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Structural and functional abnormalities of the left hemisphere, often involving the temporal lobe were frequently observed in schizophrenia. However, negative and discrepant findings were also reported. Our study aimed to investigate the presence of lateralized impairment of event-related potentials, recorded during a tonal dichotic listening task, in a group of clinically stabilized patients with schizophrenia.
The ERP component N100, related to sensory processing of stimuli and generated in the temporal lobe cortex, was investigated. A passive dichotic listening task was used in order to exclude the effect of attention impairment on the observed ERP abnormalities.
Patients with schizophrenia showed a pattern of hemispheric lateralization comparable with that observed in healthy controls. In both groups, dichotic listening inhibited the augmenting pattern of N100 amplitude with increasing tone intensity. However, patients failed to demonstrate the augmenting pattern of the N100 also with monaural tones, over the left temporal leads. This abnormality did not correlate with the severity of psychopathology. A role of antipsychotic treatment was excluded as the N100 showed a normal pattern of amplitude increase over right temporal leads.
Our results suggest a state of functional inhibition of the left auditory cortex, akin to that induced by dichotic listening, in subjects with schizophrenia, indipendent of psychopathology or drug therapy.
Clinical studies on cognitive effects of second generation antipsychotics produced disappointing findings probably due to the heterogeneity of the clinical populations under investigation, as well as to poor sensitivity of neurocognitive indices. Event-Related Potentials (ERPs) provide a functional measure of electrical brain activity time-locked to discrete stages of information processing. They have been widely used as putative biological markers of cognitive abnormalities in schizophrenia and represent useful indices in the investigation of the cognitive effects of psychotropic drugs.
The present study investigated the effect of risperidone, haloperidol and placebo on N1 and P3 in male healthy subjects.
ERPs were recorded during a three-tone oddball task in which target, standard and rare-nontarget tones were randomly presented. Subjects had to press a button when hearing a target tone. Amplitude and topography of the ERP component maps at peak latencies were compared across conditions. If a significant drug effect was obtained, changes in the cortical sources of the corresponding ERP component were analyzed using Low-Resolution Electromagnetic Tomography (LORETA).
The amplitude of N1 for attended stimuli and of P3 for rare-nontargets (P3a) was significantly increased only by risperidone. No significant change was observed in overall topographic features and in LORETA cortical sources of the same components. No significant drug effect was demonstrated for the latency of all the investigated components and for P3b amplitude.
Our findings suggest that risperidone has a favorable effect on early attention processes and automatic attention allocation.
To evaluate long-term treatment with ziprasidone versus haloperidol (up to 196 weeks), as assessed by PANSS negative score and and its association with quality-of-life (QLS).
The study included two treatment periods: (i) a 40-week, randomized, double-blind phase comparing ziprasidone (ZIP 80-160 mg/d given BID, N=227; ZIP 80-120 mg/d given QD, N=221) versus haloperidol (HAL 5-20 mg/d, N=151), followed by (ii) a 3-year, double-blind extension phase on the same double-blind medications (ZIP BID N=72, ZIP QD N=67, and HAL N=47, respectively). We adapted the Andreasen et al. approach to define negative symptom remission based on attainment of a score ≤3 (mild or less) for at least 6 months on all 7 PANSS negative symptom items. MMRM and GEE models were applied to analyze mean changes in PANSS negative, negative symptom remission rate, and QLS scores over time.
In the 40-week core study, ziprasidone was associated with greater improvement in efficacy and QLS outcomes than haloperidol, but the differences were not statistically significant (p>0.05). However, MMRM analysis of PANSS negative and QLS scores over 196 weeks demonstrated differential treatment effects favoring ziprasidone (80-160 mg/d BID vs. haloperidol) (all p<0.05). Ziprasidone-treated subjects (given BID) were significantly more likely to achieve negative symptom remission (46%) than haloperidol-treated (32%) subjects (p<0.05) during the continuation phase; while ziprasidone given QD (46%) showed a trend to enhanced remission (p<0.08).
These findings support the potential for enhanced social and functional outcomes during long-term treatment with an atypical antipsychotic agent.
Several factor analytic studies have shown than anhedonia and avolition are included in the same factor, suggesting that motivational deficits in schizophrenia are related to a reduced experience of pleasure; however other studies have not confirmed this hypothesis. More recently, it has been hypothesized that avolition is related to a difficulty in anticipating reward value and\or regulating behavior on the basis of the associations between value and action.
This study is aimed to verify an impairment of reward anticipation in patients with deficit schizophrenia (DS), but not in those with non-deficit schizophrenia (NDS) and its association with primary negative symptoms, using event-related potentials (ERPs).
ERPs were recorded in 11 patients with DS, 23 patients with NDS and 23 healthy controls (HC), during anticipation of five different outcomes, small (SR) or large (LR) reward, small (SP) or large (LP) punishment or no-outcome (NO), and during feedback processing.
Patients did not differ from HC on indices of anticipatory or consummatory anhedonia, but they showed reduced motivation. During reward anticipation, only patients with primary and persistent avolition showed ERPs abnormalities, with respect to HC, in the early processing stages and a reduced activity of cortical generators in the cingulate, in the temporal-occipital and fronto-parietal regions, that are involved in the attention modulation and visual perceptual processing.
Our data suggest that anhedonia and avolition are partially independent constructs and that avolition is related to the inability to modulate attention and amplify visual perceptual processing of reward stimuli.
Previous studies have reported that patient with schizophrenia have preserved hedonic capacity, but impaired ability to anticipate future reward (anticipatory anhedonia) that, according to some authors, may underlie other aspects of negative symptoms, such as avolition.
The aim of our study was to demonstrate an impairment of reward anticipation in patients with deficit schizophrenia (DS), characterized by primary and persistent negative symptoms, but not in those with non-deficit schizophrenia (NDS) with respect to healthy controls (HC), by means of functional magnetic resonance imaging (fMRI).
fMRI was recorded during the execution of the ’Monetary Incentive Delay’ task in 11 patients with DS, 23 patients with NDS and 23 HC, during the anticipation of five different outcomes, small (SR) or large (LR) reward, small (SP) or large (LP) punishment or no-outcome (NO).
The ventral striatum response to reward anticipation was preserved in subjects with schizophrenia. Only patients with DS, compared with HC, showed a significant reduction in the left caudate during the anticipation of reward. The reduced activity of the caudate correlated with the scores for avolition but not for anhedonia.
Our preliminary data suggest an involvement of the caudate in the abnormal processing of reward stimuli in patients with DS and show that avolition and anhedonia are subtended by different functional abnormalities.
The Mismatch Negativity (MMN) is an event-related potential (ERP) sensitive to early auditory deviance detection and has been shown to be reduced in patients with schizophrenia. Moreover, MMN amplitude reduction to duration deviant tones was found to be related to functional outcomes particularly, to social cognition and real-life functioning.
In the context of a multicentre study of the Italian Network for Research on Psychoses, our study focused on the investigation of early auditory discrimination components in relation to functioning in real-life in patients with schizophrenia.
ERPs were recorded in 64 chronic, stabilized patients with schizophrenia during the presentation of standard, duration deviants and frequency deviants tones while watching a cartoon. The Specific Level of Functioning (SLOF) scale was used to measure real-life functioning. Psychopathology, neurocognition and social cognition were measured by state of art instruments. Regression analyses were carried out using SLOF domains as dependent variables and MMN, psychopathology, neurocognition, extrapyramidal symptoms and social cognition as independent predictors.
Latency of MMN entered the regression equation only for the SLOF domain of common activities explaining less variance than social cognition and positive symptoms.
In stabilized patients with schizophrenia pre-attentive deficits, as indexed by MMN and P3a amplitude reduction, do not show any association with psychopathology or functioning. Latency of MMN was an independent predictor of some aspects of functioning with a smaller effect than social cognition and psychopathology domains.
Patients with schizophrenia often show a reduced ability to experience pleasure, but previous studies demonstrated that they are more characterized by “anticipatory anhedonia”, rather than a deficit in experiencing pleasure itself (“consummatory anhedonia”). However, the brain circuits related to anticipation of pleasure and processing of reward signals in schizophrenia are yet unclear.
We aimed to examine reward anticipation and feedback processing using event-related potentials (ERPs) in 24 stabilized patients with schizophrenia and 14 healthy controls.
ERPs were recorded during a Monetary Incentive Delay task during anticipation of five different outcomes, small (SR) or large (LR) reward, small (SP) or large (LP) punishment or no-outcome (NO), and during feedback processing.
Patients had lower scores on TEPS anticipatory pleasure and BIS/BAS fun-seeking scales and higher scores for anhedonia and punishment sensitivity, than controls. The anticipation-related negativity was reduced in patients. Controls, but not patients, showed a larger amplitude for LP versus NO and LR. Fronto-central amplitude in patients was inversely correlated with TEPS anticipatory pleasure. The feedback-related negativity had a lower amplitude for LR than for all other conditions in controls, but not in patients. Only in controls, FRN was inversely correlated with TEPS consummatory pleasure.
The frontal negativity during outcome anticipation discriminate punishment from other outcomes only in controls. The lower the amplitude of this component, the greater the deficit in anticipatory pleasure. As to FRN, only controls modulate the frontal negativity during processing of outcome and this modulation is associated with consummatory pleasure.
Negative symptoms are the psychopathological domain most associated to poor outcome in patients with schizophrenia (SCZ). Insight into their pathophysiology might contribute to develop innovative treatments for the syndrome. Recently, it has been hypothesized that avolition is related to a difficulty in anticipating reward or integrating value and action.
Our study aimed to investigate abnormalities of reward anticipation in SCZ and evaluate associations of negative symptoms dimensions with the same abnormalities using electrophysiological indices.
ERPs were recorded during the execution of 'Monetary Incentive Delay' task in 30 SCZ patients stabilized on second generation antipsychotics and 23 and healthy controls (HC). Measures of anticipatory and consummatory pleasure, trait anhedonia and motivation were obtained in all subjects. A measure of avolition independent of anhedonia was obtained in patients.
Patients did not differ from HC with respect to trait anhedonia and experience of pleasure but showed a deficit of motivation. Unlike HC, P3 amplitude in patients did not discriminate stimuli relevance in the early interval and was higher for the anticipation of loss in the late interval. In SCZ, early P3 amplitude for loss and reward anticipation was inversely related to social anhedonia but not to avolition.
Patients with preserved experience and anticipation of reward seem unable to integrate the relevance and rewarding value of future events in the context of their ongoing task. Our results indicate that anhedonia and avolition are partially independent constructs and that SCZ might integrate better loss than reward.
P300 is an event-related potential (ERP) thought to reflect attention, working memory and context integration and has been shown to be consistently reduced in patients with Schizophrenia. Despite a possible relation between P300 components and cognitive deficits in Schizophrenia has been hypothesized, few studies addressed this hypothesis.
In the context of a multicenter study of the Italian Network for Research on Psychoses, our study focused on the investigation of auditory P300 component in relation to clinical and cognitive domains in patients with Schizophrenia.
ERPs were recorded in 64 chronic, stabilized patients with Schizophrenia during a standard oddball task. N1 and P3b latency and amplitude were assessed at Fz and Pz, respectively. State of art instruments was used for clinical assessment. Cognitive indices (from the seven cognitive domains of the Measurement and Treatment of Cognition in Schizophrenia, MATRICS) were expressed as Z-scores from an Italian normative sample.
Correlation analysis revealed associations of P3b latency with age, education, PANSS-DIS, processing speed, working memory, St. Hans parkinsonism subscale. In a multiple linear regression model, processing speed was an independent significant predictor of P3b latency.
For the first time, a strong relation between P3b latency and processing speed impairment was shown in Schizophrenia. Processing speed is considered a central factor in the relation between cognitive deficits and functional outcome in chronic schizophrenia. The association with P3b latency might shed lights in the neural basis of this complex construct.
In the conclusions, the book editors assess the existing national and international regulatory frameworks in the light of the five foundational principles that they identified by reading international bioethics law in conjunction with international human rights standards: (i) freedom of research; (ii) benefit sharing; (iii) solidarity; (iv) respect for dignity; and (v) the obligation to respect and to protect the rights and individual freedoms of others. Their analysis reveals four issues common to most national regulatory frameworks as well as the international framework: (i) The prohibition to create embryos for research embryos cannot be reconciled with the right to science and the rights of science; (ii) limitations to scientific freedom based on vague laws are not truly limitations “determined by law”; (iii) limitations to scientific freedom based on obsolete laws are not limitations accepted in a “democratic society”; (iv) ne plus ultra prohibitions breach the right of everyone to benefit from scientific and technological progress and the principle of benefit sharing. The editors conclude by sketching an international governance framework that promotes science and technological development while being mindful and respectful of international human rights standards, as well as the different sensitivities with which citizens from different parts of the world approach the question of human germline genome modification.
In this chapter, we review the key elements of the larger international and transnational framework within which the national legal regimes regulating human germline genome modification exist. Part I is a quick primer to international law and international human rights for the benefit of those who are not familiar with them. Part II presents the relevant norms of international bioethics law, including three main declarations adopted by UNESCO touching on human genome modification. It discusses also the relevant governance activities of the World Health Organization, Organisation for Economic Co-operation and Development and civil society, nationally and transnationally. Part III discusses relevant international human standards, and in particular the so-called ‘right to science’ and the ‘rights of science’. Finally, Part IV discusses how these rights can contribute to the emerging international regulatory framework. This chapter argues that, by itself, international bioethics law and its instruments provide a narrow and inadequate description of the range of human rights that must be taken into account in the conversation on the regulation of germline engineering. These instruments must be integrated with the broader international human rights law corpus. When they are integrated, five key principles emerge as foundations of the emerging regulatory framework: freedom of research; benefit sharing; solidarity; respect for dignity; and the obligation to respect and to protect the rights and individual freedoms of others.
In this Introduction (Chapter 1), we discuss the science of human genome modification in general, how it relates to human reproduction, and the specific advances that CRISPR/Cas 9 represents and the family of tools it has generated to date. We then explain the methodology we followed preparing this book, including how countries were selected and what we chose to focus on and why.