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Marjan de Vries,1 Oliver HG Wilder-Smith,2 Marijtje LA Jongsma,3 Emanuel N van den Broeke,1 Martijn Arns,5,6 Harry van Goor,1 Clementina M van Rijn4 1Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2Department of Anesthesiology, Pain and Palliative Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 3Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; 4Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; 5Research Institute Brainclinics Nijmegen, Nijmegen, The Netherlands; 6Department of Experimental Psychology, Utrecht University, Utrecht, The Netherlands Objectives: Electroencephalography (EEG) may be a promising source of physiological biomarkers accompanying chronic pain. Several studies in patients with chronic neuropathic pain have reported alterations in central pain processing, manifested as slowed EEG rhythmicity and increased EEG power in the brain's resting state. We aimed to investigate novel potential markers of chronic pain in the resting state EEG of patients with chronic pancreatitis. Participants: Resting state EEG data from 16 patients with persistent abdominal pain due to chronic pancreatitis (CP) were compared to data from healthy controls matched for age, sex and education. Methods: The peak alpha frequency (PAF) and power amplitude in the alpha band (7.5–13 Hz) were compared between groups in four regions of interest (frontal, central, parietal, and occipital) and were correlated with pain duration. Results: The average PAF was lowered in CP patients compared with that in healthy controls, observed as a statistically significant between-group effect (mean 9.9 versus 9.5 Hz; P=0.049). Exploratory post hoc analysis of average PAF per region of interest revealed a significant difference, particularly in the parietal and occipital regions. In addition, we observed a significant correlation between pain duration and PAF and showed increased shifts in PAF with longer pain durations. No significant group differences were found in peak power amplitudes. Conclusion: CP pain is associated with alterations in spontaneous brain activity, observed as a shift toward lower PAF. This shift correlates with the duration of pain, which demonstrates that PAF has the potential to be a clinically feasible biomarker for chronic pain. These findings could be helpful for assisting diagnosis, establishing optimal treatment, and studying efficacy of new therapeutic agents in chronic pain patients. Keywords: chronic pain, neuropathic pain, chronic pancreatitis, electroencephalography, EEG, alpha oscillations, peak frequency

Emanuel N van den Broeke,1 Marjan de Vries,1 Harry van Goor,3 Kris CP Vissers,1 Clementina M van Rijn,2 Oliver HG Wilder-Smith11Department of Anesthesiology, Pain and Palliative Medicine, Pain and Nociception Neuroscience Research Group, 2Donders Institute for Brain, Cognition and Behavior, 3Department of Surgery, Radboud University Nijmegen Medical Centre, HB Nijmegen, The NetherlandsBackground: Women who undergo breast cancer surgery have a high risk of developing persistent pain. We investigated brain processing of painful stimuli using electroencephalograms (EEG) to identify event-related potentials (ERPs) in patients with persistent pain after breast cancer treatment.Methods: Nineteen patients (eight women with persistent pain, eleven without persistent pain), who were surgically treated more than 1 year previously for breast cancer (mastectomy, lumpectomy, and axillary lymph node dissection) and/or had chemoradiotherapy, were recruited and compared with eleven healthy female volunteers. A block of 20 painful electrical stimuli was applied to the calf, somatopically remote from the initially injured or painful area. Simultaneously an EEG was recorded, and a visual analog scale (VAS) pain rating obtained.Results: In comparison with healthy volunteers, breast cancer treatment without persistent pain is associated with accelerated stimulus processing (reduced P260 latency) and shows a tendency to be less intense (lower P260 amplitude). In comparison to patients without persistent pain, persistent pain after breast cancer treatment is associated with stimulus processing that is both delayed (ie, increased latency of the ERP positivity between 250–310 ms [P260]), and enhanced (ie, enhanced P260 amplitude).Conclusion: These results show that treatment and persistent pain have opposite effects on cortical responsiveness.Keywords: breast cancer surgery, persistent pain, nerve injury, event-related potentials, pain processing

The role of the hippocampus (Hp) in absence epileptic networks and the effect of endocannabinoid system on this network remain enigmatic. Here, using adapted nonlinear Granger causality, we compared the differences in network strength in four intervals (baseline or interictal, preictal, ictal and postictal) in two hours before (Epoch 1) and six hours (epochs 2, 3 and 4) after the administration of three different doses of the endocannabinoid agonist WIN55,212-2 (WIN) or solvent. Local field potentials were recorded for eight hours in 23 WAG/Rij rats in the Frontal (FC), Parietal PC), Occipital Cortex (OC) and in the hippocampus (Hp). The four intervals were visually marked by an expert neurophysiologist and the strength of couplings between electrode pairs were calculated in both directions. Ictally, a strong decrease in coupling strength was found between Hp and FC, as well as a large increase bidirectionally between PC and FC and unidirectionally from FC and PC to OC, and from FC to Hp over all epochs. The highest dose of WIN increased the couplings strength from FC to Hp and from OC to PC during 4 and 2 hr respectively in all intervals, and decreased the FC to PC coupling strength postictally in epoch 2. A single rat showed generalized convulsive seizures after the highest dose: this rat shared not only coupling changes with the other rats in the same condition, but showed many more. WIN reduced SWD number in epoch 2 and 3, their mean duration increased in epochs 3 and 4. Conclusions:during SWDs FC and PC are strongly coupled and drive OC, while at the same time the influence of Hp to FC is diminished. The first is in agreement with the cortical focus theory, the latter demonstrates an involvement of the hippocampus in SWD occurrence and that ictally the hippocampal control of the cortico-thalamo-cortical system is lost. WIN causes dramatic network changes which have major consequences for the decrease of SWDs, the occurrence of convulsive seizures, and the normal cortico-cortical and cortico-hippocampal interactions., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The interaction between pain and cognition includes a concurrent negative effect of pain on cognitive performance and an analgesic effect of cognitive distraction on pain experience. The purpose of this exploratory study was to investigate the role of pain intensity and task complexity on this interaction., Methods: Two experiments were conducted in healthy volunteers. In both experiments, participants completed 3 conditions: a pain only condition (consisting of the cold pressor test), a cognition only condition (consisting of the cognitive task) and a combined condition (concurrent administration of the cold pressor and cognitive task). In experiment I, participants performed one out of three possible tasks that differed in cognitive load (low, medium, high). In experiment II the parameters of the pain stimulus, induced by a cold pressor test, were adapted and only the high load cognitive task was employed. Pain scores, reaction times, and accuracy rates were recorded., Results: In experiment I, cognitive distraction significantly decreased pain scores, irrespective of the cognitive load of the task. Pain did not affect cognitive performance. In experiment II, pain diminished accuracy rates. No effect of cognitive distraction on pain was observed. Individual characteristics did not noticeably influence the interaction between pain and cognition., Conclusions: The results of this study suggest a two-way interaction, however no evidence for a simultaneous bidirectional relationship was found. Cognitive distraction successfully reduces pain, up until a certain point where this relationship is reversed, and pain starts to interfere with cognitive performance. This may imply that priorities shift at a certain pain-threshold, however further research should confirm this hypothesis. This study could contribute to further understanding of cognitive mechanisms related to pain perception., (© 2021 Elisabeth J. Lier et al., published by De Gruyter, Berlin/Boston.)

Objective: During motor execution (ME), mu power is diminished over the contralateral hemisphere and increased over the ipsilateral hemisphere, which has been associated with cortical activation of the contralateral motor areas and inhibition of the ipsilateral motor areas respectively. The influence of action observation (AO) and motor imagery (MI) on mu power is less clear, especially in children, and remains to be studied in children with unilateral cerebral palsy (uCP)., Methods: We determined mu power during ME, AO, and MI of 45 typically developing (TD) children and 15 children with uCP over both hemispheres, for each hand., Results: In TD children, over the left hemisphere mu power was lowered during ME when the right hand was used. In line, over the right hemisphere mu power was lowered when the left hand was addressed. In addition, during AO and MI increased mu power was observed when the right hand was addressed. In children with uCP, over the spared hemisphere mu power was diminished during ME when the less-affected hand was used. However, over the lesioned hemisphere, no mu changes were observed., Conclusions: The results of TD children fit the activation/inhibition model of mu power., Significance: The results of children with uCP suggest that the lesioned hemisphere is unresponsive to the motor tasks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Vigabatrin increases GABA concentrations by inhibiting GABA transaminase. In previous studies, it was shown that vigabatrin increases the incidence of Spike and Wave Discharges (SWD) in the WAG/Rij rat model for absence epilepsy. Since following a single dose of vigabatrin GABA concentrations are known to be increased for several days, the present study sheds light on how the previously described changes in SWD characteristics develop over a longer time frame. To achieve this, we injected adult WAG/Rij rats with 500 mg/kg and recorded their EEG for 48 h. SWD were quantified, and their peak frequencies were calculated. Our results showed three rapid onset effects: a sharp increase in SWD incidence, from 12.5 /hour to 133/hour), this increase lasted only 4.4 h, an increase in mean SWD duration, from 4.6 s to 8.1 s and a drop in peak frequency, from 8 to 6 Hz. Since it takes several hours before GABA concentrations are sufficiently increased, we propose that these immediate effects are caused by direct stimulation of both GABA A and GABA B receptors by the molecule vigabatrin. Next, the mean SWD duration decreased below baseline values after 4.4 h. Hazard rate analysis showed that this is caused by an increased probability of short SWD. We argue that these changes are caused by increased activation of both GABA A and GABA B receptors in the frontal cortex and the thalamus, and more specifically, in the Reticular Thalamic Nucleus (RTN). After approximately 34 h, the probability of short SWD returned to normal. This suggests the occurrence of downregulation of GABA receptors. The decrease in peak frequency was still present 48 h after injection. It has been argued that the balance between GABA A and GABA B receptor-mediated activity in the RTN is crucial for controlling this SWD characteristic. It can be concluded that a single dose of vigabatrin results in remarkable and opposite effects over time: an initial, proabsence effect is followed by an antiabsence effect., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

A single injection of the cannabinoid agonist R(+)WIN55,212-2 (WIN) is known to cause an increase of the mean duration of spontaneously occurring spike-and-wave discharges (SWDs) in rats of the WAG/Rij strain, a genetic model for absence epilepsy. The aim of the present study was to establish whether repeated activation of CB 1 receptors with WIN leads to tolerance in its effect on SWD parameters, spectral density, and behavior over time. Adult male WAG/Rij rats (n = 16) were treated with WIN (6 mg/kg) or vehicle (olive oil). Injections (s.c.) took place 3 times per week during 2 weeks. Electroencephalogram (EEG) recordings, each lasting 24 h, were made 3 times: immediately before the first injection (baseline), immediately after the first injection (acute treatment), and after 2 weeks of treatment (subchronic treatment). The recordings were analyzed regarding incidence, durations of SWDs, and hazard rates of the durations of SWDs, the latter to describe SWD stopping probabilities. Putative changes in the spectral content of the EEG before and after WIN during active and passive behaviors were additionally investigated. Spike-and-wave discharge incidence was not affected by the acute and subchronic treatments. The mean duration of the SWDs was significantly longer than controls in the acute WIN-treated animals [11.9-s standard error of the mean (SEM): 0.64 compared with 8.4-s SEM: 0.25] as well as in subchronically treated animals (11.5-s SEM: 1.00 compared with 8.4-s SEM: 0.25). Hazard rates were significantly lower for WIN-treated animals at SWD durations in the 5.04-20.16-s range on both occasions. No effects of WIN on the frequency spectrum of the ongoing EEG were found, neither acutely nor after repeated administration. Evidence for tolerance was not found. The results on the mean duration and hazard rates suggest that stimulating the endocannabinoid system affects the SWD stopping mechanism, resulting in more long SWDs. We speculate that this effect is likely to be a direct result of CB 1 receptor agonism and a subsequent decrease in the availability of gamma-aminobutyric acid (GABA) in the reticular thalamic nucleus, which further weakens, in WAG/Rij rats already disturbed, the stopping mechanism of the SWDs., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Using the EEG recordings of patients with endometriosis-related chronic pelvic pain, we have examined the effective connectivity within the cortical pain-related network during rest and during pain-related imagery. During rest, an altered connectivity was hypothesized between cortical somatosensory pain areas and regions involved in emotional and cognitive modulation of pain. During pain-related imagery, alterations in prefrontal-temporal connectivity were expected. The effective connectivity was estimated using the Directed Transfer Function method. Differences between endometriosis patients and controls were found in the beta band (14-25 Hz). During rest, endometriosis was associated with an increased connectivity from the left dorsolateral prefrontal cortex to the left somatosensory cortex and also from the left somatosensory cortex to the orbitofrontal cortex and the right temporal cortex. These results might be related to sustained activation of the somatosensory pain system caused by the ongoing pain. During pain-related imagery, endometriosis patients showed an increased connectivity from the left dorsolateral prefrontal cortex to the right temporal cortex. This finding might point to impaired emotional regulation when processing pain-related stimuli, or it might be related to altered memorization of pain experiences. Results of this study open up new directions in chronic pain research aimed at exploring the beta band connectivity alterations. PERSPECTIVE: This study examined the pain system's dynamics in endometriosis patients with chronic pelvic pain during resting-state and pain-related mental imagery. The results could contribute to the development of new therapies using guided mental imagery., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Absence-epileptic seizures appear in the EEG as Spike and Wave Discharges (SWDs). Typical SWDs develop spontaneously in WAG/Rij rats, an inbred Wistar strain. Atypical SWDs however were reported in studies in which the cholesterol synthesis inhibitor AY-9944 was administered to neonatal Wistar rats, causing absence-like seizures later in life. Atypical SWDs seemed to differ from typical SWDs in 3 aspects: lower peak frequency, longer duration, and involvement of the hippocampus. The aim of the present study was to investigate the effect of AY-9944 on typical SWDs. Male Wistar and WAG/Rij rats were injected with 7.5 mg/kg AY-9944 or saline postnatally. After 6 months, EEGs were recorded from the cortex and the hippocampus. Incidence, duration and peak frequency of the SWDs were determined. The SWD stopping probability was estimated by hazard rate analysis. Hippocampal involvement was assessed by cross correlation analysis of the hippocampus and cortex channels. The Wistar rats unexpectedly showed a high incidence of spontaneous SWDs. The AY-treatment increased the total SWD duration in both Wistar and WAG/Rij rats: the incidence was 1.6 times higher and the mean SWD duration was 1.4 times longer than in the saline-treated rats. The peak frequency of the SWDs did not change. The hazard rates were lower in the AY-treated rats, so some very long SWDs were observed. Cross correlations of spiky activity in the hippocampus pointed to volume conduction rather than to genuine SWD activity in this area. In summary, we found no indication that SWDs in AY-treated animals differ from typical SWDs. However, since saline-treated rats had many spontaneous SWDs, other rat strains might respond differently. With respect to the mechanism, the appearance of long SWDs suggests that the SWD stopping mechanism is affected by the treatment. We speculate that this effect is due to changes in the distribution of GABA-ergic and glutamatergic receptors in lipid rafts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The role of state anxiety and state fear in placebo effects is still to be determined. We aimed to investigate the effect of fear of movement-related pain (FMRP) and contextual pain related anxiety (CPRA) on the magnitude of placebo analgesia induced by verbal suggestion. Fifty-six female participants completed a modified voluntary joystick movement paradigm (VJMP) where half participated in a predictable pain condition (PC), in which one of the joystick movements is always followed by pain and the other movement is never followed by pain, and half in an unpredictable pain condition (UC), in which pain was delivered unpredictably. By varying the level of pain predictability, FMRP and CPRA were induced in PC and UC respectively. Colour stimuli were presented at the beginning of each trail. Half of the participants were verbally informed that the green or red colour indicated less painful stimuli (experimental groups), the other half did not receive any suggestion (control groups). We measured self-reported pain intensity, expectancy of pain intensity (PC only), pain related fear and anxiety (eyeblink startle response and self-ratings) and avoidance behaviour (movement-onset latency and duration). The results indicate that the placebo effect was successfully induced in both experimental conditions. In the PC, the placebo effect was predicted by expectancy. Despite the fact that FMRP and CPRA were successfully induced, no difference was found in the magnitude of the placebo effect between PC and UC. Concluding, we did not find a divergent effect of fear and anxiety on placebo analgesia., Competing Interests: The authors have declared that no competing interests exist.

Pain catastrophizing - defined as a tendency to exaggerate the threat value or seriousness of experienced pain ‑ has been shown to be a risk factor for pain chronification. However, the neural basis of pain catastrophizing remains unclear and requires thorough investigation. This study aimed to explore the relationship between pain catastrophizing and effective connectivity of the pain systems in healthy participants. EEG data were collected during an induced state of pain‑related negative, depressive, positive and neutral mental imagery conditions, and pain catastrophizing tendencies were measured by the Pain Catastrophizing Scale. The Directed Transfer Function, a method based on Granger causality principles, was used to assess the effective connectivity. Linear mixed effects analyses revealed a negative relationship between pain catastrophizing and beta information flow from the right temporal cortex to the frontal regions and a positive relationship between pain catastrophizing and increased beta information flow from the right somatosensory cortices to the right temporal cortices when thinking about pain. These patterns were not found in other imagery conditions. Taken together, this study suggests that individual differences in pain catastrophizing might be related to an altered frontotemporal regulatory loop and increased connectivity between pain and affective systems. Our study reveals connectivity patterns related to pain catastrophizing tendencies that are detectable even in pain‑free, healthy individuals.

Objective: To explore how pain intensity and pain cognition are related to health-related quality of life (HRQoL) in women with endometriosis., Design: Cross-sectional questionnaire-based survey., Setting: Multidisciplinary referral center., Patient(s): Women with laparoscopically and/or magnetic resonance imaging-proven endometriosis (n = 50) and healthy control women (n = 42)., Intervention(s): For HRQoL, two questionnaires: the generic Short Form Health Survey (SF-36) and the Endometriosis Health Profile 30 (EHP-30). For pain cognition, three questionnaires: the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), and the Pain Anxiety Symptoms Scale (PASS). For pain intensity, the verbal Numeric Rating Scale (NRS)., Main Outcome Measure(s): Association between pain intensity and pain cognition with HRQoL in women with endometriosis, and the differences in HRQoL and pain cognition between women with endometriosis and healthy controls., Result(s): Health-related quality of life was statistically significantly impaired in women with endometriosis as compared with healthy control women. The variables of pain intensity and pain cognition were independent factors influencing the HRQoL of women with endometriosis. Patients with endometriosis had statistically significantly more negative pain cognition as compared with controls. They reported more pain anxiety and catastrophizing, and they were hypervigilant toward pain., Conclusion(s): Pain cognition is independently associated with the HRQoL in endometriosis patients. Clinicians should be aware of this phenomenon and may consider treating pain symptoms in a multidimensional, individualized way in which the psychological aspects are taken into account. In international guidelines on management of women with endometriosis more attention should be paid to the psychological aspects of care., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Empathy describes the ability to understand another person's feelings. Psychopathy is a disorder that is characterized by a lack of empathy. Therefore, empathy and psychopathy are interesting traits to investigate with respect to experiencing and observing pain. The present study aimed to investigate pain empathy and pain sensitivity by measuring event-related potentials (ERPs) extracted from the ongoing EEG in an interactive setup. Each participant fulfilled subsequently the role of "villain" and "victim". In addition, mode of control was modulated resulting in four different conditions; passive villain, active villain, active victim and passive victim. Response-, visual- and pain ERPs were compared between the four conditions. Furthermore, the role of psychopathic traits in these outcomes was investigated. Our findings suggested that people experience more conflict when hurting someone else than hurting themselves. Furthermore, our results indicated that self-controlled pain was experienced as more painful than uncontrolled pain. People that scored high on psychopathic traits seemed to process and experience pain differently. According to the results of the current study, social context, attention and personality traits seem to modulate pain processing and the empathic response to pain in self and others. The within-subject experimental design described here provides an excellent approach to further unravel the influence of social context and personality traits on social cognition.

Recent reports show that focusing attention on the location where pain is expected can enhance its perception. Moreover, crossing the hands over the body's midline is known to impair the ability to localise stimuli and decrease tactile and pain sensations in healthy participants. The present study investigated the role of transient spatial attention on the perception of painful and non-painful electrical stimuli in conditions in which a match or a mismatch was induced between skin-based and external frames of reference (uncrossed and crossed hands positions, respectively). We measured the subjective experience (Numerical Rating Scale scores) and the electrophysiological response elicited by brief electric stimuli by analysing the P3 component of Event-Related Potentials (ERPs). Twenty-two participants underwent eight painful and eight non-painful stimulus blocks. The electrical stimuli were applied to either the left or the right hand, held in either a crossed or uncrossed position. Each stimulus was preceded by a direction cue (leftward or rightward arrow). In 80% of the trials, the arrow correctly pointed to the spatial regions where the stimulus would appear (congruent cueing). Our results indicated that congruent cues resulted in increased pain NRS scores compared to incongruent ones. For non-painful stimuli such an effect was observed only in the uncrossed hands position. For both non-painful and painful stimuli the P3 peak amplitudes were higher and occurred later for incongruently cued stimuli compared to congruent ones. However, we found that crossing the hands substantially reduced the cueing effect of the P3 peak amplitudes elicited by painful stimuli. Taken together, our results showed a strong influence of transient attention manipulations on the NRS ratings and on the brain activity. Our results also suggest that hand position may modulate the strength of the cueing effect, although differences between painful and non-painful stimuli exist.

Little is known regarding inter-individual differences in attentional biases for pain-related information; more knowledge is crucial, since these biases have been associated with differences in pain processing as well as in predicting the risk of postoperative pain. The present study investigated EEG correlates of attentional bias patterns for pain-related information, with specific focus on avoidance- and vigilance-like behavior. Forty-one participants performed a dot-probe task, where neutral and pain-related words were used to create neutral, congruent, incongruent, and double (two pain-related words) trials. EEG was recorded, which was used to generate ERP's of the word-processing phase and the post-dot phase. Participants were placed in two subgroups based on the direction of their attentional bias (either positive; toward the pain-related words, or negative; away from pain-related words). Using t-profiles, four latency windows were identified on which the two subgroups differed significantly. These latency windows yield areas which correspond with the P1-N1 domain and the P3b for the word-processing phase, while the post-dot phase latency windows cover the areas of the P200 and the P3b. The two subgroups show differences on congruent, incongruent, and the double trials, but interestingly also on the neutral trials. Most notably, the area in the word-phase associated with the P3b is diminished in the subgroup showing a negative bias. The deflections associated with both early and late attentional components, including the P3B, as well as a positive deflection in the timeframe of proposed response evaluation processes differ significantly between subgroups. In this study we demonstrated that different attentional biases exist in the healthy population, by showing differences in ERP's. We also show differences in processing neutral trials, which suggests there are fundamental differences between these groups in processing words in general.

Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of "muscle spasms" were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition., Competing Interests: The authors [NB, LH, CK] were employees of Abbott He Healthcare Products BV (formerly Solvay Pharmaceuticals), Weesp, The Netherlands, more than 5 years before publication of this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Ruminations are repetitive thoughts associated with symptoms, causes, and consequences of one's negative feelings. The objective of this study was to explore the neuronal basis of depressive rumination in a non-clinical population within the context of emotional control. Participants scoring high or low on the tendency to ruminate scale took part in the EEG experiment. Their EEG data were collected during a state of induced depressive ruminations and compared with positive and neutral conditions. We hypothesized that both groups would differ according to the level of activation and effective connectivity among the structures involved in the emotional control circuit. Clustering of independent components, together with effective connectivity (Directed Transfer Function), was performed using the EEG signal. The main findings involved decreased activation of the left dorsolateral prefrontal cortex (DLPFC) and increased activation of the left temporal lobe structures in the highly ruminating group. The latter result was most pronounced during the ruminative condition. Decreased information from the left DLPFC to the left temporal lobe structures was also found, leading to the conclusion that hypoactivation of the left DLPFC and its inability to modulate the activation of the left temporal lobe structures is crucial for the ruminative tendencies.

Purpose: Spike-and-wave discharges (SWDs) recorded in the cortical EEGs of WAG/Rij rats are the hallmark for absence epilepsy in this model. Although this type of epilepsy was long regarded as a form of primary generalized epilepsy, it is now recognized that there is an initiation zone - the perioral region of the somatosensory cortex. However, networks involved in spreading the seizure are not yet fully known. Previously, the dynamics of coupling between different layers of the perioral cortical region and between these zones and different thalamic nuclei was studied in time windows around the SWDs, using nonlinear Granger causality. The aim of the present study was to investigate, using the same method, the coupling dynamics between different regions of the cortex and between these regions and the hippocampus., Methods: Local field potentials were recorded in the frontal, parietal, and occipital cortices and in the hippocampus of 19 WAG/Rij rats. To detect changes in coupling reliably in a short time window, in order to provide a good temporal resolution, the innovative adapted time varying nonlinear Granger causality method was used. Mutual information function was calculated in addition to validate outcomes. Results of both approaches were tested for significance., Results: The SWD initiation process was revealed as an increase in intracortical interactions starting from 3.5s before the onset of electrographic seizure. The earliest preictal increase in coupling was directed from the frontal cortex to the parietal cortex. Then, the coupling became bidirectional, followed by the involvement of the occipital cortex (1.5s before SWD onset). There was no driving from any cortical region to hippocampus, but a slight increase in coupling from hippocampus to the frontoparietal cortex was observed just before SWD onset. After SWD onset, an abrupt drop in coupling in all studied pairs was observed. In most of the pairs, the decoupling rapidly disappeared, but driving force from hippocampus and occipital cortex to the frontoparietal cortex was reduced until the SWD termination., Conclusion: Involvement of multiple cortical regions in SWD initiation shows the fundamental role of corticocortical feedback loops, forming coupling architecture and triggering the generalized seizure. The results add to the ultimate aim to construct a complete picture of brain interactions preceding and accompanying absence seizures in rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

An acute brain insult can cause a spectrum of primary and secondary pathologies including increased risk for epilepsy, mortality and neurodegeneration. The endocannabinoid system, involved in protecting the brain against network hyperexcitability and excitotoxicity, is profoundly dysregulated by acute brain insults. We hypothesize that post-insult dysregulation of the endocannabinoid signaling may contribute to deleterious effects of an acute brain injury and potentiation of endocannabinoid transmission soon after an insult may reduce its pathological outcomes. Effects of an acute post-insult administration of the endocannabinoid receptor agonist WIN55,212-2 on early seizure occurrence, animal mortality and hippocampal cell loss were studied in the lithium-pilocarpine status model. A single dose of WIN55,212-2 (5mg/kg) administered four hours after the end of status epilepticus (SE) reduced the incidence of early seizures during the first two post-SE days though did not change their duration and latency. Brief 4-6-Hz spike-wave discharges appeared de novo in the latent post-SE period and the acute administration of WIN55,212-2 also reduced the incidence of the epileptiform events. A single dose of WIN55,212-2 administered soon after SE improved survival of animals and reduced cell loss in the dentate hilus but did not prevent appearance of spontaneous recurrent seizures in the chronic period. Thus, a brief pharmacological stimulation of the endocannabinoid system soon after a brain insult exerts beneficial effects on its pathological outcome though does not prevent epileptogenesis., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: Ethosuximide (ETX) is the drug of choice for the treatment of patients with absence seizures - taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects failed in ETX-therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, has been proposed as a new anti-absence drug. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172, and whether cognition is affected during and after chronic ETX treatment., Method: EEG's were recorded before and after a challenge with VU0360172 in chronic ETX and in control WAG/Rij rats during and after treatment. Rats were also exposed to a cue discrimination learning task in a Y-maze both during and after treatment. At the end of the experiment, mGlu5 receptors were quantified by Western Blot analysis., Results: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action in the control group. VU0360172 kept its anti-absence action in chronic ETX treated rats both during and after treatment, without time and dose dependency. This anti-absence effect of VU0360172 in both groups matched the lack of differences in mGluR5 expression. Chronic ETX enhanced the number of completed trials, the number of correct choices in the Y-maze and the number of consumed sucrose pallets., Significance: VU0360172 maintains its anti-absence effects after chronic treatment; as such, VU0360172 can also be used as a adjunctive therapy in patients with absence epilepsy. The enhanced motivation and cognitive performance by ETX might be mediated by the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Research Question: Recent discoveries have challenged the traditional view that the thalamus is the primary source driving spike-and-wave discharges (SWDs). At odds, SWDs in genetic absence models have a cortical focal origin in the deep layers of the perioral region of the somatosensory cortex. The present study examines the effect of unilateral and bilateral surgical resection of the assumed focal cortical region on the occurrence of SWDs in anesthetized WAG/Rij rats, a well described and validated genetic absence model., Methods: Male WAG/Rij rats were used: 9 in the resected and 6 in the control group. EEG recordings were made before and after craniectomy, after unilateral and after bilateral removal of the focal region., Results: SWDs decreased after unilateral cortical resection, while SWDs were no longer noticed after bilateral resection. This was also the case when the resected areas were restricted to layers I-IV with layers V and VI intact., Conclusions: These results suggest that SWDs are completely abolished after bilateral removal of the focal region, most likely by interference with an intracortical columnar circuit. The evidence suggests that absence epilepsy is a network type of epilepsy since interference with only the local cortical network abolishes all seizures.

Background: Modulation of the endocannabinoid (eCB) transmission is a promising approach to treating epilepsy. Animal models can be used to investigate this approach. Krushinsky-Molodkina (KM) rats have, genetically, audiogenic epilepsy. Moreover, in these animals, repeated induction of audiogenic seizures results in a progressive prolongation of the seizures, known as audiogenic kindling., Methods: The present study evaluated, in these KM rats, acute and long-term effects of a single dose of 4 mg/kg of the cannabinoid-receptor agonist WIN55,212-2., Results: Administration of the single dose of WIN55,212-2 one hour before the 4th seizure delayed the kindling process by two weeks, without any acute effect on the audiogenic seizures., Conclusions: This result suggests that short-term potentiation of the eCB system might modify the epileptogenic disease process in patients with a progressive course of epilepsy., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: High-frequency electrical stimulation (HFS) of human skin induces not only an increased pain sensitivity in the conditioning area but also an increased pain sensitivity to mechanical punctate stimuli in the non-conditioned surrounding skin area. The aim of the present study was to investigate whether this heterotopically increased mechanical pain sensitivity can be facilitated through the induction of negative expectations., Methods: In two independent conditions [a nocebo (n = 15) and control condition (n = 15)], we applied mechanical pain stimuli before, directly after, 10 min and 20 min after HFS in the skin area surrounding the conditioning area, and measured the reported pain intensity [visual analogue scale (VAS)]. All subjects (of both conditions) received a written instruction about the HFS protocol, but only the instruction in the nocebo condition was extended by the following text (in Dutch): 'After the HFS, your skin will become more sensitive to the pinprick stimulation'., Results: Our results clearly show that induced expectations of increased mechanical pain sensitivity after HFS facilitates the reported pain intensity after HFS more than when no information is given., Conclusions: This study shows for the first time that brain mechanisms, via the induction of negative expectations, can facilitate heterotopic mechanical hyperalgesia after HFS of human skin., (© 2013 European Pain Federation - EFIC®)

Background: High Frequency electrical Stimulation (HFS) of the skin induces enhanced brain responsiveness expressed as enhanced Event-Related Potential (ERP) N1 amplitude to stimuli applied to the surrounding unconditioned skin in healthy volunteers. The aim of the present study was to investigate whether this enhanced ERP N1 amplitude could be a potential marker for altered cortical sensory processing in patients with persistent pain after surgery., Materials and Methods: Nineteen male patients; 9 with and 10 without persistent pain after inguinal hernia repair received HFS. Before, directly after and thirty minutes after HFS evoked potentials and the subjective pain intensity were measured in response to electric pain stimuli applied to the surrounding unconditioned skin., Results: The results show that, thirty minutes after HFS, the ERP N1 amplitude observed at the conditioned arm was statistically significantly larger than the amplitude at the control arm across all patients. No statistically significant differences were observed regarding ERP N1 amplitude between patients with and without persistent pain. However, thirty minutes after HFS we did observe statistically significant differences of P2 amplitude at the conditioned arm between the two groups. The P2 amplitude decreased in comparison to baseline in the group of patients with pain., Conclusion: The ERP N1 effect, induced after HFS, was not different between patients with vs. without persistent pain. The decreasing P2 amplitude was not observed in the patients without pain and also not in the previous healthy volunteer study and thus might be a marker for altered cortical sensory processing in patients with persistent pain after surgery.

The beneficial effects of chronic and early pharmacological treatment with ethosuximide on epileptogenesis were studied in a genetic absence epilepsy model comorbid for depression. It was also investigated whether there is a critical treatment period and treatment length. Cortical excitability in the form of electrical evoked potentials, but also to cortico-thalamo-cortical network activity (spike-wave discharges, SWD and afterdischarges), white matter changes representing extra cortico-thalamic functions and depressive-like behavior were investigated. WAG/Rij rats received either ethosuximide for 2 months (post natal months 2-3 or 4-5), or ethosuximide for 4 months (2-5) in their drinking water, while control rats drank plain water. EEG measurements were made during treatment, and 6 days and 2 months post treatment. Behavioral test were also done 6 days post treatment. DTI was performed ex vivo post treatment. SWD were suppressed during treatment, and 6 days and 2 months post treatment in the 4 month treated group, as well as the duration of AD elicited by cortical electrical stimulation 6 days post treatment. Increased fractional anisotropy in corpus callosum and internal capsula on DTI was found, an increased P8 evoked potential amplitude and a decreased immobility in the forced swim test. Shorter treatments with ETX had no large effects on any parameter. Chronic ETX has widespread effects not only within but also outside the circuitry in which SWD are initiated and generated, including preventing epileptogenesis and reducing depressive-like symptoms. The treatment of patients before symptom onset might prevent many of the adverse consequences of chronic epilepsy., (© 2013.)

Objective: The aim of the present study was to investigate whether patients with persistent pain after breast cancer treatment show an enhanced and slowed dominant alpha activity in their electroencephalogram (EEG) recorded during rest in comparison with patients that also had undergone breast cancer treatment but do not have pain., Methods: The spontaneous EEG was recorded during rest and before painful stimulation of the calf and analyzed with spectral analysis (Fast Fourier Transformation). Outcome measures, i.e., alpha indices (center of gravity and overall amplitude), were statistically tested between patients with and without persistent pain., Results: In comparison with patients without pain, patients with persistent pain after breast cancer treatment show more alpha activity in their spontaneous EEG observed from parietal-occipital brain regions., Conclusion: Persistent pain after breast cancer treatment affects spontaneous brain activity, which might influence cognitive functioning., (Wiley Periodicals, Inc.)

N-palmitoylethanolamine (PEA), an endogenous fatty acid ethanolamide, plays a key role in the regulation of the inflammatory response and pain through, among others, activation of nuclear peroxisome proliferator-activated receptors (PPAR-α). Endogenous cannabinoids play a protective role in several central nervous system (CNS) disorders, particularly those associated with neuronal hyperexcitability. We investigated the effects of PEA and the role of PPAR-α in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-α antagonist (GW6471) and a synthetic CB1 receptor antagonist/inverse agonist (SR141716) were administered to WAG/Rij rats in order to evaluate the effects on epileptic spike-wave discharges (SWDs) on EEG recordings. We studied also the effects of PEA co-administration with SR141716 and GW6471 and compared these effects with those of AEA to evaluate PEA mechanism of action and focusing on CB1 receptors and PPAR-α. Both PEA and AEA administration significantly decreased SWDs parameters (absence seizures). In contrast, GW6471 was devoid of effects while SR141716 had pro-absence effects. The co-administration of SR141716 with PEA or AEA completely blocked the anti-absence effects of these compounds. GW6471 antagonized PEA's effects whereas it did not modify AEA's effects. Furthermore, we have also measured PEA, AEA and 2-AG (2-arachidonoylglycerol) brain levels identifying significant differences between epileptic and control rats such as decreased PEA levels in both thalamus and cortex that might contribute to absence epilepsy. Our data demonstrate that PEA has anti-absence properties in the WAG/Rij rat model and that such properties depend on PPAR-α and indirect activation of CB1 receptors. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: In a previous article reporting group data, we presented event-related potentials (ERPs), which were evoked by randomly presented target stimuli in a 'learning-oddball' task. These ERPs contained a large N2-P3 complex that decreased and a Contingent Negative Variation (CNV) that increased when the targets were presented in a regular fashion. Using the learning-oddball paradigm, the aim of the present paper was to determine ERP effects of introducing regularity in individual participants., Methods: The data from the previous study were re-analyzed at the level of the individual participant, extracting individual sigmoid curves by means of wavelet-denoising and focusing on RTs, and CNV, N2, and P3 ERP components., Results: Most participants displayed significant sigmoid curves with respect to the P3 component (22 of the 24 participants - 22/24), the N2 component (20/24), and/or the CNV (19/24) component. In contrast, reaction times (RTs) appeared less sensitive to incidental learning (15/24). Modest correlations were observed between RTs and N2 component amplitudes., Conclusions: It is possible to extract significant ERP changes to introducing regularity in individual participants., Significance: Tracking ERP changes within the learning-oddball paradigm might be a useful tool to assess pattern detection capacities in individual patients., (Copyright © 2012 International Federation of Clinical Neurophysiology. All rights reserved.)

High-frequency conditioning electrical stimulation (HFS) of human skin induces an increased pain sensitivity to mechanical stimuli in the surrounding nonconditioned skin. The aim of this study was to investigate the effect of HFS on reported pain sensitivity to single electrical stimuli applied within the area of conditioning stimulation. We also investigated the central nervous system responsiveness to these electrical stimuli by measuring event-related potentials (ERPs). Single electrical test stimuli were applied in the conditioned area before and 30 min after HFS. During electrical test stimulation, the reported pain intensity (numerical rating scale) and EEG (ERPs) were measured. Thirty minutes after conditioning stimulation, we observed a decrease of reported pain intensity at both the conditioned and control (opposite arm) skin site in response to the single electrical test stimuli. In contrast, we observed enhanced ERP amplitudes after HFS at the conditioned skin site, compared with control site, in response to the single electrical test stimuli. Recently, it has been proposed that ERPs, at least partly, reflect a saliency detection system. Therefore, the enhanced ERPs might reflect enhanced saliency to potentially threatening stimuli.

The aim of this study was to track recall performance and event-related potentials (ERPs) across multiple trials in a digit-learning task. When a sequence is practiced by repetition, the number of errors typically decreases and a learning curve emerges. Until now, almost all ERP learning and memory research has focused on effects after a single presentation and, therefore, fails to capture the dynamic changes that characterize a learning process. However, the current study used a free-recall task in which a sequence of ten auditory digits was presented repeatedly. Auditory sequences of ten digits were presented in a logical order (control sequences) or in a random order (experimental sequences). Each sequence was presented six times. Participants had to reproduce the sequence after each presentation. EEG recordings were made at the time of the digit presentations. Recall performance for the control sequences was close to asymptote right after the first learning trial, whereas performance for the experimental sequences initially displayed primacy and recency effects. However, these latter effects gradually disappeared over the six repetitions, resulting in near-asymptotic recall performance for all digits. The performance improvement for the middle items of the list was accompanied by an increase in P300 amplitude, implying a close correspondence between this ERP component and the behavioral data. These results, which were discussed in the framework of theories on the functional significance of the P300 amplitude, add to the scarce empirical data on the dynamics of ERP responses in the process of intentional learning., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: High frequency electrical stimulation (HFS) of primary nociceptive afferents in humans induce a heightened sensitivity in the surrounding non-stimulated skin area. Several studies suggest that this heterotopic effect is the result of central (spinal) plasticity. The aim of this study is to investigate HFS-induced central plasticity of sensory processing at the level of the brain using the electroencephalogram (EEG). To this end we measured evoked potentials in response to noxious electrical pinprick-like stimuli applied in the heterotopic skin area before, directly after and 30 minutes after HFS., Results: We observed potential cortical electrophysiological correlates of heterotopic facilitation. Two different cortical correlates were found; the first one was a lateralized effect, i.e. a larger N100 amplitude on the conditioned arm than the control arm 30 minutes after end of HFS. This was comparable with the observed lateralized effect of visual analogue scale (VAS) scores as response to the mechanical punctate stimuli. The second correlate seems to be a more general (non-lateralized) effect, because the result affects both arms. On average for both arms the P200 amplitude increased significantly 30 minutes after end of HFS with respect to baseline., Conclusions: We suggest that for studying heterotopic nociceptive facilitation the evoked brain response is suitable and relevant for investigating plasticity at the level of the brain and is perhaps a more sensitive and reliable marker than the perceived pain intensity (e.g. VAS).

The question whether decapitation is a humane method of euthanasia in awake animals is being debated. To gather arguments in this debate, obsolete rats were decapitated while recording the EEG, both of awake rats and of anesthetized rats. Following decapitation a fast and global loss of power of the EEG was observed; the power in the 13-100 Hz frequency band, expressing cognitive activity, decreased according to an exponential decay function to half the initial value within 4 seconds. Whereas the pre-decapitation EEG of the anesthetized animals showed a burst suppression pattern quite different from the awake animals, the power in the postdecapitation EEG did not differ between the two groups. This might indicate that either the power of the EEG does not correlate well with consciousness or that consciousness is briefly regained in the anesthetized group after decapitation. Remarkably, after 50 seconds (awake group) or 80 seconds (anesthetized group) following decapitation, a high amplitude slow wave was observed. The EEG before this wave had more power than the signal after the wave. This wave might be due to a simultaneous massive loss of membrane potentials of the neurons. Still functioning ion channels, which keep the membrane potential intact before the wave, might explain the observed power difference. Two conclusions were drawn from this experiment. It is likely that consciousness vanishes within seconds after decapitation, implying that decapitation is a quick and not an inhumane method of euthanasia. It seems that the massive wave which can be recorded approximately one minute after decapitation reflects the ultimate border between life and death. This observation might have implications in the discussions on the appropriate time for organ donation.

Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity (depression, sleep disturbance), use of opioids, and premorbid alcohol abuse. The cognitive profiles of 16 patients with severe pain due to chronic pancreatitis were determined using an extensive neuropsychological test battery. Data from three cognitive domains (psychomotor performance, memory, executive functions) were compared to data from healthy controls matched for age, gender and education. Multivariate multilevel analysis of the data showed decreased test scores in patients with chronic pancreatitis pain in different cognitive domains. Psychomotor performance and executive functions showed the most prominent decline. Interestingly, pain duration appeared to be the strongest predictor for observed cognitive decline. Depressive symptoms, sleep disturbance, opioid use and history of alcohol abuse provided additional explanations for the observed cognitive decline in some of the tests, but to a lesser extent than pain duration. The negative effect of pain duration on cognitive performance is compatible with the theory of neurodegenerative properties of chronic pain. Therefore, early and effective therapeutic interventions might reduce or prevent decline in cognitive performance, thereby improving outcomes and quality of life in these patients.

Effects of the cannabinoid antagonist rimonabant on the EEG were investigated in healthy, non-epileptic rats. The drug was administered orally at 30 mg/kg/day for 3 weeks. The EEG was recorded continuously. In 3 out of 13 rats, limbic convulsive seizures, which were not related to the time of drug administration, were observed after 5-8 days. We hypothesize that an accumulation of micro-injuries in the brain is responsible for these "spontaneous" seizures.

Purpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB₁) receptors., Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of "presymptomatic" 2-month old and "symptomatic" 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB₁ receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB₁ receptor agonist, R(+)WIN55,212-2 (3-12 mg/kg, s.c.), given alone or combined with the CB₁ receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.)., Results: Data showed a reduction of CB₁ receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB₁ receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB₁ receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251., Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB₁ receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB₁ receptors are targeted by novel antiabsence drugs., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Long-term potentiation (LTP) is a cellular model of synaptic plasticity and reflects an increase of synaptic strength. LTP is also present in the nociceptive system and is believed to be one of the key mechanisms involved in the manifestations of chronic pain. LTP manifested as an increased response in pain perception can be induced in humans using high-frequency electrical stimulation (HFS). The aim of this study was to induce spinal heterosynaptic LTP using HFS and investigate its heterotopic effects on event-related potentials (ERPs) to repeated nonpainful cutaneous stimuli as a possible electrophysiological cortical correlate of sensitization. Twenty-two healthy subjects were randomly assigned to one of the two experimental conditions: HFS and control stimulation. Before and after the stimulation, both conditions received heterotopic mechanical (pinprick) and paired nonpainful electrical test stimuli to quantify and confirm the effects of HFS on the behavioral level. ERPs to paired nonpainful electrical stimulation were measured simultaneously. Conditioning HFS resulted in significant heterotopic effects after 30 min, including increased perceived intensity in response to (pinprick) mechanical and paired nonpainful electrical stimulation compared with control. The paired nonpainful electrical stimuli were accompanied by significantly enhanced responses regarding the ERP N1-P2 peak-to-peak and P300 amplitude compared with control. These findings suggest that HFS is capable of producing heterosynaptic spinal LTP that can be measured not only behaviorally but also using ERPs.

Purpose: To study anticonvulsive and antiepileptogenic effects of singe levetiracetam (LEV) administration in the model of audiogenic kindling., Methods: Rats of Krushinsky-Molodkina (KM) strain genetically susceptible to severe audiogenic seizures received one intraperitoneal injection of saline, low (6 mg/kg) or high (50 mg/kg) dose of LEV before or after audiogenic kindling. One hour postinjection, an audiogenic seizure was induced to assess anticonvulsive effect of LEV in nonkindled and kindled rats. To examine antiepileptogenic activity of LEV, nonkindled rats injected with the drug or saline were kindled with repeated sound stimulations. Audiogenic kindling development manifested in an appearance and progressive prolongation of an additional seizure phase, post-tonic-clonus. The latency and duration of audiogenic seizures and the duration of every seizure phase (running, tonic, post-tonic-clonic) were measured., Results: One hour posttreatment, LEV dose-dependently lengthened the latency and reduced the duration of audiogenic seizures in both nonkindled and kindled rats. The seizure shortening resulted from selective suppression of tonic and kindled post-tonic-clonic phases. The dose of 50 mg/kg completely blocked tonic and clonic convulsions 1 h postinjection. The anticonvulsive effect of LEV was more pronounced in kindled than in nonkindled rats. Single LEV injection in the dose of 50 mg/kg prior audiogenic kindling significantly suppressed subsequent kindling progression indicating profound antiepileptogenic potency of the drug., Conclusions: The present study shows that LEV exerts both short-lasting anticonvulsive effect on audiogenic seizures and very long-lasting antiepileptogenic effect on audiogenic kindling. Remarkably, a single injection of LEV is enough to significantly suppress kindling progression in KM rats.

The effects of vigabatrin, which increases GABA concentrations by inhibiting GABA transaminase, on spike and wave discharges (SWDs) in the electroencephalogram of WAG/Rij rats were studied. Vigabatrin increased the incidence and duration of the SWDs, suggesting a quantitative GABA(A)ergic involvement in the mechanism(s) underlying the starting and stopping of an ongoing SWD. Also, vigabatrin decreased the SWD peak frequency, suggesting an important role of GABA(B) in the mechanism(s) underlying the peak frequency of the SWDs. Vigabatrin gradually changed the course of the hazard rates of the SWD durations, suggesting a qualitative GABAergic role in the mechanism(s) underlying the stopping of an ongoing SWD.

In this study, the effects of vigabatrin on spike-and-wave discharges (SWDs) were measured in WAG/Rij rats, an animal model of absence epilepsy. Vigabatrin was used with the aim of enhancing GABAergic neurotransmission, and in this way to investigate the role of this process in the properties of SWDs. The study was carried out both in the rat, in vivo, and also using a computational model, in order to test different mechanisms that may account for the changes in SWDs after vigabatrin. The model parameters, representing GABA levels, were changed according to the known, and assumed, mechanism of action of the drug. The results show that the computational model can most adequately simulate the data obtained in vivo on the assumption that the enhancement of GABAergic neurotransmission due to application of vigabatrin is most pronounced at the level of the thalamic relay nuclei (TC cells). Furthermore, vigabatrin was shown to affect both the SWD starting and stopping mechanisms, as reflected by hazard rates. Based on these results, we suggest that GABAergic neurotransmission in TC cells is actively involved in the SWD termination.

In the present paper we consider the on-off intermittency phenomena observed in time series of spontaneous paroxysmal activity in rats with genetic absence epilepsy. The method to register and analyze the electroencephalogram with the help of continuous wavelet transform is also suggested.

Objective: The main aim was to track the dynamics of pattern-learning using single-trial event-related potentials (ERPs). A new 'learning-oddball' paradigm was employed presenting eight random targets (the 'no-pattern') followed by eight regular targets (the 'pattern'). In total, six repetitions of the 'no-pattern' followed by the 'pattern' were presented., Methods: We traced the dynamics of learning by measuring responses to 16 (eight random-eight regular) targets. Since this alternation of the 'no-pattern' followed by the 'pattern' was repeated six times, we extracted single-trial responses to all 96 targets to determine if learning occurred more rapidly with each repetition of the 'pattern.', Results: Following random targets, ERPs contained a marked P3-N2 component that decreased to regular targets, whereas a contingent negative variation (CNV) appeared. ERP changes could be best described by sigmoid 'learning' curves. Single-trial analyses showed that learning occurred more rapidly over repetitions and suggested that the CNV developed prior to the decay of the N2-P3 component., Conclusions: We show a new paradigm-analysis methodology to track learning processes directly from brain signals., Significance: Single-trial ERPs analyses open a wide range of applications. Tracking the dynamic structure of cognitive functions may prove crucial in the understanding of learning and in the study of different pathologies.