A Rome Working Team Report on Brain-Gut Behavior Therapies for Disorders of Gut-Brain Interaction.

BACKGROUND AND AIMS: This Rome Foundation Working Team Report reflects the consensus of an international interdisciplinary team of experts regarding the use of behavioral interventions, specifically brain-gut behavior therapies (BGBTs), in patients with disorders of gut-brain interaction (DGBIs). METHODS: The committee members reviewed the extant scientific literature and, when possible, addressed gaps in this literature through the lens of their clinical and scientific expertise. The Delphi method was used to create consensus on the goals, structure, and framework before writing the report. The report is broken into 5 parts: 1) definition and evidence for BGBT, 2) the gut-brain axis as the mechanistic basis for BGBT, 3) targets of BGBTs, 4) common and unique therapeutic techniques seen in BGBT, and 5) who and how to refer for BGBT. RESULTS: We chose to not only review for the reader the 5 existing classes of BGBT and their evidence, but to connect DGBI-specific behavioral targets and techniques as they relate directly, or in some cases indirectly, to the gut-brain axis. In doing so, we expect to increase gastrointestinal providers' confidence in identifying and referring appropriate candidates for BGBT and to support clinical decision making for mental health professionals providing BGBT. CONCLUSIONS: Both gastrointestinal medical providers and behavioral health providers have an opportunity to optimize care for DGBIs through a collaborative integrated approach that begins with an effective patient-provider relationship, thoughtful communication about the brain-gut axis and, when appropriate, a well communicated referral to BGBT.

Circadian disruption and human health.

Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a unique opportunity for personalized/precision medicine and overall societal well-being. In this Review, we discuss the implications of circadian disruption for human health using a bench-to-bedside approach. Evidence from preclinical and translational science is applied to a clinical and population-based approach. Given the broad implications of circadian regulation for human health, this Review focuses its discussion on selected examples in neurologic, psychiatric, metabolic, cardiovascular, allergic, and immunologic disorders that highlight the interrelatedness between circadian disruption and human disease and the potential of circadian-based interventions, such as bright light therapy and exogenous melatonin, as well as chronotherapy to improve and/or modify disease outcomes.

Predictors of neurofeedback training outcome: A systematic review.

Neurofeedback (NF), a training tool aimed at enhancing neural self-regulation, has been suggested as a complementary treatment option for neuropsychiatric disorders. Despite its potential as a neurobiological intervention directly targeting neural alterations underlying clinical symptoms, the efficacy of NF for the treatment of mental disorders has been questioned recently by negative findings obtained in randomized controlled trials (e.g., Cortese et al., 2016). A possible reason for insufficient group effects of NF trainings vs. placebo could be related to the high rate of participants who fail to self-regulate brain activity by NF ("non-learners"). Another reason could be the application of standardized NF protocols not adjusted to individual differences in pathophysiology. Against this background, we have summarized information on factors determining training and treatment success to provide a basis for the development of individualized training protocols and/or clinical indications. The present systematic review included 25 reports investigating predictors for the outcome of NF trainings in healthy individuals as well as patients affected by mental disorders or epilepsy. We selected these studies based on searches in EBSCOhost using combinations of the keywords "neurofeedback" and "predictor/predictors". As "NF training" we defined all NF applications with at least two sessions. The best available evidence exists for neurophysiological baseline parameters. Among them, the target parameters of the respective training seem to be of particular importance. However, particularities of the different experimental designs and outcome criteria restrict the interpretability of some of the information we extracted. Therefore, further research is needed to gain more profound knowledge about predictors of NF outcome.

The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.

Effects of Mindfulness-Based Interventions on Biomarkers and Low-Grade Inflammation in Patients with Psychiatric Disorders: A Meta-Analytic Review.

Mindfulness-Based Interventions (MBIs) present positive effects on mental health in diverse populations. However, the detailed associations between MBIs and biomarkers in patients with psychiatric disorders remain poorly understood. The aim of this study was to examine the effects of MBIs on biomarkers in psychiatric illness used to summarise the effects of low-grade inflammation. A systematic review of PubMed, EMBASE, PsycINFO, and the Cochrane Library was conducted. Effect sizes (ESs) were determined by Hedges' g and the number needed to treat (NNT). Heterogeneity was evaluated. A total of 10 trials with 998 participants were included. MBIs showed significant improvements in the event-related potential amplitudes in attention-deficit hyperactivity disorder, the methylation of serotonin transporter genes in post-traumatic stress disorder, the salivary levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in depression, and the blood levels of adrenocorticotropic hormone (ACTH), IL-6, and TNF-α in generalised anxiety disorder. MBIs showed low but significant effects on health status related to biomarkers of low-grade inflammation (g = -0.21; 95% confidence interval (CI) -0.41 to -0.01; NNT = 8.47), with no heterogeneity (I2 = 0; 95% CI 0 to 79). More trials are needed to establish the impact of MBIs on biomarkers in psychiatric illness.

[The Italian contribution to studies on the biological rhythms implicated in psychiatric disorders]. / Il contributo italiano agli studi sui ritmi biologici implicati nei disturbi psichiatrici.

This editorial summarizes the main studies, carried out in the last 10 years, by various Italian research groups, on the alterations of circadian rhythms in psychiatric disorders. The results of these researches, as well as those obtained in various international contexts, encourage to teach in the medical schools for psychiatry, about the new chronoterapeutic interventions and the implementation of combined therapies for increasingly personalized psychiatric therapies.

The Mentalizing Approach to Psychopathology: State of the Art and Future Directions.

Mentalizing is the capacity to understand others and oneself in terms of internal mental states. It is assumed to be underpinned by four dimensions: automatic-controlled, internally-externally focused, self-other, and cognitive-affective. Research suggests that mental disorders are associated with different imbalances in these dimensions. Addressing the quality of mentalizing as part of psychosocial treatments may benefit individuals with various mental disorders. We suggest that mentalizing is a helpful transtheoretical and transdiagnostic concept to explain vulnerability to psychopathology and its treatment. This review summarizes the mentalizing approach to psychopathology from a developmental socioecological evolutionary perspective. We then focus on the application of the mentalizing approach to personality disorders, and we review studies that have extended this approach to other types of psychopathology, including depression, anxiety, and eating disorders. We summarize core principles of mentalization-based treatments and preventive interventions and the evidence for their effectiveness. We conclude with recommendations for future research.

Device-Based Modulation of Neurocircuits as a Therapeutic for Psychiatric Disorders.

Device-based neuromodulation of brain circuits is emerging as a promising new approach in the study and treatment of psychiatric disorders. This work presents recent advances in the development of tools for identifying neurocircuits as therapeutic targets and in tools for modulating neurocircuits. We review clinical evidence for the therapeutic efficacy of circuit modulation with a range of brain stimulation approaches, including subthreshold, subconvulsive, convulsive, and neurosurgical techniques. We further discuss strategies for enhancing the precision and efficacy of neuromodulatory techniques. Finally, we survey cutting-edge research in therapeutic circuit modulation using novel paradigms and next-generation devices.

Inflammatory Response and Treatment-Resistant Mental Disorders: Should Immunotherapy Be Added to Pharmacotherapy?

Treatment resistance continues to challenge and frustrate mental health clinicians and provoke psychiatric researchers to seek additional explanatory theories for psychopathology. Because the inflammatory process activates symptoms of depression, anxiety, and psychosis, it is a reasonable route to follow for primary and/or indirect contribution to mental disorders. The current article reviews the research literature regarding the role the inflammatory process and immune system play in mental disorders as well as novel treatments under investigation for resistant depression, anxiety, substance use, and psychotic disorders. [Journal of Psychosocial Nursing and Mental Health Services, 58(1), 11-16.].

Lighting as an aid for recovery in hospitalized psychiatric patients: a randomized controlled effectiveness trial.

Purpose: Artificial indoor lighting can disturb sleep and increase depressive symptoms; both common complaints in psychiatric inpatients. In this trial we aimed to improve sleep in psychiatric inpatients using a circadian lighting environment.Patients and methods: Investigator-blinded parallel-group randomised controlled effectiveness trial in an inpatient psychiatric ward with adjustable lighting. Admitted patients received a pre-set circadian lighting environment (intervention group) or lighting as usual (control group). The primary outcome was the Pittsburg Sleep Quality Index (PSQI) and secondary outcomes included the Major Depression Inventory and WHO-5 Well-Being Index.Results: We assessed 74 patients and included 54 (27 treated and 27 controls). Treated patients reported a non-significant change in mean sleep quality by -1.02 points on the PSQI (95% CI: -3.17; 1.12) and controls by -0.59 points (95% CI: -2.52; 1.33), difference -0.43 (95% CI: -3.05; 2.2, p-value .74). Similarly, treated patients reported a non-significant change in depressive symptoms and well-being compared to controls. Qualitative data indicated no serious side-effects and no patients in the intervention group were submitted to involuntary measures. Collection of data was non-complete and missing data from self-reported questionnaires amounted to 52.5%.Conclusions: The intervention showed no effect on sleep quality, mood or well-being. The circadian lighting environment was safe in our small and diverse patient sample. The trial integrated well with routine clinical care and our sample reflected the heterogeneity of the target population.

Auditory mismatch detection, distraction, and attentional reorientation (MMN-P3a-RON) in neurological and psychiatric disorders: A review.

Involuntary attention allows for the detection and processing of novel and potentially relevant stimuli that lie outside of cognitive focus. These processes comprise change detection in sensory contexts, automatic orientation toward this change, and the selection of adaptive responses, including reorientation to the original goal in cases when the detected change is not relevant for task demands. These processes have been studied using the Event-Related Potential (ERP) technique and have been associated to the Mismatch Negativity (MMN), the P3a, and the Reorienting Negativity (RON) electrophysiological components, respectively. This has allowed for the objective evaluation of the impact of different neuropsychiatric pathologies on involuntary attention. Additionally, these ERP have been proposed as alternative measures for the early detection of disease and the tracking of its progression. The objective of this review was to integrate the results reported to date about MMN, P3a, and RON in different neurological and psychiatric disorders. We included experimental studies with clinical populations that reported at least two of these three components in the same experimental paradigm. Overall, involuntary attention seems to reflect the state of cognitive integrity in different pathologies in adults. However, if the main goal for these ERP is to consider them as biomarkers, more research about their pathophysiological specificity in each disorder is needed, as well as improvement in the general experimental conditions under which these components are elicited. Nevertheless, these ERP represent a valuable neurophysiological tool for early detection and follow-up of diverse clinical populations.

The role of the brain-gut-microbiota axis in psychology: The importance of considering gut microbiota in the development, perpetuation, and treatment of psychological disorders.

INTRODUCTION: The prevalence of psychological disorders remains stable despite steady increases in pharmacological treatments suggesting the need for auxiliary treatment options. Consideration of the brain-gut-microbiota axis (BGMA) has made inroads into reconceptualizing psychological illness from a more holistic perspective. While our understanding of the precise role of gut microbiota (GM) in psychological illness is in its infancy, it represents an attractive target for novel interventions. METHOD: An extensive review of relevant literature was undertaken. RESULTS: Gut microbiota are proposed to directly and indirectly influence mood, cognition, and behavior which are key components of mental health. This paper outlines how GM may be implicated in psychological disorders from etiology through to treatment and prevention using the Four P model of case formulation. CONCLUSION: Moving forward, integration of GM into the conceptualization and treatment of psychological illness will require the discipline of psychology to undergo a significant paradigm shift. While the importance of the GM in psychological well-being must be respected, it is not proposed to be a panacea, but instead, an additional arm to a multidisciplinary approach to treatment and prevention.

Current Understanding of Religion, Spirituality, and Their Neurobiological Correlates.

Religion and spirituality (R/S) have been prominent aspects of most human cultures through the ages; however, scientific inquiry into this phenomenon has been limited. We conducted a systematic literature review of research on the neurobiological correlates of R/S, which resulted in 25 reports studying primarily R/S with electroencephalography, structural neuroimaging (MRI), and functional neuroimaging (fMRI, PET). These studies investigated a wide range of religions (e.g., Christianity, Buddhism, Islam) and R/S states and behaviors (e.g., resting state, prayer, judgments) and employed a wide range of methodologies, some of which (e.g., no control group, varying measures of religiosity, small sample sizes) raise concerns about the validity of the results. Despite these limitations, the findings of these studies collectively suggest that the experience of R/S has specific neurobiological correlates and that these correlates are distinct from non-R/S counterparts. The findings implicate several brain regions potentially associated with R/S development and behavior, including the medial frontal cortex, orbitofrontal cortex, precuneus, posterior cingulate cortex, default mode network, and caudate. This research may suggest future clinical applications and interventions related to R/S and various disorders, including mood, anxiety, psychotic, pain, and vertiginous disorders. Further studies with more rigorous study designs are warranted to elucidate the neurobiological mechanisms of R/S and their potential clinical applications.

Homeless, Ill, and Psychiatrically Complex: The Grueling Carousel of Cassandra Lee.

Ask any clinical ethics consultant, and they can tell you about their transformative cases. Some stick with us because all roads led nowhere. Cassandra Lee had a history of pulling out lines and tubes and a distaste of warming blankets. Her admission marked her thirtieth over the past year. Many of the challenges facing the hospital caring for her were not unique: significant psychiatric issues, prolonged nonadherence to medical advice, and end-of-life decision-making combined to create an ethically dense and vexing situation. Ms. Lee, like so many patients, was suffering because of system failures.

A pragmatic effectiveness randomized controlled trial of the duration of psychiatric hospitalization in a trans-diagnostic sample of patients with acute mental illness admitted to a ward with either blue-depleted evening lighting or normal lighting conditions.

BACKGROUND: There is increasing recognition of the need to stabilize sleep-wake cycles in individuals with major mental disorders. As such, clinicians and researchers advocate the use of interventions targeted at sleep and circadian dysrhythmias as an adjunct to the standard treatments offered for acute illness episodes of a broad range of diagnoses. To determine the trans-diagnostic generalizability of chronotherapy, we explore the benefits of admitting individuals with an acute illness episode to a psychiatric inpatient unit where changes in light exposure are integrated into the therapeutic environment. METHODS/DESIGN: A two-arm, pragmatic effectiveness, randomized controlled treatment trial, where individuals admitted for acute inpatient psychiatric care will be allocated to a ward with blue-depleted evening light or to a ward with the same layout and facilities but lacking the new lighting technology. The trial will test whether the experimental lighting conditions offer any additional benefits beyond those associated with usual treatment in an acute psychiatric inpatient unit. The main objectives are to examine any differences between groups in the mean duration of hospitalization in days. Additional analyses will compare group differences in symptoms, functioning, medication usage, and side effects and whether length of stay is associated with stability of sleep-wake cycles and circadian rhythms. Ancillary investigations should determine any benefits according to diagnostic subgroups and potential drawbacks such as any adverse effects on the well-being of professionals working across both wards. DISCUSSION: This unit offers a unique opportunity to explore how exposure to different lighting conditions may modify sleep-wake cycles and how any changes in sleep-wake cycle may impact on the clinical and functional outcomes of individuals experiencing an acute episode of a severe mental disorder that requires inpatient care. The findings could influence the future design of hospital units offering care to patients with mental or physical disorders. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03788993 . Retrospectively registered on 28 December 2018.

Dissociative identity as a continuum from healthy mind to psychiatric disorders: Epistemological and neurophenomenological implications approached through hypnosis.

The topic of multiple personality, redefined as Dissociative Identity Disorders (DIDs) in the DSM-5, is an intriguing and still debated disorder with a long history and deep cultural and epistemological implications, extending up to the idea of possession. Hypnosis is an appealing and valuable model to manipulate subjective experience and get an insight on both the physiology and the pathophysiology of the mind-brain functioning; it and has been closely connected with DIDs and possession since its origin in 18th century and as recently proved the capacity to yield a loss of sense of agency, mimicking delusions of alien control and spirit possession. In this study we report on five very uncommon "hypnotic virtuosos" (HVs) free from any psychiatric disorder, spontaneously undergoing the emergence of multiple identities during neutral hypnosis; this allowed us to check the relationship between their experience and fMRI data. During hypnosis the subjects underwent spontaneous non-intrusive experiences of other selves which were not recalled after the end of the session, due to post-hypnotic amnesia. The fMRI showed a significant decrease of connectivity in the Default Mode Network (DMN) especially between the posterior cingulate cortex and the medial prefrontal cortex. Our results and their contrast with the available data on fMRI in DIDs allows to draw the hypothesis of a continuum between healthy mind - where multiple identities may coexist at unconscious level and may sometimes emerge to the consciousness - and DIDs, where multiple personalities emerge as dissociated, ostensibly autonomous components yielding impaired functioning, subject's loss of control and suffering. If this is the case, it seems more reasonable to refrain from seeking for a clear-cut limit between normality (anyway a conventional, statistical concept) and pathology, and accept a grey area in between, where ostensibly odd but non-pathological experiences may occur (including so-called non-ordinary mental expressions) without calling for treatment but, rather, for being properly understood.

Auditory Steady State Response; nature and utility as a translational science tool.

The auditory steady-state response (ASSR) has been used to detect auditory processing deficits in patients with psychiatric disorders. However, the methodology of ASSR recording from the brain surface has not been standardized in preclinical studies, limiting its use as a translational biomarker. The sites of maximal ASSR in humans are the vertex and/or middle frontal area, although it has been suggested that the auditory cortex is the source of the ASSR. We constructed and validated novel methods for ASSR recording using a switchable pedestal which allows ASSR recording alternatively from temporal or parietal cortex with a wide range of frequencies in freely moving rats. We further evaluated ASSR as a translational tool by assessing the effect of ketamine. The ASSR measured at parietal cortex did not show clear event-related spectral perturbation (ERSP) or inter-trial coherence (ITC) in any frequency bands or a change with ketamine. In contrast, the ASSR at temporal cortex showed clear ERSP and ITC where 40 Hz was maximal in both gamma-band frequencies. Ketamine exerted a biphasic effect in ERSP at gamma bands. These findings suggest that temporal cortex recording with a wide frequency range is a robust methodology to detect ASSR, potentially enabling application as a translational biomarker in psychiatric and developmental disorders.

An Active Inference Approach to Interoceptive Psychopathology.

Interoception refers to the process by which the nervous system senses and integrates signals originating from within the body, providing a momentary mapping of the body's internal landscape and its relationship to the outside world. Active inference is based on the premise that afferent sensory input to the brain is constantly shaped and modified by prior expectations. In this review we propose that interoceptive psychopathology results from two primary interoceptive dysfunctions: First, individuals have abnormally strong expectations of the situations that elicit bodily change (i.e., hyperprecise priors), and second, they have great difficulty adjusting these expectations when the environment changes (i.e., context rigidity). Here we discuss how these dysfunctions potentially manifest in mental illness and how interventions aimed at altering interoceptive processing can help the brain create a more realistic model of its internal state.

The effects of psychiatric history and age on self-regulation of the default mode network.

Real-time neurofeedback enables human subjects to learn to regulate their brain activity, effecting behavioral changes and improvements of psychiatric symptomatology. Neurofeedback up-regulation and down-regulation have been assumed to share common neural correlates. Neuropsychiatric pathology and aging incur suboptimal functioning of the default mode network. Despite the exponential increase in real-time neuroimaging studies, the effects of aging, pathology and the direction of regulation on neurofeedback performance remain largely unknown. Using real-time fMRI data shared through the Rockland Sample Real-Time Neurofeedback project (N = 136) and open-access analyses, we first modeled neurofeedback performance and learning in a group of subjects with psychiatric history (na = 74) and a healthy control group (nb = 62). Subsequently, we examined the relationship between up-regulation and down-regulation learning, the relationship between age and neurofeedback performance in each group and differences in neurofeedback performance between the two groups. For interpretative purposes, we also investigated functional connectomics prior to neurofeedback. Results show that in an initial session of default mode network neurofeedback with real-time fMRI, up-regulation and down-regulation learning scores are negatively correlated. This finding is related to resting state differences in the eigenvector centrality of the posterior cingulate cortex. Moreover, age correlates negatively with default mode network neurofeedback performance, only in absence of psychiatric history. Finally, adults with psychiatric history outperform healthy controls in default mode network up-regulation. Interestingly, the performance difference is related to no up-regulation learning in controls. This finding is supported by marginally higher default mode network centrality during resting state, in the presence of psychiatric history.