Development of a classifier for gambling disorder based on functional connections between brain regions.

AIM: Recently, a machine-learning (ML) technique has been used to create generalizable classifiers for psychiatric disorders based on information of functional connections (FCs) between brain regions at resting state. These classifiers predict diagnostic labels by a weighted linear sum (WLS) of the correlation values of a small number of selected FCs. We aimed to develop a generalizable classifier for gambling disorder (GD) from the information of FCs using the ML technique and examine relationships between WLS and clinical data. METHODS: As a training dataset for ML, data from 71 GD patients and 90 healthy controls (HCs) were obtained from two magnetic resonance imaging sites. We used an ML algorithm consisting of a cascade of an L1-regularized sparse canonical correlation analysis and a sparse logistic regression to create the classifier. The generalizability of the classifier was verified using an external dataset. This external dataset consisted of six GD patients and 14 HCs, and was collected at a different site from the sites of the training dataset. Correlations between WLS and South Oaks Gambling Screen (SOGS) and duration of illness were examined. RESULTS: The classifier distinguished between the GD patients and HCs with high accuracy in leave-one-out cross-validation (area under curve (AUC = 0.89)). This performance was confirmed in the external dataset (AUC = 0.81). There was no correlation between WLS, and SOGS and duration of illness in the GD patients. CONCLUSION: We developed a generalizable classifier for GD based on information of functional connections between brain regions at resting state.

Framing effects on financial and health problems in gambling disorder.

Gambling disorder (GD) patients show excessively risky decision-making in the financial domain. We aimed to clarify whether GD patients show risky decision-making in domain-general or in domain-specific. Furthermore, we also investigated the effect of the well-known cognitive bias, the framing effect on GD's decision-making under risk. Sixty-two male GD patients and 74 age-matched healthy male controls (HC) conducted a risky choice task in which they should choose solutions for difficult situations between a sure and a risky option that had the same expectations. Six situations were prepared for each financial and health domain. For each domain, three situations were presented with options using positive frames, and the other three situations were presented with options using negative frames. The results showed that GD chose more risky options in the financial domain with positive frames than HC, but chose comparably in the financial domain with negative frames, whereas GD and HC chose comparably in the health domain regardless of the frames. Thus, GD showed risky decision-making in domain-specific. In addition, the results indicate the importance of considering the influence of the framing effect for assessment of risky decision-making by GD. Domains and the influence of the framing effect should be considered when decision-making patterns of neuropsychiatric disorders are studied.

A positive shift in resting-state functional connectivity between the insula and default mode network regions reflects the duration of illness in gambling disorder patients without lifetime substance abuse.

The insula is considered an important structure involved in addiction and in the context of dynamic activity switching between large-scale brain networks, such as the default mode network (DMN) and the central executive network. Although insular-DMN resting-state functional connectivity (rsFC), which could affect such switching, has been examined in substance addiction populations, the results have been inconsistent, partly because of the confounding neural effects of the abused substances. To investigate this subject, using MRI, we examined insular-DMN rsFC in gambling disorder (GD) patients without a history of substance use. We examined rsFC between insular seeds and DMN regions of interest during rest in 23 GD patients and 27 age-, sex-, handedness-, and high education rate-matched healthy control (HC) subjects. We found a positive shift in insular-DMN rsFC in GD patients compared with HC subjects. Furthermore, the connectivity strength between insular seed regions and DMN regions was positively correlated with illness duration in GD patients. This alteration might affect switching between large-scale brain networks, potentially leading to a preoccupation with gambling as well as various types of cognitive impairments. Our results could clarify the controversial findings regarding substance addiction and enhance the system-level understanding of addiction.

Inter-subject correlation of temporoparietal junction activity is associated with conflict patterns during flexible decision-making.

Although behavioral flexibility and conflict regulation may rely on executive function, the mechanism underlying these relationships remains obscure. We studied whether subjects' conflict ratings were associated with right dorsolateral prefrontal cortex (rDLPFC) and temporoparietal junction (rTPJ) activity during flexible decision-making in a moral dilemma task using inter-subject correlation (ISC)-based approach (i.e., brain-behavior correlation matrices analysis). We observed a statistically significant positive correlation between the ISC matrix of rTPJ and conflict-scores. This implies that similar rTPJ activity patterns across subjects were associated with similar conflict-rating patterns across subjects. Our findings suggest that rTPJ activity may be also related to conflicting experience.

Exaggerated envy and guilt measured by economic games in Japanese women with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) patients are assumed to express high levels of guilt and envy. Ultimatum game (UG) is a standard behavioral task that focuses on interpersonal behavior when splitting a sum of money between two players. UG studies consistently demonstrate that people tend to decrease their inequity in outcomes, one explanation being that economically irrational decision-making may partly arise from the emotions guilt and envy. We assumed that AN patients would perform excessively fair in UG, reflecting high guilt and envy. METHODS: We utilized UG to investigate the characteristics of guilt and envy among 24 Japanese AN patients and 22 age-matched healthy controls (HC). The relation between the outcome of UG and decision strategy confirmed by post-experimental questionnaires was analyzed. RESULTS: As proposer, AN offered a larger amount to the responder compared with HC (p = 0.002) while, on the other hand, as responder, AN demanded much higher allocation to accept the offer compared with HC (p = 0.026). Regarding the strategy as responder, AN put more emphasis on fairness and less emphasis on monetary reward compared with HC (p = 0.046, p = 0.042, respectively). CONCLUSIONS: The results indicate that Japanese AN patients demonstrate strong preference for fairness, with high guilt and high envy. High sensitivity to guilt and envy of AN patients can affect not only their own behavior concerning eating attitude and body shape, but also decision-making in interpersonal situations. Behavioral experimental settings among social situations will enable us to evaluate and help actual decision-making in the real life of patients.

An fMRI study of decision-making under sunk costs in gambling disorder.

The sunk cost effect is the tendency to continue an investment, or take an action, even though it has higher future costs than benefits, if costs of time, money, or effort were previously incurred. This type of decision bias is pervasive in real life and has been studied in various disciplines. Previous studies and clinical observations suggest that decision-making under sunk costs is altered in gambling disorder (GD). However, the neural mechanisms of decision-making under sunk costs in GD remain largely unknown, and so is their association with the clinical characteristics of this patient group. Here, by combining functional magnetic resonance imaging and the task that demonstrated a clear example of the sunk cost effect, we investigated the neural correlates during decision-making under sunk costs in GD. We found no significant differences in the strength of the sunk cost effect between the GD and healthy control (HC) groups. However, the strength of the sunk cost effect in patients with GD showed a significant negative correlation with abstinence period and a marginally significant positive correlation with the duration of illness. We also found a reduction in the neural activation in the dorsal medial prefrontal cortex during decision-making under sunk costs for the GD group compared with the HC group. Furthermore, in patients with GD, the levels of activation in this area negatively correlated with the duration of illness. These findings have important clinical implications. This study will contribute to a better understanding of the mechanisms underlying altered decision-making abilities in GD.

Self-efficacy modulates the neural correlates of craving in male smokers and ex-smokers: an fMRI study.

The regulation of cue-induced craving for cigarettes is a key factor in smoking cessation. Outcomes of smoking cessation have been linked to self-efficacy, faith in one's own ability, in smokers. However, no study has examined the neural basis of self-efficacy during the control of craving. We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. During scanning, participants were instructed (1) to view smoking-related images passively, (2) to view the smoking-related images with a strategy focused on self-efficacy to control cue-induced craving or (3) to view neutral images. In smokers, the self-efficacy strategy significantly reduced self-reported craving. This strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex in smokers compared with ex-smokers. Furthermore, smokers showed increased effective connectivity between rmPFC and hippocampus and between pregenual anterior cingulate cortex and parahippocampus gyrus when employing the self-efficacy strategy compared with ex-smokers. The magnitude of the rmPFC-hippocampus connectivity was positively correlated with self-reported self-efficacy. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment. The current study provides evidence for understanding the vunderlying cognitive and neurobiological mechanisms involved in the control of craving to smoke cigarettes.

Additive Effect of Cigarette Smoking on Gray Matter Abnormalities in Schizophrenia.

It is widely known that there is a high prevalence of cigarette smoking in schizophrenia. One of the explanations is the self-medication hypothesis. Based on this hypothesis, it has been suggested that nicotine has procognitive effect or even neuroprotective effect in schizophrenia. However, cigarettes contain numerous neurotoxic substances, making the net effect of cigarette smoking on brain function and structure complex. Indeed, recent studies have called into question the self-medication hypothesis. We aimed to test whether there is an interaction between diagnosis and smoking status in gray matter volume, ie, whether smoking has specific effects on gray matter or whether main effects of these 2 variables additively affect common brain regions. Magnetic resonance imaging (MRI) images were obtained from 4 groups: (1) normal controls with no smoking history, (2) normal controls currently smoking and/or with a past history of smoking, (3) schizophrenia patients with no smoking history, and (4) schizophrenia patients currently smoking and/or with a past history of smoking. We used voxel-based morphometry to compare gray matter volumes among the 4 groups. We did not find any interaction between diagnosis and smoking, but we did find negative additive effects of schizophrenia diagnosis and smoking status in the left prefrontal cortex. The decrease in left prefrontal volume was associated with greater numbers of cigarette pack years and severe positive and negative symptoms. The current findings do not support the neuroprotective effect of smoking on gross brain structure in schizophrenia, emphasizing the necessity of longitudinal studies to test causal relationships among these variables.

Role of Spontaneous Brain Activity in Explicit and Implicit Aspects of Cognitive Flexibility under Socially Conflicting Situations: A Resting-state fMRI Study using Fractional Amplitude of Low-frequency Fluctuations.

We are constantly exposed to socially conflicting situations in everyday life, and cognitive flexibility is essential for adaptively coping with such difficulties. Flexible goal choice and pursuit are not exclusively conscious, and therefore cognitive flexibility involves both explicit and implicit forms of processing. However, it is unclear how individual differences in explicit and implicit aspects of flexibility are associated with neural activity in a resting state. Here, we measured intrinsic fractional amplitude of low-frequency fluctuations (fALFF) by resting-state functional magnetic resonance imaging (RS-fMRI) as an indicator of regional brain spontaneous activity, together with explicit and implicit aspects of cognitive flexibility using the Cognitive Flexibility Scale (CFS) and Implicit Association Test (IAT). Consistent with the dual processing theory, there was a strong association between explicit aspects of flexibility (CFS score) and "rationalism" thinking style and between implicit aspects (IAT effect) and "experientialism." The level of explicit flexibility was also correlated with fALFF values in the left lateral prefrontal cortex, whereas the level of implicit flexibility was correlated with fALFF values in the right cerebellum. Furthermore, the fALFF values in both regions predicted individual preference for flexible decision-making strategy in a vignettes simulation task. These results add to our understanding of the neural mechanisms underlying flexible decision-making for solving social conflicts. More generally, our findings highlight the utility of RS-fMRI combined with both explicit and implicit psychometric measures for better understanding individual differences in social cognition.

Collaborative roles of Temporoparietal Junction and Dorsolateral Prefrontal Cortex in Different Types of Behavioural Flexibility.

Behavioural flexibility is essential for everyday life. This involves shifting attention between different perspectives. Previous studies suggest that flexibility is mainly subserved by the dorsolateral prefrontal cortex (DLPFC). However, although rarely emphasized, the temporoparietal junction (TPJ) is frequently recruited during flexible behaviour. A crucial question is whether TPJ plays a role in different types of flexibility, compared to its limited role in perceptual flexibility. We hypothesized that TPJ activity during diverse flexibility tasks plays a common role in stimulus-driven attention-shifting, thereby contributing to different types of flexibility, and thus the collaboration between DLPFC and TPJ might serve as a more appropriate mechanism than DLPFC alone. We used fMRI to measure DLPFC/TPJ activity recruited during moral flexibility, and examined its effect on other domains of flexibility (economic/perceptual). Here, we show the additional, yet crucial role of TPJ: a combined DLPFC/TPJ activity predicted flexibility, regardless of domain. Different types of flexibility might rely on more basic attention-shifting, which highlights the behavioural significance of alternatives.

Common and differential brain abnormalities in gambling disorder subtypes based on risk attitude.

Studying brain abnormalities in behavioral addiction including GD enables us to exclude possible confounding effects of exposure to neurotoxic substances, which should provide important insight that can lead to a better understanding of addiction per se. There have been a few brain structural magnetic resonance imaging studies for GD, although the results have been inconsistent. On the other hand, GD was suggested to be a heterogeneous disorder in terms of risk attitude. We aimed to examine the heterogeneity of GD by combining a behavioral economics task and voxel-based morphometry. Thirty-six male GD patients and 36 healthy male control subjects underwent a task for estimation of loss aversion, which can assess risk attitude in real-life decision-making. The GD patients were divided into two groups based on their level of loss aversion, low and high. While both groups showed common gray matter volume reduction in the left supramarginal gyrus and bilateral posterior cerebellum, high loss-aversion GD showed pronounced reduction in the left posterior cerebellum and additional reduction in the bilateral medial orbitofrontal cortex. Our study suggests that the heterogeneity of GD is underpinned at the brain structural level. This result might be useful for understanding neurobiological mechanisms and for the establishment of precise treatment strategies for GD.

Ambiguity aversion in schizophrenia: An fMRI study of decision-making under risk and ambiguity.

When making decisions in everyday life, we often have to choose between uncertain outcomes. Economic studies have demonstrated that healthy people tend to prefer options with known probabilities (risk) than those with unknown probabilities (ambiguity), which is referred to as "ambiguity aversion." However, it remains unclear how patients with schizophrenia behave under ambiguity, despite growing evidence of their altered decision-making under uncertainty. In this study, combining economic tools and functional magnetic resonance imaging (fMRI), we assessed the attitudes toward risk/ambiguity and investigated the neural correlates during decision-making under risk/ambiguity in schizophrenia. Although no significant difference in attitudes under risk was observed, patients with schizophrenia chose ambiguity significantly more often than the healthy controls. Attitudes under risk and ambiguity did not correlate across patients with schizophrenia. Furthermore, unlike in the healthy controls, activation of the left lateral orbitofrontal cortex was not increased during decision-making under ambiguity compared to under risk in schizophrenia. These results suggest that ambiguity aversion, a well-established subjective bias, is attenuated in patients with schizophrenia, highlighting the need to distinguish between risk and ambiguity when assessing decision-making under these situations. Our findings, comprising important clinical implications, contribute to improved understanding of the mechanisms underlying altered decision-making in patients with schizophrenia.

Neural mechanisms and personality correlates of the sunk cost effect.

The sunk cost effect, an interesting and well-known maladaptive behavior, is pervasive in real life, and thus has been studied in various disciplines, including economics, psychology, organizational behavior, politics, and biology. However, the neural mechanisms underlying the sunk cost effect have not been clearly established, nor have their association with differences in individual susceptibility to the effect. Using functional magnetic resonance imaging, we investigated neural responses induced by sunk costs along with measures of core human personality. We found that individuals who tend to adhere to social rules and regulations (who are high in measured agreeableness and conscientiousness) are more susceptible to the sunk cost effect. Furthermore, this behavioral observation was strongly mediated by insula activity during sunk cost decision-making. Tight coupling between the insula and lateral prefrontal cortex was also observed during decision-making under sunk costs. Our findings reveal how individual differences can affect decision-making under sunk costs, thereby contributing to a better understanding of the psychological and neural mechanisms of the sunk cost effect.

Heterogeneity of Loss Aversion in Pathological Gambling.

Pathological gambling (PG) is characterized by continual repeated gambling behavior despite negative consequences. PG is considered to be a disorder of altered decision-making under risk, and behavioral economics tools were utilized by studies on decision-making under risk. At the same time, PG was suggested to be a heterogeneous disorder in terms of personality traits as well as risk attitude. We aimed to examine the heterogeneity of PG in terms of loss aversion, which means that a loss is subjectively felt to be larger than the same amount of gain. Thirty-one male PG subjects and 26 male healthy control (HC) subjects underwent a behavioral economics task for estimation of loss aversion and personality traits assessment. Although loss aversion in PG subjects was not significantly different from that in HC subjects, distributions of loss aversion differed between PG and HC subjects. HC subjects were uniformly classified into three levels (low, middle, high) of loss aversion, whereas PG subjects were mostly classified into the two extremes, and few PG subjects were classified into the middle range. PG subjects with low and high loss aversion showed a significant difference in anxiety, excitement-seeking and craving intensity. Our study suggested that PG was a heterogeneous disorder in terms of loss aversion. This result might be useful for understanding cognitive and neurobiological mechanisms and the establishment of treatment strategies for PG.

Insular Gray Matter Volume and Objective Quality of Life in Schizophrenia.

Improving quality of life has been recognized as an important outcome for schizophrenia treatment, although the fundamental determinants are not well understood. In this study, we investigated the association between brain structural abnormalities and objective quality of life in schizophrenia patients. Thirty-three schizophrenia patients and 42 age-, sex-, and education-matched healthy participants underwent magnetic resonance imaging. The Quality of Life Scale was used to measure objective quality of life in schizophrenia patients. Voxel-based morphometry was performed to identify regional brain alterations that correlate with Quality of Life Scale score in the patient group. Schizophrenia patients showed gray matter reductions in the frontal, temporal, limbic, and subcortical regions. We then performed voxel-based multiple regression analysis in these regions to identify any correlations between regional gray matter volume and Quality of Life Scale scores. We found that among four subcategories of the scale, the Instrumental Role category score correlated with gray matter volume in the right anterior insula in schizophrenia patients. In addition, this correlation was shown to be mediated by negative symptoms. Our findings suggest that the neural basis of objective quality of life might differ topographically from that of subjective QOL in schizophrenia.

Functional relevance of the precuneus in verbal politeness.

Non-competitive and non-threatening aspects of social hierarchy, such as politeness, are universal among human cultures, and might have evolved from ritualized submission in primates; however, these behaviors have rarely been studied. Honorific language is a type of polite linguistic communication that plays an important role in human social interactions ranging from everyday conversation to international diplomacy. Here, functional magnetic resonance imaging (fMRI) revealed selective precuneus activation during a verbal politeness judgment task, but not other linguistic-judgment or social-status recognition tasks. The magnitude of the activation was correlated with the task performance. Functional suppression of the activation using cathodal transcranial direct-current stimulation reduced performance in the politeness task. These results suggest that the precuneus is an essential hub of the verbal politeness judgment.

Insular activation during reward anticipation reflects duration of illness in abstinent pathological gamblers.

Pathological gambling (PG) is a chronic mental disorder characterized by a difficulty restraining gambling behavior despite negative consequences. Although brain abnormalities in patients with substance use disorders are caused by repetitive drug use and recover partly with drug abstinence, the relationship between brain activity and duration of illness or abstinence of gambling behavior in PG patients remains unclear. Here, using functional magnetic resonance imaging, we compared the brain activity of 23 PG patients recruited from a treatment facility with 27 demographically-matched healthy control subjects during reward anticipation, and examined the correlations between brain activity and duration of illness or abstinence in PG patients. During reward anticipation, PG patients showed decreased activity compared to healthy controls in a broad range of the reward system regions, including the insula cortex. In PG patients, activation in the left insula showed a significant negative correlation with illness duration. Our findings suggest that insular activation during reward anticipation may serve as a marker of progression of pathological gambling.

Altered brain response to others׳ pain in major depressive disorder.

BACKGROUND: Empathy has a central role in successful interpersonal engagement. Several studies have reported altered empathy in major depressive disorder (MDD), which could lead to interpersonal difficulties. However, the neural basis of altered empathy in the disorder is still largely unknown. To address this, we performed functional magnetic resonance imaging that tested empathy for others׳ pain in MDD patients. METHODS: Eleven patients with MDD and 11 age-, gender-, handedness-, and education level-matched healthy control subjects were studied. We compared MDD patients and healthy controls for their regional hemodynamic responses to visual perception of videos showing human hands in painful situations. We also assessed subjective pain ratings of the videos in each group. RESULTS: The MDD patients showed lower pain ratings for the painful videos compared with the healthy controls. In addition, the MDD patients showed reduced cerebral activation in the left middle cingulate cortex, and the right somatosensory-related cortices, whereas they showed greater cerebral activation in the left inferior frontal gyrus. LIMITATIONS: We relied on a relatively small sample size and could not exclude effects of medications. CONCLUSIONS: These results suggest that in MDD patients the altered neural activations in these regions may be associated with a deficit in the identification of pain in others. This study adds to our understanding of the neural mechanism involved in empathy in MDD.

Global association between cortical thinning and white matter integrity reduction in schizophrenia.

Previous neuroimaging studies have revealed that both gray matter (GM) and white matter (WM) are altered in several morphological aspects in schizophrenia patients. Although several studies reported associations between GM and WM alterations in restricted regions, the existence of a global association between GM and WM pathologies is unknown. Considering the wide distribution of GM morphological changes and the profound genetic background of WM abnormalities, it would be natural to postulate a global association between pathologies of GM and WM in schizophrenia. In this investigation, we studied 35 schizophrenia patients and 35 healthy control subjects using T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) and investigated the association between GM thickness and WM fractional anisotropy (FA) as a proxy of pathology in each tissue. To investigate cortical thickness, surface-based analysis was used. The mean cortical thickness for the whole brain was computed for each hemisphere, and group comparisons were performed. For DTI data, mean FA for the whole brain was calculated, and group comparisons were performed. Subsequently, the correlation between mean cortical thickness and mean FA was investigated. Results showed that the mean cortical thickness was significantly thinner, and the mean FA was significantly lower in schizophrenia patients. Only in the patient group the mean cortical thickness and mean FA showed significant positive correlations in both hemispheres. This correlation remained significant even after controlling for demographic and clinical variables. Thus, our results indicate that the GM and WM pathologies of schizophrenia are intertwined at the global level.