Limbic Hyperactivity Research Articles

Brain responses in aggression-prone individuals: A systematic review and meta-analysis of functional magnetic resonance imaging (fMRI) studies of anger- and aggression-eliciting tasks

Reactive aggression in response to perceived threat or provocation is part of humans' adaptive behavioral repertoire. However, high levels of aggression can lead to the violation of social and legal norms. Understanding brain function in individuals with high levels of aggression as they process anger- and aggression-eliciting stimuli is critical for refining explanatory models of aggression and thereby improving interventions. Three neurobiological models of reactive aggression – the limbic hyperactivity, prefrontal hypoactivity, and dysregulated limbic-prefrontal connectivity models – have been proposed. However, these models are based on neuroimaging studies involving mainly non-aggressive individuals, leaving it unclear which model best describes brain function in those with a history of aggression.We conducted a systematic literature search (PubMed and Psycinfo) and Multilevel Kernel Density meta-analysis (MKDA) of nine functional magnetic resonance imaging (fMRI) studies (eight included in the between-group analysis [i.e., aggression vs. control groups], five in the within-group analysis). Studies examined brain responses to tasks putatively eliciting anger and aggression in individuals with a history of aggression alone and relative to controls.Individuals with a history of aggression exhibited greater activity in the superior temporal gyrus and in regions comprising the cognitive control and default mode networks (right posterior cingulate cortex, precentral gyrus, precuneus, right inferior frontal gyrus) during reactive aggression relative to baseline conditions. Compared to controls, individuals with a history of aggression exhibited increased activity in limbic regions (left hippocampus, left amygdala, left parahippocampal gyrus) and temporal regions (superior, middle, inferior temporal gyrus), and reduced activity in occipital regions (left occipital cortex, left calcarine cortex).These findings lend support to the limbic hyperactivity model in individuals with a history of aggression, and further indicate altered temporal and occipital activity in anger- and aggression-eliciting conditions involving face and speech processing.

Limbic links to paranoia: increased resting-state functional connectivity between amygdala, hippocampus and orbitofrontal cortex in schizophrenia patients with paranoia

Paranoia is a frequent and highly distressing experience in psychosis. Models of paranoia suggest limbic circuit pathology. Here, we tested whether resting-state functional connectivity (rs-fc) in the limbic circuit was altered in schizophrenia patients with current paranoia. We collected MRI scans in 165 subjects including 89 patients with schizophrenia spectrum disorders (schizophrenia, schizoaffective disorder, brief psychotic disorder, schizophreniform disorder) and 76 healthy controls. Paranoia was assessed using a Positive And Negative Syndrome Scale composite score. We tested rs-fc between bilateral nucleus accumbens, hippocampus, amygdala and orbitofrontal cortex between groups and as a function of paranoia severity. Patients with paranoia had increased connectivity between hippocampus and amygdala compared to patients without paranoia. Likewise, paranoia severity was linked to increased connectivity between hippocampus and amygdala. Furthermore, paranoia was associated with increased connectivity between orbitofrontal and medial prefrontal cortex. In addition, patients with paranoia had increased functional connectivity within the frontal hubs of the default mode network compared to healthy controls. These results demonstrate that current paranoia is linked to aberrant connectivity within the core limbic circuit and prefrontal cortex reflecting amplified threat processing and impaired emotion regulation. Future studies will need to explore the association between limbic hyperactivity, paranoid ideation and perceived stress.

Limbic Hyperactivity in Response to Emotionally Neutral Stimuli in Schizophrenia: A Neuroimaging Meta-Analysis of the Hypervigilant Mind.

It has long been assumed that paranoid ideation may stem from an aberrant limbic response to threatening stimuli. However, results from functional neuroimaging studies using negative emotional stimuli have failed to confirm this assumption. One of the potential reasons for the lack of effect is that study participants with psychosis may display aberrant brain responses to neutral material rather than to threatening stimuli. The authors conducted a functional neuroimaging meta-analysis to test this hypothesis. A literature search was performed with PubMed, Google Scholar, and Embase to identify functional neuroimaging studies examining brain responses to neutral material in patients with psychosis. A total of 23 studies involving schizophrenia patients were retrieved. Using t-maps of peak coordinates to calculate effect sizes, a random-effects model meta-analysis was performed with the anisotropic effect-size version of Seed-based d Mapping software. In schizophrenia patients relative to healthy control subjects, increased activations were observed in the left and right amygdala and parahippocampus and the left putamen, hippocampus, and insula in response to neutral stimuli. Given that several limbic regions were found to be more activated in schizophrenia patients than in control subjects, the results of this meta-analysis strongly suggest that these patients confer aberrant emotional significance to nonthreatening stimuli. In theory, this abnormal brain reactivity may fuel delusional thoughts. Studies are needed in individuals at risk of psychosis to determine whether aberrant limbic reactivity to neutral stimuli is an early neurofunctional marker of psychosis vulnerability.

Emotional fMR auditory paradigm demonstrates normalization of limbic hyperactivity after cognitive behavior therapy for auditory hallucinations

To date, no study has evaluated the effects on brain function of cognitive behavior therapy (CBT) for persistent auditory hallucinations. This study explored the changes in brain activation associated with an emotional auditory paradigm when patients with schizophrenia and auditory hallucinations were treated with CBT. Functional magnetic resonance (fMR) imaging data were obtained from 55 subjects (17 patients with schizophrenia in the therapy group, 24 patients with schizophrenia in the control patient group, and 14 healthy control subjects). The patients in the experimental group were treated with 16–20 bi-weekly sessions of CBT, whereas the patients in the control group received treatment as usual. fMR images were obtained at baseline, 9 and 14months after enrollment. Patients who received CBT showed significant decrease in brain activation in right and left amygdalae, and the left middle temporal gyrus, compared to both control groups. Significantly reductions in the brain activation of therapy patients were found in both amygdalae, but also in the left superior temporal gyrus and the right superior frontal gyrus at 14-month follow-up. Significant and stable reductions in the abnormal activation of key limbic regions appear to be attributable to the CBT during an emotional auditory paradigm in patients with schizophrenia and persistent auditory hallucinations. These results point to the availability of a biological imaging biomarker for CBT effects in patients with persistent auditory hallucinations.

Blast-Induced Tinnitus and Elevated Central Auditory and Limbic Activity in Rats: A Manganese-Enhanced MRI and Behavioral Study

Blast-induced tinitus is the number one service-connected disability that currently affects military personnel and veterans. To elucidate its underlying mechanisms, we subjected 13 Sprague Dawley adult rats to unilateral 14 psi blast exposure to induce tinnitus and measured auditory and limbic brain activity using manganese-enhanced MRI (MEMRI). Tinnitus was evaluated with a gap detection acoustic startle reflex paradigm, while hearing status was assessed with prepulse inhibition (PPI) and auditory brainstem responses (ABRs). Both anxiety and cognitive functioning were assessed using elevated plus maze and Morris water maze, respectively. Five weeks after blast exposure, 8 of the 13 blasted rats exhibited chronic tinnitus. While acoustic PPI remained intact and ABR thresholds recovered, the ABR wave P1-N1 amplitude reduction persisted in all blast-exposed rats. No differences in spatial cognition were observed, but blasted rats as a whole exhibited increased anxiety. MEMRI data revealed a bilateral increase in activity along the auditory pathway and in certain limbic regions of rats with tinnitus compared to age-matched controls. Taken together, our data suggest that while blast-induced tinnitus may play a role in auditory and limbic hyperactivity, the non-auditory effects of blast and potential traumatic brain injury may also exert an effect.

Neural correlates of distraction in borderline personality disorder before and after dialectical behavior therapy.

Neural underpinnings of emotion dysregulation in borderline personality disorder (BPD) are characterized by limbic hyperactivity and disturbed prefrontal activity. It is unknown whether neural correlates of emotion regulation change after a psychotherapy which has the goal to improve emotion dysregulation in BPD, such as dialectical behavioral therapy (DBT). We investigated distraction as a main emotion regulation strategy before and after DBT in female patients with BPD. Thirty-one BPD patients were instructed to either passively view or memorize letters before being confronted with negative or neutral pictures in a distraction task during functional magnetic resonance imaging. This paradigm was applied before and after a 12-week residential DBT-based treatment program. We compared the DBT group to 15 BPD control patients, who continued their usual, non-DBT-based treatment or did not have any treatment, and 22 healthy participants. Behaviorally, BPD groups and healthy participants did not differ significantly with respect to alterations over time. On the neural level, BPD patients who received DBT-based treatment showed an activity decrease in the right inferior parietal lobe/supramarginal gyrus during distraction from negative rather than neutral stimuli when compared to both control groups. This decrease was correlated with improvement in self-reported borderline symptom severity. DBT responders exhibited decreased right perigenual anterior cingulate activity when viewing negative (rather than neutral) pictures. In conclusion, our findings reveal changes in neural activity associated with distraction during emotion processing after DBT in patients with BPD. These changes point to lower emotional susceptibility during distraction after BPD symptom improvement.

Neural basis of social cognition in bipolar disorder

This article review studies social and interpersonal functioning in patients with bipolar disorder (BD), and reports on the neurobiological underpinnings of the dysfunctions in emotion recognition, i.e. one of the main domains of social cognition. A bibliographical research of controlled studies from 1967 to 2015 was completed in PubMed and PsycINFO using the keywords: "fMRI", "emotion comprehension", "emotion perception", "affect comprehension", "affect perception", "facial expression", "prosody", "theory of mind", "mentalizing", "attributional style", "social perception", "empathy" and "bipolar disorder" or "unipolar depression". Limbic hyperactivity, with a lack of appropriate cortical control, has been reported in subjects with BD during social interactions. This is particularly evident during the acute affective episodes but may persist during the euthymic phases. Deficits in emotion regulation, including neural systems implicated both in voluntary and automatic emotion regulatory subprocesses, are present in DB, particularly for what pertains to social interactions and interpersonal functioning. Patients with bipolar disorder may present a dysfunction in the cortical ability to modulate the limbic system, which may show hyperactivity during social interactions. More studies are needed, including studies to evaluate treatment implications.

Functional dysconnection in the prefrontal-amygdala circuitry in unaffected siblings of patients with bipolar I disorder.

Bipolar I disorder (BD) is a highly heritable disorder characterized by mood swings between high-energy and low-energy states. Amygdala hyperactivity and cortical inhibitory hypoactivity [e.g., of the dorsolateral prefrontal cortex (dlPFC)] have been found in patients with BD, as evidenced by their abnormal resting-state functional connectivity (FC) and glucose utilization (GU). However, it has not been determined whether functional abnormalities of the dlPFC-amygdala circuit exist in unaffected, healthy siblings of the patients with BD (BDsib). Twenty euthymic patients with BD, 20 unaffected matching BDsib of the patient group, and 20 well-matched healthy control subjects were recruited. We investigated seed-based FC (seeds: dlPFC) with resting-state functional magnetic resonance imaging and GU in the regions of interest (e.g., dlPFC and amygdala) using (18) F-fluorodeoxyglucose positron emission tomography. The FC in the dlPFC (right)-amygdala circuit was statistically abnormal in patients with BD and BDsib, but only the patients with BD demonstrated hypoactive GU bilaterally in the dlPFC and hyperactive GU bilaterally in the amygdala. Facilitating differentiation between the BD groups, the altered FC between dlPFC (right) and amygdala (left) was even more prominent in the patients with BD (p < 0.05). There was a dysfunctional connection with intact GU in the dlPFC-amygdala circuit of the BDsib, which highlights the vulnerability in families with BD. Diminished top-down control from the bilateral dlPFC, which prevents adequate inhibition of limbic hyperactivity, might mediate the development of BD.

Neural Correlates of Disturbed Emotion Processing in Borderline Personality Disorder: A Multimodal Meta-Analysis

BackgroundDisturbances in the processing and regulation of emotions are core symptoms of borderline personality disorder (BPD). To further elucidate neural underpinnings of BPD, the present meta-analysis summarizes functional neuroimaging findings of emotion processing tasks, as well as structural neuroimaging findings, and investigates multimodally affected brain regions. MethodsCombined coordinate- and image-based meta-analyses were calculated using anisotropic effect size signed differential mapping. Nineteen functional neuroimaging studies investigating the processing of negative compared with neutral stimuli in a total of 281 patients with BPD and 293 healthy control subjects (HC) were included. In addition, 10 studies investigating gray matter abnormalities in 263 patients with BPD and 278 HC were analyzed. ResultsCompared with HC, BPD patients showed relatively increased activation of the left amygdala and posterior cingulate cortex, along with blunted responses of the bilateral dorsolateral prefrontal cortex, during the processing of negative emotional stimuli. The multimodal analysis identified the left amygdala to be characterized by a combination of functional hyperactivity and smaller gray matter volume compared with HC. Hyperresponsivity of the amygdala was moderated by medication status of the patient samples. Medication-free samples were characterized by limbic hyperactivity, whereas no such group differences were found in patients currently taking psychotropic medication. ConclusionsResults strengthen the assumption that dysfunctional dorsolateral prefrontal and limbic brain regions are a hallmark feature of BPD and therefore are consistent with the conceptualization of BPD as an emotion dysregulation disorder.

Tracking functional brain changes in patients with depression under psychodynamic psychotherapy using individualized stimuli.

ObjectiveNeurobiological models of depression posit limbic hyperactivity that should normalize after successful treatment. For psychotherapy, though, brain changes in patients with depression show substantial variability. Two critical issues in relevant studies concern the use of unspecific stimulation experiments and relatively short treatment protocols. Therefore changes in brain reactions to individualized stimuli were studied in patients with depression after eight months of psychodynamic psychotherapy.Methods18 unmedicated patients with recurrent major depressive disorder were confronted with individualized and clinically derived content in a functional MRI experiment before (T1) and after eight months (T2) of psychodynamic therapy. A control group of 17 healthy subjects was also tested twice without intervention. The experimental stimuli were sentences describing each participant's dysfunctional interpersonal relationship patterns derived from clinical interviews based on Operationalized Psychodynamic Diagnostics (OPD).ResultsAt T1 patients showed enhanced activation compared to controls in several limbic and subcortical regions, including amygdala and basal ganglia, when confronted with OPD sentences. At T2 the differences in brain activity between patients and controls were no longer apparent. Concurrently, patients had improved significantly in depression scores.ConclusionsUsing ecologically valid stimuli, this study supports the model of limbic hyperactivity in depression that normalizes after treatment. Without a control group of untreated patients measured twice, though, changes in patients' brain activity could also be attributed to other factors than psychodynamic therapy.

Early Life Stress and Trauma and Enhanced Limbic Activation to Emotionally Valenced Faces in Depressed and Healthy Children

Previous studies have examined the relationships between structural brain characteristics and early life stress in adults. However, there is limited evidence for functional brain variation associated with early life stress in children. We hypothesized that early life stress and trauma would be associated with increased functional brain activation response to negative emotional faces in children with and without a history of depression. Psychiatric diagnosis and life events in children (starting at age 3-5 years) were assessed in a longitudinal study. A follow-up magnetic resonance imaging (MRI) study acquired data (N = 115 at ages 7-12, 51% girls) on functional brain response to fearful, sad, and happy faces relative to neutral faces. We used a region-of-interest mask within cortico-limbic areas and conducted regression analyses and repeated-measures analysis of covariance. Greater activation responses to fearful, sad, and happy faces in the amygdala and its neighboring regions were found in children with greater life stress. Moreover, an association between life stress and left hippocampal and globus pallidus activity depended on children's diagnostic status. Finally, all children with greater life trauma showed greater bilateral amygdala and cingulate activity specific to sad faces but not the other emotional faces, although right amygdala activity was moderated by psychiatric status. These findings suggest that limbic hyperactivity may be a biomarker of early life stress and trauma in children and may have implications in the risk trajectory for depression and other stress-related disorders. However, this pattern varied based on emotion type and history of psychopathology.

Prolonged hemodynamic response during incidental facial emotion processing in inter-episode bipolar I disorder

This fMRI study examined whether hemodynamic responses to affectively-salient stimuli were abnormally prolonged in remitted bipolar disorder, possibly representing a novel illness biomarker. A group of 18 DSM-IV bipolar I-diagnosed adults in remission and a demographically-matched control group performed an event-related fMRI gender-discrimination task in which face stimuli had task-irrelevant neutral, happy or angry expressions designed to elicit incidental emotional processing. Participants' brain activation was modeled using a "fully informed" SPM5 basis set. Mixed-model ANOVA tested for diagnostic group differences in BOLD response amplitude and shape within brain regions-of-interest selected from ALE meta-analysis of previous comparable fMRI studies. Bipolar-diagnosed patients had a generally longer duration and/or later-peaking hemodynamic response in amygdala and numerous prefrontal cortex brain regions. Data are consistent with existing models of bipolar limbic hyperactivity, but the prolonged frontolimbic response more precisely details abnormalities recognized in previous studies. Prolonged hemodynamic responses were unrelated to stimulus type, task performance, or degree of residual mood symptoms, suggesting an important novel trait vulnerability brain dysfunction in bipolar disorder. Bipolar patients also failed to engage pregenual cingulate and left orbitofrontal cortex-regions important to models of automatic emotion regulation-while engaging a delayed dorsolateral prefrontal cortex response not seen in controls. These results raise questions about whether there are meaningful relationships between bipolar dysfunction of specific ventromedial prefrontal cortex regions believed to automatically regulate emotional reactions and the prolonged responses in more lateral aspects of prefrontal cortex.

Limbic hyperactivity associated to verbal memory deficit in schizophrenia

In schizophrenia there seems to be an inefficient activation of prefrontal and hippocampal regions. Patients tend to show worse cognitive performance in functions subserved by those regions as compared to healthy controls in spite of higher regional activation. However, the association between activation abnormalities and cognitive deficits remains without being understood. In the present study, we compared cerebral perfusion using single-photon emission tomography (SPECT) in patients and controls to study the association between activation patterns and cognitive performance in this disease. The SPECT studies were simultaneously obtained with an electrophysiological recording during a P300 paradigm to elicit P3a and P3b components. We included 23 stable patients with paranoid schizophrenia and 29 healthy controls that underwent clinical and cognitive assessments. Patients with schizophrenia showed an increased perfusion in the right hippocampus with respect to healthy controls, they also displayed a statistically significant inverse association between perfusion in the left hippocampus and verbal memory performance. Healthy controls showed an inverse association between perfusion in the left dorsolateral prefrontal (DLPFC) region and working memory performance. P3b but not P3a amplitude was significantly lower in patients. The limbic overactivation in the patients may contribute to their cognitive deficits in verbal memory.

Limbic System Activity and Drug Dreaming in Drug-Addicted Subjects

Several studies have noticed that drug-addicted subjects frequently report dreams the contents of which are related to their abnormal urge to use the drug to which they are addicted (i.e., drug craving). In B. Johnson’s hypothesis, the mesolimbic-mesocortical dopaminergic system, identified by Solms as essential in the generation of dreaming, is exactly the one that, when upregulated by addictive drugs exposure, is responsible for drug craving and related drug dreams. These dopaminergic circuits arise from the ventral tegmentum and have substantial projections in limbic structures. The aim of this study is to investigate the limbic activity, assessed by means of the Limbic System Checklist, LSCL-33, of drug-addicted subjects in relation to their drug dreaming. Consistent with Johnson’s hypothesis, results show that drug-addicted subjects who reported drug dreams had significantly higher LSCL-33 scores than did the control group, which did not have drug dreams. The LSCL-33 scores of drug-addicted subjects are similar to those obtained from temporal-lobe epilepsy subjects. The results of the study provide a clinical exemplification of the neuropsychoanalytic model and are consistent with previous literature that found a correlation between limbic hyperactivity and dreams with a strong emotional/motivational connotation. From the neurobiological background of the drug dreams observed in this study and in previous literature, an account of drug-dream onset is proposed.

Emotional face processing in schizophrenia

Recent studies of face processing deficits in people with schizophrenia have begun to shed light on the answers to four important questions: What is the major component of the deficit? Does it have a neurobiological basis? When does it appear in development? Can it be remediated? Eye contact is especially important for recognizing fearful expressions. Patients with schizophrenia avoid gazing at important facial feature regions (especially eyes) and are particularly impaired in recognizing fear. Patients were thought to exhibit decreased amygdala activity when viewing fearful faces; however, more recent studies have revealed limbic hyperactivity in patients when viewing nonfearful and fearful faces compared with baseline. Amygdala hyperactivity can also be detected when people with schizophrenia fail to appropriately recognize fear faces. Studies indicate that there are developmental changes in amygdala activation, including limbic hyperactivity to fear faces during adolescence, a critical time for the onset of schizophrenia. New treatment strategies can increase gaze to the eye region, which could improve emotional recognition in patients. These findings suggest that there may soon be more options for overcoming specific problems in emotional face evaluation in people who have schizophrenia.

Differences in cortical activity between methamphetamine-dependent and healthy individuals performing a facial affect matching task

As individuals who abuse methamphetamine (MA) often exhibit socially maladaptive behaviors such as violence and aggression, it is possible that they respond abnormally to social cues. To investigate this issue, we exposed 12 MA-dependent participants (abstinent 5–16 days) and 12 healthy comparison participants to fearful and angry faces while they performed an affect matching task during functional magnetic resonance imaging (fMRI). Although the groups did not differ in task performance, the healthy participants showed more task-related activity than the MA-dependent participants in a set of cortical regions consisting of the ventrolateral prefrontal cortex (VLPFC), temporoparietal junction (TPJ), anterior and posterior temporal cortex, and fusiform gyrus in the right hemisphere, and the cuneus in the left hemisphere. In contrast, the MA-dependent participants showed more task-related activity than the healthy participants in the dorsal anterior cingulate cortex (dACC). As expected, the task elicited activation of the amygdala in both groups; however, contrary to expectation, we found no difference between groups in this activation. Dorsal ACC hyperactivity, along with high self-ratings of hostility and interpersonal sensitivity in the MA-dependent group, suggest a hyper-sensitivity to socially threatening cues in the MA-dependent participants, while lower VLPFC activation could point to a deficit in integrating socio-emotional information and/or regulating this limbic hyperactivity. Additional activation differences in neural circuitry related to social cognition (TPJ, anterior, and posterior temporal cortex) suggest further socio-emotional deficits. Together, the results point to cortical abnormalities that could underlie the socially inappropriate behaviors often shown by individuals who abuse MA.

Amygdala reactivity to emotional faces at high and low intensity in generalized social phobia: A 4-Tesla functional MRI study

Using functional magnetic resonance imaging, we measured amygdala reactivity to faces varying on emotional intensity in subjects with generalized social phobia (GSP) and matched healthy controls, and observed greater bilateral activation to high (vs. low) intensity expressions in the phobic group, suggesting that more arousing social–emotional cues contribute to limbic hyperactivity in GSP.

Anatomical and functional cerebral variables associated with basal symptoms but not risperidone response in minimally treated schizophrenia

In schizophrenia, structural and functional cerebral variables show an unclear association with clinical features and their value as predictors of response to a typical antipsychotic agents has yet to be determined. The goal of this study was to investigate the relationships between clinical variables (baseline syndromes and response to risperidone) and anatomo-functional brain variables. We studied 19 minimally treated patients with schizophrenia of recent onset using magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) under resting conditions. The following brain variables were studied: volume of the cerebrospinal fluid (CSF) and gray matter (GM) of the dorsolateral prefrontal cortex (DLPFC) and temporal lobe; hippocampal metabolic activity and volume; and metabolic activity of the DLPFC, temporal lobe, putamen and caudate. Anatomical volume measurements were corrected for age and intracranial size using regression parameters determined from a matched sample of control subjects. Using stepwise multiple regression, we assessed the relation between these brain measures and basal scores of symptom dimensions (positive, disorganization, negative and total), as well as their change in response to risperidone. We found that positive and disorganization symptoms improved with risperidone treatment and that hippocampal metabolism, DLPFC CSF volume, and temporal CSF volume predicted baseline symptoms. However, none of the brain measures predicted response to treatment. We conclude that there is evidence of a significant association between basal symptoms and DLPFC atrophy and limbic hyperactivity at rest in recent-onset schizophrenic patients.

Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins.

Soman, a potent acetylcholinesterase inhibitor, induces status epilepticus in rats followed by conspicuous neuropathology, most prominent in piriform cortex and the CA3 region of the hippocampus. Cholinergic seizures originate in striatal-nigral pathways and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in a full-blown status epilepticus. This leads to neurochemical changes, some of which may be neuroprotective whereas others may cause brain damage. Pretreatment with lithium sensitizes the brain to cholinergic seizures. Likewise, other agents that increase limbic hyperactivity may sensitize the brain to cholinergic agents. The hyperactivity associated with the seizure state leads to an increase in intracellular calcium, cellular edema and metal delocalization producing an oxidative stress. These changes induce the synthesis of stress-related proteins such as heat shock proteins, metallothioneins and heme oxygenases. We show that soman-induced seizures cause a depletion in tissue glutathione and an increase in tissue 'catalytic' iron, metallothioneins and heme oxygenase-1. The oxidative stress induces the synthesis of stress-related proteins, which are indicators of 'stress' and possibly provide neuroprotection. These findings suggest that delocalization of iron may catalyze Fenton-like reactions, causing progressive cellular damage via free radical products.

Differential response of cortical–limbic neuropotentiated compulsive mice to dopamine D 1 and D 2 receptor antagonists

We previously created transgenic mice in which dopamine D 1 receptor-expressing (D1+) neurons in regional subsets of the cortex and amygdala express a neuropotentiating cholera toxin (CT) transgene. These `D1CT' mice engage in complex biting, locomotor and behavioral perseverance–repetition abnormalities that resemble symptoms of human compulsive disorders associated with cortical–limbic hyperactivity. Because excessive cortical–limbic stimulation of striatal motor pathways may play a critical role in causing compulsive disorders, we examined the responsiveness of D1CT mice to dopamine D 1 and D 2 receptor antagonists. D1CT mice were found to be largely resistant to the cataleptic action of the D 1 receptor antagonist SCH23390. The abnormal repetitive leaping of D1CT mice was similarly unaffected by SCH23390. In contrast, the D1CT mice displayed supersensitivity to cataleptic induction by the D 2 receptor antagonist sulpiride. These data are consistent with the hypothesis that complex compulsions are mediated by chronic excessive corticostriatal (and/or amygdalostriatal) glutamatergic stimulation of the striatal direct and indirect motor pathways.