A Review of Recent Low-dose Research and Recommendations for Moving Forward.

ABSTRACT: The linear no-threshold (LNT) model has been the regulatory "law of the land" for decades. Despite the long-standing use of LNT, there is significant ongoing scientific disagreement on the applicability of LNT to low-dose radiation risk. A review of the low-dose risk literature of the last 10 y does not provide a clear answer, but rather the body of literature seems to be split between LNT, non-linear risk functions (e.g., supra- or sub-linear), and hormetic models. Furthermore, recent studies have started to explore whether radiation can play a role in the development of several non-cancer effects, such as heart disease, Parkinson's disease, and diabetes, the mechanisms of which are still being explored. Based on this review, there is insufficient evidence to replace LNT as the regulatory model despite the fact that it contributes to public radiophobia, unpreparedness in radiation emergency response, and extreme cleanup costs both following radiological or nuclear incidents and for routine decommissioning of nuclear power plants. Rather, additional research is needed to further understand the implications of low doses of radiation. The authors present an approach to meaningfully contribute to the science of low-dose research that incorporates machine learning and Edisonian approaches to data analysis.

Comparison of unitary synaptic currents generated by indirect and direct pathway neurons of the mouse striatum.

Two subtypes of striatal spiny projection neurons, iSPNs and dSPNs, whose axons form the "indirect" and "direct" pathways of the basal ganglia respectively, both make synaptic connections in the external globus pallidus (GPe), but are usually found to have different effects on behavior. Activation of the terminal fields of iSPNs or dSPNs generated compound currents in almost all GPe neurons. To determine whether iSPNs and dSPNs have the same or different effects on pallidal neurons, we studied the unitary synaptic currents generated in GPe neurons by action potentials in single striatal neurons. We used optogenetic excitation to elicit repetitive firing in a small number of nearby SPNs, producing sparse barrages of inhibitory postsynaptic currents (IPSCs) in GPe neurons. From these barrages, we isolated sequences of IPSCs with similar time courses and amplitudes, which presumably arose from the same SPN. There was no difference between the amplitudes of unitary IPSCs generated by the indirect and direct pathways. Most unitary IPSCs were small, but a subset from each pathway were much larger. To determine the effects of these unitary synaptic currents on the action potential firing of GPe neurons, we drove SPNs to fire as before, and recorded the membrane potential of GPe neurons. Large unitary potentials from iSPNs and dSPNs perturbed the spike timing of GPe neurons in a similar way. Most SPN-GPe neuron pairs are weakly connected, but a subset of pairs in both pathways are strongly connected.

Differential functional organization of amygdala-medial prefrontal cortex networks in macaque and human.

Over the course of evolution, the amygdala (AMG) and medial frontal cortex (mPFC) network, involved in behavioral adaptation, underwent structural changes in the old-world monkey and human lineages. Yet, whether and how the functional organization of this network differs remains poorly understood. Using resting-state functional magnetic resonance imagery, we show that the functional connectivity (FC) between AMG nuclei and mPFC regions differs between humans and awake macaques. In humans, the AMG-mPFC FC displays U-shaped pattern along the corpus callosum: a positive FC with the ventromedial prefrontal (vmPFC) and anterior cingulate cortex (ACC), a negative FC with the anterior mid-cingulate cortex (MCC), and a positive FC with the posterior MCC. Conversely, in macaques, the negative FC shifted more ventrally at the junction between the vmPFC and the ACC. The functional organization divergence of AMG-mPFC network between humans and macaques might help understanding behavioral adaptation abilities differences in their respective socio-ecological niches.

Propagation of Oscillations in the Indirect Pathway of the Basal Ganglia.

Oscillatory signals propagate in the basal ganglia from prototypic neurons in the external globus pallidus (GPe) to their target neurons in the substantia nigra pars reticulata (SNr), internal pallidal segment, and subthalamic nucleus. Neurons in the GPe fire spontaneously, so oscillatory input signals can be encoded as changes in timing of action potentials within an ongoing spike train. When GPe neurons were driven by an oscillatory current in male and female mice, these spike-timing changes produced spike-oscillation coherence over a range of frequencies extending at least to 100 Hz. Using the known kinetics of the GPe→SNr synapse, we calculated the postsynaptic currents that would be generated in SNr neurons from the recorded GPe spike trains. The ongoing synaptic barrage from spontaneous firing, frequency-dependent short-term depression, and stochastic fluctuations at the synapse embed the input oscillation into a noisy sequence of synaptic currents in the SNr. The oscillatory component of the resulting synaptic current must compete with the noisy spontaneous synaptic barrage for control of postsynaptic SNr neurons, which have their own frequency-dependent sensitivities. Despite this, SNr neurons subjected to synaptic conductance changes generated from recorded GPe neuron firing patterns also became coherent with oscillations over a broad range of frequencies. The presynaptic, synaptic, and postsynaptic frequency sensitivities were all dependent on the firing rates of presynaptic and postsynaptic neurons. Firing rate changes, often assumed to be the propagating signal in these circuits, do not encode most oscillation frequencies, but instead determine which signal frequencies propagate effectively and which are suppressed.SIGNIFICANCE STATEMENT Oscillations are present in all the basal ganglia nuclei, include a range of frequencies, and change over the course of learning and behavior. Exaggerated oscillations are a hallmark of basal ganglia pathologies, and each has a specific frequency range. Because of its position as a hub in the basal ganglia circuitry, the globus pallidus is a candidate origin for oscillations propagating between nuclei. We imposed low-amplitude oscillations on individual globus pallidus neurons at specific frequencies and measured the coherence between the oscillation and firing as a function of frequency. We then used these responses to measure the effectiveness of oscillatory propagation to other basal ganglia nuclei. Propagation was effective for oscillation frequencies as high as 100 Hz.

The relevance of the unique anatomy of the human prefrontal operculum to the emergence of speech.

Identifying the evolutionary origins of human speech remains a topic of intense scientific interest. Here we describe a unique feature of adult human neuroanatomy compared to chimpanzees and other primates that may provide an explanation of changes that occurred to enable the capacity for speech. That feature is the Prefrontal extent of the Frontal Operculum (PFOp) region, which is located in the ventrolateral prefrontal cortex, adjacent and ventromedial to the classical Broca's area. We also show that, in chimpanzees, individuals with the most human-like PFOp, particularly in the left hemisphere, have greater oro-facial and vocal motor control abilities. This critical discovery, when combined with recent paleontological evidence, suggests that the PFOp is a recently evolved feature of human cortical structure (perhaps limited to the genus Homo) that emerged in response to increasing selection for cognitive and motor functions evident in modern speech abilities.

A Review of Thromboelastography for Nurses.

BACKGROUND: Thromboelastography is a viscoelastic test with multiple potential advantages over conventional coagulation tests in various disease states. Thromboelastography rapidly provides qualitative and quantitative information related to a patient's coagulation status. OBJECTIVE: To describe recent studies of the use of thromboelastography in various clinical states and how thromboelastography is used in coagulation management. METHODS: A literature review using the MEDLINE and PubMed databases was conducted. The updated methodology for integrated reviews by Whittemore and Knafl was followed. Coauthors evaluated separate areas that were independently reviewed by other coauthors to ensure appropriateness for inclusion. RESULTS: The use of thromboelastography for various clinical conditions with challenging hemostatic profiles has increased. This integrative review covers the use of thromboelastography in patients with trauma, medication-induced coagulopathy, acute and chronic liver failure, and cardiothoracic surgery. Potential future directions are also discussed. DISCUSSION: Thromboelastography has numerous potential benefits over conventional coagulation tests for assessing coagulation status in patients in various clinical states. Nurses can support clinical decisions to use the most appropriate test for their patients. CONCLUSIONS: Each team member should be involved in assessing the usefulness of thromboelastography. Critical care nurses and the multidisciplinary team must identify patients in whom its use is warranted, interpret the results, and provide appropriate interventions in response to the results and clinical status of the patient.

Outcome of stereo-electroencephalography with single-unit recording in drug-refractory epilepsy.

OBJECTIVE: The aim of this study was to evaluate the utility and safety of "hybrid" stereo-electroencephalography (SEEG) in guiding epilepsy surgery and in providing information at single-neuron levels (i.e., single-unit recording) to further the understanding of the mechanisms of epilepsy and the neurocognitive processes unique to humans. METHODS: The authors evaluated 218 consecutive patients undergoing SEEG procedures from 1993 through 2018 at a single academic medical center to assess the utility and safety of this technique in both guiding epilepsy surgery and providing single-unit recordings. The hybrid electrodes used in this study contained macrocontacts and microwires to simultaneously record intracranial EEG and single-unit activity (hybrid SEEG). The outcomes of SEEG-guided surgical interventions were examined, as well as the yield and scientific utility of single-unit recordings in 213 patients who participated in the research involving single-unit recordings. RESULTS: All patients underwent SEEG implantation by a single surgeon and subsequent video-EEG monitoring (mean of 10.2 electrodes per patient and 12.0 monitored days). Epilepsy networks were localized in 191 (87.6%) patients. Two clinically significant procedural complications (one hemorrhage and one infection) were noted. Of 130 patients who underwent subsequent focal epilepsy surgery with a minimum 12-month follow-up, 102 (78.5%) underwent resective surgery and 28 (21.5%) underwent closed-loop responsive neurostimulation (RNS) with or without resection. Seizure freedom was achieved in 65 (63.7%) patients in the resective group. In the RNS group, 21 (75.0%) patients achieved 50% or greater seizure reduction. When the initial period of 1993 through 2013 before responsive neurostimulator implantation in 2014 was compared with the subsequent period of 2014 through 2018, the proportion of SEEG patients undergoing focal epilepsy surgery grew from 57.9% to 79.7% due to the advent of RNS, despite a decline in focal resective surgery from 55.3% to 35.6%. A total of 18,680 microwires were implanted in 213 patients, resulting in numerous significant scientific findings. Recent recordings from 35 patients showed a yield of 1813 neurons, with a mean yield of 51.8 neurons per patient. CONCLUSIONS: Hybrid SEEG enables safe and effective localization of epileptogenic zones to guide epilepsy surgery and provides unique scientific opportunities to investigate neurons from various brain regions in conscious patients. This technique will be increasingly utilized due to the advent of RNS and may prove a useful approach to probe neuronal networks in other brain disorders.

A revised perspective on the evolution of the lateral frontal cortex in primates.

Detailed neuroscientific data from macaque monkeys have been essential in advancing understanding of human frontal cortex function, particularly for regions of frontal cortex without homologs in other model species. However, precise transfer of this knowledge for direct use in human applications requires an understanding of monkey to hominid homologies, particularly whether and how sulci and cytoarchitectonic regions in the frontal cortex of macaques relate to those in hominids. We combine sulcal pattern analysis with resting-state functional magnetic resonance imaging and cytoarchitectonic analysis to show that old-world monkey brains have the same principles of organization as hominid brains, with the notable exception of sulci in the frontopolar cortex. This essential comparative framework provides insights into primate brain evolution and a key tool to drive translation from invasive research in monkeys to human applications.

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons.

Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input-output properties of pacemaking neurons can be characterized by the phase-resetting curve (PRC), which describes the sensitivity of interspike interval (ISI) length to inputs arriving at different phases of the firing cycle. Here we determined PRCs of putative DA neurons in the substantia nigra pars compacta in brain slices from male and female mice using gramicidin-perforated current-clamp recordings with electrical noise stimuli applied through the patch pipette. On average, and compared with nearby putative GABA neurons, DA neurons showed a low, nearly constant level of sensitivity across most of the ISI, but individual cells had PRCs showing relatively greater sensitivity at early or late phases. Pharmacological experiments showed that DA neuron PRCs are shaped by small-conductance calcium-activated potassium and Kv4 channels, which limit input sensitivity across early and late phases of the ISI. Our results establish the PRC as a tractable experimental measurement of individual DA neuron input-output relationships and identify two of the major ionic conductances that limit perturbations to rhythmic firing. These findings have applications in modeling and for identifying biophysical changes in response to disease or environmental manipulations.

Spontaneous Activity of the Local GABAergic Synaptic Network Causes Irregular Neuronal Firing in the External Globus Pallidus.

Autonomously firing GABAergic neurons in the external globus pallidus (GPe) form a local synaptic network. In slices, most GPe neurons receive a continuous inhibitory synaptic barrage from 1 or 2 presynaptic GPe neurons. We measured the barrage's effect on the firing rate and regularity of GPe neurons in male and female mice using perforated patch recordings. Silencing the firing of parvalbumin-positive (PV+) GPe neurons by activating genetically expressed Archaerhodopsin current increased the firing rate and regularity of PV- neurons. In contrast, silencing Npas1+ GPe neurons with Archaerhodopsin had insignificant effects on Npas1- neuron firing. Blocking spontaneous GABAergic synaptic input with gabazine reproduced the effects of silencing PV+ neuron firing on the firing rate and regularity of Npas1+ neurons and had similar effects on PV+ neuron firing. To simulate the barrage, we constructed conductance waveforms for dynamic clamp based on experimentally measured inhibitory postsynaptic conductance trains from 1 or 2 unitary local connections. The resulting inhibition replicated the effect on firing seen in the intact active network in the slice. We then increased the number of unitary inputs to match estimates of local network connectivity in vivo As few as 5 unitary inputs produced large increases in firing irregularity. The firing rate was also reduced initially, but PV+ neurons exhibited a slow spike-frequency adaptation that partially restored the rate despite sustained inhibition. We conclude that the irregular firing pattern of GPe neurons in vivo is largely due to the ongoing local inhibitory synaptic barrage produced by the spontaneous firing of other GPe neurons.SIGNIFICANCE STATEMENT Functional roles of local axon collaterals in the external globus pallidus (GPe) have remained elusive because of difficulty in isolating local inhibition from other GABAergic inputs in vivo, and in preserving the autonomous firing of GPe neurons and detecting their spontaneous local inputs in slices. We used perforated patch recordings to detect spontaneous local inputs during rhythmic firing. We found that the autonomous firing of single presynaptic GPe neurons produces inhibitory synaptic barrages that significantly alter the firing regularity of other GPe neurons. Our findings suggest that, although GPe neurons receive input from only a few other GPe neurons, each local connection has a large impact on their firing.

Local inhibition in a model of the indirect pathway globus pallidus network slows and deregularizes background firing, but sharpens and synchronizes responses to striatal input.

The external segment of globus pallidus (GPe) is a network of oscillatory neurons connected by inhibitory synapses. We studied the intrinsic dynamic and the response to a shared brief inhibitory stimulus in a model GPe network. Individual neurons were simulated using a phase resetting model based on measurements from mouse GPe neurons studied in slices. The neurons showed a broad heterogeneity in their firing rates and in the shapes and sizes of their phase resetting curves. Connectivity in the network was set to match experimental measurements. We generated statistically equivalent neuron heterogeneity in a small-world model, in which 99% of connections were made with near neighbors and 1% at random, and in a model with entirely random connectivity. In both networks, the resting activity was slowed and made more irregular by the local inhibition, but it did not show any periodic pattern. Cross-correlations among neuron pairs were limited to directly connected neurons. When stimulated by a shared inhibitory input, the individual neuron responses separated into two groups: one with a short and stereotyped period of inhibition followed by a transient increase in firing probability, and the other responding with a sustained inhibition. Despite differences in firing rate, the responses of the first group of neurons were of fixed duration and were synchronized across cells.

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

Frontal cortical functional connectivity is impacted by anaesthesia in macaques.

A critical aspect of neuroscience is to establish whether and how brain networks evolved across primates. To date, most comparative studies have used resting-state functional magnetic resonance imaging (rs-fMRI) in anaesthetized nonhuman primates and in awake humans. However, anaesthesia strongly affects rs-fMRI signals. The present study investigated the impact of the awareness state (anaesthesia vs. awake) within the same group of macaque monkeys on the rs-fMRI functional connectivity organization of a well-characterized network in the human brain, the cingulo-frontal lateral network. Results in awake macaques show that rostral seeds in the cingulate sulcus exhibited stronger correlation strength with rostral compared to caudal lateral frontal cortical areas, while more caudal seeds displayed stronger correlation strength with caudal compared to anterior lateral frontal cortical areas. Critically, this inverse rostro-caudal functional gradient was abolished under anaesthesia. This study demonstrated a similar functional connectivity (FC) organization of the cingulo-frontal cortical network in awake macaque to that previously uncovered in the human brain pointing toward a preserved FC organization from macaque to human. However, it can only be observed in awake state suggesting that this network is sensitive to anaesthesia and warranting significant caution when comparing FC patterns across species under different states.

From theory to bedside: Implementation of fluid stewardship in a medical ICU pharmacy practice.

PURPOSE: Intravenous fluids are the most commonly prescribed medication in the intensive care unit (ICU) and can have a negative impact on patient outcomes if not utilized properly. Fluid stewardship aims to heighten awareness and improve practice in fluid therapy. This report describes a practical construct for implementation of fluid stewardship services and characterizes the pharmacist's role in fluid stewardship practice. SUMMARY: Fluid stewardship services were integrated into an adult medical ICU at a large community hospital. Data characterizing these services over a 2-year span are reported and categorized based on the 4 rights (right patient, right drug, right route, right dose) and the ROSE (rescue, optimization, stabilization, evacuation) model of fluid administration. The review encompassed 305 patients totaling 905 patient days for whom 2,597 pharmacist recommendations were made, 19% of which were related to fluid stewardship. This corresponded to an average of 1.52 fluid stewardship recommendations per patient. Within the construct of the 4 rights, 39% of recommendations were related to the right patient, 33% were related to the right route, 17% were related to the right drug, and 11% were related to the right dose. By the ROSE model, 1% of recommendations were related to the rescue phase, 3% were related to optimization, 79% were related to stabilization, and 17% were related to evacuation. CONCLUSION: Implementation of fluid stewardship pharmacy services in a community hospital medical ICU is feasible. Integration of this practice contributed to 19% of pharmacy recommendations. The most common recommendations involved evaluation of the patient for the appropriateness of fluid therapy during the stabilization phase. The impact of fluid stewardship on patient outcomes needs to be explored.

Kinematic and Kinetic Predictors of Y-Balance Test Performance.

BACKGROUND: The Y-Balance Test (YBT) assesses dynamic stability and neuromuscular control of the lower extremity. Several authors have analyzed kinematic predictors of YBT performance with conflicting results, but the influence of kinetic factors is not well understood. PURPOSE: To examine kinematic predictors of YBT performance and determine the joint kinetics which predict YBT performance. STUDY DESIGN: Cross-sectional study. METHODS: Thirty-one physically active individuals performed YBT trials on a force plate while whole body kinematics were recorded using a motion capture system. Sagittal, frontal, and transverse plane joint kinematics and joint moments were calculated at maximum reach in each YBT reach direction. Variables correlated with reach distances at the p < 0.2 level were entered into a stepwise linear regression. RESULTS: In the anterior direction, knee flexion and torso rotation (R2 =0.458, p<0.001) and knee extensor and hip abductor moments (R2 =0.461, p<0.001) were the best kinematic and kinetic predictors of reach distance. In the posterior medial direction, hip flexion, ankle dorsiflexion, and ankle rotation accounted for 45.8% of the variance in reach direction (p<0.001) while hip and knee extensor, and hip abductor moments explained 72.6% of the variance in reach distance (p<0.001). In the posterior lateral direction, hip flexion and pelvic rotation (R2 =0.696, p<.001) and hip extensor moments (R2 =0.433, p=0.001) were the best kinematic and kinetic predictors of reach distance. CONCLUSION: The ability to generate large hip and knee joint moments in the sagittal and frontal plane are critical for YBT performance. LEVEL OF EVIDENCE: 3.

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns.

We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the external globus pallidus (GPe): they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highlighted the dissociable roles of GPe neurons in regulating movement and anxiety-like behavior. We concluded that Npr3+ neurons and Kcng4+ neurons are distinct subclasses of Npas1+ neurons and PV+ neurons, respectively. Finally, by examining local collateral connectivity, we inferred the circuit mechanisms involved in the motor patterns observed with optogenetic perturbations. In summary, by identifying mouse lines that allow for manipulations of GPe neuron subtypes, we created new opportunities for interrogations of cellular and circuit substrates that can be important for motor function and dysfunction.SIGNIFICANCE STATEMENT Within the basal ganglia, the external globus pallidus (GPe) has long been recognized for its involvement in motor control. However, we lacked an understanding of precisely how movement is controlled at the GPe level as a result of its cellular complexity. In this study, by using transgenic and cell-specific approaches, we showed that genetically-defined GPe neuron subtypes have distinct roles in regulating motor patterns. In addition, the in vivo contributions of these neuron subtypes are in part shaped by the local, inhibitory connections within the GPe. In sum, we have established the foundation for future investigations of motor function and disease pathophysiology.

Periodic unitary synaptic currents in the mouse globus pallidus during spontaneous firing in slices.

Neurons in the external globus pallidus (GPe) are autonomous pacemakers, but their spontaneous firing is continually perturbed by synaptic input. Because GPe neurons fire rhythmically in slices, spontaneous inhibitory synaptic currents (IPSCs) should be evident there. We identified periodic series of IPSCs in slices, each corresponding to unitary synaptic currents from one presynaptic cell. Optogenetic stimulation of the striatal indirect pathway axons caused a pause and temporal resetting of the periodic input, confirming that it arose from local neurons subject to striatal inhibition. We determined the firing statistics of the presynaptic neurons from the unitary IPSC statistics and estimated their frequencies, peak amplitudes, and reliabilities. To determine what types of GPe neurons received the spontaneous inhibition, we recorded from genetically labeled parvalbumin (PV) and Npas1-expressing neurons. Both cell types received periodic spontaneous IPSCs with similar frequencies. Optogenetic inhibition of PV neurons reduced the spontaneous IPSC rate in almost all neurons with active unitary inputs, whereas inhibition of Npas1 neurons rarely affected the spontaneous IPSC rate in any neurons. These results suggest that PV neurons provided most of the active unitary inputs to both cell types. Optogenetic pulse stimulation of PV neurons at light levels that can activate cut axons yielded an estimate of connectivity in the fully connected network. The local network is a powerful source of inhibition to both PV and Npas1 neurons, which contributes to irregular firing and may influence the responses to external synaptic inputs.NEW & NOTEWORTHY Brain circuits are often quiet in slices. In the globus pallidus, network activity continues because of the neurons' rhythmic autonomous firing. In this study, synaptic currents generated by the network barrage were measured in single neurons. Unitary synaptic currents arising from single presynaptic neurons were identified by their unique periodicity. Periodic synaptic currents were large and reliable, even at the cell's natural firing rates, but arose from a small number of other globus pallidus neurons.

The midcingulate cortex and temporal integration.

The ability to integrate information across time at multiple timescales is a vital element of adaptive behavior, because it provides the capacity to link events separated in time, extract useful information from previous events and actions, and to construct plans for behavior over time. Here we make the argument that this information integration capacity is a central function of the midcingulate cortex (MCC), by reviewing the anatomical, intrinsic network, neurophysiological, and behavioral properties of MCC. The MCC is the region of the medial wall situated dorsal to the corpus callosum and sometimes referred to as dACC. It is positioned within the densely connected core network of the primate brain, with a rich diversity of cognitive, somatomotor and autonomic connections. Furthermore, the MCC shows strong local network inhibition which appears to control the metastability of the region-an established feature of many cortical networks in which the neural dynamics move through a series of quasi-stationary states. We propose that the strong local inhibition in MCC leads to particularly long dynamic state durations, and so less frequent transitions. Apparently as a result of these anatomical features and synaptic and ionic determinants, the MCC cells display the longest neuronal timescales among a range of recorded cortical areas. We conclude that the anatomical position, intrinsic properties, and local network interactions of MCC make it a uniquely positioned cortical area to perform the integration of diverse information over time that is necessary for behavioral adaptation.