Publications by authors named "Yuliya S Nikolova"

26 Publications

  • Page 1 of 1

Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.

Neuropsychopharmacology 2021 Sep 29. Epub 2021 Sep 29.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.
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http://dx.doi.org/10.1038/s41386-021-01189-xDOI Listing
September 2021

Cognitive impairment and depression: Meta-analysis of structural magnetic resonance imaging studies.

Neuroimage Clin 2021 Sep 16;32:102830. Epub 2021 Sep 16.

Brain and Mind Research Programme, Central European Institute of Technology, Masaryk University (CEITEC MU), 5 Kamenice, Brno 62500, Czech Republic; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1L8, Canada.

Longitudinal comorbidity of depression and cognitive impairment has been reported by number of epidemiological studies but the underlying mechanisms explaining the link between affective problems and cognitive decline are not very well understood. Imaging studies have typically investigated patients with major depressive disorder (MDD) and mild cognitive impairment (MCI) separately and thus have not identified a structural brain signature common to these conditions that may illuminate potentially targetable shared biological mechanisms. We performed a meta-analysis of. 48 voxel-based morphometry (VBM) studies of individuals with MDD, MCI, and age-matched controls and demonstrated that MDD and MCI patients had shared volumetric reductions in a number of regions including the insula, superior temporal gyrus (STG), inferior frontal gyrus, amygdala, hippocampus, and thalamus. We suggest that the shared volumetric reductions in the insula and STG might reflect communication deficits and infrequent participation in mentally or socially stimulating activities, which have been described as risk factors for both MCI and MDD. We also suggest that the disease-specific structural changes might reflect the disease-specific symptoms such as poor integration of emotional information, feelings of helplessness and worthlessness, and anhedonia in MDD. These findings could contribute to better understanding of the origins of MDD-MCI comorbidity and facilitate development of early interventions.
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http://dx.doi.org/10.1016/j.nicl.2021.102830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473769PMC
September 2021

Impact of Prenatal Stress on Amygdala Anatomy in Young Adulthood: Timing and Location Matter.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Aug 3. Epub 2021 Aug 3.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Exposure to maternal stress in utero has long-term implications for the developing brain and has been linked with a higher risk of depression. The amygdala, which develops during the early embryonic stage and is critical for emotion processing, might be particularly sensitive.

Methods: Using data from a neuroimaging follow-up of the European Longitudinal Study of Pregnancy and Childhood prenatal birth cohort (n = 129, 47% men, 23-24 years old), we studied the impact of prenatal stress during the first and second halves of pregnancy on the volume of the amygdala and its nuclei in young adult offspring. We further evaluated the relationship between amygdala anatomy and offspring depressive symptomatology. Amygdala nuclei were parcellated using FreeSurfer's automated segmentation pipeline. Depressive symptoms were measured via self-report using the Beck Depression Inventory.

Results: Exposure to stress during the first half of pregnancy was associated with smaller accessory basal (Cohen's f = 0.27, false discovery rate [FDR]-corrected p [p] = .03) and cortical (Cohen's f = 0.29, p = .03) nuclei volumes. This effect remained significant after correcting for sex, stress during the second half of pregnancy, maternal age at birth, birth weight, maternal education, and offspring's age at magnetic resonance imaging. These two nuclei showed a quadratic relationship with Beck Depression Inventory scores in young adulthood, where both smaller and larger volumes were associated with more depressive symptoms (accessory basal nucleus: adj. R = 0.05, p = .015; cortical nucleus: adj. R = 0.04, p = .015).

Conclusions: We conclude that exposure to stress during the first half of pregnancy might have long-term implications for amygdala anatomy, which may in turn predict the experience of depressive symptoms in young adulthood.
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http://dx.doi.org/10.1016/j.bpsc.2021.07.009DOI Listing
August 2021

Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density.

Neuropharmacology 2021 06 14;190:108562. Epub 2021 Apr 14.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Canada; Departments of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada. Electronic address:

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p < 0.05). Reduced ACC correlated with increased behavioral emotionality (r = -0.56; p = 0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r = 0.35, p < 0.05), which also correlated with increased behavioral emotionality (r = -0.44, p < 0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108562DOI Listing
June 2021

Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms.

Transl Psychiatry 2020 11 24;10(1):410. Epub 2020 Nov 24.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.

Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/- 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.
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http://dx.doi.org/10.1038/s41398-020-01093-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686479PMC
November 2020

Neuroanatomical signatures of anorexia nervosa psychopathology: An exploratory MRI/DTI study in a mixed sample enriched for disease vulnerability.

Psychiatry Res Neuroimaging 2021 01 17;307:111228. Epub 2020 Nov 17.

Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

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http://dx.doi.org/10.1016/j.pscychresns.2020.111228DOI Listing
January 2021

Temporally and sex-specific effects of maternal perinatal stress on offspring cortical gyrification and mood in young adulthood.

Hum Brain Mapp 2020 12 3;41(17):4866-4875. Epub 2020 Oct 3.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.

Maternal stress during pregnancy and shortly thereafter is associated with altered offspring brain development that may increase risk of mood and anxiety disorders. Cortical gyrification is established during the prenatal period and the first 2 years of life and is altered in psychiatric disorders. Here, we sought to characterize the effects of perinatal stress exposure on offspring gyrification patterns and mood dysregulation in young adulthood. Participants included 85 young adults (56.5% women; 23-24 years) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) with perinatal stress data across four distinct timepoints and structural MRI data from young adulthood. Perinatal stress exposure was measured as maternal stress during first and second half of pregnancy, first 6 months, and 6-18 months after birth. Cortical gyrification and mood dysregulation were quantified using local gyrification index (LGI), computed with Freesurfer, and the Profile of Mood States questionnaire, respectively. Perinatal stress predicted cortical gyrification in young adulthood, and its timing influenced location, direction, and sex-specificity of effects. In particular, whereas early prenatal stress was associated with sex-dependent medium-to-large effects in large temporal, parietal, and occipital regions (f = 0.19-0.38, p < .001), later perinatal stress was associated with sex-independent small-to-medium effects in smaller, more anterior regions (f = 0.10-0.19, p < .003). Moreover, in females, early prenatal stress predicted higher LGI in a large temporal region, which was further associated with mood disturbance in adulthood (r = 0.399, p = .006). These findings point out the long-term implications of perinatal stress exposure for cortical morphology and mood dysregulation.
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http://dx.doi.org/10.1002/hbm.25163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643354PMC
December 2020

Older molecular brain age in severe mental illness.

Mol Psychiatry 2021 Jul 6;26(7):3646-3656. Epub 2020 Jul 6.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15312, USA.

Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular, and structural changes that are robust on the group level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20-90 years. Individual estimates of "molecular age" were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as "delta age". Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRS and PRS), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r = 0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer's disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.
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http://dx.doi.org/10.1038/s41380-020-0834-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785531PMC
July 2021

Maternal Depressive Symptoms During Pregnancy and Brain Age in Young Adult Offspring: Findings from a Prenatal Birth Cohort.

Cereb Cortex 2020 06;30(7):3991-3999

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada.

Maternal depression during pregnancy is associated with elevated risk of anxiety and depression in offspring, but the mechanisms are incompletely understood. Here we conducted a neuroimaging follow-up of a prenatal birth cohort from the European Longitudinal Study of Pregnancy and Childhood (n = 131; 53% women, age 23-24) to test whether deviations from age-normative structural brain development in young adulthood may partially underlie this link. Structural brain age was calculated based on previously published neuroanatomical age prediction models using cortical thickness maps from healthy controls aged 6-89. Brain age gap was computed as the difference between chronological and structural brain age. Participants also completed self-report measures of anxiety and mood dysregulation. Further, mothers of a subset of participants (n = 103, 54% women) answered a self-report questionnaire in 1990-1992 about depressive symptoms during pregnancy. Higher exposure to maternal depressive symptoms in utero showed a linear relationship with elevated brain age gap, which showed a quadratic relationship with anxiety and mood dysregulation in the young adult offspring. Our findings suggest that exposure to maternal depressive symptoms in utero may be associated with accelerated brain maturation and that deviations from age-normative structural brain development in either direction predict more anxiety and dysregulated mood in young adulthood.
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http://dx.doi.org/10.1093/cercor/bhaa014DOI Listing
June 2020

Genetic variation in dopamine neurotransmission and motor development of infants born extremely-low-birthweight.

Dev Med Child Neurol 2020 06 6;62(6):750-757. Epub 2019 Nov 6.

Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Aim: To determine if genetic variation associated with decreased dopamine neurotransmission predicts a decrease in motor development in a convenience cohort study of infants born extremely-low-birthweight (ELBW).

Method: Four hundred and ninety-eight infants born ELBW had genome-wide genotyping and a neurodevelopmental evaluation at 18 to 22 months of age, corrected for preterm birth. A polygenic risk score (PRS) was created to combine into one predictor variable the hypothesized influences on motor development of alleles at seven independent single nucleotide polymorphisms previously associated with relative decreases in both dopamine neurotransmission and motor learning, by summing the number of alleles present in each infant (range=0-14). The motor development outcome was the Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development, Second Edition. The linear regression models were adjusted for seven clinical and four genetic ancestry covariates. The mean PRS of infants with cerebral palsy (CP) was compared to those without CP.

Results: PRS was inversely related to PDI (p=0.011). Each 1-point increase in PRS resulted in an average decrease in PDI of 1.37 points. Patients with CP did not have a greater mean PRS than those without (p=0.67), both with and without adjustment for covariates.

Interpretation: Genetic variation that favors a decrease in dopamine neurotransmission predisposes to a decrease in motor development in infants born ELBW, but not to the diagnosis of CP.

What This Paper Adds: Genetic variation in dopamine neurotransmission was associated with a decrease in motor development in infants born at an extremely-low-birthweight. It does not predispose to the diagnosis of cerebral palsy.
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http://dx.doi.org/10.1111/dmcn.14383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200269PMC
June 2020

Residual avoidance: A new, consistent and repeatable readout of chronic stress-induced conflict anxiety reversible by antidepressant treatment.

Neuropharmacology 2019 07 8;153:98-110. Epub 2019 May 8.

Campbell Family Mental Health Research Institute of CAMH, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Stress-related illnesses such as major depressive and anxiety disorders are characterized by maladaptive responses to stressful life events. Chronic stress-based animal models have provided critical insight into the understanding of these responses. Currently available assays measuring chronic stress-induced behavioral states in mice are limited in their design (short, not repeatable, sensitive to experimenter-bias) and often inconsistent. Using the Noldus PhenoTyper apparatus, we identified a new readout that repeatedly assesses behavioral changes induced by chronic stress in two mouse models i.e. chronic restraint stress (CRS) and chronic unpredictable mild stress (UCMS). The PhenoTyper test consists of overnight monitoring of animals' behavior in home-cage setting before, during and after a 1hr light challenge applied over a designated food zone. We tested the reproducibility and reliability of the PhenoTyper test in assessing the effects of chronic stress exposure, and compared outcomes with commonly-used tests. While chronic stress induced heterogeneous profiles in classical tests, CRS- and UCMS-exposed mice showed a very consistent response in the PhenoTyper test. Indeed, CRS and UCMS mice continue avoiding the lit zone in favor of the shelter zone. This "residual avoidance" after the light challenge, lasted for hours beyond termination of the challenge, was not observed after acute stress and was consistently found throughout stress exposure in both models. Chronic stress-induced residual avoidance was alleviated by chronic imipramine treatment but not acute diazepam administration. This behavioral index should be instrumental for studies aiming to better understand the trajectory of chronic stress-induced deficits and potentially screen novel anxiolytics and antidepressants.
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http://dx.doi.org/10.1016/j.neuropharm.2019.05.005DOI Listing
July 2019

Dopamine genetic risk is related to food addiction and body mass through reduced reward-related ventral striatum activity.

Appetite 2019 02 5;133:24-31. Epub 2018 Oct 5.

Duke University, Durham, NC, USA.

The prevalence rate of obesity continues to rise in the U.S., but effective treatment options remain elusive resulting in increased emphasis on prevention. One such area of prevention research capitalizes on the relatively novel behavioral construct of food addiction, which has been implicated in obesity. Food addiction reflects an individual's propensity for compulsive eating despite negative consequences, and shares not only symptoms with both eating and substance use disorders but also genetic and neural correlates within neural reward-circuitry modulated by dopamine. Here, we examined associations between food addiction scores, body mass index (BMI), reward-related ventral striatum activity, and a polygenic score approximating dopamine signaling in 115 non-Hispanic Caucasian young adult university students. As predicted, polygenic dopamine scores were related to ventral striatum activity, which in turn was associated with higher food addiction scores. In addition, food addiction was related to BMI. An exploratory post-hoc path analysis further indicated that polygenic scores were indirectly related to both food addiction and BMI, in part, through ventral striatum activity. Collectively, our results provide evidence supporting the utility of food addiction in weight gain prevention research by establishing links with known risk-related neural and genetic biomarkers.
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http://dx.doi.org/10.1016/j.appet.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488021PMC
February 2019

Shifting priorities: highly conserved behavioral and brain network adaptations to chronic stress across species.

Transl Psychiatry 2018 01 22;8(1):26. Epub 2018 Jan 22.

Campbell Family Mental Health Research Institute of CAMH, Toronto, Canada.

Parallel clinical and preclinical research have begun to illuminate the biological basis of stress-related disorders, including major depression, but translational bridges informing discrete mechanistic targets for intervention are missing. To address this critical need, we used structural MRI in a mouse model and in a large human sample to examine stress effects on brain structure that may be conserved across species. Specifically, we focused on a previously unexplored approach, whole-brain structural covariance, as it reflects synchronized changes in neuroanatomy, potentially due to mutual trophic influences or shared plasticity across regions. Using the unpredictable chronic mild stress (UCMS) paradigm in mouse we first demonstrate that UCMS-induced elevated behavioral emotionality correlates with increased size of the amygdala and other corticolimbic regions. We further identify focal increases in the amygdala's 'hubness' (degree and strength) set against the background of a global stress-related loss of network clustering and modularity. These macroscopic changes are supported on the molecular level by increased postsynaptic density-95 protein in the amygdala, consistent with stress-induced plastic changes and synaptic strengthening. Finally, we provide clinical evidence that strikingly similar structural network reorganization patterns exist in young adults reporting high childhood trauma and increased mood symptoms. Collectively, we provide initial translational evidence for a conserved stress-related increase in amygdala-centered structural synchrony, as measured by enhanced structural covariance, which is paralleled by a decrease in global structural synchrony. This putative trade-off reflected in increased amygdala-centered plastic changes at the expense of global structural dedifferentiation may represent a mechanistic pathway for depression and related psychopathology.
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http://dx.doi.org/10.1038/s41398-017-0083-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802514PMC
January 2018

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging.

Neurobiol Aging 2017 10 5;58:180-190. Epub 2017 Jul 5.

Campbell Family Mental Health Research Institute of CAMH, Neurobiology of Depression and Aging, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

The orbitofrontal cortex (OFC) is vulnerable to normal and pathologic aging. Currently, layer resolution large-scale proteomic studies describing "normal" age-related alterations at OFC are not available. Here, we performed a large-scale exploratory high-throughput mass spectrometry-based protein analysis on OFC layer 2/3 from 15 "young" (15-43 years) and 18 "old" (62-88 years) human male subjects. We detected 4193 proteins and identified 127 differentially expressed (DE) proteins (p-value ≤0.05; effect size >20%), including 65 up- and 62 downregulated proteins (e.g., GFAP, CALB1). Using a previously described categorization of biological aging based on somatic tissues, that is, peripheral "hallmarks of aging," and considering overlap in protein function, we show the highest representation of altered cell-cell communication (54%), deregulated nutrient sensing (39%), and loss of proteostasis (35%) in the set of OFC layer 2/3 DE proteins. DE proteins also showed a significant association with several neurologic disorders; for example, Alzheimer's disease and schizophrenia. Notably, despite age-related changes in individual protein levels, protein co-expression modules were remarkably conserved across age groups, suggesting robust functional homeostasis. Collectively, these results provide biological insight into aging and associated homeostatic mechanisms that maintain normal brain function with advancing age.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581682PMC
October 2017

A Neural "Tuning Curve" for Multisensory Experience and Cognitive-Perceptual Schizotypy.

Schizophr Bull 2017 07;43(4):801-813

Institute of Mental Health Research, Brain and Mind Research Centre, University of Ottawa, Ottawa, ON, Canada.

Our coherent perception of external events is enabled by the integration of inputs from different senses occurring within a range of temporal offsets known as the temporal binding window (TBW), which varies from person to person. A relatively wide TBW may increase the likelihood that stimuli originating from different environmental events are erroneously integrated and abnormally large TBW has been found in psychiatric disorders characterized by unusual perceptual experiences. Despite strong evidence of inter-individual differences in TBW, both within clinical and nonclinical populations, the neurobiological underpinnings of this variability remain unclear. We adopted an integrated strategy linking TBW to temporal dynamics in functional magnetic resonance imaging (fMRI)-resting-state activity and cortical excitation/inhibition (E/I) balance. E/I balance was indexed by glutamate/Gamma-AminoButyric Acid (GABA) concentrations and common variation in glutamate and GABA genes in a healthy sample. Stronger resting-state long-range temporal correlations, indicated by larger power law exponent (PLE), in the auditory cortex, robustly predicted narrower audio-tactile TBW, which was in turn associated with lower cognitive-perceptual schizotypy. Furthermore, PLE was highest and TBW narrowest for individuals with intermediate levels of E/I balance, with shifts towards either extreme resulting in reduced multisensory temporal precision and increased schizotypy, effectively forming a neural "tuning curve" for multisensory experience and schizophrenia risk. Our findings shed light on the neurobiological underpinnings of multisensory integration and its potentially clinically relevant inter-individual variability.
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http://dx.doi.org/10.1093/schbul/sbw174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472158PMC
July 2017

Can we identify meaningful epigenetic effects on human brain function and related risk for mental illness?

Epigenomics 2016 10 7;8(10):1307-1310. Epub 2016 Sep 7.

Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC 27708, USA.

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http://dx.doi.org/10.2217/epi-2016-0099DOI Listing
October 2016

FRAS1-related extracellular matrix 3 (FREM3) single-nucleotide polymorphism effects on gene expression, amygdala reactivity and perceptual processing speed: An accelerated aging pathway of depression risk.

Front Psychol 2015 16;6:1377. Epub 2015 Sep 16.

Campbell Family Mental Health Research Institute of CAMH Toronto, ON, Canada ; Department of Psychiatry, University of Pittsburgh Pittsburgh, PA, USA ; Department of Psychiatry, Department of Pharmacology and Toxicology, University of Toronto Toronto, ON, Canada.

The A allele of the FRAS1-related extracellular matrix protein 3 (FREM3) rs7676614 single nucleotide polymorphism (SNP) was linked to major depressive disorder (MDD) in an early genome-wide association study (GWAS), and to symptoms of psychomotor retardation in a follow-up investigation. In line with significant overlap between age- and depression-related molecular pathways, parallel work has shown that FREM3 expression in postmortem human brain decreases with age. Here, we probe the effect of rs7676614 on amygdala reactivity and perceptual processing speed, both of which are altered in depression and aging. Amygdala reactivity was assessed using a face-matching BOLD fMRI paradigm in 365 Caucasian participants in the Duke Neurogenetics Study (DNS) (192 women, mean age 19.7 ± 1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trail Making Test (TMT). The effect of rs7676614 on FREM3 mRNA brain expression levels was probed in a postmortem cohort of 169 Caucasian individuals (44 women, mean age 50.8 ± 14.9). The A allele of rs7676614 was associated with blunted amygdala reactivity to faces, slower reaction times in the face-matching condition (p < 0.04), as well as marginally slower performance on TMT Part B (p = 0.056). In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age. The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05). Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.
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http://dx.doi.org/10.3389/fpsyg.2015.01377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584966PMC
October 2015

Can we observe epigenetic effects on human brain function?

Trends Cogn Sci 2015 Jul 4;19(7):366-73. Epub 2015 Jun 4.

Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA.

Imaging genetics has identified many contributions of DNA sequence variation to individual differences in brain function, behavior, and risk for psychopathology. Recent studies have extended this work beyond the genome by mapping epigenetic differences, specifically gene methylation in peripherally assessed DNA, onto variability in behaviorally and clinically relevant brain function. These data have generated understandable enthusiasm for the potential of such research to illuminate biological mechanisms of risk. We use our research on the effects of genetic and epigenetic variation in the human serotonin transporter on brain function to generate a guardedly optimistic opinion that the available data encourage continued research in this direction, and suggest strategies to promote faster progress.
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http://dx.doi.org/10.1016/j.tics.2015.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486509PMC
July 2015

Beyond genotype: serotonin transporter epigenetic modification predicts human brain function.

Nat Neurosci 2014 Sep 3;17(9):1153-5. Epub 2014 Aug 3.

Laboratory of NeuroGenetics, Department of Psychology &Neuroscience, and Institute for Genome Sciences &Policy, Duke University, Durham, North Carolina, USA.

We examined epigenetic regulation in regards to behaviorally and clinically relevant human brain function. Specifically, we found that increased promoter methylation of the serotonin transporter gene predicted increased threat-related amygdala reactivity and decreased mRNA expression in postmortem amygdala tissue. These patterns were independent of functional genetic variation in the same region. Furthermore, the association with amygdala reactivity was replicated in a second cohort and was robust to both sampling methods and age.
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http://dx.doi.org/10.1038/nn.3778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146649PMC
September 2014

Uncinate fasciculus fractional anisotropy correlates with typical use of reappraisal in women but not men.

Emotion 2013 Jun 11;13(3):385-390. Epub 2013 Feb 11.

Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Institute for Genome Sciences & Policy, Duke University.

Emotion regulation refers to strategies through which individuals influence their experience and expression of emotions. Two typical strategies are reappraisal, a cognitive strategy for reframing the context of an emotional experience, and suppression, a behavioral strategy for inhibiting emotional responses. Functional neuroimaging studies have revealed that regions of the prefrontal cortex modulate amygdala reactivity during both strategies, but relatively greater downregulation of the amygdala occurs during reappraisal. Moreover, these studies demonstrated that engagement of this modulatory circuitry varies as a function of gender. The uncinate fasciculus is a major structural pathway connecting regions of the anterior temporal lobe, including the amygdala to inferior frontal regions, especially the orbitofrontal cortex. The objective of the current study was to map variability in the structural integrity of the uncinate fasciculus onto individual differences in self-reported typical use of reappraisal and suppression. Diffusion tensor imaging was used in 194 young adults to derive regional fractional anisotropy values for the right and left uncinate fasciculus. All participants also completed the Emotion Regulation Questionnaire. In women but not men, self-reported typical reappraisal use was positively correlated with fractional anisotropy values in a region of the left uncinate fasciculus within the orbitofrontal cortex. In contrast, typical use of suppression was not significantly correlated with fractional anisotropy in any region of the uncinate fasciculus in either men or women. Our data suggest that in women typical reappraisal use is specifically related to the integrity of white matter pathways linking the amygdala and prefrontal cortex.
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http://dx.doi.org/10.1037/a0031163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094171PMC
June 2013

Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala.

Biol Mood Anxiety Disord 2012 Nov 14;2:19. Epub 2012 Nov 14.

Laboratory of NeuroGenetics, Department of Psychology & Neuroscience and Institute for Genome Sciences & Policy, Duke University, NC 27708, Durham, USA.

Unlabelled:

Background: Research into neural mechanisms of drug abuse risk has focused on the role of dysfunction in neural circuits for reward. In contrast, few studies have examined the role of dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically regarded as a risk factor for mood and anxiety disorders, threat-related amygdala reactivity may serve as a protective factor against substance use disorders, particularly in individuals with exaggerated responsiveness to reward.

Findings: We used well-established neuroimaging paradigms to probe threat-related amygdala and reward-related ventral striatum reactivity in a sample of 200 young adult students from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking were assessed using self-report. We found a significant three-way interaction between threat-related amygdala reactivity, reward-related ventral striatum reactivity, and recent stress, wherein individuals with higher reward-related ventral striatum reactivity exhibit higher levels of problem drinking in the context of stress, but only if they also have lower threat-related amygdala reactivity. This three-way interaction predicted both contemporaneous problem drinking and problem drinking reported three-months later in a subset of participants.

Conclusions: These findings suggest complex interactions between stress and neural responsiveness to both threat and reward mediate problem drinking. Furthermore, they highlight a novel protective role for threat-related amygdala reactivity against drug use in individuals with high neural reactivity to reward.
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http://dx.doi.org/10.1186/2045-5380-2-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502334PMC
November 2012

Neurogenetics of depression: a focus on reward processing and stress sensitivity.

Neurobiol Dis 2013 Apr 1;52:12-23. Epub 2012 Jun 1.

BRAIN Laboratory, Department of Psychology, Washington University in St. Louis, Box 1125, One Brookings Drive, St. Louis, MO 63130, USA.

Major depressive disorder (MDD) is etiologically complex and has a heterogeneous presentation. This heterogeneity hinders the ability of molecular genetic research to reliably detect the small effects conferred by common genetic variation. As a result, significant research efforts have been directed at investigating more homogenous intermediate phenotypes believed to be more proximal to gene function and lie between genes and/or environmental effects and disease processes. In the current review we survey and integrate research on two promising intermediate phenotypes linked to depression: reward processing and stress sensitivity. A synthesis of this burgeoning literature indicates that a molecular genetic approach focused on intermediate phenotypes holds significant promise to fundamentally improve our understanding of the pathophysiology and etiology of depression, which will be required for improved diagnostic definitions and the development of novel and more efficacious treatment and prevention strategies. We conclude by highlighting challenges facing intermediate phenotype research and future development that will be required to propel this pivotal research into new directions.
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http://dx.doi.org/10.1016/j.nbd.2012.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570616PMC
April 2013

Ventral striatum reactivity to reward and recent life stress interact to predict positive affect.

Biol Psychiatry 2012 Jul 24;72(2):157-63. Epub 2012 Apr 24.

Department of Psychology and Neuroscience and Institute for Genome Sciences and Policy, Duke University, Durham, NC 27705, USA.

Background: Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects.

Methods: Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants.

Results: Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma.

Conclusions: The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.
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http://dx.doi.org/10.1016/j.biopsych.2012.03.014DOI Listing
July 2012

Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry.

Biol Psychiatry 2012 Apr 20;71(7):627-32. Epub 2012 Jan 20.

Department of Psychiatry, University of Pittsburgh, Pennsylvania 15219, USA.

Background: Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology.

Methods: Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter knockout mouse, a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans was conducted to identify genes with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples.

Results: Comparative analysis identified genes with conserved transcript changes in amygdala (n = 29) and cingulate cortex (n = 19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative polymerase chain reaction, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity.

Conclusions: This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to major depressive disorder and other affective disorders.
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http://dx.doi.org/10.1016/j.biopsych.2011.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307939PMC
April 2012

Multilocus genetic profile for dopamine signaling predicts ventral striatum reactivity.

Neuropsychopharmacology 2011 Aug 18;36(9):1940-7. Epub 2011 May 18.

Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.

Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT (158)Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene-environment interactions research establishing trajectories of risk for psychopathology.
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http://dx.doi.org/10.1038/npp.2011.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154113PMC
August 2011
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