G.M. Giordano

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.

Excimer laser photoablative filtration surgery: histology and ultrastructure in 4 human cadaver eyes.

The purpose of this study was to verify the feasibility of ab externe layer-by-layer excimer laser photoablative removal of limbal tissue down to the trabecular meshwork and to assess the damage caused by this procedure to the neighbouring structures. Excimer laser photoablation (193 nm) can remove layers of corneal tissue effectively with little or no damage to the adjacent areas. Previous experimental studies have demonstrated a decrease in outflow resistance after ab-externo photoablative removal of juxtacanalicular tissue. We have performed ab-externo photoablative removal of limbal tissue overlying the trabecular meshwork in four freshly enucleated eyes from our Eye Bank. The beam of an excimer laser (wavelength 193 nm; fluence 180 mJ/Sq.cm) was shaped using a metal mask with a rectangular opening of 1.2×2.5 mm. After removing the conjunctiva, photoablation was carried out at maximum surgical microscope magnification (40 x) until trabecular meshwork appeared at the bottom of the crater. Light microscopy showed that craters had smooth walls and their base reached the Schlemms canal area; all structures appeared of normal morphology. Transmission electron microscopy showed a thin layer of amorphous material or pseudomembrane on the side walls of the crater; corneoscleral collagen fibers were abruptly interrupted and undistorted. At the bottom of the crater the trabecular meshwork and Schlemms canal tissues appeared normal.

Neurobiology of Schizophrenia: Electrophysiological Indices

The objective of the WPA section on Psychoneurobiology is the promotion of the integration of findings from research fields such as neurophysiology, psychology, neuropsychology and psychiatry. This chapter focuses on the importance of electroencephalographic (EEG) studies for the section’s objectives and especially for (a) the study of functional brain abnormalities related to liability to psychosis and schizophrenia pathophysiology and (b) characterization of schizophrenia psychopathological dimensions. The introduction will highlight the importance of EEG investigations in psychiatry, outlining a model of brain function, based on the notion of state-dependent information processing, and providing examples relevant to schizophrenia research. The second paragraph will summarize the current state of knowledge about resting state EEG connectivity in subjects with schizophrenia (SCZ) and draw some tentative conclusions about the possible links to the range of cognitive and behavioural abnormalities observed in these patients. The third paragraph will illustrate findings from event-related potential (ERP) studies of subjects at risk for psychosis who later develop schizophrenia-spectrum disorders. Some of the ERP parameters are proposed as biomarkers of the transition to psychosis and, if further validated, can be used to identify subjects for early interventions. The final paragraph of the chapter will summarize findings relevant to the characterization of the psychopathological dimensions of schizophrenia.

F111. ELECTROPHYSIOLOGICAL CORRELATES OF AVOLITION-APATHY DOMAIN IN SCHIZOPHRENIA

Abstract Background Negative symptoms represent a core feature of schizophrenia. They have been associated to poor functional outcome, worse quality of life and poor response to pharmacological treatment. Several factor analytic studies have reported that negative symptoms can be divided into two domains referred to as Avolition-apathy which includes Avolition, Anhedonia and Asociality and the Expressive deficit domain, which includes Alogia and Blunted affect. Avolition-apathy has been associated to a dysfunction of brain circuits involved in motivation, in particular to those related to the ability to anticipate pleasure and learn from rewards. It is highly controversial whether Avolition-apathy and all subcomponent symptoms share the same neurobiological underpinnings. Our study, using brain electrical microstates (MS) which reflect global, subsecond patterns of functional connectivity, had two primary aims: 1) to identify differences between healthy controls (HC) and clinically stable people with schizophrenia (SCZ) in brain electrical microstate parameters and 2) to investigate the associations of the microstate parameters with the Avolition-apathy domain and its subcomponent symptoms. Methods We analyzed multichannel resting EEGs in 142 SCZ and in 64 HC, recruited within the add-on EEG study of the Italian Network for Research on Psychoses. The microstate analysis was performed using an in-house plugin for Brain Vision Analyzer. Based on the microstate map templates from a large normative study, each moment of the ongoing EEGs was assigned to one of four microstates (MS) classes (MS-A, MS-B, MS-C, MS-D). Microstates were then quantified in terms of relative time contribution, duration and occurrence. Negative symptoms were assessed using the Brief Negative Symptoms Scale (BNSS): Avolition-apathy was obteined by summing the scores on the subscales Anhedonia (consummatory and anticipatory anhedonia), Avolition and Asociality; Expressive deficit was computed by summing the scores on the subscales Blunted Affect and Alogia. Analysis of variance (ANOVA) was used to test group differences on MS parameters. Pearson’s r coefficients were computed to investigate the correlations of MS parameters with the negative symptom domains and subcomponent symptoms. Results There was no significant group difference in sex (p=0.073) and age (p=0.547) between SCZ and HC. SCZ, in comparison to HC, showed increased contribution (p=0.009) and duration (p=0.016) of MS-C. As regard to negative symptoms, the total score of the BNSS was positively correlated with the contribution of MS-A (r= 0.19, p<0.03). Avolition-apathy domain (r=0.22, p<0.01), anticipatory anhedonia (r=0.20, p=0.02), avolition (r=0.20, p=0.02) and asociality (r=0.25, p=0.003), but not consummatory anhedonia (r=0.13, p=0.13), were positively correlated with the contribution of MS-A. There was no correlation between Expressive deficit and MS-A parameters. Discussion Our findings, in line with previous studies, showed an increased contribution of MS-C in SCZ. MS-C was not associated with clinical features, thus probably representing a trait marker of the disease. In addition, our results support different neurophysiological correlates of the two negative symptom domains and suggest that only anticipatory anhedonia, but not consummatory anhedonia, might be linked to the Avolition-apathy domain. These findings are in line with studies reporting an intact ability to experience in the moment pleasure and an impairment in pleasure anticipation (anticipatory anhedonia) in people with schizophrenia.

F114. DISORGANIZATION AND COGNITIVE DYSFUNCTIONS IN SCHIZOPHRENIA: A STUDY OF RESTING STATE EEG

Abstract Background A disorganization factor was found by several factor-analytic studies of schizophrenia symptoms. This factor does not appear to be affected by age, severity of other symptoms and chronicity of illness. A greater severity of disorganization is associated with poor functioning. Despite the general similarity of different factorial model, there is no consensus about which symptoms have to be included in the disorganization factor. Using the Positive and Negative Syndrome Scale (PANSS), Conceptual disorganization’ (P2), ‘Difficulty in abstract thinking’ (N5) and ‘Poor attention’ (G11) were core features of the disorganization factor. The overlap of these items with neurocognitive functions is still debated. However, the heterogeneity of this factor and its neurobiological basis should be further investigated. In the context of the multicenter study of the Italian Network for Research on Psychoses, the main aims of our study were to investigate electrophysiological and neurocognitive correlates of the disorganization factor, and to assess if each PANSS item, loading on the disorganization factor, could be underpinned by similar electrophysiological or cognitive alterations. Methods Resting state EEGs were recorded for 5 minutes in 145 stabilized subjects with schizophrenia (SCZ) and 69 matched healthy controls (HC). The disorganization factor was evaluated using three PANSS items: P2, N5, and G11 (4). Neurocognitive functions were assessed using the MATRICS Consensus Cognitive Battery (MCCB). Spectral amplitude was quantified in nine frequency bands. All statistical analyses of the scalp multichannel spectral amplitude (SAmp) data were performed using RAGU software. Statistical comparisons between the SAmp maps of SCZ and HC were assessed by topographic analyses of variance (TANOVA). In SCZ, topographic analyses of covariance (TANCOVA) evaluated correlations between SAmp and disorganization, its constituent items and MCCB domains. Furthermore, Pearson’s correlations were performed between disorganization and its constituent items and MCCB neurocognitive domains. Results TANOVA, comparing the group SAmp maps revealed increased Delta, Theta, and Beta1 and decreased Alpha2 SAmp in SCZ. In the SCZ group, disorganization was significantly correlated to the Alpha1 SAmp. This relation was negative and most pronounced at occipital sites. At the items level, only N5 showed the same negative correlation at occipital sites. MCCB neurocognitive composite score was associated with disorganization factor, and its constituent items P2 and N5. No significant correlation between Alpha1 SAmp and MCCB cognitive domains was observed. Discussion Our findings illustrate the heterogeneity of disorganization dimension and a partial overlap with neurocognitive domains. ‘Difficulty in abstract thinking’ showed a unique association with Alpha1 activity, which is thought to be involved in the construction of conceptual maps. Furthermore, the observed association of Alpha1 with ‘Difficulty in abstract thinking’ suggests that some aspects of disorganization could be underpinned by the impairment of basic neurobiological functions that are only partially evaluated using MCCB.

Neurophysiological correlates of Avolition-apathy in schizophrenia: A resting-EEG microstates study

Background The “Avolition-apathy” domain of the negative symptoms was found to include different symptoms by factor analytic studies on ratings derived by different scales. In particular, the relationship of anhedonia with this domain is controversial. Recently introduced negative symptom rating scales provide a better assessment of anhedonia, allowing the distinction of anticipatory and consummatory aspects, which might be related to different psychopathological dimensions. The study of associations with external validators, such as electrophysiological, brain imaging or cognitive indices, might shed further light on the status of anhedonia within the Avolition-apathy domain. Objectives We used brain electrical microstates (MSs), which represent subsecond periods of quasi-stable scalp electrical field, associated with resting-state neural networks (and thus with global patterns of functional connectivity), to test whether the component symptoms of Avolition-apathy share the same correlates. Method We analyzed multichannel resting EEGs in 142 individuals with schizophrenia (SCZ) and in 64 healthy controls (HC), recruited within the add-on EEG study of the Italian Network for Research on Psychoses. Relative time contribution, duration and occurrence of four MS classes (MS-A/-B/-C/−D) were calculated. Group differences on MS parameters (contribution and duration) and their associations with negative symptom domains (assessed using the Brief Negative Symptoms Scale) were investigated. Results SCZ, in comparison to HC, showed increased contribution and duration of MS-C. The contribution of MS-A positively correlated with Avolition-apathy, but not with Expressive deficit. Within the Avolition-apathy domain, anticipatory anhedonia, avolition and asociality, but not consummatory anhedonia, showed the same correlations with MS-A contribution. Conclusion Our findings support the existence of distinct electrophysiological correlates of Avolition-apathy with respect to Expressive deficit, and lend support to the hypothesis that only the anticipatory component of anhedonia shares the same pathophysiological underpinnings of the Avolition-apathy domain.

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.

VTA-insula connectivity and avolition in subjects with schizophrenia

Introduction Avolition represents an important domain of negative symptoms in schizophrenia with a strong impact on functional outcome. Primary and persistent avolition is refractory to available pharmacological and psychological treatments. A better understanding of its pathophysiological mechanisms is fundamental to promote development of new treatments. Recent models of avolition converge on dopaminergic circuits involved in motivation and its translation in goal-directed behavior. Deficits in task-related activation or connectivity within mesolimbic and mesocortical dopamine circuits were reported in schizophrenia but the relationship with avolition was not fully established. Aims The present study aimed to investigate resting-state functional connectivity (RS-FC) within the motivation circuits in schizophrenia patients and its relationships with primary and persistent avolition. Methods RS-FC, using VTA as a seed region, was investigated in 22 healthy controls (HC) and in 26 schizophrenia patients (SCZ) divided in high (HA) and low avolition (LA) subgroups. Avolition was assessed using the Schedule for the Deficit Syndrome. Results HA, in comparison to LA and HC, showed significantly reduced RS-FC with the right ventrolateral prefrontal cortex (R-VLPFC), right insula (R-INS) and right lateral occipital cortex (R-LOC). The RS-FC of these regions was negatively correlated to avolition. Conclusions Our findings demonstrate that avolition in schizophrenia is linked to dysconnection of VTA from key cortical regions involved in retrieval of outcome values of instrumental actions to motivate behavior.