Publications by authors named "Michelle Z L Kee"

9 Publications

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Salivary cytokine cluster moderates the association between caregivers perceived stress and emotional functioning in youth.

Brain Behav Immun 2021 Mar 2. Epub 2021 Mar 2.

Douglas Mental Health University Institute, Douglas Research Center, McGill University, Montreal, QC, Canada; Ludmer Centre for Neuroinformatics and Mental Health and Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada. Electronic address:

Some individuals exposed to early life stress show evidence of enhanced systemic inflammation and are at greater risk for psychopathology. In the current study, caregivers and their offspring (0-17 years) were recruited at a pediatric clinic visit at the University of California, San Francisco (UCSF). Mothers and seven-year-old children from the Growing Up inSingaporeTowards healthy Outcomes (GUSTO) prospective birth cohort were used as a replication cohort. Caregivers perceived stress was measured to determine potential intergenerational effects on the children's functioning and inflammation levels. Children's emotional functioning in the UCSF cohort was evaluated using the Pediatric Quality of Life (PedsQL) inventory. Child emotional and behavioral functioning was measured using the Child Behavior Checklist (CBCL) in GUSTO. Saliva was collected from the children and salivary levels of IL-6, IL-1β, IL-8 and TNF-α were measured using an electrochemiluminescent cytokine multiplex panel. Child IL-6, IL-1β, IL-8 cytokine levels were clustered into low, average, and high cytokine cluster groups using hierarchical cluster analysis. We did not find that salivary cytokine clusters were significantly associated with children's emotional or behavioral function. However, cytokine clusters did significantly moderate the association between increased caregiver perceived stress and reduced child emotional functioning (UCSF cohort) and increased Attention-Deficit-Hyperactivity (ADH) problems (GUSTO cohort, uncorrected Cohen's F2 = 0.02). Using a cytokine clustering technique may be useful in identifying those children exposed to increased caregiver perceived stress that are at risk of emotional and attention deficit hyperactivity problems.
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http://dx.doi.org/10.1016/j.bbi.2021.02.025DOI Listing
March 2021

Maternal Distress and Offspring Neurodevelopment: Challenges and Opportunities for Pre-clinical Research Models.

Front Hum Neurosci 2021 12;15:635304. Epub 2021 Feb 12.

Department of Psychiatry, Faculty of Medicine, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Pre-natal exposure to acute maternal trauma or chronic maternal distress can confer increased risk for psychiatric disorders in later life. Acute maternal trauma is the result of unforeseen environmental or personal catastrophes, while chronic maternal distress is associated with anxiety or depression. Animal studies investigating the effects of pre-natal stress have largely used brief stress exposures during pregnancy to identify critical periods of fetal vulnerability, a paradigm which holds face validity to acute maternal trauma in humans. While understanding these effects is undoubtably important, the literature suggests maternal stress in humans is typically chronic and persistent from pre-conception through gestation. In this review, we provide evidence to this effect and suggest a realignment of current animal models to recapitulate this chronicity. We also consider candidate mediators, moderators and mechanisms of maternal distress, and suggest a wider breadth of research is needed, along with the incorporation of advanced -omics technologies, in order to understand the neurodevelopmental etiology of psychiatric risk.
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http://dx.doi.org/10.3389/fnhum.2021.635304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907173PMC
February 2021

Preconception origins of perinatal maternal mental health.

Arch Womens Ment Health 2021 Jan 23. Epub 2021 Jan 23.

Translational Neuroscience Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore, Singapore.

Perinatal maternal symptoms of depression and anxiety compromise psychosocial function and influence developmental outcomes in the offspring. The onset of symptoms remains unclear with findings that suggest a preconceptual origin. We addressed this issue with a prospective analysis of anxiety and depressive symptom profiles from preconception through to parturition. Women were recruited into a preconception study to assess (a) variation in symptom levels of depression and anxiety from pre- to post-conception and (b) if the symptom network profiles of depression and anxiety change from pre-conception to post-conception. A within-subject intraclass correlation analyses revealed that symptoms of depression or anxiety in the preconception phase strongly predicted those across pregnancy and into the early postnatal period. The symptom network analysis revealed that the symptom profiles remained largely unchanged from preconception into the second trimester. Our findings suggest that for a significant portion of women, maternal mental health remains stable from preconception into pregnancy. This finding highlights the need for early intervention studies on women's mental health to be targeted during the preconception period and to be extended across the population.
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http://dx.doi.org/10.1007/s00737-020-01096-yDOI Listing
January 2021

Investigating the association between labour epidural analgesia and postpartum depression: A prospective cohort study.

Eur J Anaesthesiol 2020 Sep;37(9):796-802

From the Department of Women's Anaesthesia, KK Women's and Children's Hospital (CWT, BLS), Duke-NUS Medical School (CWT, BLS), Centre for Quantitative Medicine, Duke-NUS Medical School (RS), Singapore Institute for Clinical Sciences (MZLK, MJM), Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore (MJM) and Department of Psychiatry, McGill University, Montreal, Quebec, Canada (MJM).

Background: Postpartum depression (PPD) affects 10 to 15% of women and is associated with socio-economic burden and maternal morbidity. Recent studies showed that epidural analgesia may be associated with the development of PPD, although this association remains inconclusive.

Objective: To investigate the role of perinatal demographic, analgesic and psychological factors that may be related to PPD.

Design: Prospective, longitudinal multiethnic cohort study.

Setting: Singapore's two major public maternity institutions.

Patients: Pregnant women recruited during antenatal consultation and with follow-up 3 months postdelivery at Singapore hospitals with maternity services.

Intervention: None.

Main Outcome Measures: The primary outcome of PPD was assessed 3 months postdelivery using the Edinburgh Postnatal Depression Scale to investigate an association with the use of labour epidural analgesia. The associations between PPD and anxiety and depression at 26 weeks' gestation predelivery were also evaluated. Demographic, analgesic, psychological factors and intrapartum data were analysed.

Results: There were 651 women with 152 cases (23.3%) of PPD and 499 controls (76.7%) at 3 months after childbirth. There was no significant difference between women who received labour epidural analgesia (95 of 385, 24.7%) and those who did not receive epidural analgesia (57 of 266, 21.4%) (unadjusted odds ratio 1.20, 95% confidence interval 0.83 to 1.75, P = 0.3361) in the incidence of PPD 3 months postdelivery. Predelivery anxiety and depression were positively associated with PPD 3 months postdelivery.

Conclusion: Our study did not demonstrate an association between PPD at 3 months postdelivery and labour epidural analgesia.

Trial Registration: NCT01174875.
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http://dx.doi.org/10.1097/EJA.0000000000001236DOI Listing
September 2020

Positive Maternal Mental Health, Parenting, and Child Development.

Biol Psychiatry 2020 02 16;87(4):328-337. Epub 2019 Oct 16.

Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada; Sackler Program for Epigenetics and Psychobiology, McGill University, Montreal, Quebec, Canada. Electronic address:

While maternal mental health is an important influence on child development, the existing literature focuses primarily on negative aspects of maternal mental health, particularly symptoms of depression, anxiety, or states of distress. We provide a review of the evidence on the potential importance of positive mental health for both mother and child. The evidence suggests that positive mental health is a distinct construct that is associated with improved birth outcomes and potentially with specific forms of parenting that promote both academic achievement and socioemotional function. We review studies that provide a plausible biological basis for the link between positive mental health and parenting, focusing on oxytocin-dopamine interactions. We caution that the evidence is largely preliminary and suggest directions for future research, noting the importance of identifying the operative dimensions of positive maternal mental health in relation to specific outcomes. We suggest that the inclusion of positive maternal mental health provides the potential for a more comprehensive understanding of parental influences on child development.
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http://dx.doi.org/10.1016/j.biopsych.2019.09.028DOI Listing
February 2020

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

Proc Natl Acad Sci U S A 2020 09 14;117(38):23329-23335. Epub 2019 Oct 14.

Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada V5Z 4H4;

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset ( = 1,032), with performance assessed in a separate test dataset ( = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.
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http://dx.doi.org/10.1073/pnas.1820843116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519312PMC
September 2020

A microfluidic device to sort cells based on dynamic response to a stimulus.

PLoS One 2013 8;8(11):e78261. Epub 2013 Nov 8.

Microfluidics Systems Biology Lab, Institute of Molecular and Cell Biology, Singapore, Singapore.

Single cell techniques permit the analysis of cellular properties that are obscured by studying the average behavior of cell populations. One way to determine how gene expression contributes to phenotypic differences among cells is to combine functional analysis with transcriptional profiling of single cells. Here we describe a microfluidic device for monitoring the responses of single cells to a ligand and then collecting cells of interest for transcriptional profiling or other assays. As a test, cells from the olfactory epithelium of zebrafish were screened by calcium imaging to identify sensory neurons that were responsive to the odorant L-lysine. Single cells were subsequently recovered for transcriptional profiling by qRT-PCR. Responsive cells all expressed TRPC2 but not OMP, consistent with known properties of amino-acid sensitive olfactory neurons. The device can be adapted for other areas in biology where there is a need to sort and analyze cells based on their signaling responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826715PMC
March 2015

Probing the function of neuronal populations: combining micromirror-based optogenetic photostimulation with voltage-sensitive dye imaging.

Neurosci Res 2013 Jan 17;75(1):76-81. Epub 2012 Dec 17.

Laboratory of Synaptic Circuitry, Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.

Recent advances in our understanding of brain function have come from using light to either control or image neuronal activity. Here we describe an approach that combines both techniques: a micromirror array is used to photostimulate populations of presynaptic neurons expressing channelrhodopsin-2, while a red-shifted voltage-sensitive dye allows optical detection of resulting postsynaptic activity. Such technology allowed us to control the activity of cerebellar interneurons while simultaneously recording inhibitory responses in multiple Purkinje neurons, their postsynaptic targets. This approach should substantially accelerate our understanding of information processing by populations of neurons within brain circuits.
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http://dx.doi.org/10.1016/j.neures.2012.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594342PMC
January 2013

Imaging activity of neuronal populations with new long-wavelength voltage-sensitive dyes.

Brain Cell Biol 2008 Dec 14;36(5-6):157-72. Epub 2009 Feb 14.

Laboratory of Synaptic Circuitry, Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, 2 Jalan Bukit Merah, Singapore 169547, Singapore.

We have assessed the utility of five new long-wavelength fluorescent voltage-sensitive dyes (VSD) for imaging the activity of populations of neurons in mouse brain slices. Although all the five were capable of detecting activity resulting from activation of the Schaffer collateral-CA1 pyramidal cell synapse, they differed significantly in their properties, most notably in the signal-to-noise ratio of the changes in dye fluorescence associated with neuronal activity. Two of these dyes, Di-2-ANBDQPQ and Di-1-APEFEQPQ, should prove particularly useful for imaging activity in brain tissue and for combining VSD imaging with the control of neuronal activity via light-activated proteins such as channelrhodopsin-2 and halorhodopsin.
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http://dx.doi.org/10.1007/s11068-009-9039-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663446PMC
December 2008