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

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

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

Treatment of Alice in Wonderland Syndrome and Verbal Auditory Hallucinations Using Repetitive Transcranial Magnetic Stimulation:A Case Report with fMRI Findings

Background: Alice in Wonderland syndrome (AIWS) is a rare cluster of CNS symptoms characterized by visual distortions (i.e. metamorphopsias), body image distortions, time distortions, and deja experiences. Verbal auditory hallucinations (VAHs) are the most prevalent type of hallucination in adults with or without a history of psychiatric illness. Here, we report the case of a woman with AIWS, long-lasting VAHs, and various additional perceptual and mood symptoms. Methods: Semi-structured interviews were used to assess symptoms, and functional MRI (fMRI) was employed to localize cerebral activity during self-reported VAHs. Treatment consisted of repetitive transcranial magnetic stimulation (rTMS) at a frequency of 1 Hz at T3P3, overlying Brodmann's area 40. Results: Activation during VAHs was observed bilaterally in the basal ganglia, the primary auditory cortex, the association auditory cortex, the temporal poles, and the anterior cingulated gyrus. The left and right inferior frontal gyri (Broca's area and its contralateral homologue) were involved, along with the dorsolateral prefrontal cortex. Interestingly, synchronized activation was observed in the primary visual cortex (areas V1 and V2), and the bilateral dorsal visual cortex. The higher visual association cortex also showed significant, but less prominent, activation. During the second week of rTMS treatment, not only the VAHs, but also the other sensory deceptions/distortions and mood symptoms showed complete remission. The patient remained free of any symptoms during a 4-month follow-up phase. After 8 months, when many of the original symptoms had returned, a second treatment phase with rTMS was again followed by complete remission. Conclusions: This case indicates that VAHs and metamorphopsias in AIWS are associated with synchronized activation in both auditory and visual cortices. It also indicates that local rTMS treatment may have global therapeutic effects, suggesting an effect on multiple brain regions in a distributed network. Although a placebo effect cannot be ruled out, this case warrants further investigation of the effects of rTMS treatment in AIWS. Copyright (C) 2011 S. Karger AG, Base

The Same or Different? A Phenomenological Comparison of Auditory Verbal Hallucinations in Healthy and Psychotic Individuals

Objective: Whereas auditory verbal hallucinations (AVHs) are most characteristic of schizophrenia, their presence has frequently been described in a continuum, ranging from severely psychotic patients to schizotypal personality disorder patients to otherwise healthy participants. It remains unclear whether AVHs at the outer borders of this spectrum are indeed the same phenomenon. Furthermore, specific characteristics of AVHs may be important indicators of a psychotic disorder. Method: To investigate differences and similarities in AVHs in psychotic and nonpsychotic individuals, the phenomenology of AVHs in 118 psychotic outpatients was compared to that in 11 otherwise healthy individuals, both experiencing AVHs at least once a month. The study was performed between September 2007 and March 2010 at the University Medical Center, Utrecht, the Netherlands. Characteristics of AVHs were quantified using the Psychotic Symptoms Rating Scales Auditory Hallucinations subscale. Results: The perceived location of voices (inside/outside the head), the number of voices, loudness, and personification did not differentiate between psychotic and healthy individuals. The most prominent differences between AVHs in healthy and psychotic individuals were the emotional valence of the content, the frequency of AVHs, and the control subjects had over their AVHs (all P values <.001). Age at onset of AVHs was at a significantly younger age in the healthy individuals (P <.001). In our sample, the negative emotional valence of the content of AVHs could accurately predict the presence of a psychotic disorder in 88% of the participants. Conclusions: We cannot ascertain whether AVHs at the outer borders of the spectrum should be considered the same phenomenon, as there are both similarities and differences. The much younger age at onset of AVHs in the healthy subjects compared to that in psychotic patients may suggest a different pathophysiology. The high predictive value of the emotional content of voices implies that inquiring after the emotional content of AVHs may be a crucial step in the diagnosis of psychotic disorders in individuals hearing voices. J Clin Psychiatry 2011;72(3):320-325 (C) Copyright 2011 Physicians Postgraduate Press, Inc