions to support rural providers. The release of the results of a Parliamentary inquiry into rural health and care in the UK provides an opportunity to compare US and UK efforts to support rural health and share lessons learned from the USA. METHODS: This presentation reviews the results of a study of US federal and state policy efforts to support rural providers dating back to the early 1970s. The lessons learned from these efforts can inform the work of the UK as it addresses the recommendations discussed in the February 2022 report from the Parliamentary inquiry. The presentation will review the major recommendations identified in the report and compare US efforts to address similar challenges. RESULTS: The results of the inquiry indicate that the USA and UK share common challenges and inequalities in rural healthcare access. The Inquiry Panel made 12 recommendations for change under four broad headings:Build understanding of the distinctive needs of rural areas;Deliver services suited to the specific needs of rural places;Develop a structural and regulatory framework that fosters adaption and innovation; andDevelop integrated services that provide holistic, person-centered care. DISCUSSION: This presentation will be of interest to policymakers in the USA, the UK, and other countries working to improve rural healthcare systems.

Risk-taking bias in human decision-making is encoded via a right-left brain push-pull system.

A person's decisions vary even when options stay the same, like when a gambler changes bets despite constant odds of winning. Internal bias (e.g., emotion) contributes to this variability and is shaped by past outcomes, yet its neurobiology during decision-making is not well understood. To map neural circuits encoding bias, we administered a gambling task to 10 participants implanted with intracerebral depth electrodes in cortical and subcortical structures. We predicted the variability in betting behavior within and across patients by individual bias, which is estimated through a dynamical model of choice. Our analysis further revealed that high-frequency activity increased in the right hemisphere when participants were biased toward risky bets, while it increased in the left hemisphere when participants were biased away from risky bets. Our findings provide electrophysiological evidence that risk-taking bias is a lateralized push-pull neural system governing counterintuitive and highly variable decision-making in humans.

Improved identification and differentiation from epileptiform activity of human hippocampal sharp wave ripples during NREM sleep.

In rodents, pyramidal cell firing patterns from waking may be replayed in nonrapid eye movement sleep (NREM) sleep during hippocampal sharp wave ripples (HC-SWR). In humans, HC-SWR have only been recorded with electrodes implanted to localize epileptogenicity. Here, we characterize human HC-SWR with rigorous rejection of epileptiform activity, requiring multiple oscillations and coordinated sharp waves. We demonstrated typical SWR in those rare HC recordings which lack interictal epileptiform spikes (IIS) and with no or minimal seizure involvement. These HC-SWR have a similar rate (~12 min-1 on average, variable across NREM stages and anterior/posterior HC) and apparent intra-HC topography (ripple maximum in putative stratum pyramidale, slow wave in radiatum) as rodents, though with lower frequency (~85 Hz compared to ~140 Hz in rodents). Similar SWR are found in HC with IIS, but no significant seizure involvement. These SWR were modulated by behavior, being largely absent (<2 min-1 ) except during NREM sleep in both Stage 2 (~9 min-1 ) and Stage 3 (~15 min-1 ), distinguishing them from IIS. This study quantifies the basic characteristics of a strictly selected sample of SWR recorded in relatively healthy human hippocampi.

An exploratory data analysis method for identifying brain regions and frequencies of interest from large-scale neural recordings.

High-resolution whole brain recordings have the potential to uncover unknown functionality but also present the challenge of how to find such associations between brain and behavior when presented with a large number of regions and spectral frequencies. In this paper, we propose an exploratory data analysis method that sorts through a massive quantity of multivariate neural recordings to quickly extract a subset of brain regions and frequencies that encode behavior. This approach combines existing tools and exploits low-rank approximation of matrices without a priori selection of regions and frequency bands for analysis. In detail, the spectral content of neural activity across all frequencies of each recording contact is computed and represented as a matrix. Then, the rank-1 approximation of the matrix is computed using singular value decomposition and the associated singular vectors are extracted. The temporal singular vector, which captures the salient features of the spectrogram, is then correlated to the trial-varying behavioral signal. The distribution of correlations for each brain region is efficiently computed and used to find a subset of regions and frequency bands of interest for further examination. As an illustration, we apply this approach to a data set of local field potentials collected using stereoelectroencephalography from a human subject performing a reaching task. Using the proposed procedure, we produced a comprehensive set of brain regions and frequencies related to our specific behavior. We demonstrate how this tool can produce preliminary results that capture neural patterns related to behavior and aid in formulating data-driven hypotheses, hence reducing the time it takes for any scientist to transition from the exploratory to the confirmatory phase.

Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study.

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.

Techniques for placement of stereotactic electroencephalographic depth electrodes: Comparison of implantation and tracking accuracies in a cadaveric human study.

OBJECTIVE: Stereotactic electroencephalography (SEEG) is used for the evaluation and identification of the epileptogenic zone (EZ) in patients suffering from medically refractory seizures and relies upon the accurate implantation of depth electrodes. Accurate implantation is critical for identification of the EZ. Multiple electrodes and implantation systems exist, but these have not previously been systematically evaluated for implantation accuracy. This study compares the accuracy of two SEEG electrode implantation methods. METHODS: Thirteen "technique 1" electrodes (applying guiding bolts and external stylets) and 13 "technique 2" electrodes (without guiding bolts and external stylets) were implanted into four cadaver heads (52 total of each) according to each product's instructions for use using a stereotactic robot. Postimplantation computed tomography scans were compared to preimplantation computed tomography scans and to the previously defined targets. Electrode entry and final depth location were measured by Euclidean coordinates. The mean errors of each technique were compared using linear mixed effects models. RESULTS: Primary analysis revealed that the mean error difference of the technique 1 and 2 electrodes at entry and target favored the technique 1 electrode implantation accuracy (P < 0.001). Secondary analysis demonstrated that orthogonal implantation trajectories were more accurate than oblique trajectories at entry for technique 1 electrodes (P = 0.002). Furthermore, deep implantations were significantly less accurate than shallow implantations for technique 2 electrodes (P = 0.005), but not for technique 1 electrodes (P = 0.50). SIGNIFICANCE: Technique 1 displays greater accuracy following SEEG electrode implantation into human cadaver heads. Increased implantation accuracy may lead to increased success in identifying the EZ and increased seizure freedom rates following surgery.

Therapeutic mechanisms of high-frequency stimulation in Parkinson's disease and neural restoration via loop-based reinforcement.

High-frequency deep brain stimulation (HFS) is clinically recognized to treat parkinsonian movement disorders, but its mechanisms remain elusive. Current hypotheses suggest that the therapeutic merit of HFS stems from increasing the regularity of the firing patterns in the basal ganglia (BG). Although this is consistent with experiments in humans and animal models of Parkinsonism, it is unclear how the pattern regularization would originate from HFS. To address this question, we built a computational model of the cortico-BG-thalamo-cortical loop in normal and parkinsonian conditions. We simulated the effects of subthalamic deep brain stimulation both proximally to the stimulation site and distally through orthodromic and antidromic mechanisms for several stimulation frequencies (20-180 Hz) and, correspondingly, we studied the evolution of the firing patterns in the loop. The model closely reproduced experimental evidence for each structure in the loop and showed that neither the proximal effects nor the distal effects individually account for the observed pattern changes, whereas the combined impact of these effects increases with the stimulation frequency and becomes significant for HFS. Perturbations evoked proximally and distally propagate along the loop, rendezvous in the striatum, and, for HFS, positively overlap (reinforcement), thus causing larger poststimulus activation and more regular patterns in striatum. Reinforcement is maximal for the clinically relevant 130-Hz stimulation and restores a more normal activity in the nuclei downstream. These results suggest that reinforcement may be pivotal to achieve pattern regularization and restore the neural activity in the nuclei downstream and may stem from frequency-selective resonant properties of the loop.

Dynamics of Propofol-Induced Loss of Consciousness Across Primate Neocortex.

UNLABELLED: The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. SIGNIFICANCE STATEMENT: How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.

Developing Program Performance Measures for Rural Emergency Medical Services.

BACKGROUND: The development of measures to monitor and evaluate the performance and quality of emergency medical services (EMS) systems has been a focus of attention for many years. The Medicare Rural Hospital Flexibility Program (Flex Program), established by Congress in 1997, provides grants to states to implement initiatives to strengthen rural healthcare delivery systems, including better integration of EMS into those systems of care. OBJECTIVE: Building on national efforts to develop EMS performance measures, we sought to identify measures relevant to the rural communities and hospitals supported by the Flex Program. The measures are intended for use in monitoring rural EMS performance at the community level as well as for use by State Flex Programs and the Federal Office of Rural Health Policy (FORHP) to demonstrate the impact of the Flex Program. METHODS: To evaluate the performance of EMS in rural communities, we conducted a literature search, reviewed research on performance measures conducted by key EMS organizations, and recruited a panel of EMS experts to identify and rate rurally-relevant EMS performance measures as well as emergent protocols for episodes of trauma, ST Elevation Myocardial Infarction (STEMI), and stroke. The rated measures were assessed for inclusion in the final measure set. RESULTS: The Expert Panel identified 17 program performance measures to support EMS services in rural communities. These measures monitor the capacity of local agencies to collect and report quality and financial data, use the data to improve agency performance, and train rural EMS employees in emergent protocols for all age groups. CONCLUSION: The system of care approach on which this rural EMS measures set is based can support the FORHP's goal of better focusing State Flex Program activity to improve program impact on the performance of rural EMS services in the areas of financial viability, quality improvement, and local/regional health system performance.

Report on the International Workshop on Drug Prevention and Treatment in Rural Settings Organized by United Nation Office on Drugs and Crime (UNODC) and World Health Organization (WHO).

Very little evidence has been reported in literature regarding the misuse of substances in rural areas. Despite the common perception of rural communities as a protective and risk-mitigating environment, the scientific literature demonstrated the existence of many risk factors in rural communities. The Drug Prevention and Health Branch (DHB) of the United Nations Office on Drugs and Crime (UNODC), and the World Health Organization (WHO), in June 2016, organized a meeting of experts in treatment and prevention of SUDs in rural settings. The content presented during the meeting and the related discussion have provided materials for the preparation of an outline document, which is the basis to create a technical tool on SUDs prevention and treatment in rural settings. The UNODC framework for interventions in rural settings is a technical tool aimed to assist policy makers and managers at the national level. This paper is a report on UNODC/WHO efforts to improve the clinical conditions of people affected by SUDs and living in rural areas. The purpose of this article is to draw attention on a severe clinical and social problem in a reality forgotten by everyone.

Pain anticipatory phenomena in patients with central poststroke pain: a magnetoencephalography study.

Central poststroke pain (CPSP) is characterized by hemianesthesia associated with unrelenting chronic pain. The final pain experience stems from interactions between sensory, affective, and cognitive components of chronic pain. Hence, managing CPSP will require integrated approaches aimed not only at the sensory but also the affective-cognitive spheres. A better understanding of the brain's processing of pain anticipation is critical for the development of novel therapeutic approaches that target affective-cognitive networks and alleviate pain-related disability. We used magnetoencephalography (MEG) to characterize the neural substrates of pain anticipation in patients suffering from intractable CPSP. Simple visual cues evoked anticipation while patients awaited impending painful (PS), nonpainful (NPS), or no stimulus (NOS) to their nonaffected and affected extremities. MEG responses were studied at gradiometer level using event-related fields analysis and time-frequency oscillatory analysis upon source localization. On the nonaffected side, significantly greater responses were recorded during PS. PS (vs. NPS and NOS) exhibited significant parietal and frontal cortical activations in the beta and gamma bands, respectively, whereas NPS (vs. NOS) displayed greater activation in the orbitofrontal cortex. On the affected extremity, PS (vs. NPS) did not show significantly greater responses. These data suggest that anticipatory phenomena can modulate neural activity when painful stimuli are applied to the nonaffected extremity but not the affected extremity in CPSP patients. This dichotomy may stem from the chronic effects of pain on neural networks leading to habituation or saturation. Future clinically effective therapies will likely be associated with partial normalization of the neurophysiological correlates of pain anticipation.

Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model.

Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of the cerebellar output, a treatment approach that has been shown to improve postischemia motor recovery in a rodent model of cortical infarcts. Long-Evans rats were pretrained on the pasta-matrix retrieval task, followed by induction of focal cortical ischemia and implantation of a macroelectrode in the contralesional lateral cerebellar nucleus. Animals were assigned to one of three treatment groups pseudorandomly to balance severity of poststroke motor deficits: REGULAR stimulation, BURST stimulation, or SHAM. Treatment initiated 2 weeks post surgery and continued for 5 weeks. At the end, animals were randomly selected for perilesional intracortical microstimulation mapping and tissue sampling for Western blot analysis or contributed tissue for 3D electron microscopy. Evidence of enhanced cortical plasticity with therapeutically effective stimulation is shown, marked by greater perilesional reorganization in stimulation- treated animals versus SHAM. BURST stimulation was significantly effective for promoting distal forepaw cortical representation. Stimulation-treated animals showed a twofold increase in synaptic density compared with SHAM. In addition, treated animals demonstrated increased expression of synaptic markers of long-term potentiation and plasticity, including synaptophysin, NMDAR1, CaMKII, and PSD95. These findings provide a critical foundation of how deep cerebellar stimulation may guide plastic reparative reorganization after nonprogressive brain injury and indicate strong translational potential.

Defense-like behaviors evoked by pharmacological disinhibition of the superior colliculus in the primate.

Stimulation of the intermediate and deep layers of superior colliculus (DLSC) in rodents evokes both orienting/pursuit (approach) and avoidance/flight (defense) responses (Dean et al., 1989). These two classes of response are subserved by distinct output projections associated with lateral (approach) and medial (defense) DLSC (Comoli et al., 2012). In non-human primates, DLSC has been examined only with respect to orienting/approach behaviors, especially eye movements, and defense-like behaviors have not been reported. Here we examined the profile of behavioral responses evoked by activation of DLSC by unilateral intracerebral infusions of the GABA(A) receptor antagonist, bicuculline methiodide (BIC), in nine freely moving macaques. Across animals, the most consistently evoked behavior was cowering (all animals), followed by increased vocalization and escape-like behaviors (seven animals), and attack of objects (three animals). The effects of BIC were dose-dependent within the range 2.5-14 nmol (threshold dose of 4.6 nmol). The behaviors and their latencies to onset did not vary across different infusion sites within DLSC. Cowering and escape-like behaviors resembled the defense-like responses reported after DLSC stimulation in rats, but in the macaques these responses were evoked from both medial and lateral sites within DLSC. Our findings are unexpected in the context of an earlier theoretical perspective (Dean et al., 1989) that emphasized a preferential role of the primate DLSC for approach rather than defensive responses. Our data provide the first evidence for induction of defense-like behaviors by activation of DLSC in monkeys, suggesting that the role of DLSC in responding to threats is conserved across species.

Single-neuron responses in the human nucleus accumbens during a financial decision-making task.

Linking values to actions and evaluating expectations relative to outcomes are both central to reinforcement learning and are thought to underlie financial decision-making. However, neurophysiology studies of these processes in humans remain limited. Here, we recorded the activity of single human nucleus accumbens neurons while subjects performed a gambling task. We show that the nucleus accumbens encodes two signals related to subject behavior. First, we find that under relatively predictable conditions, single neuronal activity predicts future financial decisions on a trial-by-trial basis. Interestingly, we show that this activity continues to predict decisions even under conditions of uncertainty (e.g., when the probability of winning or losing is 50/50 and no particular financial choice predicts a rewarding outcome). Furthermore, we find that this activity occurs, on average, 2 s before the subjects physically manifest their decision. Second, we find that the nucleus accumbens encodes the difference between expected and realized outcomes, consistent with a prediction error signal. We show this activity occurs immediately after the subject has realized the outcome of the trial and is present on both the individual and population neuron levels. These results provide human single neuronal evidence that the nucleus accumbens is integral in making financial decisions.

Electrical stimulation-evoked dopamine release in the primate striatum.

BACKGROUND: Primate studies demonstrate that high-frequency electrical stimulation (HFS) of the caudate can enhance learning. Importantly, in these studies, stimulation was applied following the execution of behavior and the effect persisted into subsequent trials, suggesting a change in plasticity rather than a momentary facilitation of behavior. OBJECTIVES/METHODS: Although the mechanism of HFS-enhanced learning is not understood, evidence suggests that dopamine plays a critical role. Therefore, we used in vivo amperometry to evaluate the effects of HFS on striatal dopamine release in the anesthetized primate. While this does not directly examine dopamine during learning, it provides insight with relation to dopamine dynamics during electrical stimulation and specifically between different stimulation parameters and striatal compartments. RESULTS: We demonstrate that HFS results in significantly more dopamine release in the striatum compared to low-frequency stimulation. In addition, electrical stimulation operates differentially on specific neuronal elements, as the parameters for dopamine release are different for the caudate, putamen and medial forebrain bundle. CONCLUSIONS: While not direct evidence, these data suggest that HFS evokes significant dopamine release which may play a role in stimulation-enhanced learning. Moreover, these data suggest a means to modulate extracellular dopamine with a high degree of temporal and spatial precision for either research or clinical applications.

Twenty-five years of the Medicare Rural Hospital Flexibility Program: The past as prologue.

PURPOSE: The Medicare Rural Hospital Flexibility (Flex) Program and the Critical Access Hospital (CAH) provider type are now 25 years old. Since the inception of the program, the needs of CAHs have evolved greatly. This article describes the history of the limited-service hospital model that led to the creation of CAHs, the evolution and impact of the Flex Program on CAHs, and the trends likely to impact CAHs and rural healthcare in the future. It concludes with recommendations to address these future needs. METHODS: This review of the 25-year history of the Flex Program and CAHs is based on a detailed analysis of the literature on the limited-service hospital model and CAHs, the evaluation reports of the Flex Tracking and Flex Monitoring Teams, and the author's 25-year history with the program. FINDINGS: The Flex Program has made important contributions to the viability of rural hospitals through the conversion of 1,360 CAHs. The program has encouraged attention on CAH quality of care and the role of CAHs in addressing the population health needs of their communities. It has further encouraged the development of a robust rural health policy and advocacy infrastructure that has heightened attention on the needs of rural providers and communities. CONCLUSIONS: The needs of CAHs and rural delivery systems have evolved greatly since the implementation of the Flex Program. The 25th anniversary of the program is an ideal time to re-evaluate and update the program to support CAHs in adapting to the fast-changing healthcare environment.

Internal states as a source of subject-dependent movement variability are represented by large-scale brain networks.

Humans' ability to adapt and learn relies on reflecting on past performance. These experiences form latent representations called internal states that induce movement variability that improves how we interact with our environment. Our study uncovered temporal dynamics and neural substrates of two states from ten subjects implanted with intracranial depth electrodes while they performed a goal-directed motor task with physical perturbations. We identified two internal states using state-space models: one tracking past errors and the other past perturbations. These states influenced reaction times and speed errors, revealing how subjects strategize from trial history. Using local field potentials from over 100 brain regions, we found large-scale brain networks such as the dorsal attention and default mode network modulate visuospatial attention based on recent performance and environmental feedback. Notably, these networks were more prominent in higher-performing subjects, emphasizing their role in improving motor performance by regulating movement variability through internal states.

Basal ganglia neurons dynamically facilitate exploration during associative learning.

The basal ganglia (BG) appear to play a prominent role in associative learning, the process of pairing external stimuli with rewarding responses. Accumulating evidence suggests that the contributions of various BG components may be described within a reinforcement learning model, in which a broad repertoire of possible responses to environmental stimuli are evaluated before the most profitable one is chosen. The striatum receives diverse cortical inputs, providing a rich source of contextual information about environmental cues. It also receives projections from midbrain dopaminergic neurons, whose phasic activity reflects a reward prediction error signal. These coincident information streams are well suited for evaluating responses and biasing future actions toward the most profitable response. Still lacking in this model is a mechanistic description of how initial response variability is generated. To investigate this question, we recorded the activity of single neurons in the globus pallidus internus (GPi), the primary BG output nucleus, in nonhuman primates (Macaca mulatta) performing a motor associative learning task. A subset (29%) of GPi neurons showed learning-related effects, decreasing firing during the early stages of learning, then returning to higher baseline rates as associations were mastered. On a trial-by-trial basis, lower firing rates predicted exploratory behavior, whereas higher rates predicted an exploitive response. These results suggest that, during associative learning, BG output is initially permissive, allowing exploration of a variety of responses. Once a profitable response is identified, increased GPi activity suppresses alternative responses, sharpening the response profile and encouraging exploitation of the profitable learned behavior.

Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex.

Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.