E. Merlotti

The cortical generators of P3a and P3b: a LORETA study.

The P3 is probably the most well known component of the brain event-related potentials (ERPs). Using a three-tone oddball paradigm two different components can be identified: the P3b elicited by rare target stimuli and the P3a elicited by the presentation of rare non-target stimuli. Although the two components may partially overlap in time and space, they have a different scalp topography suggesting different neural generators. The present study is aimed at defining the scalp topography of the two P3 components by means of reference-independent methods and identifying their electrical cortical generators by using the low-resolution electromagnetic tomography (LORETA). ERPs were recorded during a three-tone oddball task in 32 healthy, right-handed university students. The scalp topography of the P3 components was assessed by means of the brain electrical microstates technique and their cortical sources were evaluated by LORETA. P3a and P3b showed different scalp topography and cortical sources. The P3a electrical field had a more anterior distribution as compared to the P3b and its generators were localized in cingulate, frontal and right parietal areas. P3b sources included bilateral frontal, parietal, limbic, cingulate and temporo-occipital regions. Differences in scalp topography and cortical sources suggest that the two components reflect different neural processes. Our findings on cortical generators are in line with the hypothesis that P3a reflects the automatic allocation of attention, while P3b is related to the effortful processing of task-relevant events.

Double dissociation of N1 and P3 abnormalities in deficit and nondeficit schizophrenia

It has been proposed that the presence of enduring, idiopathic negative symptoms define a group of patients with a disease (deficit schizophrenia, DS) that is separate from other forms of schizophrenia (nondeficit schizophrenia, NDS). Although several findings support this hypothesis, the possibility that DS represents the severe end of a single schizophrenia continuum cannot be excluded yet. We tested the hypothesis that DS and NDS differ relative to event-related potentials (ERPs). Amplitude, scalp topography and cortical sources of the ERP components were assessed in clinically stable DS and NDS outpatients and in matched healthy subjects (HCS). Twenty subjects per group were recruited. Among the subjects who completed the target detection task, there were no group difference in accuracy. For N1, only patients with DS, as compared with HCS, showed an amplitude reduction over the scalp central leads and a reduced current source density in cingulate and parahippocampal gyrus. For P3, only patients with NDS, as compared with HCS, showed a lateralized amplitude reduction over the left posterior regions and reduced current source density in left temporal and bilateral frontal, cingulate and parietal areas. The DS and NDS groups differed significantly from each other with regard to N1 amplitude and topography, as well as P3 amplitude and cortical sources. The N1 was affected in DS but not in NDS patients, whereas P3 was affected in NDS only. This double dissociation is consistent with the hypothesis that DS represents a separate disease entity within schizophrenia.

Pharmaco-EEG in Psychiatry

In spite of its origins deeply rooted in the discipline, pharmaco-EEG applications in psychiatry remain limited to its achievements in the field of psychotropic drugs classification and, in few instances, discovery. In the present paper two attempts to transfer pharmaco-EEG methods to psychiatric clinical routine will be described: 1) monitoring of psychotropic drug toxicity at the central nervous system level, and 2) prediction of clinical response to treatment with psychotropic drugs. Both applications have been the object of several investigations providing promising and sometimes consistent findings which, however, had no impact on clinical practice. For the first topic, the review is limited to antipsychotics, lithium and recreational drugs, as for other psychotropic drugs mostly case studies are available, while for the response prediction it will include antipsychotics, antidepressants, anxiolytics, psychostimulants and nootropics. In spite of several methodological limitations, pharmaco-EEG studies dealing with monitoring of antipsychotic- and lithium-induced EEG abnormalities went close to, but never became, a clinical routine. EEG studies of recreational drugs are flawed by several limitations, and failed, so far, to identify reliable indices of CNS toxicity to be used in clinical settings. Several QEEG studies on early predictors of treatment response to first generation antipsychotics have produced consistent findings, but had no clinical impact. For other psychotropic drug classes few and inconsistent reports have appeared. Pharmaco-EEG had the potential for important clinical applications, but so far none of them entered clinical routine. The ability to upgrade theories and methods and promote large scale studies represent the future challenge.

Executive hypercontrol in obsessive-compulsive disorder: electrophysiological and neuropsychological indices

OBJECTIVE Neuropsychological, brain imaging and electrophysiological research have consistently shown a dysfunction of fronto-striato-thalamic pathways in subjects with obsessive-compulsive disorder (OCD). The functional meaning of the observed dysfunction in the pathogenesis of OCD is still debated. In the present study the hypothesis that it might be related to a hyperactive executive control is explored by means of neuropsychological and electrophysiological measures. METHODS Multilead quantitative EEG (QEEG) characteristics and neuropsychological performance on tests exploring executive functions, attention, short-term memory and the ability to learn supraspan recurring sequences were investigated in 32 drug-free patients with DSM-IV OCD. Multilead QEEG characteristics were also investigated in 32 healthy controls, matched with patients for age, gender and handedness. RESULTS A decrease of the slow alpha-band power in OCD as compared to healthy subjects was observed. A significant negative correlation between the slow alpha-band power and the time to complete a neuropsychological test exploring executive functions was found: the more reduced the slow alpha-band power, the slower the performance on this test. CONCLUSIONS The topographic distribution of the observed QEEG abnormalities, as well as their correlations with neuropsychological indices, suggest an increased activation of frontal networks in OC patients. SIGNIFICANCE Study findings support the presence of a hyperactivity of attention/executive control mechanisms in obsessive-compulsive patients.

Induced Gamma Activity and Event-Related Coherence in Schizophrenia

Evidence has been provided that high frequency oscillations within the gamma band reflect mechanisms of cortical integration. In the light of recently proposed pathophysiological models of schizophrenia, suggesting a disturbance of the functional connectivity within distributed neural networks, it has been hypothesized that abnormalities in the gamma band underlie perceptual and cognitive dysfunctions in patients with schizophrenia. In the present study we investigated evoked and induced 40-Hz gamma power as well as frontoparietal and frontotem-poral event-related coherence in patients with deficit and nondeficit schizophrenia and in matched healthy controls. In patients, correlations between gamma oscillations and psychopathological dimensions were also investigated. A reduction of both induced gamma power and event-related coherence was observed in patients with nondeficit schizophrenia, but not in those with deficit schizophrenia. Our findings support the hypothesis that deficit and nondeficit schizophrenia represent separate disease entities, suggesting the presence of a poor integration of the neuronal activity within distributed neural network only in the subgroup of schizophrenic patients without primary and persistent negative symptoms. Associations between an excess of gamma oscillations and psychopathological dimensions were observed, suggesting that abnormal thoughts, behaviors and perceptions might be related to the formation of inappropriate neural connections.

The Brief Negative Symptom Scale (BNSS): Independent validation in a large sample of Italian patients with schizophrenia.

BACKGROUND The Brief Negative Symptom Scale (BNSS) was developed to address the main limitations of the existing scales for the assessment of negative symptoms of schizophrenia. The initial validation of the scale by the group involved in its development demonstrated good convergent and discriminant validity, and a factor structure confirming the two domains of negative symptoms (reduced emotional/verbal expression and anhedonia/asociality/avolition). However, only relatively small samples of patients with schizophrenia were investigated. Further independent validation in large clinical samples might be instrumental to the broad diffusion of the scale in clinical research. METHODS The present study aimed to examine the BNSS inter-rater reliability, convergent/discriminant validity and factor structure in a large Italian sample of outpatients with schizophrenia. RESULTS Our results confirmed the excellent inter-rater reliability of the BNSS (the intraclass correlation coefficient ranged from 0.81 to 0.98 for individual items and was 0.98 for the total score). The convergent validity measures had r values from 0.62 to 0.77, while the divergent validity measures had r values from 0.20 to 0.28 in the main sample (n=912) and in a subsample without clinically significant levels of depression and extrapyramidal symptoms (n=496). The BNSS factor structure was supported in both groups. CONCLUSIONS The study confirms that the BNSS is a promising measure for quantifying negative symptoms of schizophrenia in large multicenter clinical studies.

Neurobiological background of negative symptoms

Studies investigating neurobiological bases of negative symptoms of schizophrenia failed to provide consistent findings, possibly due to the heterogeneity of this psychopathological construct. We tried to review the findings published to date investigating neurobiological abnormalities after reducing the heterogeneity of the negative symptoms construct. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, genetics and neurobiology of schizophrenia. We searched PubMed with the keywords “negative symptoms,” “deficit schizophrenia,” “persistent negative symptoms,” “neurotransmissions,” “neuroimaging” and “genetic.” Additional articles were identified by manually checking the reference lists of the relevant publications. Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included. Structural and functional imaging studies addressed the issue of neurobiological background of negative symptoms from several perspectives (considering them as a unitary construct, focusing on primary and/or persistent negative symptoms and, more recently, clustering them into factors), but produced discrepant findings. The examined studies provided evidence suggesting that even primary and persistent negative symptoms include different psychopathological constructs, probably reflecting the dysfunction of different neurobiological substrates. Furthermore, they suggest that complex alterations in multiple neurotransmitter systems and genetic variants might influence the expression of negative symptoms in schizophrenia. On the whole, the reviewed findings, representing the distillation of a large body of disparate data, suggest that further deconstruction of negative symptomatology into more elementary components is needed to gain insight into underlying neurobiological mechanisms.

Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases.

Primary and persistent negative symptoms (PPNS) represent an unmet need in the care of people with schizophrenia. They have an unfavourable impact on real-life functioning and do not respond to available treatments. Underlying etiopathogenetic mechanisms of PPNS are still unknown. The presence of primary and enduring negative symptoms characterizes deficit schizophrenia (DS), proposed as a separate disease entity with respect to non-deficit schizophrenia (NDS). More recently, to reduce the heterogeneity of negative symptoms by using criteria easily applicable in the context of clinical trials, the concept of persistent negative symptoms (PNS) was developed. Both PNS and DS constructs include enduring negative symptoms (at least 6months for PNS and 12months for DS) that do not respond to available treatments. PNS exclude secondary negative symptoms based on a cross-sectional evaluation of severity thresholds on commonly used rating scales for positive symptoms, depression and extrapyramidal side effects; the DS diagnosis, instead, excludes all potential sources of secondary negative symptoms based on a clinical longitudinal assessment. In this paper we review the evolution of concepts and assessment modalities relevant to PPNS, data on prevalence of DS and PNS, as well as studies on clinical, neuropsychological, brain imaging electrophysiological and psychosocial functioning aspects of DS and PNS.

The Specific Level of Functioning Scale: Construct validity, internal consistency and factor structure in a large Italian sample of people with schizophrenia living in the community

BACKGROUND The study aimed to assess the construct validity, internal consistency and factor structure of the Specific Levels of Functioning Scale (SLOF), a multidimensional instrument assessing real life functioning. METHODS The study was carried out in 895 Italian people with schizophrenia, all living in the community and attending the outpatient units of 26 university psychiatric clinics and/or community mental health departments. The construct validity of the SLOF was analyzed by means of the multitrait-multimethod approach, using the Personal and Social Performance (PSP) Scale as the gold standard. The factor structure of the SLOF was examined using both an exploratory principal component analysis and a confirmatory factor analysis. RESULTS The six factors identified using exploratory principal component analysis explained 57.1% of the item variance. The examination of the multitrait-multimethod matrix revealed that the SLOF factors had high correlations with PSP factors measuring the same constructs and low correlations with PSP factors measuring different constructs. The confirmatory factor analysis (CFA) corroborated the 6-factor structure reported in the original validation study. Loadings were all significant and ranged from a minimum of 0.299 to a maximum of 0.803. The CFA model was adequately powered and had satisfactory goodness of fit indices (comparative fit index=0.927, Tucker-Lewis index=0.920 and root mean square error of approximation=0.047, 95% CI 0.045-0.049). CONCLUSION The present study confirms, in a large sample of Italian people with schizophrenia living in the community, that the SLOF is a reliable and valid instrument for the assessment of social functioning. It has good construct validity and internal consistency, and a well-defined factor structure.

Neurocognitive individualized training versus social skills individualized training: A randomized trial in patients with schizophrenia

Rehabilitation programs integrating cognitive remediation (CR) and psychosocial rehabilitation are often implemented as they seem to yield greater improvements in functional outcome than stand alone treatment approaches. Mechanisms underlying synergistic effects of combining CR with psychosocial interventions are not fully understood. Disentangling the relative contribution of each component of integrated programs might improve understanding of underlying mechanisms. In the present study we compared the efficacy of two components of our rehabilitation program [the Neurocognitive Individualized Training (NIT) and the Social Skills Individualized Training (SSIT)]. Seventy-two patients with schizophrenia or schizoaffective disorder were randomly assigned to one of two treatment groups. Changes in cognitive, psychopathological and real-world functioning indices after 6 and 12 months were compared between the two groups. After both 6 and 12 months, NIT produced an improvement of attention, verbal memory and perseverative aspects of executive functioning, while SSIT produced a worsening of visuo-spatial memory and attention and no significant effect on the other cognitive domains. As to the real-world functioning, NIT produced a significant improvement of interpersonal relationships, while SSIT yielded a significant improvement of QLS instrumental role subscale. According to our findings, cognitive training is more effective than social skills training on several cognitive domains and indices of real-world functioning relevant to subjects relationships with other people. Integrated approaches might target different areas of functional impairment but should be planned carefully and individually to fully exploit the synergistic potential.