Michael R. Salzberg

NMDA Receptor Hypofunction Leads to Generalized and Persistent Aberrant γ Oscillations Independent of Hyperlocomotion and the State of Consciousness

Background The psychotomimetics ketamine and MK-801, non-competitive NMDA receptor (NMDAr) antagonists, induce cognitive impairment and aggravate schizophrenia symptoms. In conscious rats, they produce an abnormal behavior associated with a peculiar brain state characterized by increased synchronization in ongoing γ (30–80 Hz) oscillations in the frontoparietal (sensorimotor) electrocorticogram (ECoG). This study investigated whether NMDAr antagonists-induced aberrant γ oscillations are correlated with locomotion and dependent on hyperlocomotion-related sensorimotor processing. This also implied to explore the contribution of intracortical and subcortical networks in the generation of these pathophysiological ECoG γ oscillations. Methodology/Principal Findings Quantitative locomotion data collected with a computer-assisted video tracking system in combination with ECoG revealed that ketamine and MK-801 induce highly correlated hyperlocomotion and aberrant γ oscillations. This abnormal γ hyperactivity was recorded over the frontal, parietal and occipital cortices. ECoG conducted under diverse consciousness states (with diverse anesthetics) revealed that NMDAr antagonists dramatically increase the power of basal γ oscillations. Paired ECoG and intracortical local field potential recordings showed that the ECoG mainly reflects γ oscillations recorded in underlying intracortical networks. In addition, multisite recordings revealed that NMDAr antagonists dramatically enhance the amount of ongoing γ oscillations in multiple cortical and subcortical structures, including the prefrontal cortex, accumbens, amygdala, basalis, hippocampus, striatum and thalamus. Conclusions/Significance NMDAr antagonists acutely produces, in the rodent CNS, generalized aberrant γ oscillations, which are not dependent on hyperlocomotion-related brain state or conscious sensorimotor processing. These findings suggest that NMDAr hypofunction-related generalized γ hypersynchronies represent an aberrant diffuse network noise, a potential electrophysiological correlate of a psychotic-like state. Such generalized noise might cause dysfunction of brain operations, including the impairments in cognition and sensorimotor integration seen in schizophrenia.

Elevated anxiety and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common causation.

The explanation for the increased prevalence of neuropsychiatric disorders in epilepsy patients is uncertain, with both biological and psychosocial factors proposed. Increasing evidence supports the idea of shared neurobiological processes leading both to seizures and to behavioral, emotional and cognitive disturbance. This study addresses this using Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of human generalized epilepsy. We subjected GAERS (n=47) and Non-Epileptic Control rats (NEC; n=73) to behavioral measures of depression and anxiety at 7 and 13 weeks of age, ages prior to and after seizure onset. We employed the Sucrose-Preference Test (SPT), the Elevated Plus Maze (EPM), and the Open Field Arena (OFA). GAERS exhibited significantly greater levels of both depression- and anxiety-like behaviors on all measures, including reduced consumption of sucrose solution in the SPT; lower percentage of time in the open arms of the EPM; and reduced exploratory activity and less time spent in the inner area of the OFA. These differences were evident at both 7 and 13 weeks of age, before and after the onset of epilepsy. Increased anxiety- and depressive-like behaviors are observed in GAERS. These behavioral differences exist before the onset of seizures indicating that they are not secondary consequences of seizures, and suggest shared factors in the biological diathesis underlying the two kinds of disorder. Studying affective disturbance in animal models of epilepsy may illuminate the pathogenesis of affective disorder more generally, as well as modeling psychiatric comorbidities common in epilepsy patients.

Early postnatal stress confers enduring vulnerability to limbic epileptogenesis.

Purpose: Early life stress has enduring behavioral and neuroendocrine effects, particularly in hippocampus and amygdala. This may be relevant to mesial temporal lobe epilepsy (MTLE) that arises from these structures. In rats, we tested the hypothesis that early postnatal stress, in the form of maternal separation (MS), creates vulnerability to limbic epileptogenesis in adult life.

Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients

Objectives: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. Methods: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. Results: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). Conclusions: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype.

Experimental traumatic brain injury induces a pervasive hyperanxious phenotype in rats

Mood disturbances, including depression and anxiety disorders, are common and disabling long-term sequelae of traumatic brain injury (TBI). These psychiatric conditions have generally been considered psychosocial consequences of the trauma, but neurobiological alterations and causes have also been implicated. Using a rat model of TBI (lateral fluid-percussion injury), this longitudinal study seeks to assess anxiety and depression-like behaviors following experimental TBI. Male Wistar rats (n = 20) received a severe (approximately 3.5 atmosphere) pressure pulse directed to the right sensorimotor cortex, or sham surgery (n = 15). At 1, 3, and 6 months following injury, all rats underwent four assessments of anxiety and depression-like behaviors: exposure to an open field, elevated plus maze test, the forced swim test, and the sucrose preference test. Injured animals displayed increased anxiety-like behaviors throughout the study, as evidenced by reduced time spent (p = 0.014) and reduced entries (p < 0.001) into the center area of the open field, and reduced proportion of time in the open arms of the plus maze (p = 0.015), compared to sham-injured controls. These striking changes were particularly evident 1 and 3 months after injury. No differences were observed in depression-like behaviors in the forced swim test (a measure of behavioral despair) and the sucrose preference test (a measure of anhedonia). This report provides the first evidence of persistent anxiety-like disturbances in an experimental model of TBI. This finding indicates that the common occurrence of these symptoms in human sufferers is likely to have, at least in part, a neurobiological basis. Studies in this model could provide insight into the mechanisms underlying affective disturbance in brain-injured patients.

Neuropsychiatric morbidity in focal epilepsy

BACKGROUND Previous work has identified elevated prevalence rates for psychiatric disorders in individuals with medically refractory focal epilepsy, particularly temporal lobe epilepsy. Many studies were undertaken before the advent of video electroencephalogram monitoring (VEM) and magnetic resonance imaging (MRI). AIMS To investigate which characteristics of the focal epilepsy syndromes are associated with the presence of depression or psychosis. METHOD Three hundred and nineteen individuals with focal epilepsy admitted for VEM were seen over an 11-year period. The lifetime history of depression and psychosis, epileptic site, laterality and type of lesion were determined by clinical assessment, VEM and MRI scan. RESULTS There was a significant association between the prevalence of depressive symptoms and non-lesional focal epilepsy. There were no significant differences in prevalence of neuropsychiatric disorders between the groups with temporal lobe epilepsy and those with extratemporal lobe epilepsy. CONCLUSIONS These findings contrast with previous findings in smaller cohorts. The association between non-lesional focal epilepsy and depression may be due to the effects of a more diffuse epileptogenic area.

Depression in temporal lobe epilepsy surgery patients: An FDG-PET study

Summary:  Purpose: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery.

Acute administration of typical and atypical antipsychotics reduces EEG gamma power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in gamma power

A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.

Anxiolytic effects of rapid amygdala kindling, and the influence of early life experience in rats

The incidence of psychiatric disturbances is elevated in temporal lobe epilepsy (TLE) patients. Early life stressful events are believed to have a major impact on mental health later in life, and increasing evidence suggests that such stresses may also promote a vulnerability to TLE. This study investigated whether subjecting rats to early life stress exacerbated mood and cognitive disturbances associated with the development of epilepsy. On postnatal days 2-14, rat pups were separated from their dams for either 180 min/day (handling and maternal separation--HMS180, modelling early life stress) or 15 min/day (control handling and maternal separation--HMS15). At 7 weeks, rats were implanted with a bipolar electrode into the left amygdala. Following recovery, one group of rats from each litter underwent rapid amygdala kindling (RAK) epileptogenesis, while another underwent sham kindling. One week following this, rats were subjected to behavioural tests assessing anxiety and cognition. HMS180-exposed rats kindled faster than HMS15 rats (p<0.0001). RAK induced a potent anxiolytic effect as evidenced by increased % time spent in the open arms of the elevated plus maze, compared with sham kindled rats (p<0.0001). This anxiolytic effect was also observed in the open field task, as evidenced by increased time spent in the inner area (p=0.010). Neither RAK nor maternal separation had any effect on cognitive function in the Morris water maze. We conclude that maternal separation stress accelerates limbic epileptogenesis in adult rats, and that RAK induces potent anxiolytic effects that are not influenced by such early life stressful events.

Chronic Low-Dose Corticosterone Supplementation Enhances Acquired Epileptogenesis in the Rat Amygdala Kindling Model of TLE

Mesial temporal lobe epilepsy (MTLE) is associated with high rates of depression and anxiety. A bidirectional causal relationship has been suggested, with these psychiatric comorbidities themselves enhancing epileptogenesis, possibly via hypercortisolemia. We examined the effects on epileptogenesis of chronic supplementation with low-dose corticosterone (CS) in the electrical amygdala kindling rat model. Adult Wistar rats were ovariectomized and implanted with bipolar electrodes into the left amygdala. After 1 week recovery, one group (n=7) had CS (3 mg/100 ml—approx. 4.5 mg/kg/day) and a control group saline (n=7) added to their drinking water, and both groups underwent twice daily electrical stimulations. Rats were culled 2 weeks after reaching the fully kindled state. A stereological optical fractionator technique was used to estimate the number of CA1 pyramidal cells in the hippocampus ipsilateral to the stimulations. Fewer stimulations were required in the CS-supplemented rats than in controls to reach the fully kindled state (32 vs 81, p<0.03, Students t-test) and the first Class V seizure (14 vs 57, p<0.05). The mean after-discharge length was greater in the CS group (p=0.03, repeated measures analysis of variance). There was no difference in the mean number of CA1 neurons (1.05 × 105 vs 1.04 × 105, p=0.98). These data demonstrate that low-dose CS enhances epileptogenesis in this model of MTLE. This provides support for the hypothesis that chronic hypercortisolemia, as a result of stress, anxiety, and/or depression, may facilitate the development and progression of epilepsy in patients with MTLE. The lack of difference in hippocampal CA1 neurons indicates that the mechanism does not primarily involve pyramidal cell loss.