Publications by authors named "Kody G Kennedy"

5 Publications

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Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder.

J Affect Disord 2021 Jun 28;289:135-143. Epub 2021 Apr 28.

University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD.

Methods: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions.

Results: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC.

Limitations: Cross-sectional design, modest sample size.

Conclusions: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.
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http://dx.doi.org/10.1016/j.jad.2021.04.040DOI Listing
June 2021

Clinical and neurostructural characteristics among youth with familial and non-familial bipolar disorder: Family history and youth bipolar disorder.

J Affect Disord 2021 03 29;282:1315-1322. Epub 2020 Dec 29.

Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, 100 Stokes St, Toronto, ON, M6J 1H4, Canada; Department of Psychiatry, University of Toronto, 250 College Street, 8th floor, Toronto, ON, M5T 1R8, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Rm 4207 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. Electronic address:

Background: Bipolar disorder (BD) is highly heritable and often severe, particularly when illness onset occurs early in life. There is limited knowledge regarding the clinical and neurostructural correlates of family history of BD among youth with BD.

Methods: Clinical characteristics were evaluated in 197 youth with BD, ages 13-20 years, including 87 with familial BD and 110 with non-familial BD. Structural neuroimaging was examined in a subsample of familial BD (n=39), non-familial BD (n=42), and healthy control (HC, n=58) youth. Region of interest (ROI) analyses of anterior cingulate cortex (ACC), inferior frontal gyrus (IFG), and amygdala were complemented by whole-brain vertex-wise analyses.

Results: Youth with familial BD had more family history of other psychiatric disorders, less severe worst manic episode, and less treatment with lithium, selective serotonin reuptake inhibitor (SSRI) antidepressants, and any lifetime psychiatric medications. None of these findings survived after correction for multiple comparisons. There were no significant between-group differences in ROI analyses. In whole-brain analyses, significant differences in cortical thickness were as follows: familial and non-familial BD < HC in left precentral gyrus and right inferior parietal lobe; familial BD < HC in left superior frontal gyrus; non-familial BD < HC in right precentral gyrus.

Limitations: Relatives did not complete full diagnostic interviews.

Conclusions: There were relatively few differences in clinical and neurostructural correlates related to family history of BD in youth with BD. Current findings suggest that family history of BD is not a strong contributor to the clinical or neuroimaging phenotypes in youth with BD.
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http://dx.doi.org/10.1016/j.jad.2020.12.146DOI Listing
March 2021

Elevated lipids are associated with reduced regional brain structure in youth with bipolar disorder.

Acta Psychiatr Scand 2021 Jun 16;143(6):513-525. Epub 2021 Feb 16.

Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Objective: Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid-brain structure association in BD or youth.

Methods: This study examined low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1-weighted images, among participants ages 13-20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within-group analyses were undertaken. Exploratory vertex-wise analyses further investigated group differences in the lipid-brain structure association.

Results: There were significant group differences in the association of LDL-C (β = -0.29 p = 0.001), and TC (β = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (β = -0.25 p = 0.01) and area (β = -0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL-C (β = -0.27 p = 0.007) and reduced HDL-C (β = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second-generation antipsychotic users did not alter these results. Vertex-wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex.

Conclusion: Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid-brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary.
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http://dx.doi.org/10.1111/acps.13278DOI Listing
June 2021

Neurostructural Correlates of Cannabis Use in Adolescent Bipolar Disorder.

Int J Neuropsychopharmacol 2021 Mar;24(3):181-190

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada.

Background: Little is known regarding the association of cannabis use with brain structure in adolescents with bipolar disorder (BD). This subject is timely, given expanded availability of cannabis contemporaneously with increased social acceptance and diminished societal constraints to access. Therefore, we set out to examine this topic in a sample of adolescents with BD and healthy control (HC) adolescents.

Methods: Participants included 144 adolescents (47 BD with cannabis use [BDCB+; including 13 with cannabis use disorder], 34 BD without cannabis use [BDCB-], 63 HC without cannabis use) ages 13-20 years. FreeSurfer-processed 3T MRI with T1-weighted contrast yielded measures of cortical thickness, surface area (SA), and volume. Region of interest (amygdala, hippocampus, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) analyses and exploratory vertex-wise analysis were undertaken. A general linear model tested for between-group differences, accounting for age, sex, and intracranial volume.

Results: Vertex-wise analysis revealed significant group effects in frontal and parietal regions. In post-hoc analyses, BDCB+ exhibited larger volume and SA in parietal regions, and smaller thickness in frontal regions, relative to HC and BDCB-. BDCB- had smaller volume, SA, and thickness in parietal and frontal regions relative to HC. There were no significant region of interest findings after correcting for multiple comparisons.

Conclusion: This study found that cannabis use is associated with differences in regional brain structure among adolescents with BD. Future prospective studies are necessary to determine the direction of the observed association and to assess for dose effects.
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http://dx.doi.org/10.1093/ijnp/pyaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968618PMC
March 2021

Clinical and neuroimaging correlates of cardiorespiratory fitness in adolescents with bipolar disorder.

Bipolar Disord 2021 May 30;23(3):274-283. Epub 2020 Sep 30.

Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.

Introduction: Cardiovascular disease (CVD) is exceedingly prevalent, and occurs prematurely in individuals with bipolar disorder (BD). Cardiorespiratory fitness (CRF), arguably the most important modifiable CVD risk factor, is also associated with brain structure and function. There is a gap in knowledge regarding CRF in BD, particularly in relation to brain structure.

Methods: Adolescents with BD (n = 54) and healthy controls (HC; n = 53) completed semi-structured diagnostic interviews, self-report questionnaires, and 20 minutes of cardiorespiratory exercise at 60-80% of estimated maximum heart rate (HR) on a bicycle ergometer. Average power (watts/kg) within this HR range served as a previously validated proxy for CRF. Brain magnetic resonance imaging (MRI) structural analysis was done using FreeSurfer. Analyses controlled for age and sex.

Results: CRF was significantly lower in BD vs HC (0.91 ± 0.32 vs 1.01 ± 0.30, p = 0.03, F = 4.66, df=1, η =0.04). Within BD, greater depression symptoms were associated with lower CRF (P = .02), and greater physical activity (PA) was associated with greater CRF (P < .001). In multivariable analyses, there were significant main effects of diagnosis (HC>BD; P = .03) and sex (M > F; P < .001) on power. Significant predictors of power within BD included male sex (P = .02) and PA (P = .002) but not depression symptoms (P = .29). Significant diagnosis by CRF interaction effects was found in frontal, parietal, and occipital cortical regions.

Conclusion: CRF was reduced among adolescents with BD, particularly women, related in part to depression symptoms and inactivity and was differentially associated with regional brain structure. Studies seeking to improve CRF as a means of reducing psychiatric symptoms of BD are warranted.
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http://dx.doi.org/10.1111/bdi.12993DOI Listing
May 2021