Neuroscience and mental illness

In this chapter we discuss recent advances in our understanding of the biology of mental illness. Alongside important social and psychological factors, the biology of psychiatric disorders plays an important role in their development and prognosis. The inclusion of this chapter in this report reflects the need to widen public awareness of the quality and breadth of scientific work currently under way to help those suffering from mental illness. There is a stark mismatch between the funding for such research and the considerable cost of these disorders to our society, exacerbated by the recent disengagement of many pharmaceutical companies from research related to brain disorders. Translating the promising findings presented here into improved clinical care requires this mismatch to be addressed urgently. One way of doing this is by building bridges between the diverse fields involved in the common pursuit of the promotion of public mental health, which is one of the aims of this chapter. It would be impossible to summarise the entire field of biological psychiatry for such a chapter. Instead, we have adopted a ‘horizon-scanning’ approach to demonstrate the variety of techniques used in this area, and to highlight a few examples that are more likely to have a rapid impact on patients’ care. The chapter is divided, by technique, into sections covering neuroimaging, neuropsychology, genetics, blood-based biomarkers and animal and cellular models of disease. Some of the work presented here is already available clinically, such as the genetic analysis in autism. Other work could have widespread clinical utility within the next 10 years, especially in the area of ‘personalised’ treatment – identifying a priori the best treatment for the individual patient. However, translating this neuroscience research into better patient care requires sustained support of experimental medicine and clinical trials. It is our hope that this chapter demonstrates how biological research may aid diagnosis, risk stratification and the development of novel medications for the treatment of mental illnesses. Rather than distancing psychiatry from important psychological and social factors, much of modern biological research is aimed at understanding how these factors interact to produce disease states. Biological advances are likely to play a valuable part in the holistic management of patients. We write this chapter to advocate that the biomedical and psychosocial models of mental illness are not antithetical, but are in fact increasingly conceptualised within a single unifying framework. While most of the important factors determining the risk and course of mental illnesses can be measured in a clinical interview, rather than in a laboratory, neuroscience research offers the exciting opportunity to understand the mechanisms by which these factors affect their clinical action. Unfortunately, at a public health level it appears that, while a biological model of mental illness enhances the acceptance of treatment, it does not seem to be associated with a reduction in stigma among the general population. Our understanding of the biological correlates of mental health and illness is growing exponentially. As showcased in this chapter, we are beginning to see how this understanding could be developed to improve the medical care patients with mental illness receive, and to widen our understanding of mental illness as a truly bio-psycho-social construct

The association between maternal childhood trauma and offspring childhood psychopathology: a mediation analysis from the ALSPAC cohort

Background: Studies have shown that a mother’s history of child maltreatment is associated with her child’s experience of internalising and externalising difficulties. Aims: To characterise the mediating pathways that underpin this association. Method: Data on a mother’s history of child maltreatment, depression during pregnancy, postnatal depression, maladaptive parenting practices and her child’s experience of maltreatment and internalising and externalising difficulties were analysed in an ALSPAC sample of 9,397 mother-child dyads followed prospectively from pregnancy to age 13. Results: Maternal history of child maltreatment was significantly associated with offspring internalising and externalising difficulties. Maternal antenatal depression, postnatal depression and offspring child maltreatment were observed to significantly mediate this association independently. Conclusions: Psychological and psychosocial interventions focused around treating maternal depression, particularly during pregnancy, and safeguarding against adverse childhood experiences could be offered to mothers with traumatic childhood histories to help protect against psychopathology in the next generation

Nutritional and immunological factors in breast milk: A role in the intergenerational transmission from maternal psychopathology to child development

Perinatal psychopathologies affect more than 25% of women during and after their gestational period. These psychiatric disorders can potentially determine important biological variations in their organisms, affecting many different physiological and metabolic pathways. Of relevance, any of these changes occurring in the mother can alter the normal composition of breast milk, particularly the concentration of nutritional and inflammatory components, which play a role in child brain functioning and development. Indeed, there is evidence showing that changes in milk composition can contribute to cognitive impairments and alterations in mental abilities in children. This review aims to shed light on the unique intergenerational role played by breast milk composition, from maternal psychopathologies to child development

White matter integrity as a predictor of response to treatment in first episode psychosis

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response

Experiences of acquired brain injury survivors participating in online and hybrid performance arts programmes: an ethnographic study

Background: Performance arts can benefit people with acquired brain injury (ABI). This study explored the online delivery during COVID-19 restrictions, of a performance art intervention through the experiences of participants, artists and facilitators. Methods: Two community-based programmes were delivered. Online ethnographic observations and semi-structured interviews with participants, artists and facilitators were completed. Results: The programmes benefited participants by addressing loneliness and isolation; building confidence through peer support; improving physical limitations through movement; improving communication through music and vocal work; and using poetry, visual arts, metaphor and performance to make sense of participants’ experiences. Participants had mixed experiences of participation, but it was an acceptable alternative to in-person arts interventions for those who overcame digital challenges. Conclusions: ABI survivors can engage in online performance art programmes and find participation valuable for their health, well-being, and recovery. More work is needed to explore the generalisability of these findings, especially given digital poverty

Identification of a miRNAs signature associated with exposure to stress early in life and enhanced vulnerability for schizophrenia: New insights for the key role of miR-125b-1-3p in neurodevelopmental processes

Epidemiological and clinical studies have provided evidence for a role of both genetic and environmental factors, such as stressful experiences early in life, in the pathogenesis of Schizophrenia (SZ) and microRNAs (miRNAs) have been suggested to play a key role in the interplay between the environment and our genome. In this study, we conducted a miRNOme analysis in different samples (blood of adult subjects exposed to childhood trauma, brain (hippocampus) of rats exposed to prenatal stress and human hippocampal progenitor cells treated with cortisol) and we identified miR-125b-1-3p as a down-regulated miRNA in all the three datasets. Interestingly, a significant down-regulation was observed also in SZ patients exposed to childhood trauma. To investigate the biological systems targeted by miR-125b-1-3p and also involved in the effects of stress, we combined the list of biological pathways modulated by predicted and validated target genes of miR-125b-1-3p, with the biological systems significantly regulated by cortisol in the in vitro model. We found, as common pathways, the CXCR4 signaling, the G-alpha signaling, and the P2Y Purigenic Receptor Signaling Pathway, which are all involved in neurodevelopmental processes. Our data, obtained from the combining of miRNAs datasets across different tissues and species, identified miR-125b-1-3p as a key marker associated with the long-term effects of stress early in life and also with the enhanced vulnerability of developing SZ. The identification of such a miRNA biomarker could allow the early detection of vulnerable subjects for SZ and could provide the basis for the development of preventive therapeutic strategies

Adverse Childhood Life Events and Postpartum Mood Episodes in Bipolar Disorder

Background: The early postpartum has been established as a period of increased vulnerability for psychiatric mood illness. Women with bipolar disorder (BD) in particular are at elevated risk of postnatal depression (PND) and of postpartum psychosis (PP). Though adverse childhood life events (ACLEs) have been implicated in the aetiology of PND, this has rarely been studied in relation to PP. Furthermore, despite being at high risk of relapse following childbirth, little research has assessed the relationship between ACLEs and postnatal mood episodes (PNEs) exclusively in women with BD. Therefore, our aim was to explore associations between ACLEs and occurrence of both PND and PP in a large sample of women with BD. Methods: Participants were 665 parous women with BD who had been recruited into the Bipolar Disorder Research Network study. Diagnoses and lifetime psychopathology were obtained via a semi-structured interview (SCAN). Postnatal psychiatric history and experience of 7 ACLEs were also assessed. Where available, all information obtained at interview was confirmed from psychiatric case notes. Women were classified into three groups according to postnatal psychiatric history: 1) those who had experienced no postnatal mood episode (no PNE, n=224), 2) women with a history of PND (n=223) and 3) women who had experienced PP (n=208). A Pearson’s chi-square test was used to compare the prevalence of each type of ACLE between women in the no PNE group and those with a history of PND or PP. Results: Women with PND were significantly more likely to have experienced emotional, sexual or physical abuse in childhood compared with women who had no history of a PNE (p<0.05). In particular, childhood sexual abuse was reported significantly more in the PND than the no PNE group (P<0.05). In contrast, there were no significant differences in the frequency of reporting of any ACLEs between women who had no PNE and those with PP. Conclusions: Our findings indicate that childhood abuse, sexual abuse in particular, is associated with PND among women with BD. In contrast, we found no evidence for an association between any ACLE and PP, suggesting that biological factors are likely to play a more important role in the aetiology of psychosis in the early postpartum

Same donor laparoscopic liver and kidney procurement for sequential living donor liver-kidney transplantation in primary hyperoxaluria type i

Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages.

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression-notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine