By: Kourtney J. Gorham at The University of Regina for EPSY 836 – Neuropsychology (Instructor Louise Burridge)
Anatomical and Physiological Changes to the Brain Due to Prenatal Alcohol Exposure (PAE)
Alcohol is a teratogen that has detrimental effects on the developing fetus, often causing anatomical and physiological changes to the brain. When a pregnant mother consumes alcohol, it enters through the placenta and impacts fetal development through cellular and structural impairments (Brown, Connor, Adler, & Langton, 2012; Lebel, Roussotte, & Sowell, 2011). According to Nash and Davies (2017), the fetus’s blood-alcohol level matches the mother’s blood-alcohol level after an hour or two. However, due to reuptake of amniotic fluid, the blood-alcohol level can remain high for longer (Nash & Davies, 2017). Additional factors such as the mother’s metabolism and health, the amount of alcohol consumed, the frequency of consumption, and the point in fetal development when the insult occurred all contribute to overall fetal health (Brown et al., 2012; Kolb, Whishaw, & Teskey, 2019; Nash & Davies, 2017). It is generally agreed that the first trimester – particularly during the second through eighth weeks when the brain structures start to form and DNA synthesis occurs – is a critical time period when the effects of alcohol can be quite damaging (Brown et al., 2012; Kolb et al., 2019; Saskatchewan Prevention Institute, n.d.). For instance, Lebel et al. (2011) found that facial dysmorphology likely occurs when alcohol is consumed during the third and fourth weeks of fetal development. However, there is no safe time or safe level of alcohol to consume during pregnancy (CanFASD, 2019; FASD Network of Saskatchewan [FASD Network], 2017; Osterman, 2011; Saskatchewan Prevention Institute, n.d.; Zizzo & Racine, 2017) and even one drink per day has been found to lower IQ levels (Nash & Davies, 2017). For researchers, caregivers, educators, healthcare providers, speech pathologists, occupational therapists, and psychologists alike, knowledge about the anatomical and physiological changes to the brain due to prenatal alcohol exposure (PAE) is crucial for implementing appropriate supports and interventions.
For four decades we have known about the harmful effects of alcohol on the developing fetus (Glass et al., 2017), yet insults still occur. PAE can lead to a diagnosis of Fetal Alcohol Spectrum Disorder (FASD) – a lifelong disability that can impact an individual’s behavioral, cognitive, physical, and sensory domains (CanFASD, 2019; FASD Network, 2017). FASD has both neurocognitive and neurobehavioral implications, as PAE damages the Central Nervous System (CNS) in the developing fetus (Brown et al., 2012; Nash & Davies, 2017; Gorham, 2019; Popova, Lange, Burd, & Rehm, 2015). In fact, Chen, Maier, Parnell, and West (2003) found that cognitive and behavioral challenges are caused by the CNS damage rather than Intelligence Quotient (IQ) or other contributing factors alone. Despite this general understanding, the Canada FASD Research Network [CanFASD] (2019) reports that prevalence rates of FASD are 4% or 1.4 million Canadians. At least 1% of individuals in Saskatchewan have FASD with many more going undiagnosed (FASD Network, 2017). This may be because approximately 50% of adult pregnancies and 80% of adolescent pregnancies are unplanned (Nash & Davies, 2017). Nash and Davies (2017) found that only 9.4% of adults and 13.4% of teenagers drank during pregnancy, with each trimester seeing a reduction in drinking behaviors. This is compared to the 50% of adult women and 22% of teenage girls that drank before pregnancy (Nash & Davies, 2017). Thus, many individuals cease alcohol use once aware of their pregnancy but social inequalities, lack of education, and previous addictions may contribute to continued use in some cases (Migliorini et al., 2015), making PAE a societal reality (Gorham, 2019).
While we have known prevalence rates, it can be hard to get exact information about the amount, frequency of use, and developmental time of insult. Deciphering between abnormalities in the brain caused by PAE versus comorbid diagnoses – such as Attention Deficit Hyperactivity Disorder (40-90% of cases) and Specific Learning Disorders (17-35% of cases) (Glass et al., 2017) – and/or other substances used prenatally further complicates research (Lebel et al., 2011). Factors such as maternal metabolism, nutrition, and genetics also are hard to account for and testing theories is often unethical, thus resulting in animal studies that do not always translate to humans (Brown et al., 2012; Nash & Davies, 2017). Furthermore, while diagnosis of FASD involves a combination of facial abnormalities, tenth percentile growth deficits, and structural and functional CNS abnormalities (Brown et al., 2012), differences in brain structure and presentation occurs among individuals with PAE but who may or may not meet formal diagnostic criteria (Brown et al. 2012; Nash & Davies, 2017). Various anatomical and physiological abnormalities due to PAE have been observed, with the following showing up most frequently in the literature: microcephaly, reduced white and gray matter volumes, malformations in the frontal, parietal, and temporal lobes, corpus callosum abnormalities, and neural loss and communication issues (Lebel et al., 2011).
Anatomical Abnormalities: Microcephaly and Reduced White and Gray Matter Volumes
Reduced head size, called microcephaly, and reduced brain size and volume has been found in those prenatally exposed to alcohol (Chen et al., 2003; Fryer et al., 2012; Lebel et al., 2011; Nash & Davies, 2017; Stephen et al., 2012). The effects can be exasperated by being prenatally exposed to smoking in addition to alcohol (Nash & Davies, 2017). According to the Center for Disease Control and Prevention [CDC] (2018), microcephaly can lead to developmental delays, seizures, cognitive impairments, hearing and vision problems, and general issues with movement and balance – presentations often found in those with PAE.
Neuroanatomical abnormalities such as reduced white and gray matter volumes have been found in those with PAE, even after accounting for microcephaly and reduced brain volumes overall (Lebel et al., 2011). White matter volumes are particularly abnormal in the right hemisphere (Lebel et al., 2011). Eckstrand et al. (2012) found that the white matter loss lends itself to structural dysmorphology. Furthermore, Chen et al. (2003) found reduced white matter volumes in the parietal lobe and cerebral cortex. This can cause complications such as an abnormal metabolic rate of the thalamus and decreased communication to parts of the brain, such as the caudate nucleus (Chen et al., 2003).
Gray matter regions such as the caudate nucleus, thalamus, amygdala, hippocampus, basal ganglia, putamen, and pallidum appear to be particularly vulnerable to the effects of PAE (Eckstrand et al., 2012; Fryer et al., 2012; Lebel et al., 2011; Sharma & Hill, 2017; Zhou et al., 2015). Studies have shown that these areas are smaller (Lebel et al., 2011; Sharma & Hill, 2017), with certain areas seeing volume reductions of three to eleven percent (Zhou et al., 2015). This has vast implications on the individual, as these regions are responsible for important tasks: species-related behavior, memories, and emotions (amygdala and hippocampus); spatial perception (hippocampus); sensory integration (thalamus); and voluntary movement, attention control, explicit and reinforced learning, reward salience, and cognitive control mediation (basal ganglia) (Fryer et al., 2012; Kolb et al., 2019). For instance, Lebel et al. (2011) found that hippocampal volume and verbal abilities have an inverse relationship. Furthermore, Fryer et al. (2012) found that a reduction of volume in the caudate nuclei predicted lower neuropsychological performance, even after IQ was controlled for. They found that there was a decreased amount of glucose being metabolized in the caudate nuclei, impacting responses during behavior inhibition tasks. The caudate nuclei help with cognitive control and verbal learning and recall (Fryer et al., 2012) so it makes sense that abnormalities in this area would impact cognitive performance. It has been proposed that there is a dose-dependent relationship between alcohol consumption and caudate and gray matter volumes (Eckstrand et al., 2012; Fryer et al., 2012), but the specific dose has yet to be determined.
Anatomical Abnormalities: Frontal, Parietal, and Temporal Lobes
While the occipital lobe is relatively spared by the effects of alcohol, the same cannot be said for the frontal, parietal, and temporal lobes (Eckstrand et al., 2012; Lebel et al., 2011). These areas of the brain are responsible for executive functioning, voluntary movement, decision-making (frontal lobe), goal-oriented movement (parietal lobe), and senses, language, emotional processing, and facial recognition (temporal lobe), among many other functions (Kolb et al., 2016). The frontal lobe in those with PAE contains less white and gray matter volume. The parietal and temporal lobes also have less white and gray matter volumes due to narrowness of the lobes (Lebel et al., 2011). Additional anatomical abnormalities include thicker cortices, reduced gyrification, less temporal asymmetry, and displacement of the inferior parietal and temporal regions (Lebel et al., 2011). The structural brain damage in these regions has been linked to issues in cognition (Lebel et al., 2011) and planning, initiating, and controlling voluntary movements (Nguyen, Levy, Riley, Thomas, & Simmons, 2013).
Infante et al. (2015) found that those with PAE had reduced gyrification – cortical folding in the brain to create sulci and gyri to promote neuron connections and efficiency. Increased gyrification lends itself to higher IQs because the brain is making connections efficiently (Infante et al., 2015). Cortical folding typically occurs in the third trimester but no time in fetal development is safe from the harmful effects of alcohol (Infante et al., 2015). The reduced gyrification in the frontal and temporal cortices may present as cognitive and behavioral challenges, while reduced gyrification in the parietal cortex may result in issues with working memory (Infante et al., 2015). It is important to note that reduced gyrification has been found in those with ADHD and can be hard to differentiate from PAE due to comorbidity. However, Sharma and Hill (2017) found that there was a dose-dependent relationship between alcohol use and temporal lobe fusiform gyrus decreases. Thus, PAE likely also plays a role in reduced gyrification.
Differences in overall cortical thickness were found, particularly in the frontal and parietal lobes (Infante et al., 2015; Lebel et al., 2011; Zhou et al., 2015). In typically developing children, cortical surface area decreases as a result of brain maturity and efficiency; however, in those with PAE, cortical thickness was observed (Moore et al., 2017). This may account for differences in verbal learning (Lebel et al., 2011). Glass et al. (2017) used the Wechsler Individual Achievement Test – Second Edition (WIAT-II) to compare those with PAE to a normative control group. Those with PAE performed worse, struggling most with high-order math skills followed by numerical operations, spelling, and word reading. Over half of the cases (58%) in the PAE group were at least one standard deviation (SD) from the mean on one or more academic domains. Math difficulties were a result of parietal lobe abnormalities and spelling difficulties were a result of temporal lobe abnormalities (Glass et al., 2017). Glass et al. (2017) attributed this cognitive discrepancy to atypical brain development, cortical abnormalities, and the structural changes that were observed with neuroimaging.
Anatomical and Physiological Abnormalities: Corpus Callosum
A particular area of concern is the corpus callosum – the largest white matter tract of 200 million fibres that is primarily responsible for hemispheric communication (Jacobson et al., 2017). It connects the cerebral hemispheres and provides a direct route for communication (Lebel et al., 2011; Jacobson et al., 2017; Kolb et al., 2019). The corpus callosum connects the neocortical areas and has a role in sensory, motor, and high-order communication (Jacobson et al., 2017). It develops during the second trimester during weeks 18 to 20 and increases in size during the third trimester and two years postpartum (Jacboson et al., 2017). If an individual is developing as expected, the corpus callosum will efficiently communicate from one cerebral hemisphere to another (Roebuck, Mattson, & Riley, 2002).
However, alcohol impacts genetic expression in this area of the brain (Nash & Davies, 2017). Both the shape and location of the corpus callosum are abnormal and complete or partial agenesis may occur (Eckstrand et al., 2012; Jacobson et al., 2017; Sowell et al., 2001; Sharma & Hill, 2017; Stephen et al., 2012), as well as colossal thinning (Lebel et al., 2011). The complete or partial agenesis may be due to toxic levels of alcohol being exposed during time of development or repeated insults impacting growth (Sowell et al., 2001). Lebel et al. (2011) found that the corpus callosum had smaller volume, area, and length and the shape variability increased with higher PAE. Jacobson et al. (2017) found that the corpus callosum was smaller, even after accounting for age, sex, and other prenatal toxins. Sowell et al. (2011) found that the corpus callosum was seven millimetres away on average from where it was supposed to be, impacting verbal learning and connectivity. This displacement, more so than the size discrepancy, impacts verbal learning (Lebel et al., 2011; Sowell et al., 2001), as interhemispheric communication is impaired.
In addition, the anterior cingulate cortex (ACC) – that surrounds the front of the corpus callosum – has reduced volumes and size, particularly on the right side (Infante et al., 2015; Migliorini et al., 2015; Roebuck et al., 2002). Migliorini et al. (2015) found that this resulted in slower inhibition completion time on the NEPSY-II subtests. ACC abnormalities can be attributed to executive functioning impairments, as this part of the brain has a role in conflict and error monitoring and information processing (Migliorini et al., 2015).
Various studies have shown the negative impacts of corpus callosum abnormalities due to PAE. Jacobson et al. (2017) attributed lower overall IQs and difficulties with verbal comprehension and processing speed on the Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV) to abnormalities in the corpus callosum. The midline structures, such as the hippocampus, that communicate with the corpus callosum were impacted (Jacobson et al., 2017); they surmised that the lack of transfer due to midline structural impairments likely lead to the poorer performance by the PAE group (Jacobson et al., 2017). Furthermore, Donald et al. (2016) found that in the corpus callosum there was a white matter connectivity issue. Connectivity between the caudate and executive functioning networks was limited, impairing perceptual reasoning and thalamus connectivity. Roebuck et al. (2002) found that those with PAE made more errors when information had to cross the corpus callosum but fewer errors if information was uncrossed. Thus, tasks with increased complexity resulted in more frequent errors. The interhemispheric transfer was viewed through magnetic resonance imagining (MRI) and complications were related to abnormal corpus callosum size (Roebuck et al., 2002). They found that the displacement of the corpus callosum and ineffective processing between the two hemispheres led to cognitive and psychosocial impairments. Brown et al. (2012) attributed executive functioning deficits to corpus callosum malformation due to neural communication complications. In addition, colossal thinning has been connected to poor motor skills (Lebel et al., 2011; Roebuck et al., 2002). Thus, the presentations we see in those impacted by PAE may occur because of brain connectivity and communication issues.
Physiological Abnormalities: Neural Loss and Communication Issues
Functional abnormalities, such as cellular alternations and neural loss, can occur due to PAE (Chen et al., 2003; Eckstrand et al., 2012). Nash and Davies (2017) explain that the toxic byproducts left behind by alcohol – especially in individuals without the alcohol dehydrogenase enzyme that metabolizes alcohol – can lead to abnormal cell growth and division leading to neurological system abnormalities. In other words, alcohol disrupts cell growth and migration (Eckstrand et al., 2012). Issues in cell migration – often due to agenesis, poor myelination, poor axonal integrity, or thinning – complicate transmission to dendrites in the cortex, hippocampus, and other important brain structures (Jacobson et al., 2017; Migliorini et al., 2015). Thus, PAE impacts cell migration from the production to the end site, impacting cell communication (Chen et al., 2003). Chen et al. (2003) found that there are less dendrites for communication in general. They further explain that neural loss and cell communication difficulties can present as cognitive and behavioral concerns.
PAE has detrimental effects on the developing fetus that last a lifetime. While many parts of the brain are impacted, microcephaly, reduced white and gray matter volumes, malformations in the frontal, parietal, and temporal lobes, abnormalities in the corpus callosum, and neural loss and communication issues are of most concern (Lebel et al., 2011). These anatomical and physiological impairments have far-reaching effects in areas of verbal reasoning, motor functioning, global IQ, and social abilities. Lebel et al. (2011) state that reduced size of the hippocampus and corpus callosum correlates with the number of days spent drinking in a week while pregnant. Furthermore, the amount of alcoholic beverages consumed relates to frontal lobe, caudate nuclei, and hippocampus volume decreases (Lebel et al., 2011). However, additional research is required to further understand the brain abnormalities and their effects. Assessment, interventions, and supports for those with PAE should improve as we better understand the specific CNS impairments and how the environment exasperates these anatomical and physiological abnormalities.
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