Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia.

BACKGROUND: Conditioning processes have been proposed to play a role in the development of anxiety disorders. As yet, the neurobiologic correlates of emotional learning have not been fully understood in these patients. Accordingly, brain activity was studied in subcortical and cortical regions involved in the processing of negative affect during differential aversive classical conditioning. METHODS: Twelve patients with social phobia and 12 healthy control subjects were presented with paired conditioned (CS; neutral facial expressions) and unconditioned stimuli (US; negative odor vs unmanipulated air). Functional magnetic resonance imaging (fMRI) was utilized to examine regional cerebral activity during habituation, acquisition,a nd extinction trials. Activity was measured with echo-planar-imaging (EPI), and signal intensity in individually defined anatomic regions were analyzed. RESULTS: Subjective ratings of emotional valence to the CS indicated that behavioral conditioning occurred in both groups. The presentation of CS associated with negative odor led to signal decreases in the amygdala and hippocampus of normal subjects, whereas an opposite increased activation in both regions was observed in patients. Regional differences were not found during habituation and extinction. CONCLUSIONS: Results suggest that conditioned aversive stimuli are processed in subcortical regions, with phobic patients differing from control subjects.

Subcortical correlates of craving in recently abstinent alcoholic patients.

OBJECTIVE: This study investigated functional cerebral correlates of craving in alcoholic patients and examined the state/trait characteristics of the regional cerebral network implicated in craving. METHOD: Functional magnetic resonance imaging (fMRI) was used to map cerebral response elicited by ethanol odor in 10 male patients with alcohol dependence who had undergone detoxification and 10 matched nonpatients. After 3 weeks, during which the patients underwent standardized behavioral therapy with psychopharmacological intervention, all subjects were studied a second time with fMRI to evaluate the effects of therapy on the functional cerebral correlates of craving. RESULTS: In the alcoholic patients, cue-induced craving before treatment elicited activation primarily in the subcortical-limbic region of the right amygdala/hippocampal area and in the cerebellum. After treatment, activation was found in the superior temporal sulcus, while subcortical or cerebellar participation was no longer present. Comparison subjects showed no comparable amygdala or cerebellar activation during ethanol stimulation and demonstrated no change in activation pattern between measurements. CONCLUSIONS: This investigation points to state-dependent neurobiological correlates of cue-induced craving in alcoholic patients and suggests that these correlates can be influenced by therapeutic interventions. The presence of emotional aspects of craving is suggested by amygdala activation.

Serotonin1A-receptor agonism attenuates the cocaine-induced increase in serotonin levels in the hippocampus and nucleus accumbens but potentiates hyperlocomotion: an in vivo microdialysis study.

The hippocampus and the nucleus accumbens (Nac) are important structures for the modulation of spontaneous locomotor activity. Both structures receive a serotonergic (5-HT) innervation. We have previously reported that the 5-HT(1A)-receptor antagonist WAY 100635 blocked cocaine-induced hyperactivity, while potentiating cocaine-induced 5-HT increases in the hippocampus and the Nac. In order to further investigate the relationship between extracellular 5-HT concentration and cocaine-induced behaviour, we used in vivo microdialysis to measure the effects of the 5-HT(1A)-receptor agonist 8-OH-DPAT on cocaine-induced changes in the extracellular 5-HT concentration in the hippocampus and the Nac and on behavioural activity. Following a pilot pretest in which we determined the lowest effective dose of 8-OH-DPAT for potentiating cocaine-induced hyperlocomotion, four groups of rats were given one of the following drug treatments: 8-OH-DPAT (0.2 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), 8-OH-DPAT (0.2 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 30 min apart. We found that the 5-HT(1A)-receptor agonist 8-OH-DPAT attenuated the cocaine-induced increases in 5-HT in the hippocampus and the Nac, but potentiated cocaine-induced hyperlocomotion. 5-HT metabolite measurements revealed a complex role for the 5-HT(1A)-receptor in the broad spectrum of cocaine's neurochemical effects. Altogether, these observations support an important role of the 5-HT(1A)-receptor in the hippocampus and Nac in the modulation of cocaine stimulant effects.

Emotional processing in schizophrenia across cultures: standardized measures of discrimination and experience.

Schizophrenia appears quite similar across a range of cultures. However, variability has been noted, and understanding the variant and invariant features of the disorder is necessary for elucidating its biological and environmental basis. Evidence of prominent emotion processing deficits in schizophrenia, including perceptual and experiential aspects, led us to extend the paradigm of standardized measures cross-culturally. We assessed performance of American, German, and Indian patients with schizophrenia and healthy controls on standardized emotion discrimination and experience (mood induction) procedures using happy, sad, and neutral facial expressions of Caucasian actors. Participants were 80 Americans (40 patients; 40 controls), 48 Germans (24 patients; 24 controls), and 58 Indians (29 patients; 29 controls). Face discrimination performance was impaired across patient groups, but was most impaired in those of Indian origin. Lower performance was also found in Indian controls, relative to their American and German counterparts. Mood induction produced weaker effects in all patient groups relative to their respective controls. The results supported the feasibility of cross-cultural comparisons and also emphasized the importance of poser ethnic background for facial affect identification, while poser ethnicity was less consequential for mood induction effects. Emotion processing deficits in schizophrenia may add to the clinical burden, and merit further examination.

Differential amygdala activation in schizophrenia during sadness.

Several studies have reported impaired emotion processing in schizophrenic patients. However, the corresponding functional cerebral correlates of such impairment have not been fully understood, leaving the neurobiological basis of their affective symptoms unknown. Functional magnetic resonance imaging (fMRI) was utilized to examine brain activity in subcortical and cortical regions of 13 medicated male schizophrenic patients and 13 matched healthy controls during happy and sad mood induction. Results show brain activity in the amygdala of normal controls during negative affect, which is in line with previous neuroimaging findings. Unlike controls, schizophrenic patients have not demonstrated amygdala activation during sadness despite matched ratings to normal controls indicating a similar negative affect. Recognizing that structural abnormalities exist in the amygdala of schizophrenic patients, our results provide new evidence of functional abnormalities in the limbic system.

Transcranial magnetic stimulation: no effect on mood with single pulse during learned helplessness.

1. Transcranial Magnetic Stimulation (TMS) is suggested to be an effective tool in the treatment of depression. However, the methodology most suitable for clinical application remains unclear. 2. The effect of TMS was tested in a double-blind and placebo-controlled setting on 18 healthy subjects. At the same time an established learned helplessness paradigm was applied to induce dysphoria, which consisted of unsolvable anagrams. 3. Sixty 0.5 Hz stimuli were administered at an intensity of 130% of the subject's motor threshold after the subjects were exposed to the learned helplessness situation. Using a vertically positioned coil, the stimuli were applied to the right or to the left frontal cortex, or on the occipital cortex as a placebo condition. 4. Although dysphoria was successfully induced by unsolvable anagrams, TMS on either of the two frontal locations did not influence mood. This lack of effect may be due to the stimulation characteristics employed here (low TMS intensity, and low frequency). On the other hand, the findings may reflect the neurobiological difference between experimentally induced sad mood and clinical depression.

Correspondence of emotional self-rating with facial expression.

Emotional processing abilities are difficult to measure psychometrically. Ultimately their quantification has to rely on 'subjective' judgment thereby leaving open the problem of response biases. Assessments of autonomic arousal similarly provide a mere unspecified measurement of a specific emotion. A standardized mood induction procedure capable of obtaining reliable happy and sad mood changes in healthy subjects was used to demonstrate the effectiveness of this procedure. We performed a two-part experiment using a rater-based analysis of facial expressions. This entailed analyzing the emotion portrayed in the faces. The faces of 24 healthy subjects were videotaped during the mood induction procedure of happiness and sadness, respectively. A group of 20 raters naive to the experimental task and conditions rated the facial expressions on six basic emotions. Results showed that ratings corresponded with the facial expressions, which were reflecting the mood of the task condition. Subjects' facial expressions together with self-ratings demonstrate the successful applicability of this standardized mood induction procedure for eliciting happy and sad mood.

Gender differences in regional cerebral activity during sadness.

Functional magnetic resonance imaging and echo-planar-imaging were used to investigate affect related gender differences in regional cerebral activity. The experiment was conducted using a standardized mood induction procedure. Blood-oxygen-level-dependent effect was measured in 13 male and 13 female healthy subjects, during both moods of happiness and sadness, respectively. Parallel to earlier neuroimaging findings, our results show brain activity in the amygdala of males during negative affect. Females failed to demonstrate a similar activation pattern despite matched subjective ratings of negative affect to males. Results point to differential regional cerebral correlates of emotional experience in males and females, which is suggestive of a more focal and subcortical processing of sadness in men.

A new approach to measure single-event related brain activity using real-time fMRI: feasibility of sensory, motor, and higher cognitive tasks.

Real-time fMRI is a rapidly emerging methodology that enables monitoring changes in brain activity during an ongoing experiment. In this article we demonstrate the feasibility of performing single-event sensory, motor, and higher cognitive tasks in real-time on a clinical whole-body scanner. This approach requires sensitivity optimized fMRI methods: Using statistical parametric mapping we quantified the spatial extent of BOLD contrast signal changes as a function of voxel size and demonstrate that sacrificing spatial resolution and readout bandwidth improves the detection of signal changes in real time. Further increases in BOLD contrast sensitivity were obtained by using real-time multi-echo EPI. Real-time image analysis was performed using our previously described Functional Imaging in REal time (FIRE) software package, which features real-time motion compensation, sliding window correlation analysis, and automatic reference vector optimization. This new fMRI methodology was validated using single-block design paradigms of standard visual, motor, and auditory tasks. Further, we demonstrate the sensitivity of this method for online detection of higher cognitive functions during a language task using single-block design paradigms. Finally, we used single-event fMRI to characterize the variability of the hemodynamic impulse response in primary and supplementary motor cortex in consecutive trials using single movements. Real-time fMRI can improve reliability of clinical and research studies and offers new opportunities for studying higher cognitive functions.