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 Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included.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.

Impulsiveness in patients with bulimia nervosa: electrophysiological evidence of reduced inhibitory control.

OBJECTIVES: Bulimia nervosa (BN) is associated with a deficit of self-regulatory control and impulsivity. The present study aimed to clarify whether an impaired inhibitory control due to hyperarousal underlies impulsivity in BN subjects. METHODS: Event-related potentials (ERPs) were recorded in 17 female patients with BN and 17 healthy controls during a three-tone oddball task. ERP components related to inhibition of irrelevant distractor stimuli, as well as effortful processing, were analyzed. Standardized low-resolution electromagnetic tomography (sLORETA) was used to assess ERP source activity. RESULTS: Compared to healthy controls, BN patients showed reduced amplitude and shorter latency of the N200 (N2), increased amplitude and shorter latency of the target slow wave (SW), and higher amplitude of the P300 for distractor stimuli (P3a) and for targets (P3b). sLORETA showed the following: (1) higher activity of the P3a generators in the left parietal cortex, bilateral precuneus and right frontal and anterior cingulate for distractor stimuli and (2) lower activity of the SW generators in the left medial frontal gyrus, bilateral superior frontal, anterior cingulate and cuneus for target stimuli. The reduction of the N2 latency was associated with the Barratt scores for impulsiveness. CONCLUSIONS: The observed electrophysiological abnormalities suggest a condition of hyperarousal, with impaired suppression of irrelevant stimuli due to abnormal cortical activation and reduced signal-to-noise ratio. Our findings point to functional abnormalities within a neural system that subserves attention and self-regulatory control, which may contribute to impulsive behaviors in BN.

Impact of Reward and Loss Anticipation on Cognitive Control: An Event-Related Potential Study in Subjects With Schizophrenia and Healthy Controls.

INTRODUCTION: Deficits of cognitive functions and motivation are core aspects of schizophrenia. The interaction of these deficits might contribute to impair the ability to flexibly adjust behavior in accordance with one's intentions and goals. Many studies have focused on the anterior N2 as a correlate of cognitive control based on motivational value. AIMS: Given the key role of motivation impairment in schizophrenia as a predictor of functional outcome, we aimed to study the impact of reward- and avoidance-based motivation on cognitive control using N2. METHOD: Event-related potentials were recorded during the execution of the "Monetary Incentive Delay (MID)" task in 34 patients with schizophrenia (SCZ) stabilized on second-generation antipsychotics and 22 healthy controls (HC). Cognitive domains were assessed using the MATRICS Consensus Cognitive Battery. Negative symptom domains (Avolition/apathy and Expressive deficit), as well as positive and disorganization dimensions were also assessed in SCZ. RESULTS: We did not observe any group difference in N2 amplitude or latency. In HC, N2 amplitude was significantly larger for anticipation of large loss with regard to all reward conditions and for all incentive versus neutral conditions. In SCZ, N2 amplitude did not discriminate between large loss and reward or between incentive and neutral conditions. N2 amplitude was not correlated with psychopathological dimensions or MCCB-assessed cognitive deficits in SCZ. CONCLUSION: Our data in HC are in line with the hypothesis that N2 amplitude reflects the impact of motivational salience on cognitive control. Our results in SCZ indicate a deficit in the discrimination of motivational salience to the service of cognitive control, independently of psychopathology and other cognitive deficits.

Avolition-Apathy and White Matter Connectivity in Schizophrenia: Reduced Fractional Anisotropy Between Amygdala and Insular Cortex.

The avolition/apathy domain of negative symptoms includes motivation- and pleasure-related impairments. In people with schizophrenia, structural and functional abnormalities were reported in key regions within the motivational reward system, including ventral-tegmental area (VTA), striatum (especially at the level of the nucleus accumbens, NAcc), orbitofrontal cortex (OFC), as well as amygdala (Amy) and insular cortex (IC). However, the association of the reported abnormalities with avoliton-apathy is still controversial. In the present study, we investigated white matter connectivity patterns within these regions, using a probabilistic analysis of diffusion tensor imaging (DTI) data, in male subjects with schizophrenia. Thirty-five male subjects with schizophrenia (SCZ) and 17 male healthy controls (HC) matched for age, underwent DTI. SCZ were evaluated using the Schedule for Deficit Syndrome (SDS), the Positive and Negative Syndrome Scale (PANSS), and the MATRICS Consensus Cognitive Battery (MCCB). Probabilistic tractography was applied to investigate pathways connecting the Amy and the NAcc with the OFC and IC. Reduced fractional anisotropy (FA) was observed in left Amy-ventral anterior IC connections, in SCZ compared with controls. This abnormality was negatively correlated with avolition/apathy but not with expressive deficit scores. SCZ showed also a reduced connectivity index between right NAcc and medial OFC, as compared with controls. Finally, the left NAcc-dorsal anterior IC connectivity index was negatively correlated with working memory scores. Our results indicate that only the avolition/apathy domain of negative symptoms is related to abnormal connectivity in the motivation-related circuits. The findings also demonstrate that distinct alterations underlie cognitive impairment and avolition/apathy.

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.

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.

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.

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 subject's 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.

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.

[The contribution of brain imaging to the study of panic disorder]. / Il contributo del brain imaging allo studio del disturbo di panico.

AIMS: The present review is aimed to evaluate the recent contribution of brain imaging techniques to the definition of neuroanatomofunctional models of panic disorder (PD). METHODS: Structural and functional brain imaging studies of PD, conducted from January 1993 to October 2003 and selected through a comprehensive Medline search (key-words: panic disorder, emotions, brain imaging, EEG, Event-Related Potentials, MRI, fMRI, PET, SPECT, TC) were included in the review. The Medline search has been complemented by bibliographic cross-referencing. RESULTS: The majority of the reviewed studies suggests that a dysfunction of a neural circuit encompassing prefrontal and temporo-limbic cortices is present in PD. A right hemisphere preferential involvement in PD has been shown by several studies. CONCLUSIONS: Reviewed neuroimaging studies suggest a dysfunction of frontal and temporo-limbic circuitries in PD. However, those studies cannot be considered conclusive because of several methodological limitations. Longitudinal and multi-modal studies involving larger patient samples, possibly integrated with population-based and genetic studies, would provide more insight into pathophysiological mechanisms of PD. DECLARATION OF INTEREST: Authors declare that none of them had any known real, potential, or apparent conflict of interest and that there was no business or personal interest that might be relevant to the topic of this article.