[Magneto-encephalographic (MEG) brain recordings during traumatic memory recall in women with post-traumatic stress disorder: A pilot study]. / Enregistrement magnéto-encéphalographique (MEG) de réminiscences du trauma chez des femmes souffrant de stress post-traumatique : une étude pilote.

AIM OF THE STUDY: The experiment studied the effects of a short duration exposure to traumatic memories using magneto-encephalography (MEG). PATIENTS: Nine right-handed DSM-4 PTSD patients were recruited from a unit for anxiety disorders and an organisation supporting victims of violence. In order to have a homogeneous sample, we included only women who suffered from civilian PTSD. Exclusion criteria were co-morbid major medical illness, metallic dental prostheses that would interfere in the magnetic measurement, and current drug treatment. All participants were free from neurological disease and had normal hearing. They signed a written informed consent form. An ethics committee accepted the study. METHOD: A tape-recorded voice administered a script-driven imagery. The patients had to imagine, successively, a neutral image, a traumatic memory and rest, while MEG measured brain activities across delta, theta, alpha and beta bands. Each condition lasted three minutes. Heart rate (HR), anxiety and the vividness of mental images were recorded at the end of each phase. MEG power analysis was carried out with Statistical Parametric Mapping (SPM) 8. The signals were averaged for each of the three conditions of threeminutes duration. The dependent variable was a subtracted value: (trauma - rest) - (neutral - rest). The significance threshold was set at P<0.01. RESULTS: Anxiety and HR significantly increased during the trauma condition and returned to the neutral level during rest. The vividness of the mental imagery remained stable across the three conditions. The left-brain demonstrated a statistically significant power decrease in the secondary visual cortex (BA 18-19) in the delta band, the insula (BA13) in the beta band, the insula (BA13), premotor cortex (BA 6), Broca area (BA 44), and BA 43, in the alpha band. DISCUSSION: The symptom provocation protocol was successful in eliciting subjective anxiety and HR response in relation to traumatic memories. Our MEG results are in keeping with previous neuro-imagery studies showing decreased activities in the insula and Broca area during PTSD symptom provocation. However, we did not replicate the activation in the amygdala and the cingulate and prefrontal cortex found in some studies. Moreover, the within-group design, the small sample, and the inclusion of only female patients with milder dissociative symptoms limit our conclusions. The MEG protocol we used may also explain some partial discrepancies with previous MEG studies. However, our aim was to provoke a specific autobiographic recall of a traumatic event unfolding several sequential mental images along three minutes as in exposure therapy for PTSD. CONCLUSION: Despite its limitations, this pilot study is the first to provide MEG data during trauma recall. It suggests that recalling a specific traumatic event along three minutes results in hypo-activations of the brain regions regulating language and emotions. This paves the way to recording whole sessions of specific therapies for PTSD, with MEG using the millisecond resolution. MEG might be of interest to study the suppression of traumatic memories and their activation and habituation through prolonged graduated exposure in imagination across several sessions. MEG could also be used to study the effects of medication on PTSD symptoms. A controlled replication in a larger sample including male and female patients with various traumatic experiences is needed.

Somatizing patients: Part I. Practical diagnosis.

The phenomenon of somatization, which results in unexplained physical complaints, is ubiquitous in primary care settings although it often goes unrecognized. Medical training emphasizes the identification and treatment of organic problems and may leave physicians unprepared to recognize and address somatoform complaints. As a process, somatization ranges from mild stress-related symptoms to severe debilitation. Patients at the low end of the spectrum often respond to simple reassurance, but patients who are more impaired require interventions specifically designed to avoid unnecessary exposure to dangerous, costly and frustrating diagnostic procedures and treatments.

Somatizing patients: part II. Practical management.

Somatization is the experiencing of physical symptoms in response to emotional distress. It is a common and costly disorder that is frustrating to patients and physicians. Successful treatment of somatization requires giving an acceptable explanation of the symptoms to the patient, avoiding unwarranted interventions and arranging brief but regular office visits so that the patient does not need to develop new symptoms in order to receive medical attention. Antidepressants may be helpful in many patients, as well as cognitive psychotherapy when patients are willing to participate in it. Typical problems in managing such patients can be addressed by relying on the continuity established through regular visits to the same primary care physician.

The somatizing patient.

Somatization is the experience of physical symptoms in response to emotional distress. It is common, costly, and frustrating to both the patient and physician. Successful treatment of somatization requires the physician to pursue a positive diagnosis rather than rely on a diagnosis of exclusion. Treatment consists of giving an acceptable explanation of the symptoms to the patient, avoiding unwarranted interventions, and arranging brief but regular office visits for which the patient does not need to develop a new symptom to receive medical attention.

Context-processing deficits in schizophrenia: converging evidence from three theoretically motivated cognitive tasks.

To test the hypothesis that the ability to actively represent and maintain context information in a central function of working memory and that a disturbance in this function contributes to cognitive deficits in schizophrenia, the authors modified 3 tasks--the AX version of the Continuous Performance Test, Stroop, and a lexical disambiguation task--and administered them to patients with schizophrenia as well as to depressed and healthy controls. The results suggest an accentuation of deficits in patients with schizophrenia in context-sensitive conditions and cross-task correlations of performance in these conditions. However, the results do not definitively eliminate the possibility of a generalized deficit. The significance of these findings is discussed with regard to the specificity of deficits in schizophrenia and the hypothesis concerning the neural and cognitive mechanisms that underlie these deficits.

The role of locus coeruleus in the regulation of cognitive performance.

Noradrenergic locus coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.

Prevalence of posttraumatic stress disorder and major depressive disorder in Tibetan refugee children.

OBJECTIVE: In an exploratory survey the prevalence of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) was estimated in children who escaped from Tibet and found refuge in Tibetan settlements in India. METHOD: As part of an exploratory mission of the international medical relief organization Doctors Without Borders (Medecins Sans Frontieres), 61 randomly selected children from four group homes of the Tibetan Children Village in Dharamsala, India, were interviewed for symptoms of PTSD and MDD. RESULTS: 11.5% of the children met DSM-IV criteria for PTSD, and the same proportion met criteria for MDD. Children who had arrived from Tibet more recently (in the previous 18 months) showed a tendency for greater prevalence of PTSD than children who had been refugees longer. CONCLUSION: Tibetan children who succeed in their journey into exile suffer levels of stress-related disorders comparable with those of children in war situations or those exposed to natural disasters. However, in this population, several protective factors may help reduce the level of distress over time.

Dopamine and the mechanisms of cognition: Part I. A neural network model predicting dopamine effects on selective attention.

BACKGROUND: Dopamine affects neural information processing, cognition, and behavior; however, the mechanisms through which these three levels of function are affected have remained unspecified. We present a parallel-distributed processing model of dopamine effects on neural ensembles that accounts for effects on human performance in a selective attention task. METHODS: Task performance is stimulated using principles and mechanisms that capture salient aspects of information processing in neural ensembles. Dopamine effects are simulated as a change in gain of neural assemblies in the area of release. RESULTS: The model leads to different predictions as a function of the hypothesized location of dopamine effects. Motor system effects are simulated as a change in gain over the response layer of the model. This induces speeding of reaction times but an impairment of accuracy. Cognitive attentional effects are simulated as a change in gain over the attention layer. This induces a speeding of reaction times and an improvement of accuracy, especially at very fast reaction times and when processing of the stimulus requires selective attention. CONCLUSIONS: A computer simulation using widely accepted principles of processing in neural ensembles can account for reaction time distributions and time-accuracy curves in a selective attention task. The simulation can be used to generate predictions about the effects of dopamine agonists on performance. An empirical study evaluating these predictions is described in a companion paper.

Dopamine and the mechanisms of cognition: Part II. D-amphetamine effects in human subjects performing a selective attention task.

BACKGROUND: A neural network computer model described in a companion paper predicted the effects of increased dopamine transmission on selective attention under two different hypotheses. METHODS: To evaluate these predictions we conducted an empirical study in human subjects of D-amphetamine effects on performance of the Eriksen response competition task. Ten healthy volunteers were tested before and after placebo or D-amphetamine in a double-blind cross-over design. RESULTS: D-amphetamine induced a speeding of reaction time overall and an improvement of accuracy at fast reaction times but only in the task condition requiring selective attention. CONCLUSIONS: This pattern of results conforms to the prediction of the model under the hypothesis that D-amphetamine primarily affects dopamine transmission in cognitive rather than motor networks. This suggests that the principles embodied in parallel distributed processing models of task performance may be sufficient to predict and explain specific behavioral effects of some drug actions in the central nervous system.

Selective pharmacological activation of limbic structures in human volunteers: a positron emission tomography study.

Using a pharmacological probe, procaine hydrochloride, the authors elicited consistent and selective activation of anterior limbic and paralimbic structures in normal human volunteers as documented by H215O positron emission tomography. This activation was associated with a range of emotional, somatic, and visceral experiences, often similar to those experienced during the aura of temporal lobe epilepsy. Several subjects also experienced panic attacks. This study confirms that selective anterior limbic/paralimbic activity in normal human volunteers evokes many emotional phenomena as well as common "ill-defined" symptoms observed in clinical conditions. The present combination of procaine challenge and neuroimaging provides a noninvasive procedure to probe the contribution of different anterior limbic and paralimbic structures to normal human emotions and to neuropsychiatric disorders.

Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats.

The conditioning of fear responses to a simple acoustic stimulus (pure tone) paired with footshock can be mediated by the transmission of auditory information to the lateral nucleus of the amygdala from either the auditory thalamus or the auditory cortex. We examined the processing capacity of the thalamo-amygdala pathway by making lesions of the auditory cortex and testing the extent to which conditioned fear responses generalized to tones other than the one paired with footshock. Two studies were performed, one in an anatomically constrained computational model of the fear conditioning network and the other in rats. Stimulus generalization was unaffected in both. These findings support the validity of the model as an approach to studying the neural basis of conditioned fear learning, and in addition suggest that the thalamo-amygdala pathway, possibly by the use of population coding, is capable of performing at least crude stimulus discriminations.

Anxiety disorders and the syndrome of chest pain with normal coronary arteries: prevalence and pathophysiology.

Recurrent chest pain in the presence of normal coronary arteries is a common and perplexing problem in primary care medicine and cardiology and is associated with significant morbidity and health care utilization. A series of carefully controlled prospective studies conducted over the past decade have suggested a strong association between this syndrome and the presence of anxiety disorders. Thirty percent to 50% of patients with recurrent chest pain and normal coronary arteries meet criteria for panic disorder. Generalized anxiety disorder may also be associated with this syndrome. In contrast, major depression seems strongly associated with the syndrome only when it presents as a comorbidity with panic disorder. Reluctance of nonpsychiatric physicians to diagnose and treat anxiety disorders in this population may reflect a lack of knowledge of the well-established pathophysiologic mechanisms that can mediate the association of anxiety disorders and cardiac symptoms. We propose a conceptual framework, derived from the neurologic literature and from recent studies using positron emission tomography and intravenous procaine challenge, which links anxiety and subjective cardiovascular symptoms to abnormal activity in neural circuits involving the anterior limbic system of the brain. This neuropsychiatric model of the role of anxiety disorders in the pathophysiology of chest pain in patients with normal coronary arteries is proposed to strengthen the rationale for the identification and treatment of anxiety disorders in this population by nonpsychiatric physicians.

Pharmacologic activation of limbic structures and neuroimaging studies of emotions.

Two primary paradigms have been employed to study the neurobiological basis of human emotions. These are induced emotions in normal subjects and the comparison of patients suffering from emotional disorders with normal control subjects. These traditional methods, which have limitations, may be complemented by a third approach: the experimental elicitation of affect through pharmacologic limbic stimulation with intravenous procaine hydrochloride. In this paper, the authors review their research using the direct stimulation approach. To determine whether procaine produces affectively laden experiences accompanied by a reliable change in brain activity, 10 normal subjects received two injections each of placebo (A) and procaine (B)-in ABBA order-while in a positron emission tomography (PET) scanner. In a further study, emotional responses were observed among 24 subjects (including the 10 subjects in the PET study) for a total of 80 procaine injections. Procaine was shown to induce bilateral activation of an anterior limbic network concomitant with powerful, transient emotional and other subjective phenomena as well as autonomic and endocrine responses. Considerable between-subject variability in responses was noted, suggesting that this method can be used to explore individual differences in the neurobiological basis of emotion and affective disposition. Experimental elicitation of affect through limbic stimulation with procaine, when used as part of a triangulation strategy with traditional imaging paradigms, can contribute to our understanding of emotion and its disorders, of the different components of emotion-response systems (e.g., subjective, autonomic, and endocrine), and of individual differences in affective disposition.

Computational modeling of emotion: explorations through the anatomy and physiology of fear conditioning.

Recent discoveries about the neural system and cellular mechanisms in pathways mediating classical fear conditioning have provided a foundation for pursuing concurrent connectionist models of this form of emotional learning. The models described are constrained by the known anatomy underlying the behavior being simulated. To date, implementations capture salient features of fear learning, both at the level of behavior and at the level of single cells, and additionally make use of generic biophysical constraints to mimic fundamental excitatory and inhibitory transmission properties. Owing to the modular nature of the systems model, biophysical modeling can be carried out in a single region, in this case the amygdala. Future directions include application of the biophysical model to questions about temporal summation in the two sensory input paths to amygdala, and modeling of an attentional interrupt signal that will extend the emotional processing model to interactions with cognitive systems.

Schizophrenic deficits in the processing of context. A test of a theoretical model.

BACKGROUND: Schizophrenic patients show various deficits in cognitive functions that have been difficult to understand in terms of a common unifying hypothesis. Previously described neural network models of cognitive tasks suggest that several schizophrenic performance deficits may be related to a single function-an impairment in maintaining contextual information over time and in using that information to inhibit inappropriate responses. METHODS: We tested first-episode schizophrenic patients and patients later in the course of their illness on a new variant of the Continuous Performance Test designed specifically to elicit deficits in the processing of contextual information. RESULTS: Unmedicated schizophrenic patients showed a deterioration of their signal detection performance that followed the pattern predicted by the context hypothesis, ie, they responded inappropriately when correct responding required the maintenance of context information over time to inhibit the expression of a habitual response. This deficit correlated with positive symptoms. The results also suggested that the deficit may be worse in unmedicated patients who have had a longer course of illness. Medicated patients showed a more diffuse performance deficit. CONCLUSIONS: These results support the view that a single deficit in the processing of context information may underlie various cognitive impairments observed in schizophrenia. They also suggest that such an impairment is associated with positive rather than negative symptoms, and that it may worsen with the course of the illness as in the kraepelinian view of schizophrenia.

Semantic priming in schizophrenia: an examination of spreading activation using word pronunciation and multiple SOAs.

Semantic priming in word pronunciation was examined at 5 stimulus onset asynchronies (SOAs) in 75 medicated and 25 unmedicated people with schizophrenia (SCZ) and in 10 depressed and 28 normal controls. At SOAs < 950 ms, SCZ displayed priming similar to that of normal and depressed controls. At the 950-ms SOA, SCZ displayed less priming than controls. Medication dosage, but not conceptual disorganization scores, was positively associated with priming at SOAs < 950 ms. These results suggest that prior reports of enhanced priming in schizophrenia may have been confounded by methodological problems and that automatic priming processes operate normally in SCZ. The failure of SCZ to display significant priming at the 950-ms SOA is consistent with a hypothesized disturbance in higher level processes.

An anatomically constrained neural network model of fear conditioning.

Conditioning of fear reactions to an auditory conditioned stimulus (CS) paired with a footshock unconditioned stimulus (US) involves CS transmission to the amygdala from the auditory thalamus, the auditory cortex, or both. This article presents a simple neural network model of this neural system. The model consists of modules of mutually inhibitory nonlinear units representing the different relevant anatomical structures of the thalamo-amygdala and thalamo-corticoamygdala circuitry. Frequency-specific changes produced by fear conditioning were studied at the behavioral level (stimulus generalization) and the single-unit level (receptive fields). The findings mirror effects observed in conditioning studies of animals. This computational model provides an initial grounding for explorations of how emotional information and behavior are related to anatomical and physiological observations.

Neuroleptic effects on acquisition and performance of learned behaviors: a reinterpretation.

It is well-established that dopamine facilitates motor responsiveness. However, neuroleptics--drugs that block dopaminergic transmission--do not affect equally motor responses to environmental stimuli: responses to some stimuli seem completely preserved while responses to other stimuli are greatly disturbed. For example, escape responses to a noxious stimulus are typically preserved, even when avoidance to a cue predicting the noxious stimulus is absent. In this paper, we propose a connectionist account of this differential effect. We assume that dopamine determines the "gain" of the function relating the activation of a neural ensemble to its excitatory or inhibitory input. Because such a function is necessarily non-linear, we show that the influence of gain on whether a neural ensemble reaches a "threshold" of activation is critically different for low and high excitatory drives. This analysis makes specific predictions about the effect of neuroleptics on motor responses at different stages of training.