ATLAS: An Adaptive Transfer Learning Based Pain Assessment System: A Real Life Unsupervised Pain Assessment Solution.

Undertreatment or overtreatment of pain will cause severe consequences physiologically and psychologically. Thus, researchers have made great efforts to develop automatic pain assessment approaches based on physiological signals using machine learning techniques. However, state-of-art research mainly focuses on verifying the hypothesis that physiological signals can be used to assess pain. The critical assumption of these studies is that training data and testing data have the same distribution. However, this assumption may not hold in reallife scenarios, for instance, the adoption of machine learning model by a new patient. Such real-life scenarios in which user's data is unlabeled is largely neglected in literature. This study compensates for the rift by proposing an adaptive transfer learning based pain assessment system (ATLAS), a novel adaptive learning system based on the transfer learning algorithm Transfer Components Analysis (TCA) to minimize the distance between training data and unlabeled testing data. Experiments were conducted on BioVid database, and the results showed our approach outperforms three existing traditional machine learning-based approaches and achieves an accuracy just 2.0% below the accuracy with labeled data.

Convolution Neural Network for Pain Intensity Assessment from Facial Expression.

Pain is an unpleasant feeling that can reflect a patient's health situation. Since measuring pain is subjective, time-consuming, and needs continuous monitoring, automated pain intensity detection from facial expression holds great potential for smart healthcare applications. Convolutional Neural Networks (CNNs) are recently being used to identify features, map and model pain intensity from facial images, delivering great promise in helping practitioners detect disease. Limited research has been conducted to determine pain intensity levels across multiple classes. CNNs with simple learning schemes are limited in their ability to extract feature information from images. In order to develop a highly accurate pain intensity estimation system, this study proposes a Deep CNN (DCNN) model using the transfer learning technique, where a pre-trained DCNN model is adopted by replacing its dense upper layers, and the model is tuned using painful facial. We conducted experiments on the UNBC-McMaster shoulder pain archive database to estimate pain intensity in terms of seven-level thresholds using a given facial expression image. The experiments show our method achieves a promising improvement in terms of accuracy and performance to estimate pain intensity and outperform the-state-of-the-arts models.

Deep Graph Learning for Circuit Deobfuscation.

Circuit obfuscation is a recently proposed defense mechanism to protect the intellectual property (IP) of digital integrated circuits (ICs) from reverse engineering. There have been effective schemes, such as satisfiability (SAT)-checking based attacks that can potentially decrypt obfuscated circuits, which is called deobfuscation. Deobfuscation runtime could be days or years, depending on the layouts of the obfuscated ICs. Hence, accurately pre-estimating the deobfuscation runtime within a reasonable amount of time is crucial for IC designers to optimize their defense. However, it is challenging due to (1) the complexity of graph-structured circuit; (2) the varying-size topology of obfuscated circuits; (3) requirement on efficiency for deobfuscation method. This study proposes a framework that predicts the deobfuscation runtime based on graph deep learning techniques to address the challenges mentioned above. A conjunctive normal form (CNF) bipartite graph is utilized to characterize the complexity of this SAT problem by analyzing the SAT attack method. Multi-order information of the graph matrix is designed to identify the essential features and reduce the computational cost. To overcome the difficulty in capturing the dynamic size of the CNF graph, an energy-based kernel is proposed to aggregate dynamic features into an identical vector space. Then, we designed a framework, Deep Survival Analysis with Graph (DSAG), which integrates energy-based layers and predicts runtime inspired by censored regression in survival analysis. Integrating uncensored data with censored data, the proposed model improves the standard regression significantly. DSAG is an end-to-end framework that can automatically extract the determinant features for deobfuscation runtime. Extensive experiments on benchmarks demonstrate its effectiveness and efficiency.

Parkinson Disease.

Parkinson disease is a common neurodegenerative disorder that causes progressive motor and nonmotor disability. It is diagnosed clinically and requires a detailed history and neurologic examination to exclude alternative diagnoses. Although disease-modifying therapies do not exist for Parkinson disease, effective symptomatic therapies, including dopaminergic medications and surgery, allow patients to maintain good quality of life for many years. Nonmotor symptoms, including mood, cognitive, sleep, autonomic, and gastrointestinal symptoms, should be managed by a multidisciplinary team of clinicians. Recent advances include new diagnostic criteria from the Movement Disorder Society and the addition of new symptomatic therapies for treating motor complications and nonmotor symptoms in advanced disease.

Subacute histopathological features in a case of varicella zoster virus myelitis and post-herpetic neuralgia.

INTRODUCTION: Post-herpetic neuralgia is a crippling complication of varicella zoster virus (VZV) reactivation, also known as zoster disease. In rare cases, VZV spreads to the spinal cord and causes myelitis. There is a paucity of data on spinal cord histopathology in the subacute phase of post-herpetic neuralgia and VZV myelitis. CASE DESCRIPTION: In this report, we present a case of post-herpetic neuralgia in a patient who died 5 weeks after initiation of symptoms. Autopsy limited to the spinal cord revealed severe tissue vacuolization associated with macrophage and lymphocytic infiltration that was most intense in the right posterior horn, corresponding to an area of magnetic resonance imaging (MRI) T2-weighted hyperintensity. There was some extension of the inflammatory response to the ipsilateral posterior column, dorsolateral column, precentral gray matter, and contralateral lateral column. No significant axonal or myelin loss was observed. Nerve roots and meninges were free of significant inflammation. DISCUSSION: Our findings provide histopathological insight into early subacute changes in post-herpetic neuralgia and suggest the involvement of the cord and subsequent macrophage and lymphocyte inflammatory response may lead to pain fiber irritation and the clinical pain syndrome of post-herpetic neuralgia.

Outcomes of Interventional-MRI Versus Microelectrode Recording-Guided Subthalamic Deep Brain Stimulation.

In deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD), there is debate concerning the use of neuroimaging alone to confirm correct anatomic placement of the DBS lead into the STN, versus the use of microelectrode recording (MER) to confirm functional placement. We performed a retrospective study of a contemporaneous cohort of 45 consecutive patients who underwent either interventional-MRI (iMRI) or MER-guided DBS lead implantation. We compared radial lead error, motor and sensory side effect, and clinical benefit programming thresholds, and pre- and post-operative unified PD rating scale scores, and levodopa equivalent dosages. MER-guided surgery was associated with greater radial error compared to the intended target. In general, side effect thresholds during initial programming were slightly lower in the MER group, but clinical benefit thresholds were similar. No significant difference in the reduction of clinical symptoms or medication dosage was observed. In summary, iMRI lead implantation occurred with greater anatomic accuracy, in locations demonstrated to be the appropriate functional region of the STN, based on the observation of similar programming side effect and benefit thresholds obtained with MER. The production of equivalent clinical outcomes suggests that surgeon and patient preference can be used to guide the decision of whether to recommend iMRI or MER-guided DBS lead implantation to appropriate patients with PD.

Novel mutation in MYH7 gene associated with distal myopathy and cardiomyopathy.

A 25-year-old woman had childhood-onset muscle weakness and dilated cardiomyopathy. She exhibited predominantly distal weakness with early toe walking. Dilated cardiomyopathy required cardiac transplantation at age 15 years. We identified a de-novo, heterozygous, missense mutation, c.2348G>C (p. Arg783Pro), in exon 21 of the MYH7 gene, which encodes slow skeletal muscle fiber/ß-cardiac myosin heavy chain protein, that replaces a highly conserved arginine with a proline. This novel mutation that results in the unusual combined cardiac and skeletal muscle phenotype localizes to the essential light chain binding area, a region only previously shown to be mutated in hypertrophic cardiomyopathy.

Group 5 metabotropic glutamate receptors: role in modulating cortical activity and relevance to cognition.

Group 5 metabotropic glutamate (mGlu(5)) receptors are abundant in forebrain and limbic regions and provide a novel pharmacological target for modulation of cognition. Here, we review recent advances in understanding the electrophysiology of these receptors which reveal a role for mGlu(5) receptors in the regulation of tonic and bursting modes of neuronal firing, maintenance of distinct forms of synaptic plasticity, and reversal of detrimental effects of NMDA receptor antagonism on cortical neuronal activity. Furthermore, recordings using recently developed positive allosteric modulators of the mGlu(5) receptor suggest that these agents have an electrophysiological profile comparable to the antipsychotic agent clozapine. These findings, in conjunction with behavioral evidence from preclinical studies of cognition, suggest a potential precognitive profile for the mGlu(5) receptor potentiators.

Anterior cingulate neurons represent errors and preparatory attention within the same behavioral sequence.

The anterior cingulate cortex (ACC) has been implicated in both preparatory attention (i.e., selecting behaviorally relevant stimuli) and in detecting errors. We recorded from the rat ACC and medial prefrontal cortex (mPFC), which is functionally homologous to the primate dorsolateral PFC, during an attention task. The three-choice serial reaction time task requires a rat to orient toward and divide attention between three brief (300 ms duration) light stimuli presented in random order across nose poke holes in an operant chamber. In both the ACC and mPFC, we found that neural activity was related to the level of preparatory (precue) attention and subsequent correct or incorrect choice, in that the magnitude of the single units' response to the cue was lower on incorrect trials and was not different than baseline on unattended trials. This preparatory neural activity consisted of both excitatory and inhibitory phasic responses. The number of units responding to the cue was similarly graded, in that fewer units exhibited phasic responses to the cue on incorrect and unattended trials, compared with correct trials. Although preparatory activity was found in both the ACC and mPFC, activity after incorrect nose pokes, which may be related to error detection, were only observed in the ACC. Thus, during the same behavioral sequence, the ACC encodes both error-related events and preparatory attention, whereas the mPFC only participates in preparatory attention. The finding of substantial inhibitory activity during the preparatory period suggests a critical role for inhibition of pyramidal cells in PFC-mediated cognitive functions.

Differential representation of Pavlovian-instrumental transfer by prefrontal cortex subregions and striatum.

Environmental cues that once predicted reward can restore extinguished behavior directed toward that reward. This process may be modeled by the Pavlovian-instrumental transfer (PIT) paradigm where a previously learned Pavlovian conditioned stimulus (CS) elicits a representation of the reward associated with that CS, prompts motivation toward the absent reward, and triggers an instrumental action. We recorded in the medial and orbital prefrontal cortex (mPFC and OFC) and dorsal striatum (DS) of freely moving rats during PIT and found that a Pavlovian CS, as compared with neutral or no stimuli, amplified the phasic neuronal responses to instrumental nosepokes ('transfer' event). In mPFC and OFC, but not the DS, representation of the transfer event correlated with the strength of PIT behavior. Neurons in all three regions showed CS-selective amplification of Pavlovian approaches toward the reward delivery site. Whereas striatal neurons represented transfer and approach behavior through mostly segregated neuronal subsets, overlapping subsets represented these events in the mPFC and OFC. These findings suggest that parallel phasic activation of mPFC and OFC neuronal subsets participates in the transfer from Pavlovian incentives to instrumental actions.

Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs.

Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.

Divergent plasticity of prefrontal cortex networks.

The 'executive' regions of the prefrontal cortex (PFC) such as the dorsolateral PFC (dlPFC) and its rodent equivalent medial PFC (mPFC) are thought to respond in concert with the 'limbic' regions of the PFC such as the orbitofrontal (OFC) cortex to orchestrate behavior that is consistent with context and expected outcome. Both groups of regions have been implicated in behavioral abnormalities associated with addiction and psychiatric disorders, in particular, schizophrenia and mood disorders. Theories about the pathophysiology of these disorders, however, incorporate abnormalities in discrete PFC regions independently of each other or assume they are one and the same and, thus, bunch them under umbrella of 'PFC dysfunction.' Emerging data from animal studies suggest that mPFC and OFC neurons display opposing patterns of plasticity during associative learning and in response to repeated exposure to psychostimulants. These data corroborate clinical studies reporting different patterns of activation in OFC versus dlPFC in individuals with schizophrenia or addictive disorders. These suggest that concomitant but divergent engagement of discrete PFC regions is critical for learning stimulus-outcome associations, and the execution of goal-directed behavior that is based on these associations. An atypical interplay between these regions may lead to abnormally high or low salience assigned to stimuli, resulting in symptoms that are fundamental to many psychiatric and addictive disorders, including attentional deficits, improper affective response to stimuli, and inflexible or impulsive behavior.

NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.

NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.

Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex.

BACKGROUND: Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC). METHODS: In freely moving rats, we measured the effects of the positive modulator of mGlu5 receptor 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) alone or in combination with the NMDA antagonist MK801 on 1) spontaneous firing and bursting of medial PFC (mPFC) neurons, and 2) dopamine release as measured by microdialysis in the mPFC and nucleus accumbens (NAc). RESULTS: The predominant effect of CDPPB on mPFC neurons was excitatory, leading to an overall excitatory population response. Pretreatment with CDPPB prevented MK801-induced excessive firing and reduced spontaneous bursting. In contrast, CDPPB had no significant effect on basal dopamine release as compared with control rats and did not alter MK801-induced activation of dopamine release in the mPFC and NAc. CONCLUSIONS: These results show that positive modulation of mGlu5 receptors reverses the effects of noncompetitive NMDA antagonists on cortical neuronal firing without affecting dopamine neurotransmission. Thus, these compounds may be effective in ameliorating PFC mediated behavioral abnormalities that results from NMDA receptor hypofunction.

Fine-tuning of awake prefrontal cortex neurons by clozapine: comparison with haloperidol and N-desmethylclozapine.

BACKGROUND: Mechanisms underlying clozapine's better clinical efficacy in schizophrenia remain poorly understood. The prefrontal cortex (PFC) has been implicated as a primary site for the therapeutic effects of clozapine; however, evidence for how clozapine influences the activity of PFC neurons in behaviorally relevant contexts is lacking. METHODS: Ensemble single unit recording in awake rats was used to measure the activity of PFC neurons in response to clozapine, its main metabolite N-desmethylclozapine (DMClz), and the typical antipsychotic drug haloperidol during baseline conditions and after treatment with the N-methyl-D-aspartate antagonist MK801. Behavioral stereotypy was scored during recording. RESULTS: Clozapine and DMClz but not haloperidol had an activity-dependent influence on spontaneous firing rate of PFC cells: they increased the activity of neurons with low baseline firing rates and decreased the activity of neurons with higher firing rates. Clozapine and DMClz but not haloperidol also reversed the effect of MK801 on PFC neuronal firing. This reversal was strongly correlated with blockade of MK801-induced behavioral stereotypy. CONCLUSIONS: These findings indicate that clozapine has the capacity to fine-tune spontaneous and disrupted activity of PFC neurons. This effect might contribute, in part, to the therapeutic efficacy of clozapine in schizophrenia.

Progression of cellular adaptations in medial prefrontal and orbitofrontal cortex in response to repeated amphetamine.

Recent theories on addiction implicate adaptive changes in prefrontal cortex (PFC) neurons in reinforcing and psychotomimetic properties of psychostimulants, yet little is known about how neuronal responses to these drugs change over time. Here we describe electrophysiological evidence for a progressive and sustained change in the response of PFC neurons to amphetamine during repeated exposure. In spontaneously behaving rats and in rats engaged in an instrumental responding task, we followed the activity of medial PFC (mPFC) and orbitofrontal cortex (OFC) neurons during daily exposure to amphetamine and after a post-withdrawal challenge. Repeated amphetamine increased the number of responsive neurons and the magnitude of responses and modified spontaneous burst patterns. These changes were apparent after a few exposures to amphetamine, were amplified after withdrawal, and were region specific in that repeated amphetamine increasingly produced inhibitory responses in mPFC and excitatory responses in OFC. In behaviorally engaged animals, the gradual enhancement in mPFC inhibition and OFC overactivation correlated with a progressive impairment of instrumental responding. Furthermore, these changes were evident predominately in neurons that displayed phasic responses during task-related events. These rapid-onset and sustained cellular adaptations suggest that even limited exposure to psychostimulants may reduce the influence of mPFC neurons on behavior while at the same time exaggerating information encoded by OFC neurons.

The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway.

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO-mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)-cGMP pathway. The effect of sildenafil (1-40 mg kg(-1)) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil-induced effects with NO-cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), NOS substrate L-arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose-dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L-NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO-cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L-arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO-cGMP pathway.

Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors.

Metabotropic glutamate 5 (mGlu5) receptors have been recently implicated in prefrontal cortex (PFC)-dependent executive functions because inhibition of mGlu5 receptors impairs working memory and worsens cognitive-impairing effects of NMDA receptor antagonists. To better understand the mechanisms by which mGlu5 receptors influence PFC function, we examined the effects of selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), given alone or in combination with the NMDA receptor antagonist MK801, on ensemble single unit activity in the medial PFC (mPFC) of behaving rats. MPEP decreased the spontaneous burst activity of the majority of mPFC neurons. This inhibition was selective for the most active cells because greater decreases were observed in neurons with higher baseline firing rates. MPEP augmented the effects of MK801 on burst activity, variability of spike firing and random spike activity. These findings demonstrate that in awake animals mGlu5 receptors regulate the function of PFC neurons by two related mechanisms: (i) rate-dependent excitatory influence on spontaneous burst activity; and (ii) potentiation of NMDA receptor mediated effects on firing rate and burst activity. These mechanisms support the idea that modulation of mGlu5 receptors may provide a pharmacological strategy for fine-tuning the temporal pattern of firing of PFC neurons.

The synergistic anticonvulsant effect of agmatine and morphine: possible role of alpha 2-adrenoceptors.

Recent demonstrations of the anticonvulsant properties of agmatine suggest it may be considered as a potential adjunct for protection against seizure. We investigated the possibility of an additive anticonvulsant effect between low doses of agmatine and morphine. The thresholds for the clonic seizures induced by the intravenous administration of gamma-aminobutyric acid (GABA)-antagonist, pentylenetetrazole (PTZ) were assessed in mice. Morphine at lower doses (1-3mg/kg) increased and at higher doses (30, 60 mg/kg) decreased the seizure threshold. Pretreatment with a per se non-effective dose of agmatine (1mg/kg) potentiated the anticonvulsant effect of morphine. The combination of subeffective doses of agmatine and morphine led to potent anticonvulsant effects. The pro-convulsant effect of morphine was attenuated by agmatine. Yohimbine with a dose (1mg/kg) incapable of affecting seizure threshold reversed the effect of agmatine on both anticonvulsant and pro-convulsant effects of morphine. These results suggest that agmatine potentiates the anticonvulsant effect of morphine and alpha 2-adrenoceptors may be involved in this effect.

Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats.

Systemic exposure to N-methyl-d-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)-dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.