Pathophysiological mechanisms implicated in postpartum depression.

This review aims to summarize the diverse proposed pathophysiological mechanisms contributing to postpartum depression, highlighting both clinical and basic science research findings. The risk factors for developing postpartum depression are discussed, which may provide insight into potential neurobiological underpinnings. The evidence supporting a role for neuroendocrine changes, neuroinflammation, neurotransmitter alterations, circuit dysfunction, and the involvement of genetics and epigenetics in the pathophysiology of postpartum depression are discussed. This review integrates clinical and preclinical findings and highlights the diversity in the patient population, in which numerous pathophysiological changes may contribute to this disorder. Finally, we attempt to integrate these findings to understand how diverse neurobiological changes may contribute to a common pathological phenotype. This review is meant to serve as a comprehensive resource reviewing the proposed pathophysiological mechanisms underlying postpartum depression.

Maternal psychological distress before birth influences gut immunity in mid-infancy.

BACKGROUND: Maternal pre-postnatal psychosocial distress increases the risk for childhood allergic disease. This may occur through a host immunity pathway that involves intestinal secretory immunoglobulin A (sIgA). Experimental animal models show changes in the gut microbiome and immunity of offspring when exposed to direct or prenatal maternal stress, but little is known in humans. OBJECTIVE: We determined the association between maternal depression and stress symptom trajectories and infant fecal sIgA concentrations. METHODS: 1043 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort were studied. Trajectories of maternal perceived stress and depression were based on scored scales administered in pregnancy and postpartum. sIgA was quantified in infant stool (mean age 3.7 months) with Immundiagnostik ELISA. Linear regression and logistic regression were employed to test associations. RESULTS: Very low fecal sIgA concentrations were more common in infants of mothers in the antepartum and persistent depression trajectories (6% and 2% of women, respectively). Independent of breastfeeding status at fecal sampling, infant antibiotic exposure or other covariates, the antepartum depressive symptom trajectory was associated with reduced mean infant sIgA concentrations (ß=-0.07, P < .01) and a two fold risk for lowest quartile concentrations (OR, 1.86; 95% CI: 1.02, 3.40). This lowering of sIgA yielded a large effect size in older infants (4-8 months)-breastfed and not. No associations were seen with postpartum depressive symptoms (7% of women) or with any of the perceived stress trajectories. CONCLUSION AND CLINICAL RELEVANCE: Despite improved mood postpartum and independent of breastfeeding status, mothers experiencing antepartum depressive symptoms delivered offspring who exhibited lower fecal sIgA concentrations especially in later infancy. The implications of lowered sIgA concentrations in infant stool are altered microbe-sIgA interactions, greater risk for C difficile colonization and atopic disease in later years.

Thyroid autoimmunity and risk of post-partum depression: a systematic review and meta-analysis of longitudinal studies.

PURPOSE: The aim of this study was to systematically investigate whether, and to what extent, the detection of thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing post-partum depression (PPD), a condition associated with possible adverse outcomes for both mother and offspring. We performed a systematic review and meta-analysis of longitudinal studies, assessing the incidence of PPD in women with and without anti-thyroperoxidase antibody (TPOAb) positivity. METHODS: We searched MEDLINE, EMBASE, Web of Science, Cochrane Library, and CINAHL. Methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. In the presence of even modest between-studies heterogeneity, assessed by Cochrane Q and I2 tests, risk ratios (RRs) for PPD were combined using a random effects model. Funnel plot and trim-and-fill analysis were used to assess publication bias. RESULTS: Five included studies provided information on 449 women with TPOAb-positive and 2483 TPOAb-negative women. Pooled RR indicated a significantly increased risk to develop PPD in TPOAb-positive group (RR 1.49, 95% CI 1.11-2.00; P = 0.008; I2 = 47%, Pfor heterogeneity = 0.11). Consistent with a possible publication bias, the trim-and-fill test detected two putative missing studies in the funnel plot. Nevertheless, the adjustment for publication bias produced a negligible effect on the pooled estimate (adjusted RR 1.41, 95% CI 1.18-1.68, P = 0.0002). CONCLUSIONS: Thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing PPD. Further well-designed studies are warranted to confirm this association and elucidate underlying pathophysiological mechanisms. PROSPERO REGISTRATION: CRD42019129643.

The cytokine-hormone axis - the link between premenstrual syndrome and postpartum depression.

Premenstrual syndrome (PMS) and related disorders, and postpartum depression (PPD) can affect women to the extent that their quality of life and that of their near ones can be severely impaired. This review focuses on the different theories regarding the etiologies of PMS and PPD, and attempts to draw a link between the two. Theories focus mainly on hormonal and cytokine factors throughout different phases in the female reproductive cycle. Changes in this symptomatology during pregnancy are also reviewed, as are changes in hormones and cytokine levels. Hypotheses are thus developed as to why the symptoms experienced in PMS often subside during pregnancy yet may recur and be exacerbated after birth, giving rise to the symptoms experienced in PPD.

IgM-mediated autoimmune responses to oxidative specific epitopes, but not nitrosylated adducts, are significantly decreased in pregnancy: association with bacterial translocation, perinatal and lifetime major depression and the tryptophan catabolite (TRYCAT) pathway.

Immunoglubulin (Ig)M responses directed to oxidative specific epitopes (OSEs) and nitric oxide (NO)-adducts are significantly associated with major depression and physio-somatic symptoms. End of term serum IgM responses to OSEs and NO-adducts were assayed in pregnant women with (n = 24) and without prenatal depression (n = 25) as well as in 24 non-pregnant women. Associations of IgM/IgA responses to Gram-negative gut commensal bacteria (leaky gut index) and IgA/IgM responses to tryptophan catabolites (TRYCATs) were analyzed. IgM responses to OSEs, but not NO-adducts, were significantly reduced at the end of term. There were no significant associations between IgM responses to OSEs and perinatal depression, whilst IgM responses to NO-adducts, especially NO-cysteinyl, were significantly associated with a lifetime major depression. IgM responses to OSEs and NO-cysteinyl were significantly associated with IgA/IgM responses to Gram-negative bacteria, especially Morganella morganii, Klebsiella pneumoniae and Citrobacter koseri. IgM responses to NO-adducts and OSEs, especially malondialdehyde and myristic acid, and C-reactive protein (CRP) were inversely associated with TRYCAT pathway activity, whilst a lifetime depression and Pseudomonas putida were positively associated. The attenuation of natural IgM-mediated responses to OSEs at the end of term may indicate lowered activity of this part of the compensatory (anti-)inflammatory reflex system and may be partly explained by lowered bacterial translocation. Increased IgM responses to NO-cysteinyl is a biomarker of lifetime depression and may be induced by bacterial translocation. Natural IgM-mediated autoimmune responses, increased nitrosylation and higher CRP levels may have negative regulatory effects on the TRYCAT pathway.

Bidirectional psychoneuroimmune interactions in the early postpartum period influence risk of postpartum depression.

More than 500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. Dysregulation of the immune inflammatory response and the hypothalamic-pituitary-adrenal (HPA) axis are associated with depression in other populations. While significant research on the contribution of these systems to the development of PPD has been conducted, results have been inconclusive. This is partly because few studies have focused on whether disruption in the bidirectional and dynamic interaction between the inflammatory response and the HPA axis together influence PPD. In this study, we tested the hypothesis that disruption in the inflammatory-HPA axis bidirectional relationship would increase the risk of PPD. Plasma pro- and anti-inflammatory cytokines were measured in women during the 3rd trimester of pregnancy and on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for determination of cortisol area under the curve (AUC) and depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS). Of the 152 women who completed the EPDS, 18% were depressed according to EDPS criteria within the 6months postpartum. Cortisol AUC was higher in symptomatic women on Day 14 (p=.017). To consider the combined effects of cytokines and cortisol on predicting symptoms of PPD, a multiple logistic regression model was developed that included predictors identified in bivariate analyses to have an effect on depressive symptoms. Results indicated that family history of depression, day 14 cortisol AUC, and the day 14 IL8/IL10 ratio were significant predictors of PPD symptoms. One unit increase each in the IL8/IL10 ratio and cortisol AUC resulted in 1.50 (p=0.06) and 2.16 (p=0.02) fold increases respectively in the development of PPD. Overall, this model correctly classified 84.2% of individuals in their respective groups. Findings suggest that variability in the complex interaction between the inflammatory response and the HPA axis influence the risk of PPD.

The relationship between maternal postpartum psychological state and breast milk secretory immunoglobulin A level.

BACKGROUND: Maternal psychological state may influence the passive transfer of immune factors (e.g., immunoglobulin) via the mother's breast milk. OBJECTIVE: The aim of this study was to determine whether a correlation exists between mothers' postpartum psychological state and their breast milk secretory immunoglobulin A (SIgA) levels. STUDY DESIGN: Eighty-one mothers who delivered at an urban general hospital were included in our analysis. Two weeks after delivery, we measured their breast milk SIgA levels and simultaneously documented their psychological state using the Profile of Mood States (POMS), General Health Questionnaire (GHQ), and State-Trait Anxiety Inventory (STAI) scales. RESULTS: Breast milk SIgA levels were negatively correlated with negative POMS states (tension-anxiety, depression-dejection, anger-hostility, fatigue, and confusion). A negative correlation was also observed between SIgA levels and GHQ mental health (r = -.625, P = .000), and a similar negative correlation was observed with STAI trait and state anxieties. However, no correlation existed between breast milk SIgA levels and the positive POMS state (vigor). CONCLUSIONS: These results indicate that the maternal psychological state may affect the immune properties of breast milk.

Prenatal immunologic predictors of postpartum depressive symptoms: a prospective study for potential diagnostic markers.

In postpartum depression (PPD), immunologic changes have been proposed to be involved in the disease pathology. The study evaluates the regulation of the innate and adaptive immune response over the course of late pregnancy and postpartum period and their association with the development of postpartum depressive symptoms. Furthermore, prenatal immunologic markers for a PPD were investigated. Hundred pregnant women were included. At 34th and 38th week of pregnancy as well as 2 days, 7 weeks and 6 months postpartum, immune parameters (neopterin, regulatory T cells, CXCR1, CCR2, MNP1 and CD11a) were measured by flow cytometry/ELISA, and the psychopathology was evaluated. We found that regulatory T cells were significantly increased prenatal (p=0.011) and postnatal (p=0.01) in mothers with postnatal depressive symptoms. The decrease in CXCR 1 after delivery was significantly higher in mother with postnatal depressive symptoms (p=0.032). Mothers with postnatal depressive symptoms showed already prenatal significantly elevated neopterin levels (p=0.049). Finally, regulatory T cells in pregnancy strongly predict postnatal depressive symptoms (p=0.004). The present study revealed that prenatal and postnatal immunologic parameters are associated with postpartum depressive symptoms in mothers. In addition, we found immune markers that could eventually be the base for a biomarker set that predicts postnatal depressive symptoms already during pregnancy.

Diet and the gut microbiota-immune axis in the context of perinatal mental health: Protocol for a prospective cohort study.

BACKGROUND: Physiological and psychosocial changes experienced by women during the perinatal period may put them at risk for postpartum mental health disturbances. Accumulating evidence suggests that dietary patterns may influence mental health through the modulation of the gut microbiota and its effects on host immune activity. Thus, targeting the gut microbiota via dietary intake could serve as both a preventative and therapeutic strategy in improving perinatal mental health. OBJECTIVES: Here, we present a protocol for a prospective cohort study that primarily aims to determine if diet quality during pregnancy is protective against postpartum depression severity. Secondary objectives will examine if microbiota- and blood-based inflammatory markers may be associated with the relationship between prenatal diet quality and postpartum depression severity, as well as with associations between additional dietary and mental health outcomes. METHODS AND ANALYSIS: Dietary patterns and mental health symptoms will be documented in 100 pregnant women at 4 time points during pregnancy and postpartum. Participants will also provide stool and blood samples at the same time points to determine microbiota composition and predicted function and inflammatory factors, respectively. Stool microbiota will be analyzed using 16S ribosomal RNA gene sequencing and bioinformatics tools (QIIME 2/PICRUSt2). Inflammatory factors will be determined using high-sensitivity antibody-based immunoassays. Statistical analyses will include linear mixed models and hierarchical linear mixed effect models. ETHICS: The study was approved by the Research Ethics Boards of the Royal Ottawa Health Care Group (#2022002) and of the University of Ottawa (#H-06-22-8013). Informed consent will be obtained from all participants before their enrollment. DISCUSSION: Findings from this study will help develop evidence-based dietary recommendations and potential interventions for women susceptible to or suffering from postpartum mental health issues that are accessible, noninvasive, and have potential to play a role in prevention and treatment.

Nutrition and the psychoneuroimmunology of postpartum depression.

Postpartum depression (PPD) is a relatively common and often severe mood disorder that develops in women after childbirth. The aetiology of PPD is unclear, although there is emerging evidence to suggest a psychoneuroimmune connection. Additionally, deficiencies in n-3 PUFA, B vitamins, vitamin D and trace minerals have been implicated. This paper reviews evidence for a link between micronutrient status and PPD, analysing the potential contribution of each micronutrient to psychoneuroimmunological mechanisms of PPD. Articles related to PPD and women's levels of n-3 PUFA, B vitamins, vitamin D and the trace minerals Zn and Se were reviewed. Findings suggest that while n-3 PUFA levels have been shown to vary inversely with PPD and link with psychoneuroimmunology, there is mixed evidence regarding the ability of n-3 PUFA to prevent or treat PPD. B vitamin status is not clearly linked to PPD, even though it seems to vary inversely with depression in non-perinatal populations and may have an impact on immunity. Vitamin D and the trace minerals Zn and Se are linked to PPD and psychoneuroimmunology by intriguing, but small, studies. Overall, evidence suggests that certain micronutrient deficiencies contribute to the development of PPD, possibly through psychoneuroimmunological mechanisms. Developing a better understanding of these mechanisms is important for guiding future research, clinical practice and health education regarding PPD.

Maternal psychosocial factors determining the concentrations of transforming growth factor-beta in breast milk.

BACKGROUND: Cytokines in breast milk may play crucial roles in the beneficial effects of breastfeeding in protecting against allergic and infectious diseases in infants. In particular, breast milk-borne transforming growth factor-beta (TGF-ß) has an important potential role in developing the mucosal immune system in infants. However, little is known about what factors influence TGF-ß expression in human milk. We investigated whether the behavioral and psychosocial characteristics of mothers affect breast milk TGF-ß levels. METHODS: We conducted a survey of all 139 mothers who were lactating between February and October 2010 in Koshu City, Japan. Participants completed a questionnaire and provided breast milk at the health checkups for their 3-month-old child (N = 129, 93%). Breast milk was assayed for total TGF-ß2 levels by ELISA. We took an exploratory approach based on linear and ordered logistic regressions to model TGF-ß2 concentrations with their multiple potential determinants. RESULTS: Mothers with depression or poor self-rated health had higher TGF-ß2 concentrations than mothers without depression (odds ratio for a higher TGF-ß2 quartile: 3.11, 95% confidence intervals: 1.03-9.37) or those reporting better health (odds ratio: 2.34, 1.21-4.55). Smoking, drinking alcohol, probiotics supplementation, social support, and maternal history of allergic diseases were not associated with milk TGF-ß2 levels. Milk gathered between August and October or later in the afternoon (3-4 pm vs. 12-2 pm) contained less TGF-ß2. CONCLUSION: Depression, as the consequence of psychosocial stress, may be a strong determinant of TGF-ß levels in breast milk. Seasonal and daily fluctuations in milk TGF-ß2 concentrations warrant further study.

[Immune-inflammatory and autoimmune mechanisms in postpartum depression].

Postpartum depression is a debilitating mental disorder with a high prevalence, usually related with a past psychiatric history of major depressive disorder, postpartum depression, bipolar disorder, premenstrual syndrome (PMS), and perinatal depressive symptoms during gestation. However, the existing literature does not sufficiently elucidate the pathophysiology of this clinical entity which appears in such a crucial period of woman's life. This review aims to search the available data regarding the involvement of immunological and autoimmune mechanisms in its onset. A literature review was conducted using web-based search engines provided by PubMed (for Medline database) and Google Scholar. Manuscripts in English and Greek language were included for the period 19902017. Nowadays, a large body of evidence indicates that depressive disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. However, clinical research regarding the biological mechanisms associated with PPD is a tough challenge as pregnancy and puerperium are periods of adaptive changes in pregnant women by definition. Two of the systems that have been studied as potentially contributing to the onset of PPD are: the activation of the Inflammatory Response System (IRS) and the deregulation of the Hypothalamic-PituitaryAdrenal axis (HPA). Controversial data indicate dysregulation of cytokines and other inflammatory agents in patients with PPD, as well as, a close correlation of immune-inflammatory mechanisms and kynurenine pathway. PPD has been closely associated with autoimmune diseases. It is notable that this entity shares many common traits with autoimmune diseases such as the genetic susceptibility, family history, the high correlation with other autoimmune diseases, clinical exacerbations and remissions, women's superiority in prevalence, and the possible re-occurrence during a future pregnancy. These facts suggest that the typical postpartum flare pattern, and other clinical characteristics, point towards an autoimmune etiology for PPD. There are indications that immune-inflammatory and autoimmune mechanisms may be the key to deciphering the complex pathophysiological pathways associated with the onset of PPD. Clinical studies have been insufficient to make clear the causative correlations of the underlying mechanisms involved. Future research could focus on the immune-inflammatory processes associated with the onset of the disease, as well as on potential biomarkers for an early diagnosis and an effective treatment of PPD.

Innate immune activation and depressive and anxious symptoms across the peripartum: An exploratory study.

BACKGROUND: There are complex associations between immune function and mental illness, yet studies in the perinatal period focus primarily on individual inflammatory markers and depressive symptoms only, cross-sectionally. We sought to examine associations between both depressive and anxious symptoms and immune activation longitudinally across the peripartum. METHODS: We measured mood (Beck Depression Inventory, BDI-1 A) and anxiety (State-Trait Anxiety Inventory, STATE) and levels of 23 cytokines at 5 points in pregnancy and postpartum in 51 women. Within subject cytokine trajectories over time by depressive and anxious symptom grouping were assessed using linear mixed effects models with random intercept and slope. We also undertook an exploratory cluster analysis based on third trimester cytokine values. RESULTS: Based on categorical BDI scores, IL-6 (p < 0.001), IL-15 (p = 0.047), GCSF (p = 0.003), and CCL3 (p < .001) were significantly different across time, with IL-6 (p < 0.001), IL-15 (p = 0.003), and CCL3 (p < 0.001) higher at the third trimester visit in more depressed subjects. Based on categorical STATE scores, GM-CSF significantly decreased across pregnancy for the less anxious group (p = 0.016), but not for the more anxious, and CCL3 (p = 0.017), CXCL8 (p = 0.011), and IL-6 (p < 0.001) were higher at the third trimester visit for more anxious subjects. In exploratory cluster analysis based on cytokine level, there were no differences in mood or anxiety scores, but significant differences by race/ethnicity and overweight/obesity status. Women with higher pro-inflammatory cytokine values are more likely to be Hispanics (69.2% vs. 21.4%, p = 0.015), but less likely to be African American (23.1% vs. 60.7%, p = 0.015) or overweight/obese (25% vs. 69.2%, p = 0.016) compared to women with lower pro-inflammatory cytokine values. CONCLUSION: We identified a pro-inflammatory burst at the third trimester, indicative of innate immune activation, in women with higher levels of both depressive and anxious symptoms, as well as differences in pro-inflammatory changes across time. We also found significant differences in cytokine levels by race, ethnicity, and overweight/obesity status. These results point the way toward future longitudinal work that considers race/ethnicity, timing, and weight status, and evaluates perinatal mood and anxiety disorders in the context of changing immune functioning across the peripartum.

Postpartum depression, an autoimmune disease?

Medical conditions with known etiology and typical peripartal/postpartal disease exacerbations are now, without exception, considered autoimmune in etiology. Postpartum psychiatric conditions, and especially postpartum depression, currently, however, are still not understood in their etiology. This paper suggests that the typical postpartum flare pattern, and other clinical characteristics, point towards an autoimmune etiology for (postpartum) depression. The high prevalence of (postpartum) depression led to its designation as a major public health problem. A better understanding of etiology and pathophysiology would greatly advance the, currently still inaccurate, diagnosis of the condition, and improve approaches towards prevention and treatment.

Immune, health and endocrine characteristics of depressed postpartum mothers.

The purpose of the study was to examine demographic, immune, endocrine, stress and health characteristics of depressed mothers, measured between 4 and 6 weeks postpartum, and compare them to non-depressed mothers. The top decile (N=25) of Profile of Mood States depression scores was used to categorize mothers as depressed and these data were then compared to means of the remaining mothers (N=175) in a study of stress and immunity during the postpartum. Depressed mothers were younger, had smaller birth weight infants, and their babies experienced more illness symptoms at 4-6 weeks postpartum. Depressed mothers were less likely to be breastfeeding and had lower serum prolactin levels. Depressed mothers were more likely to smoke, to have daytime sleepiness, and more symptoms of infection than non-depressed mothers. Depressed mothers also had higher perceived stress, postpartum stress, and negative life event reports. There was evidence suggesting that depressed mothers had a downregulated hypothalamic-pituitary-adrenocortical (HPA) axis, in that salivary cortisol was lower in depressed mothers. Depressed mothers also had lower serum levels of Interferon-gamma (IFN-gamma) and a lower IFN-gamma/Interleukin-10 (IL-10) ratio in both sera and in whole blood stimulated cultures, suggesting a depressed Th1/Th2 ratio in depressed mothers. The data supports the possibility that postpartum depression may be associated with a dysregulated HPA axis and possible depressed cellular immunity.

Depression after delivery: risk factors, diagnostic and therapeutic considerations.

Postpartum mood disorders can negatively affect women, their offspring, and their families when left untreated. The identification and treatment of postpartum depression remains problematic since health care providers may often not differentiate postpartum blues from depression onset. Recent studies found potentially new risk factors, etiologies, and treatments; thus, possibly improving the untreated postpartum depression rates. This integrated review examined several postpartum psychiatric disorders, postpartum blues, generalized anxiety, obsessive compulsive disorder, post-traumatic stress disorder, and postpartum psychosis for current findings on prevalence, etiologies, risk factors, and postpartum depression treatments.

Cytokines, infections, stress, and dysphoric moods in breastfeeders and formula feeders.

OBJECTIVE: To analyze relationships between stress, moods, and immunity in breastfeeding compared to formula-feeding mothers. DESIGN: A cross-sectional study of 181 healthy mothers, exclusively breastfeeding or formula feeding, studied at 4 to 6 weeks after childbirth. SETTING: Mothers were recruited in the postpartum unit of the hospital and then visited in their homes once at 4 to 6 weeks after childbirth for data collection. MAIN OUTCOME MEASURES: Stress, mood, infection symptoms, and serum levels of interferon-gamma and interleukin-10 were measured. RESULTS: Formula-feeding mothers had evidence of decreased interferon-gamma and a decreased serum Th1/Th2 ratio (interferon-gamma/interleukin-10) when perceived stress, dysphoric moods, and negative life events were high, an effect consistent with depression of cellular immunity. However, women who were breastfeeding did not show these relationships. CONCLUSIONS: The data suggest that breastfeeding confers some psychoneuroimmunological benefit to mothers, perhaps through prolactin or hypothalamic-hypophyseal-adrenocortical axis stress refractoriness.

Modeling postpartum depression in rats: theoretic and methodological issues.

The postpartum period is when a host of changes occur at molecular, cellular, physiological and behavioral levels to prepare female humans for the challenge of maternity. Alteration or prevention of these normal adaptions is thought to contribute to disruptions of emotion regulation, motivation and cognitive abilities that underlie postpartum mental disorders, such as postpartum depression. Despite the high incidence of this disorder, and the detrimental consequences for both mother and child, its etiology and related neurobiological mechanisms remain poorly understood, partially due to the lack of appropriate animal models. In recent decades, there have been a number of attempts to model postpartum depression disorder in rats. In the present review, we first describe clinical symptoms of postpartum depression and discuss known risk factors, including both genetic and environmental factors. Thereafter, we discuss various rat models that have been developed to capture various aspects of this disorder and knowledge gained from such attempts. In doing so, we focus on the theories behind each attempt and the methods used to achieve their goals. Finally, we point out several understudied areas in this field and make suggestions for future directions.