Striatal activation as a neural link between cognitive and perceptual flexibility.

Our brain continuously evaluates different perceptual interpretations of the available sensory data in order to enable flexible updates of conscious experience. Individuals' perceptual flexibility can be assessed using ambiguous stimuli that cause our perception to continuously switch between two mutually exclusive interpretations. Neural processes underlying perceptual switching are thought to involve the visual cortex, but also non-sensory brain circuits that have been implicated in cognitive processes, such as frontal and parietal regions. Perceptual flexibility varies strongly between individuals and has been related to dopaminergic neurotransmission. Likewise, there is also considerable individual variability in tasks that require flexibility in cognition, and dopamine-dependent striato-frontal signals have been associated with processes promoting cognitive flexibility. Given the anatomical and neurochemical similarities with regard to perceptual and cognitive flexibility, we here probed whether individual differences in perceptual flexibility during bistable perception are related to individual cognitive flexibility associated neural correlates. 126 healthy individuals performed rule-based task switching during functional magnetic resonance imaging (fMRI) and reported perceptual switching during the viewing of a modified version of the Necker cube. Mean phase duration as measure of perceptual flexibility correlated with task-switching associated activity in the right putamen as part of the basal ganglia. In addition, we found a tentative correlation between perceptual and cognitive flexibility. These results indicate that individual differences in cognitive flexibility and associated fronto-striatal processing contribute to differences in perceptual flexibility. Our findings thus provide empirical support for the general notion of shared mechanisms between perception and cognition.

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress.

Neuronal loss is the ultimate outcome in a variety of neurodegenerative diseases and central nerve system disorders. Understanding the sequelae of events that leads to cell death would provide insight into neuroprotective approaches. We imaged neurons in the living brain of a mouse model of Alzheimer's disease that overexpresses mutant human amyloid precursor protein and presenilin 1 and followed the death of individual neurons in real time. This mouse model exhibited limited neurodegeneration and atrophy, but we were able to identify a small fraction of vulnerable cells that would not have been detectable by using standard approaches. By exploiting a genetically encoded reporter of oxidative stress, we identified susceptible neurons by their increased redox potential. The oxidative stress was most dramatic in neurites near plaques, propagated to cell bodies, and preceded activation of caspases that led to cell death within 24 h. Thus, local oxidative stress surrounding plaques contributes to long-range toxicity and selective neuronal death in Alzheimer's disease.

Delusions and the role of beliefs in perceptual inference.

Delusions are unfounded yet tenacious beliefs and a symptom of psychotic disorder. Varying degrees of delusional ideation are also found in the healthy population. Here, we empirically validated a neurocognitive model that explains both the formation and the persistence of delusional beliefs in terms of altered perceptual inference. In a combined behavioral and functional neuroimaging study in healthy participants, we used ambiguous visual stimulation to probe the relationship between delusion-proneness and the effect of learned predictions on perception. Delusional ideation was associated with less perceptual stability, but a stronger belief-induced bias on perception, paralleled by enhanced functional connectivity between frontal areas that encoded beliefs and sensory areas that encoded perception. These findings suggest that weakened lower-level predictions that result in perceptual instability are implicated in the emergence of delusional beliefs. In contrast, stronger higher-level predictions that sculpt perception into conformity with beliefs might contribute to the tenacious persistence of delusional beliefs.

The influence of dopamine-related genes on perceptual stability.

Bistable perception is the spontaneous and automatic alternation between two different perceptual states that occurs when sensory information is ambiguous. Perceptual alternation rates are robust within individuals but vary substantially between individuals. Slowed perceptual switching has been consistently reported in patients with bipolar disorder (BPD) and has been suggested as a trait marker for this disease. Although genetic factors have been implicated in both BPD and bistable perception, the underlying biological mechanisms that mediate the observed perceptual stability in BPD remain elusive. Here, we tested the effect of two variable number tandem repeat (VNTR) polymorphisms in DRD4 and DAT1 (SLC6A3), both candidate genes for BPD with functional impact on dopaminergic neurotransmission, on bistable perception in a cohort of 108 healthy human subjects. The BPD risk allele DRD4-2R was significantly associated with slow perceptual switching. There was no effect of DAT1 genotype on bistable perception. Our findings indicate that genetic differences in dopaminergic neurotransmission linked to BPD also account for interindividual variability in bistable perception, thus providing a genetic basis for perceptual stability as a trait marker of BPD.

A multimodal neuroimaging classifier for alcohol dependence.

With progress in magnetic resonance imaging technology and a broader dissemination of state-of-the-art imaging facilities, the acquisition of multiple neuroimaging modalities is becoming increasingly feasible. One particular hope associated with multimodal neuroimaging is the development of reliable data-driven diagnostic classifiers for psychiatric disorders, yet previous studies have often failed to find a benefit of combining multiple modalities. As a psychiatric disorder with established neurobiological effects at several levels of description, alcohol dependence is particularly well-suited for multimodal classification. To this aim, we developed a multimodal classification scheme and applied it to a rich neuroimaging battery (structural, functional task-based and functional resting-state data) collected in a matched sample of alcohol-dependent patients (N = 119) and controls (N = 97). We found that our classification scheme yielded 79.3% diagnostic accuracy, which outperformed the strongest individual modality - grey-matter density - by 2.7%. We found that this moderate benefit of multimodal classification depended on a number of critical design choices: a procedure to select optimal modality-specific classifiers, a fine-grained ensemble prediction based on cross-modal weight matrices and continuous classifier decision values. We conclude that the combination of multiple neuroimaging modalities is able to moderately improve the accuracy of machine-learning-based diagnostic classification in alcohol dependence.

No evidence for abnormal priors in early vision in schizophrenia.

The predictive coding account of psychosis postulates the abnormal formation of prior beliefs in schizophrenia, resulting in psychotic symptoms. One domain in which priors play a crucial role is visual perception. For instance, our perception of brightness, line length, and motion direction are not merely based on a veridical extraction of sensory input but are also determined by expectation (or prior) of the stimulus. Formation of such priors is thought to be governed by the statistical regularities within natural scenes. Recently, the use of such priors has been attributed to a specific set of well-documented visual illusions, supporting the idea that perception is biased toward what is statistically more probable within the environment. The Predictive Coding account of psychosis proposes that patients form abnormal representations of statistical regularities in natural scenes, leading to altered perceptual experiences. Here we use classical vision experiments involving a specific set of visual illusions to directly test this hypothesis. We find that perceptual judgments for both patients and control participants are biased in accordance with reported probability distributions of natural scenes. Thus, despite there being a suggested link between visual abnormalities and psychotic symptoms in schizophrenia, our results provide no support for the notion that altered formation of priors is a general feature of the disorder. These data call for a refinement in the predictions of quantitative models of psychosis.

Neural Response Patterns During Pavlovian-to-Instrumental Transfer Predict Alcohol Relapse and Young Adult Drinking.

BACKGROUND: Pavlovian-to-instrumental transfer (PIT) describes the influence of conditioned stimuli on instrumental behaviors and is discussed as a key process underlying substance abuse. Here, we tested whether neural responses during alcohol-related PIT predict future relapse in alcohol-dependent patients and future drinking behavior in adolescents. METHODS: Recently detoxified alcohol-dependent patients (n = 52) and young adults without dependence (n = 136) underwent functional magnetic resonance imaging during an alcohol-related PIT paradigm, and their drinking behavior was assessed in a 12-month follow-up. To predict future drinking behavior from PIT activation patterns, we used a multivoxel classification scheme based on linear support vector machines. RESULTS: When training and testing the classification scheme in patients, PIT activation patterns predicted future relapse with 71.2% accuracy. Feature selection revealed that classification was exclusively based on activation patterns in medial prefrontal cortex. To probe the generalizability of this functional magnetic resonance imaging-based prediction of future drinking behavior, we applied the support vector machine classifier that had been trained on patients to PIT functional magnetic resonance imaging data from adolescents. An analysis of cross-classification predictions revealed that those young social drinkers who were classified as abstainers showed a greater reduction in alcohol consumption at 12-month follow-up than those classified as relapsers (Δ = -24.4 ± 6.0 g vs. -5.7 ± 3.6 g; p = .019). CONCLUSIONS: These results suggest that neural responses during PIT could constitute a generalized prognostic marker for future drinking behavior in established alcohol use disorder and in at-risk states.

Quantitative neurobiological evidence for accelerated brain aging in alcohol dependence.

The premature aging hypothesis of alcohol dependence proposes that the neurobiological and behavioural deficits in individuals with alcohol dependence are analogous to those of chronological aging. However, to date no systematic neurobiological evidence for this hypothesis has been provided. To test the hypothesis, 119 alcohol-dependent subjects and 97 age- and gender-matched healthy control subjects underwent structural MRI. Whole-brain grey matter volume maps were computed from structural MRI scans using voxel-based morphometry and parcelled into a comprehensive set of anatomical brain regions. Regional grey matter volume averages served as the basis for cross-regional similarity analyses and a brain age model. We found a striking correspondence between regional patterns of alcohol- and age-related grey matter loss across 110 brain regions. The brain age model revealed that the brain age of age-matched AD subjects was increased by up to 11.7 years. Interestingly, while no brain aging was detected in the youngest AD subjects (20-30 years), we found that alcohol-related brain aging systematically increased in the following age decades controlling for lifetime alcohol consumption and general health status. Together, these results provide strong evidence for an accelerated aging model of AD and indicate an elevated risk of alcohol-related brain aging in elderly individuals.

Spectral EEG abnormalities during vibrotactile encoding and quantitative working memory processing in schizophrenia.

Schizophrenia is associated with a number of cognitive impairments such as deficient sensory encoding or working memory processing. However, it is largely unclear how dysfunctions on these various levels of cortical processing contribute to alterations of stimulus-specific information representation. To test this, we used a well-established sequential frequency comparison paradigm, in which sensory encoding of vibrotactile stimuli can be assessed via frequency-specific steady-state evoked potentials (SSEPs) over primary somatosensory cortex (S1). Further, we investigated the maintenance of frequency information in working memory (WM) in terms of parametric power modulations of induced beta-band EEG oscillations. In the present study schizophrenic patients showed significantly less pronounced SSEPs during vibrotactile stimulation than healthy controls. In particular, inter-trial phase coherence was reduced. While maintaining vibrotactile frequencies in WM, patients showed a significantly weaker prefrontal beta-power modulation compared to healthy controls. Crucially, patients exhibited no general disturbances in attention, as inferred from a behavioral test and from alpha-band event-related synchronization. Together, our results provide novel evidence that patients with schizophrenia show altered neural correlates of stimulus-specific sensory encoding and WM maintenance, suggesting an early somatosensory impairment as well as alterations in the formation of abstract representations of task-relevant stimulus information.

Linking unfounded beliefs to genetic dopamine availability.

Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val (158) met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world.