Differentiating the Effects of Familial Risk for Alcohol Dependence and Prenatal Exposure to Alcohol on Offspring Brain Morphology.
- Authors
- Sharma, Vinod K; Hill, Shirley Y
- Year
- 2017
- Journal
- Alcoholism, clinical and experimental research
- PMID
- 28084631
- DOI
- 10.1111/acer.13289
- PMCID
- PMC5272865
BACKGROUND: Offspring with a family history of alcohol dependence (AD) have been shown to have altered structural and functional integrity of corticolimbic brain structures. Similarly, prenatal exposure to alcohol is associated with a variety of structural and functional brain changes. The goal of this study was to differentiate the brain gray matter volumetric differences associated with familial risk and prenatal exposure to alcohol among offspring while controlling for lifetime personal exposures to alcohol and drugs. METHODS: A total of 52 high-risk (HR) offspring from maternal multiplex families with a high proportion of AD were studied along with 55 low-risk (LR) offspring. Voxel-based morphometric analysis was performed using statistical parametric mapping (SPM8) software using 3T structural images from these offspring to identify gray matter volume differences associated with familial risk and prenatal exposure. RESULTS: Significant familial risk group differences were seen with HR males showing reduced volume of the left inferior temporal, left fusiform, and left and right insula regions relative to LR males, controlling for prenatal exposure to alcohol drugs and cigarettes. HR females showed a reduction in the right fusiform but also showed a reduction in volume in portions of the cerebellum (left crus I and left lobe 8). Prenatal alcohol exposure effects, assessed within the familial HR group, was associated with reduced right middle cingulum and left middle temporal volume. Even low exposure resulting from mothers drinking in amounts less than the median of those who drank (53 drinks or less over the course of the pregnancy) showed a reduction in volume in the right anterior cingulum and in the left cerebellum (lobes 4 and 5). CONCLUSIONS: Familial risk for AD and prenatal exposure to alcohol and other drugs show independent effects on brain morphology.
A whole brain SPM8 analysis was performed to evaluate the effects of familial/genetic risk using all participants. Using gender, ICV, SUD, and prenatal exposure to alcohol, cigarettes, and drugs as covariates revealed five clusters of voxels in which Low-Risk offspring had larger gray matter volume than High-Risk offspring. The clusters were thresholded at p<0.005 and 200 voxels with family wise error correction (pFWE<0.05). Five clusters survived the thresholding criterion: left fusiform, left insula, right lingual gyrus, left cerebellum lobe 8 and left cerebellum lobe 9.
Results of the whole brain prenatal alcohol exposure analysis in SPM8 within the high-risk sample are shown. Analyses controlled for gender, ICV, personal exposure to alcohol and cigarettes, and prenatal exposure to cigarettes and drug. The clusters were thresholded at p<0.005 and 300 voxels and family wise error correction applied. Figure 10a (left) shows the results of comparing subjects without prenatal exposure (No Exposure Group) with subjects with those whose mothers reported use that was greater than the median for those mothers who drank during pregnancy (High Exposure Group) all of whom were from the HR group. Only one cluster survived the thresholding criterion. Offspring with high exposure had reduced gray matter volume in the right middle cingulum (pFWE= 0.024, 413 voxels). Figure 10b shows the results of comparing the No Exposure Group to those offspring whose mothers drank at levels less than the median of mothers reporting any drinking during pregnancy (No Exposure vs Low Exposure) within the HR group. Two clusters survived the thresholding criterion (right anterior cingulum (pFWE= 0.030, 349 voxels) and the left cerebellum lobes 4 and 5 (pFWE= 0.001, 579 voxels).
A whole brain SPM8 analysis was conducted for male participants only to assess the effect of familial/genetic risk using ICV, SUD, and prenatal exposure to alcohol, cigarettes, and drugs as covariates. The analysis found four clusters of voxels (left inferior temporal, left fusiform, left insula, and right insula) in which Low-Risk male offspring had larger gray matter volume than did the High-Risk male offspring. The clusters were thresholded at p<0.005 and 200 voxels with family wise error correction applied (pFWE<0.05).
A whole brain SPM8 analysis was performed for female participants only to assess the effect of familial/genetic risk using ICV, SUD, and prenatal exposure to alcohol, cigarettes, and drugs as covariates. The analysis revealed three clusters of voxels (right fusiform, left cerebellum crus I, and left cerebellum lobe 8) in which Low-Risk female offspring had larger gray matter volume than High-Risk female offspring The clusters were thresholded at p<0.005 and 200 voxels and family wise error correction applied (pFWE<0.05).
The effect of familial risk group membership on the volume of the inferior temporal (left) is shown based on an analysis in which results were obtained within each gender. The risk group differences were significant for the males but not for the females.
The effect of familial risk group membership on the volume of the fusiform (left) is shown based on an analysis in which results were obtained within each gender. The results were significant for the males but not for the females.
The effect of familial risk group membership on the volume of the insula (left) is shown based on an analysis in which results were obtained within each gender. The results were significant for the males but not for the females.
The effect of familial risk group membership on the volume of the insula (right) is shown based on an analysis in which results were obtained within each gender. The results were significant for the males but not for the females.
To determine the effects of prenatal alcohol exposure on whole brain volumes while controlling for familial risk effects, an SPM8 analysis was conducted within the high-risk sample controlling for gender, ICV, and personal exposure to alcohol and cigarettes, along with prenatal exposure to cigarettes and drugs. The clusters were thresholded at p<0.005 and 300 voxels with family wise error correction applied. The prenatally exposed subjects had reduced gray matter volume in the right middle cingulum (pFWE= 0.002, 623 voxels) and the left middle temporal regions (pFWE= 0.009, 505 voxels).
The effect of prenatal alcohol exposure on the volume of the right middle cingulum in the high-risk subjects is shown.
| # | Section | Preview |
|---|---|---|
| 40 | Discussion — Prenatal Effects | In contrast to our findings for familial risk effects, prenatal exposure to alcohol was associated… |
| 41 | Discussion — Prenatal Effects | Although our MTG findings were found in association with prenatal exposure effects, others have… |
| 42 | Discussion — Prenatal Effects — Limitations | Although this study presents novel findings concerning the brain regions that are most influenced by… |
| 43 | Discussion — Prenatal Effects — Limitations | Use of ultra-high-risk alcohol dependence families, as was done in the present study, has both… |
| 44 | Discussion — Prenatal Effects — Limitations | A notable strength of our analysis was our ability to simultaneously assess familial risk, prenatal… |
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| Substance use and mental health symptoms in adults with prenatal alcohol exposure. | Hunnicutt-Ferguson K et al. | — | 2025 | → |
| Whole Genome Sequencing of Pedigrees With High Density of Substance Use and Psychiatric Disorders: A Meeting Report. | Hill SY et al. | — | 2025 | → |
| Recent breakthroughs in understanding the cerebellum's role in fetal alcohol spectrum disorder: A systematic review. | Leung ECH et al. | — | 2024 | → |
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| Alcohol use and interoception - A narrative review. | Wiśniewski P et al. | — | 2021 | → |
| It's more than just interoception: The insular cortex involvement in alcohol use disorder. | Campbell EJ et al. | — | 2021 | → |
| Convergent Evidence for Predispositional Effects of Brain Gray Matter Volume on Alcohol Consumption. | Baranger DAA et al. | — | 2020 | → |
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| Altered brain cortical maturation is found in adolescents with a family history of alcoholism. | Holla B et al. | — | 2019 | → |
| Association Between Age and Familial Risk for Alcoholism on Functional Connectivity in Adolescence. | Vaidya JG et al. | — | 2019 | → |
| DRD2 methylation and regional grey matter volumes in young adult offspring from families at ultra-high risk for alcohol dependence. | Hill SY et al. | — | 2019 | → |
| Embryonic Ethanol Exposure Affects the Early Development, Migration, and Location of Hypocretin/Orexin Neurons in Zebrafish. | Collier AD et al. | — | 2019 | → |
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| Familial Risk for Alcohol Dependence and Brain Morphology: The Role of Cortical Thickness Across the Lifespan. | Hill SY | — | 2018 | → |
| Meta-Analyses of Externalizing Disorders: Genetics or Prenatal Alcohol Exposure? | Wetherill L et al. | — | 2018 | → |
| The Cerebellar GABA<sub>A</sub>R System as a Potential Target for Treating Alcohol Use Disorder. | Rossi DJ et al. | — | 2018 | → |