Dopamine, Prediction Error and Beyond

A large body of work has linked dopaminergic signaling to learning and reward processing. It stresses the role of dopamine in reward prediction error signaling, a key neural signal that allows us to learn from past experiences, and that facilitates optimal choice behavior. Latterly, it has become clear that dopamine does not merely code prediction error size but also signals the difference between the expected value of rewards, and the value of rewards actually received, which is obtained through the integration of reward attributes such as the type, amount, probability and delay. More recent work has posited a role of dopamine in learning beyond rewards. These theories suggest that dopamine codes absolute or unsigned prediction errors, playing a key role in how the brain models associative regularities within its environment, while incorporating critical information about the reliability of those regularities. Work is emerging supporting this perspective and, it has inspired theoretical models of how certain forms of mental pathology may emerge in relation to dopamine function. Such pathology is frequently related to disturbed inferences leading to altered internal models of the environment. Thus, it is critical to understand the role of dopamine in error-related learning and inference

The Measurement of Language Lateralization with Functional Transcranial Doppler and Functional MRI: A Critical Evaluation

Cerebral language lateralization can be assessed in several ways. In healthy subjects, functional MRI (fMRI) during performance of a language task has evolved to be the most frequently applied method. Functional transcranial Doppler (fTCD) may provide a valid alternative, but has been used rarely. Both techniques have their own strengths and weaknesses and as a result may be applied in different fields of research. Until now, only one relatively small study (n = 13) investigated the correlation between lateralization indices (LIs) measured by fTCD and fMRI and showed a remarkably high correlation. To further evaluate the correlation between LIs measured with fTCD and fMRI, we compared LIs of 22 healthy subjects (12 left- and 10 right-handed) using the same word generation paradigm for the fTCD as for the fMRI experiment. LIs measured with fTCD were highly but imperfectly correlated with LIs measured with fMRI (Spearman's rho = 0.75, p < 0.001). The imperfectness of the correlation can partially be explained by methodological restrictions of fMRI as well as fTCD. Our results suggest that fTCD can be a valid alternative for fMRI to measure lateralization, particularly when costs or mobility are important factors in the study design

Auditory Hallucinations and the Brain’s Resting-State Networks: Findings and Methodological Observations

In recent years, there has been increasing interest in the potential for alterations to the brain’s resting-state networks (RSNs) to explain various kinds of psychopathology. RSNs provide an intriguing new explanatory framework for hallucinations, which can occur in different modalities and population groups, but which remain poorly understood. This collaboration from the International Consortium on Hallucination Research (ICHR) reports on the evidence linking resting-state alterations to auditory hallucinations (AH) and provides a critical appraisal of the methodological approaches used in this area. In the report, we describe findings from resting connectivity fMRI in AH (in schizophrenia and nonclinical individuals) and compare them with findings from neurophysiological research, structural MRI, and research on visual hallucinations (VH). In AH, various studies show resting connectivity differences in left-hemisphere auditory and language regions, as well as atypical interaction of the default mode network and RSNs linked to cognitive control and salience. As the latter are also evident in studies of VH, this points to a domain-general mechanism for hallucinations alongside modality-specific changes to RSNs in different sensory regions. However, we also observed high methodological heterogeneity in the current literature, affecting the ability to make clear comparisons between studies. To address this, we provide some methodological recommendations and options for future research on the resting state and hallucinations

Oscillatory Cortical Network Involved in Auditory Verbal Hallucinations in Schizophrenia

Auditory verbal hallucinations (AVH), a prominent symptom of schizophrenia, are often highly distressing for patients. Better understanding of the pathogenesis of hallucinations could increase therapeutic options. Magnetoencephalography (MEG) provides direct measures of neuronal activity and has an excellent temporal resolution, offering a unique opportunity to study AVH pathophysiology.Twelve patients (10 paranoid schizophrenia, 2 psychosis not otherwise specified) indicated the presence of AVH by button-press while lying in a MEG scanner. As a control condition, patients performed a self-paced button-press task. AVH-state and non-AVH state were contrasted in a region-of-interest (ROI) approach. In addition, the two seconds before AVH onset were contrasted with the two seconds after AVH onset to elucidate a possible triggering mechanism.AVH correlated with a decrease in beta-band power in the left temporal cortex. A decrease in alpha-band power was observed in the right inferior frontal gyrus. AVH onset was related to a decrease in theta-band power in the right hippocampus.These results suggest that AVH are triggered by a short aberration in the theta band in a memory-related structure, followed by activity in language areas accompanying the experience of AVH itself

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Dopamine, Prediction Error and Beyond

A large body of work has linked dopaminergic signaling to learning and reward processing. It stresses the role of dopamine in reward prediction error signaling, a key neural signal that allows us to learn from past experiences, and that facilitates optimal choice behavior. Latterly, it has become clear that dopamine does not merely code prediction error size but also signals the difference between the expected value of rewards, and the value of rewards actually received, which is obtained through the integration of reward attributes such as the type, amount, probability and delay. More recent work has posited a role of dopamine in learning beyond rewards. These theories suggest that dopamine codes absolute or unsigned prediction errors, playing a key role in how the brain models associative regularities within its environment, while incorporating critical information about the reliability of those regularities. Work is emerging supporting this perspective and, it has inspired theoretical models of how certain forms of mental pathology may emerge in relation to dopamine function. Such pathology is frequently related to disturbed inferences leading to altered internal models of the environment. Thus, it is critical to understand the role of dopamine in error-related learning and inference

Dissecting Auditory Verbal Hallucinations into Two Components: Audibility (Gedankenlautwerden) and Alienation (Thought Insertion)

This study proposes a theoretical framework which dissects auditory verbal hallucinations (AVH) into 2 essential components: audibility and alienation. Audibility, the perceptual aspect of AVH, may result from a disinhibition of the auditory cortex in response to self-generated speech. In isolation, this aspect leads to audible thoughts: Gedankenlautwerden. The second component is alienation, which is the failure to recognize the content of AVH as self-generated. This failure may be related to the fact that cerebral activity associated with AVH is predominantly present in the speech production area of the right hemisphere. Since normal inner speech is derived from the left speech area, an aberrant source may lead to confusion about the origin of the language fragments. When alienation is not accompanied by audibility, it will result in the experience of thought insertion. The 2 hypothesized components are illustrated using case vignettes. Copyright (C) 2010 S. Karger AG, Base

Aberrant connectivity of areas for decoding degraded speech in patients with auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) are a hallmark of psychotic experience. Various mechanisms including misattribution of inner speech and imbalance between bottom-up and top-down factors in auditory perception potentially due to aberrant connectivity between frontal and temporo-parietal areas have been suggested to underlie AVH. Experimental evidence for disturbed connectivity of networks sustaining auditory-verbal processing is, however, sparse. We compared functional resting-state connectivity in 49 psychotic patients with frequent AVH and 49 matched controls. The analysis was seeded from the left middle temporal gyrus (MTG), thalamus, angular gyrus (AG) and inferior frontal gyrus (IFG) as these regions are implicated in extracting meaning from impoverished speech-like sounds. Aberrant connectivity was found for all seeds. Decreased connectivity was observed between the left MTG and its right homotope, between the left AG and the surrounding inferior parietal cortex (IPC) and the left inferior temporal gyrus, between the left thalamus and the right cerebellum, as well as between the left IFG and left IPC, and dorsolateral and ventrolateral prefrontal cortex (DLPFC/VLPFC). Increased connectivity was observed between the left IFG and the supplementary motor area (SMA) and the left insula and between the left thalamus and the left fusiform gyrus/hippocampus. The predisposition to experience AVH might result from decoupling between the speech production system (IFG, insula and SMA) and the self-monitoring system (DLPFC, VLPFC, IPC) leading to misattribution of inner speech. Furthermore, decreased connectivity between nodes involved in speech processing (AG, MTG) and other regions implicated in auditory processing might reflect aberrant top-down influences in AVH

The influence of stimulus detection on activation patterns during auditory hallucinations

AbstractIntroductionNeuroimaging studies investigating auditory verbal hallucinations (AVH) have revealed involvement of several cortical structures. These findings may however be biased by brain activity related to stimulus detection and motor processes associated with the task to indicate the presence of AVH. Disentangling brain activation specifically related to AVH and to additional cognitive processes may help focus on the true neuronal substrates of AVH and strengthen the development of new focal treatment strategies.MethodsBrain activation during AVH as indicated by button press was compared to brain activation during auditory stimulus detection indicated by button press. We performed two neuroimaging meta-analyses, assessing 10 AVH and 11 auditory stimulus detection studies. A random-effects activation likelihood estimation was performed using GingerALE to assess commonalities and differences across AVH and stimulus detection studies.ResultsActivity in the claustrum, pulvinar area, medial geniculum body, pyramis, culmen, putamen, insula, and parahippocampal, medial frontal, precentral, postcentral, superior temporal and right inferior frontal gyri was found to be specifically related to AVH. The pars opercularis of the left inferior frontal gyrus and the left transverse temporal gyrus were activated to a similar extent during AVH and auditory stimulus detection.DiscussionDevelopment of new focal treatment strategies for AVH may focus on the areas uniquely activated in the AVH analysis. The pars opercularis and the transverse temporal gyrus may not be directly involved in the experience of AVH itself, but rather in auditory stimulus detection