Four-Week Mentalizing Imagery Therapy for Family Dementia Caregivers: A Randomized Controlled Trial with Neural Circuit Changes.

INTRODUCTION: Family caregivers of patients with dementia suffer a high burden of depression and reduced positive emotions. Mentalizing imagery therapy (MIT) provides mindfulness and guided imagery skills training to improve balanced mentalizing and emotion regulation. OBJECTIVE: Our aims were to test the hypotheses that MIT for family caregivers would reduce depression symptoms and improve positive psychological traits more than a support group (SG), and would increase dorsolateral prefrontal cortex (DLPFC) connectivity and reduce subgenual anterior cingulate cortex (sgACC) connectivity. METHODS: Forty-six caregivers participated in a randomized controlled trial comparing a 4-week MIT group (n = 24) versus an SG (n = 22). Resting state neuroimaging was obtained at baseline and post-group in 28 caregivers, and questionnaires completed by all participants. The primary outcome was change in depression; secondary measures included anxiety, mindfulness, self-compassion, and well-being. Brain networks with participation of DLPFC and sgACC were identified. Connectivity strengths of DLPFC and sgACC with respective networks were determined with dual regression. DLPFC connectivity was correlated with mindfulness and depression outcomes. RESULTS: MIT significantly outperformed SG in improving depression, anxiety, mindfulness, self-compassion, and well-being, with moderate to large effect sizes. Relative to SG, participants in MIT showed significant increases in DLPFC connectivity - exactly replicating pilot study results - but no change in sgACC. DLPFC connectivity change correlated positively with mindfulness and negatively with depression change. CONCLUSIONS: In this trial, MIT was superior to SG for reducing depression and anxiety symptoms and improving positive psychological traits. Neuroimaging results suggested that strengthening DLPFC connectivity with an emotion regulation network might be mechanistically related to MIT effects.

Mentalizing imagery therapy for depressed family dementia caregivers: Feasibility, clinical outcomes and brain connectivity changes.

BACKGROUND: Family dementia caregivers experience high rates of depression and anxiety that often go untreated due to time demands. We aimed to determine the feasibility of a brief, 4-week Mentalizing Imagery Therapy intervention, which couples mindfulness with guided imagery practices aimed at bolstering mentalizing capacity, to reduce caregiver psychological symptoms and to explore potential impact on dorsolateral prefrontal cortex connectivity. METHODS: Twenty-four family dementia caregivers with moderate depression symptoms (a score of 10 in Patient Health Questionnaire-9) were assigned to either group Mentalizing Imagery Therapy (MIT, n = 12) or a waitlist augmented by optional relaxation exercises (n = 12). Participants completed questionnaires to measure depression and anxiety at baseline and followup, and those eligible also underwent resting state functional magnetic resonance (fMRI) brain imaging at these time points. RESULTS: Eleven of 12 caregivers assigned to MIT completed the intervention and attended weekly groups 98% of the time. MIT home practice logs indicated average practice of 5 ± 2 sessions per week for 23 ± 8 min per session. All participants in waitlist completed the post-assessment. MIT participants exhibited significantly greater improvement than waitlist on self-reported depression and anxiety symptoms (p<.05) after 4 weeks. Neuroimaging results revealed increased dorsolateral prefrontal cortex connectivity with a putative emotion regulation network in the MIT group (p = .05) but not in waitlist (p = 1.0). LIMITATIONS: Sample size limitations necessitate validation of findings in larger, randomized controlled trials. CONCLUSIONS: A 4-week group MIT program was feasible for caregivers, with high levels of participation in weekly group meetings and home practice exercises.

Sex differences in default mode and dorsal attention network engagement.

Focusing on sex differences is necessary to fully understand basic neurobiological processes such as the engagement of large-scale brain networks involved in attention. Prior work suggests that women show enhanced attention during tasks of reward/punishment relative to men. Yet, sex differences in the engagement of neural networks sub serving internal and external focus has been unexplored in regard to reward and punishment. Using data from a large sample (n = 190) of healthy participants from the Human Connectome Project, we investigated sex differences in default mode network (DMN), dorsal attention network (DAN), and frontal parietal network (FPN) activation during exposure to reward and punishment. To determine if sex differences are specific to valenced stimuli, we analyzed network activation during working memory. Results indicate that, relative to men, women have increased suppression of the DMN and greater activation of the DAN during exposure to reward and punishment. Given the relative roles of these networks in internal (DMN) and external (DAN) attention, this pattern of activation suggests that women have enhanced external attention to reward and punishment. In contrast, there were no sex differences in network activation during working memory, indicating that this sex difference is specific to the processing of reward and punishment. These findings suggest a neurobiological explanation for prior work showing women have greater sensitivity to reward/punishment and are more prone to psychiatric disorders characterized by enhanced attention to such stimuli. Furthermore, given the large sample from the Human Connectome Project, the current findings provide general implications for the study of sex as a biological variable in investigation of reward processes.

Effective connectivity of brain regions underlying third-party punishment: Functional MRI and Granger causality evidence.

Third-party punishment (TPP) for norm violations is an essential deterrent in large-scale human societies, and builds on two essential cognitive functions: evaluating legal responsibility and determining appropriate punishment. Despite converging evidence that TPP is mediated by a specific set of brain regions, little is known about their effective connectivity (direction and strength of connections). Applying parametric event-related functional MRI in conjunction with multivariate Granger causality analysis, we asked healthy participants to estimate how much punishment a hypothetical perpetrator deserves for intentionally committing criminal offenses varying in levels of harm. Our results confirmed that TPP legal decisions are based on two domain-general networks: the mentalizing network for evaluating legal responsibility and the central-executive network for determining appropriate punishment. Further, temporal pole (TP) and dorsomedial prefrontal cortex (PFC) emerged as hubs of the mentalizing network, uniquely generating converging output connections to ventromedial PFC, temporo-parietal junction, and posterior cingulate. In particular, dorsomedial PFC received inputs only from TP and both its activation and its connectivity to dorsolateral PFC correlated with degree of punishment. This supports the hypothesis that dorsomedial PFC acts as the driver of the TPP activation pattern, leading to the decision on the appropriate punishment. In conclusion, these results advance our understanding of the organizational elements of the TPP brain networks and provide better insights into the mental states of judges and jurors tasked with blaming and punishing legal wrongs.

An fMRI and effective connectivity study investigating miss errors during advice utilization from human and machine agents.

As society becomes more reliant on machines and automation, understanding how people utilize advice is a necessary endeavor. Our objective was to reveal the underlying neural associations during advice utilization from expert human and machine agents with fMRI and multivariate Granger causality analysis. During an X-ray luggage-screening task, participants accepted or rejected good or bad advice from either the human or machine agent framed as experts with manipulated reliability (high miss rate). We showed that the machine-agent group decreased their advice utilization compared to the human-agent group and these differences in behaviors during advice utilization could be accounted for by high expectations of reliable advice and changes in attention allocation due to miss errors. Brain areas involved with the salience and mentalizing networks, as well as sensory processing involved with attention, were recruited during the task and the advice utilization network consisted of attentional modulation of sensory information with the lingual gyrus as the driver during the decision phase and the fusiform gyrus as the driver during the feedback phase. Our findings expand on the existing literature by showing that misses degrade advice utilization, which is represented in a neural network involving salience detection and self-processing with perceptual integration.

Neural signatures of trust in reciprocity: A coordinate-based meta-analysis.

Trust in reciprocity (TR) is defined as the risky decision to invest valued resources in another party with the hope of mutual benefit. Several fMRI studies have investigated the neural correlates of TR in one-shot and multiround versions of the investment game (IG). However, an overall characterization of the underlying neural networks remains elusive. Here, a coordinate-based meta-analysis was employed (activation likelihood estimation method, 30 articles) to investigate consistent brain activations in each of the IG stages (i.e., the trust, reciprocity and feedback stage). Results showed consistent activations in the anterior insula (AI) during trust decisions in the one-shot IG and decisions to reciprocate in the multiround IG, likely related to representations of aversive feelings. Moreover, decisions to reciprocate also consistently engaged the intraparietal sulcus, probably involved in evaluations of the reciprocity options. On the contrary, trust decisions in the multiround IG consistently activated the ventral striatum, likely associated with reward prediction error signals. Finally, the dorsal striatum was found consistently recruited during the feedback stage of the multiround IG, likely related to reinforcement learning. In conclusion, our results indicate different neural networks underlying trust, reciprocity, and feedback learning. These findings suggest that although decisions to trust and reciprocate may elicit aversive feelings likely evoked by the uncertainty about the decision outcomes and the pressing requirements of social standards, multiple interactions allow people to build interpersonal trust for cooperation via a learning mechanism by which they arguably learn to distinguish trustworthy from untrustworthy partners. Hum Brain Mapp 38:1233-1248, 2017. © 2016 Wiley Periodicals, Inc.

Advice Taking from Humans and Machines: An fMRI and Effective Connectivity Study.

With new technological advances, advice can come from different sources such as machines or humans, but how individuals respond to such advice and the neural correlates involved need to be better understood. We combined functional MRI and multivariate Granger causality analysis with an X-ray luggage-screening task to investigate the neural basis and corresponding effective connectivity involved with advice utilization from agents framed as experts. Participants were asked to accept or reject good or bad advice from a human or machine agent with low reliability (high false alarm rate). We showed that unreliable advice decreased performance overall and participants interacting with the human agent had a greater depreciation of advice utilization during bad advice compared to the machine agent. These differences in advice utilization can be perceivably due to reevaluation of expectations arising from association of dispositional credibility for each agent. We demonstrated that differences in advice utilization engaged brain regions that may be associated with evaluation of personal characteristics and traits (precuneus, posterior cingulate cortex, temporoparietal junction) and interoception (posterior insula). We found that the right posterior insula and left precuneus were the drivers of the advice utilization network that were reciprocally connected to each other and also projected to all other regions. Our behavioral and neuroimaging results have significant implications for society because of progressions in technology and increased interactions with machines.

Measurement and Comparison of Organic Compound Concentrations in Plasma, Whole Blood, and Dried Blood Spot Samples.

The preferred sampling medium for measuring human exposures of persistent organic compounds (POPs) is blood, and relevant sample types include whole blood, plasma, and dried blood spots (DBS). Because information regarding the performance and comparability of measurements across these sample types is limited, it is difficult to compare across studies. This study evaluates the performance of POP measurements in plasma, whole blood and DBS, and presents the distribution coefficients needed to convert concentrations among the three sample types. Blood samples were collected from adult volunteers, along with demographic and smoking information, and analyzed by GC/MS for organochlorine pesticides (OCPs), chlorinated hydrocarbons (CHCs), polychlorinated biphenyls (PCBs), and brominated diphenyl ethers (PBDEs). Regression models were used to evaluate the relationships between the sample types and possible effects of personal covariates. Distribution coefficients also were calculated using physically-based models. Across all compounds, concentrations in plasma were consistently the highest; concentrations in whole blood and DBS samples were comparable. Distribution coefficients for plasma to whole blood concentrations ranged from 1.74 to 2.26 for pesticides/CHCs, averaged 1.69 ± 0.06 for the PCBs, and averaged 1.65 ± 0.03 for the PBDEs. Regression models closely fit most chemicals (R (2) > 0.80), and whole blood and DBS samples generally showed very good agreement. Distribution coefficients estimated using biologically-based models were near one and did not explain the observed distribution. Among the study population, median concentrations of several pesticides/CHCs and PBDEs exceeded levels reported in the 2007-2008 National Health and Nutrition Examination Survey, while levels of other OCPs and PBDEs were comparable or lower. Race and smoking status appeared to slightly affect plasma/blood concentration ratios for several POPs. The experimentally-determined distribution coefficients can be used to compare POP exposures across studies using different types of blood-based matrices.

Association of Environmental Toxins With Amyotrophic Lateral Sclerosis.

IMPORTANCE: Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS). OBJECTIVE: To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted between 2011 and 2014 at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive, probable, probable with laboratory support, or possible ALS by revised El Escorial criteria; controls were excluded if they were diagnosed as having ALS or another neurodegenerative condition or if they had a family history of ALS in a first- or second-degree blood relative. Participants completed a survey assessing occupational and residential exposures. Blood concentrations of 122 persistent environmental pollutants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs), were measured using gas chromatography-mass spectrometry. Multivariable models with self-reported occupational exposures in various exposure time windows and environmental toxin blood concentrations were separately fit by logistic regression models. Concordance between the survey data and pollutant measurements was assessed using the nonparametric Kendall τ correlation coefficient. MAIN OUTCOMES AND MEASURES: Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs, PCBs, and BFRs. RESULTS: Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5% male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8% male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported pesticide exposure in the cumulative exposure windows was significantly associated with ALS (odds ratio [OR] = 5.09; 95% CI, 1.85-13.99; P = .002). Military service was also associated with ALS in 2 time windows (exposure ever happened in entire occupational history: OR = 2.31; 95% CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18; 95% CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental pollutants in the blood, representing cumulative occupational and residential exposure, showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.21; 95% CI, 1.06-4.60; P = .04; and cis-chlordane: OR = 5.74; 95% CI, 1.80-18.20; P = .005), 2 PCBs (PCB 175: OR = 1.81; 95% CI, 1.20-2.72; P = .005; and PCB 202: OR = 2.11; 95% CI, 1.36-3.27; P = .001), and 1 BFR (polybrominated diphenyl ether 47: OR = 2.69; 95% CI, 1.49-4.85; P = .001). There was modest concordance between survey data and the measurements of persistent environmental pollutants in blood; significant Kendall τ correlation coefficients ranged from -0.18 (Dacthal and "use pesticides to treat home or yard") to 0.24 (trans-nonachlor and "store lawn care products in garage"). CONCLUSIONS AND RELEVANCE: In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk factors.

Oxytocin influences intuitions about the relationship between belief in free will and moral responsibility.

Philosophers have proposed that laypeople can have deterministic or indeterministic intuitions about the relationship between free will and moral responsibility. However, the psychophysiological mechanisms that generate these extreme intuitions are still underexplored. Exogenous oxytocin offers a unique opportunity to gain a deeper understanding of these underlying mechanisms, since this neuropeptide influences a wide range of outcomes related to social cognition and prosociality. This study investigated the effects of intranasal oxytocin on intuitions about the relationship between free will and moral responsibility by applying a randomized, double-blind, placebo-controlled, between-subject design. Healthy male participants rated the moral responsibility of a hypothetical offender, who committed crimes in either a primed deterministic or an indeterministic universe. Under placebo, participants held the offender more morally responsible when acting in an indeterministic compared to a deterministic universe, which could be accredited to recognition of the offender's freely chosen action to commit the crimes. Under oxytocin, participants rated the offender's actions with greater leniency and similarly assigned lower moral responsibility in both universes. These findings strengthen the assumption that a person can have different intuitions about the relationship between free will and moral responsibility, which can be presumably dependent on motivational states associated with affiliation.