Altered Connectivity in Autistic Adults during Complex Facial Emotion Recognition: A Study of EEG Imaginary Coherence.

Difficulties in Facial Emotion Recognition (FER) are commonly associated with individuals diagnosed with Autism Spectrum Disorder (ASD). However, the mechanisms underlying these impairments remain inconclusive. While atypical cortical connectivity has been observed in autistic individuals, there is a paucity of investigation during cognitive tasks such as FER. It is possible that atypical cortical connectivity may underlie FER impairments in this population. Electroencephalography (EEG) Imaginary Coherence was examined in 22 autistic adults and 23 typically developing (TD) matched controls during a complex, dynamic FER task. Autistic adults demonstrated reduced coherence between both short and long range inter-hemispheric electrodes. By contrast, short range intra-hemispheric connectivity was increased in frontal and occipital regions during FER. These findings suggest altered network functioning in ASD.

Neuronal correlates of appetite regulation in patients with schizophrenia: is there a basis for future appetite dysfunction?

BACKGROUND: Given the undesired metabolic side effects of atypical antipsychotic medication it is important to understand the neuronal basis related to processing of appetite regulation in patients affected by schizophrenia. METHODS: Here we used functional magnetic resonance imaging (fMRI) to assess brain activity in response to food cues and neutral stimuli in twenty patients with schizophrenia and eleven healthy individuals. In addition to clinical and dietary habits assessments, we collected, in patients, measurements of fasting glucose, ghrelin, leptin, insulin, prolactin and lipids blood concentration and we correlated the cerebral activity with clinical and metabolic measures. RESULTS: Both groups engaged a common neuronal network while processing food cues, which included the left insula, primary sensorimotor areas, and inferior temporal and parietal cortices. Cerebral responses to appetitive stimuli in thalamus, parahippocampus and middle frontal gyri were specific only to schizophrenic patients, with parahippocampal activity related to hunger state and increasing linearly over time. Antipsychotic medication dosage correlated positively with a cognitive measure reflecting food cravings, whereas the severity of the disease correlated negatively with a cognitive measure indicating dietary restraint in eating habits. These cognitive variables correlated, in turn, with parahippocampal and thalamic neuronal activities, respectively. CONCLUSIONS: We identified a specific neural substrate underlying cognitive processing of appetitive stimuli in schizophrenia, which may contribute to appetite dysfunction via perturbations in processing of homeostatic signals in relation to external stimuli. Our results also suggest that both antipsychotic medication and the disease severity per se could amplify these effects, via different mechanisms and neuronal networks.

Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment.

There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.

Increased extrapyramidal symptoms in patients with schizophrenia and a comorbid substance use disorder.

Few data have been gathered about the impact of psychoactive substances on extrapyramidal symptoms (EPS) in schizophrenia, and so far, inconsistent results have been reported. We studied 41 outpatients with schizophrenia (based on DSM-IV criteria), who were divided into two groups: with (n = 17) and without (n = 24) a substance use disorder (alcohol, cannabis, and/or cocaine). Both groups were matched for sociodemographic data and psychiatric symptoms (Positive and Negative Syndrome Scale). EPS were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale, and all patients were stable on either quetiapine or clozapine. Patients receiving anticholinergic drugs were excluded. Analyses of variance were conducted on both groups and showed that schizophrenia patients with a comorbid substance use disorder (especially cocaine) displayed more EPS compared with non-abusing patients.

In search of anticipation in unipolar affective disorder.

Controversial evidence exists regarding the presence of the phenomenon of anticipation in affective disorder. To further evaluate this hypothesis on the unipolar pattern of the disease, we examined 21 two-generation pairs of first and second degree relatives with unipolar recurrent major depression. Biases from index-patient and from unaffected sibs were taken into consideration. A significant difference in the age at onset and episode frequency (as measure of disease severity) between parental and offspring generation was observed. The median age at onset of the parental generation was 37+/-8.2 years compared to 22+/-8.3 years in the offspring generation (p=0.001). The offspring generation also experienced an episode frequency two times greater than the parent generation (p=0.001). Anticipation was demonstrated in 95% of pairs regarding age at onset and in 84% of pairs in episode frequency. However, the observation of a birth cohort effect may possibly explain the differences in age at onset between generations in our sample.

Patterns of co-morbidity in male suicide completers.

BACKGROUND: Psychiatric co-morbidity is thought to be an important problem in suicide, but it has been little investigated. This study aims to investigate patterns of co-morbidity in a group of male suicide completers. METHOD: One hundred and fifteen male suicide completers from the Greater Montreal Area and 82 matched community controls were assessed using proxy-based diagnostic interviews. Patterns of co-morbidity were investigated using latent class analysis. RESULTS: Three subgroups of male suicide completers were identified (L2 = 171.62, df = 2012, P < 0.05). they differed significantly in the amount of co-morbidity (Kruskal-Wallis chi2 = 71.227, df = 2. P < 0.000) and exhibited different diagnostic profiles. Co-morbidity was particularly found in subjects with disorders characterized by impulsive and impulsive-aggressive traits, whereas subjects without those traits had levels of co-morbidity which were not significantly different from those of controls (chi2 = 8.17, df = 4, P = 0.086). CONCLUSIONS: Suicide completers can be divided into at least three subgroups according to co-morbidity: a low co-morbidity group, a substance-dependent group and a group exhibiting childhood onset of psychopathology.

Suicide and serotonin: study of variation at seven serotonin receptor genes in suicide completers.

Suicide is an important public health problem, accounting for a significant proportion of total mortality among young people, particularly males. There is growing and consistent evidence suggesting that genetic factors play an important role in the predisposition to suicide. Based on several lines of evidence supporting a reduced serotonergic neurotransmission in subjects who committed suicide, we investigated variation at genes that code for serotonin receptor 1B (5-HTR1B), 1Dalpha (5-HTR1Dalpha), 1E (5-HTR1E), 1F (5-HTR1F), 2C (5-HTR2C), 5A (5-HTR5A), and 6 (5-HTR6) in a total sample of 106 suicide completers and 120 normal controls. No differences were observed in allelic or genotypic distributions between groups for any of the loci investigated. Moreover, further analysis according to suicide method or psychopathology also failed to reveal differences between groups. Our results do not support a substantial role of these serotonergic receptors in suicide completion.

Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses.

Latent inhibition (LI) is an important model for understanding cognitive deficits in schizophrenia. Disruption of LI is thought to result from an inability to ignore irrelevant stimuli. The study investigated LI in schizophrenic patients by using Pavlovian conditioning of electrodermal responses in a complete within-subject design. Thirty-two schizophrenic patients (16 acute, unmedicated and 16 medicated patients) and 16 healthy control subjects (matched with respect to age and gender) participated in the study. The experiment consisted of two stages: preexposure and conditioning. During preexposure two visual stimuli were presented. one of which served as the to-be-conditioned stimulus (CSp + ) and the other one was the not-to-be-conditioned stimulus (CSp - ) during the following conditioning ( = acquisition). During acquisition, two novel visual stimuli(CSn + and CSn - ) were introduced. A reaction time task was used as the unconditioned stimulus (US). LI was defined as the difference in response differentiation observed between preexposed and non-preexposed sets of CS + and CS - . During preexposure, the schizophrenic patients did not differ in electrodermal responding from the control subjects, neither concerning the extent of orienting nor the course of habituation. The exposure to novel stimuli at the beginning of the acquisition elicited reduced orienting responses in unmedicated patients compared to medicated patients and control subjects. LI was observed in medicated schizophrenic patients and healthy controls, but not in acute unmedicated patients. Furthermore LI was found to be correlated with the duration of illness: it was attenuated in patients who had suffered their first psychotic episode.

Attentional modulation of blink startle at long, short, and very short lead intervals.

The present research investigated attentional blink startle modulation at lead intervals of 60, 240 and 3500 ms. Letters printed in Gothic or standard fonts, which differed in rated interest, but not valence, served as lead stimuli. Experiment 1 established that identifying letters as vowels/consonants took longer than reading the letters and that performance in both tasks was slower if letters were printed in Gothic font. In Experiment 2, acoustic blink eliciting stimuli were presented 60, 240 and 3500 ms after onset of the letters in Gothic and in standard font and during intertrial intervals. Half the participants (Group Task) were asked to identify the letters as vowels/consonants whereas the others (Group No-Task) did not perform a task. Relative to control responses, blinks during letters were facilitated at 60 and 3500 ms lead intervals and inhibited at the 240 ms lead interval for both conditions in Group Task. Differences in blink modulation across lead intervals were found in Group No-Task only during Gothic letters with blinks at the 3500 ms lead interval facilitated relative to control blinks. The present results confirm previous findings indicating that attentional processes can modulate startle at very short lead intervals.

TPH and suicidal behavior: a study in suicide completers.

An association between the gene that codes for tryptophan hydroxylase (TPH)-the rate-limiting enzyme in the synthesis of serotonin-and suicidal behavior has been investigated with some detail in samples of living subjects who attempted suicide. In this study, we investigated TPH and suicide completion, the most severe form of suicidal behavior. A relatively large sample of suicide completers (n = 101) was genotyped at three TPH loci (two polymorphisms in the promoter region, A-6526G and G-5806T, and one in intron 7, A218C) and compared to psychiatrically normal living controls (n = 129). Although no significant differences were found between groups for genetic variation at single loci, haplotype analysis revealed that one haplotype (-6526G -5806T 218C) was significantly more frequent among suicide cases than in normal controls (chi(2) = 11.30, df = 2, P = 0.0008; OR = 2.0 CI: 1.30-3.6). Further analyses suggested that this haplotype is particularly more frequent among subjects who committed suicide using violent methods. Similar results were observed in recent haplotype analyses in suicide attempters, which found that the equivalent of haplotype -6526G -5806T 218C was more frequent in impulsive attempters (Rotondo et al, Mol Psychiatry 1999; 4: 360-368). Our results replicate in suicide completers previous data observed in suicide attempters. These and other results continue to point to the substantial role that the gene that codes for TPH may play in the neurobiology of suicidal behavior.

The effects of change in lead stimulus modality on the modulation of acoustic blink startle.

In two experiments we investigated the effect of generalized orienting induced by changing the modality of the lead stimulus on the modulation of blink reflexes elicited by acoustic stimuli. In Experiment 1 (n = 32), participants were presented with acoustic or visual change stimuli after habituation training with tactile lead stimuli. In Experiment 2 (n = 64), modality of the lead stimulus (acoustic vs. visual) was crossed with experimental condition (change vs. no change). Lead stimulus change resulted in increased electrodermal orienting in both experiments. Blink latency shortening and blink magnitude facilitation increased from habituation to change trials regardless of whether the change stimulus was presented in the same or in a different modality as the reflex-eliciting stimulus. These results are not consistent with modality-specific accounts of attentional startle modulation.

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder.

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.

Linkage of mood disorders with D2, D3 and TH genes: a multicenter study.

BACKGROUND: It has been suggested that the dopaminergic system is involved in the pathophysiology of mood disorders. We conducted a multicenter study of families with mood disorders, to investigate a possible linkage with genes coding for dopamine receptor D2, dopamine receptor D3 and tyrosine hydroxylase (TH). METHODS: Twenty three mood disorder pedigrees collected within the framework of the European Collaborative Project on Affective Disorders were analyzed with parametric and non-parametric linkage methods. Various potential phenotypes were considered, from a narrow (only bipolar as affected) to a broad (bipolar+major depressive+schizoaffective disorders) definition of affection status. RESULTS: Parametric analyses excluded linkage for all the candidate genes, even though small positive LOD (Limit of Detection) scores were observed for TH in three families. Non-parametric analyses yielded negative results for all markers. CONCLUSION: The D2 and D3 dopamine receptors were, therefore, not a major liability factor for mood disorders in our sample, whereas TH may play a role in a subgroup of patients.

The effect of warning stimulus modality on blink startle modification in reaction time tasks.

The present study investigated the effects of lead stimulus modality on modification of the acoustic startle reflex during three reaction time tasks. In Experiment 1, participants (N = 48) were required to press a button at the offset of one stimulus (task relevant) and to ignore presentations of a second (task irrelevant). Two tones that differed in pitch or two lights served as signal stimuli. Blink startle was elicited during some of the stimuli and during interstimulus intervals. Skin conductance responses were larger during task-relevant stimuli in both groups. Larger blink facilitation during task-relevant stimuli was found only in the group presented with auditory stimuli, whereas larger blink latency shortening during task-relevant stimuli was found in both groups. Experiment 2 (N = 32) used only a task-relevant stimulus. Blink magnitude facilitation was significant only in the group presented with tones, whereas blink latency shortening was significant in both groups. Experiment 3 (N = 80) used a go/nogo task that required participants to press a button if one element of a compound stimulus ended before the second, but not if the asynchrony was reversed. The offset asynchrony was varied between groups as a manipulation of task difficulty. Startle magnitude facilitation was larger during acoustic than during visual stimuli and larger in the easy condition. The present data indicate that startle facilitation in a reaction time task is affected by stimulus modality and by task demands. The effects of the task demands seem to be independent of lead stimulus modality.

The effects of threat and nonthreat word lead stimuli on blink modification.

Two experiments examined the effects of visually presented threat and nonthreat word lead stimuli on blink modification among unselected young adults (Experiment 1, N = 35) and participants selected for low and high trait anxiety (Experiment 2, N = 60). The blink reflex was elicited by a white noise probe of 105 dB. Lead stimulus intervals of 60, 120, 240, and 2000 ms were used in both experiments. Prepulse inhibition was observed at the 240-ms interval and prepulse facilitation was observed at the 60-ms interval in both experiments. Also, greater facilitation was found in both experiments during threat words at the 60-ms interval and greater inhibition during threat words at the 240-ms interval. Experiment 2 provided some evidence that the greater facilitation during threat words than during nonthreat words at the 60-ms probe interval may be found in high trait anxious participants, but not in low trait anxious participants. The results are discussed in relation to contemporary information processing theories of anxiety.

Social adjustment and self-esteem in remitted patients with mood disorders.

Mood disorders are characterized by manic and depressive episodes alternating with normal mood. While social function is heavily impaired during episodes of illness, there are conflicting opinions about inter-episode function. The present paper focuses on self-esteem and social adjustment in remitted mood disorders patients. Patients with mood disorders (99 bipolar and 86 major depressive subjects, in remission) were compared with a group of 100 control subjects. The self-esteem scale (SES) and the social adjustment scale (SAS) were used to measure self-esteem and social adjustment, respectively, in both groups of subjects. Patients with mood disorder exhibited worse social adjustment and lower self-esteem than control subjects. These results strongly confirm previous observations of poor inter-episode function in patients with mooddisorder.

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.

Treatment resistant depression: methodological overview and operational criteria.

A wide variety of definitions are used for Treatment Resistant Depression (TRD), considering various criteria and different concepts. Some of the key issues are: the diagnosis, the treatment adequacy in terms of dose and duration, the treatment response assessment and the number of failed therapeutic trials required. Systematic research has been characterizing the concept and criteria to define the different variables involved. Lack of consensus on these issues limits comparison across clinical trials and interpretation of treatment efficacy in the management of treatment resistant patients. Through reanalyzes of available data, we point out the limits of TRD definitions and propose conceptual and operational criteria for a collaborative research project on TRD. It appears that a number of variables commonly associated to treatment resistance are independent of patients characteristics and mainly refer to misdiagnosis and inadequate treatment. The proposed criteria are intended for therapeutic trials in TRD, combining the evaluation of treatment efficiency and the validation of the concept of TRD itself. Major depression with poor response to two adequate trials of different classes of antidepressants is proposed for an operational definition of TRD. Rationale for this definition is discussed in contrast to alternative definitions.

RWMODEL II: computer simulation of the Rescorla-Wagner model of Pavlovian conditioning.

RWMODEL II simulates the Rescorla-Wagner model of Pavlovian conditioning. It is written in Delphi and runs under Windows 3.1 and Windows 95. The program was designed for novice and expert users and can be employed in teaching, as well as in research. It is user friendly and requires a minimal level of computer literacy but is sufficiently flexible to permit a wide range of simulations. It allows the display of empirical data, against which predictions from the model can be validated.