Prenatal exposure to alcohol causes enduring brain damage

Introduction

This article provides an introduction to recent research on the neurobiological bases of the enduring effects on brain function of prenatal exposure to alcohol. Given the host of other risk factors and adverse conditions likely to affect adopted and fostered children, why should this journal devote a whole issue to foetal alcohol spectrum disorders (FASD)? Dr Mary Mather offers some answers to this question in her editorial. In addition, those most relevant to this opening contribution can be listed as follows:

1. Exposure to alcohol is one of the most common risk factors to which adopted and fostered children are subjected.

Every human brain is an extraordinary creation in which endless variations are played on fundamental themes of life and mind. It is a perpetual construction site, ever changing from the first embryonic stages at which it begins to form until a few moments before death. Each is built from a large repertoire of neuronal components that are grown on site in a fluctuating biochemical and physiological climate, and the ongoing construction is flexibly adapted to unforeseeable circumstances as they occur. Human brains are built from more than 80 billion neurons, connected by more than 176,000 kilometres of myelinated axonal cables, via about 100 trillion adaptable connections called synapses. Minds are of course much more than a pile of neurons, just as a house is much more than a pile of bricks, but minds badly built and from deficient components are greatly disadvantaged, as are houses that are badly designed and constructed from deficient materials. Furthermore, although it has general long-term goals and guidelines for approaching them, brain construction occurs without anything analogous to an architect’s drawing of the intended house, because there is no such thing as an ‘intended’ human brain. In addition to all of this, feedback on progress towards the long-term goals is ambiguous, partial and not wholly reliable. The feats performed by nature in creating such things as human brains are therefore truly awesome. Among the most impressive are the abilities by which we flexibly regulate the formation of our percepts, thoughts, emotions and actions so that they are well adapted to both current circumstances and long-term goals. These feats include the ability to attend purposefully to selected things while suppressing reactions to irrelevant distractions and controlling inappropriate impulses. At its best, this produces wise decisions that take lots of relevant information into account, including large amounts of personal, inter-personal and social information.

Abilities that help us do these things are built into the brain at both the level of specialised brain regions, such as that of the prefrontal cortex (PFC), and at the level of individual neurons, such as that of pyramidal neurons in the cortex. These neurons are called pyramidal because their cell bodies have approximately the shape of a pyramid, although the neuron as a whole is much more like that of a tall tree in which the trunk is called the apical dendrite and the roots the basal dendrites. Dendrites are the branch- and root-shaped parts of a neuron via which it receives signals from other neurons. Each neuron sends signals to thousands of others via a thin cable called the axon that emerges directly from their cell body. Pyramidal neurons are excitatory and constitute the workhorses of the cortex. They make up about 80% of all cortical neurons. The remaining neurons are mostly inhibitory, and both they and the pyramidal cells are affected by prenatal exposure to alcohol (Granato, 2006; Gruerri, Basinet and Riley, 2009). ¹

Given the huge difficulties faced by brain development and by its continuing adaptation throughout life, it should be no surprise that the processes by which this is achieved can go awry in so many different ways. I assume that few birth mothers would knowingly make those difficulties even greater. Therefore one aim of this article is to review the evidence showing that early exposure to alcohol does just that: it makes a near-impossible feat even harder. In addition to encouraging abstinence during pregnancy, an understanding of the enduring effects of prenatal exposure to alcohol on the brain may help guide the design of therapies and management strategies. It should also increase compassion for affected people and their carers, who have to grapple with those effects on a daily basis.

The terminology in current use to refer to brain damage due to prenatal exposure to alcohol is varied. FASD is one of the more commonly used terms, but can be misleading for at least three reasons. First, it is derived from the earlier term foetal alcohol syndrome (FAS). Facial deformations are the most obvious distinguishing characteristic of FAS, but they only occur when there have been unusually high levels of exposure during the first prenatal trimester, i.e. the first three months of gestation, which is when the face is being formed. The brain continues to develop throughout gestation and its growth can be harmed by levels of exposure below that required to produce facial deformations. It is therefore common for brain development to be affected by exposure to alcohol in the absence of any obvious effects on facial appearance. Second, classifying a disorder as FASD implies that there is a single dimension or spectrum of severity on which any particular individual can be placed. This is simply a convenient myth. The effects of exposure to alcohol during development vary from individual to individual in so many ways that they cannot be adequately characterised by any single measure of severity. Third, the notion of a single measure of severity suggests that there might be a safe level of exposure below which there is no harm. I know of no psychological or neurobiological evidence for the idea of a threshold below which there is no harm and above which there is a great deal. Alcohol-related neurodevelopmental defects (ARND) is a less used but more accurate description, hence the use of FASD/ARND as the umbrella term to refer to the broad class of effects with which this article is concerned.

People affected by FASD/ARND and their carers often report that being given the diagnosis changed the course of their lives for the better. This is because it helps them to understand the nature and cause of some of their disabilities and thus how to better deal with them. It is important to realise, however, that these disabilities vary widely from one person to the next, so that when such a diagnosis is given what is then needed is an insightful and individual understanding of its implications for that particular person.

The annual burden imposed by FASD/ARND on the healthcare budget of Canada, where the condition is well recognised and understood, has been estimated to be above $5 billion. Though it is not a major focus of research in the UK, a search for ‘fetal alcohol’ in PubMed, an archive of worldwide medical publications, recently retrieved more than 14,500 articles (Granato and De Giorgio, 2015). Even if my research were focused specifically on FASD/ARND, which it is not, it would be impossible for me to review more than a small fraction of so many publications. Instead, the central aim of this article is simply to show why that research strongly suggests that prenatal exposure to alcohol causes enduring brain damage. Although the term ‘alcohol’ is used throughout, it refers specifically to ethanol in the case of the rigorously controlled animal studies.

Evidence that symptoms of FASD/ARND are due to prenatal exposure to alcohol

As expected given its complexity, many things influence brain development, so how do we know that it is the alcohol that causes some of the cognitive, emotional and social difficulties associated with FASD/ARND and not other disadvantages? Many affected children are born into an environment of malnutrition and drug abuse, together with poor socio-economic lifestyles and neglectful parenting. It could be argued that these other factors are the cause of all or most of the symptoms of FASD/ARND. However, rigorous scientific studies have now dealt with the issue convincingly. As in the analogous case of smoking and lung cancer, epidemiological and other data provide strong circumstantial evidence against this argument. There is still room for doubt, but as with smoking and lung cancer, such uncertainties can be removed by experimental studies using non-human animals in which the relevant neuronal anatomy and physiology are sufficiently close to those of humans. Such studies now clearly show that exposure to alcohol in the early stages of brain development brings about enduring brain damage, and they have begun to outline the dosage and timing factors of alcohol use during pregnancy that contribute to variations in the brain damage and behavioural impairments caused (Guerri, et al., 2009). Species that have been used to study the effects of prenatal exposure to alcohol include non-human primates, but most of these studies have used rodents (Cudd, 2005). Rodents’ brains, though smaller, are composed of neurons that are nearly indistinguishable from those of humans, so it is most likely that the effects observed in these animals apply to humans too. Those studies show that the effects caused can vary greatly from case to case, depending on many aspects of the individual and the exposure, such as the levels of alcohol reaching the foetal brain, the duration and pattern of exposure, and its timing relative to the stage of brain development. These factors all greatly influence the type and the extent of damage (Guerri, et al., 2009). One simple common finding is that the extent of the harm caused increases with the amount of alcohol to which the developing brain is exposed. In addition, the ability of the mother’s and foetus’s physiology to metabolise alcohol influences the risk of alcohol-induced defects. The specific brain structures affected and the magnitude of the damage are strongly influenced by the developmental timing of exposure. The facial feature deformities that are associated with FAS arise only when high blood-alcohol levels occur during early embryonic stages, such as the first trimester in humans but also applicable to mice and macaque monkeys (Guerri, Bazinet and Riley, 2009).

Exposure to alcohol affects brain development throughout all prenatal stages, but it influences different aspects of that development at different points. The damage caused by prenatal exposure to alcohol is therefore in some ways analogous to that resulting from a car crash in that there are endless variations on the exact type of damage, with no predictable pattern common to all. There is no evidence for a threshold in the amount of exposure to alcohol below which there is no damage. On the contrary, there is evidence that even ‘moderate’ amounts of exposure to alcohol can be harmful (e.g. Abate, et al., 2008; Valenzuela, et al., 2012). One way in which even low amounts of alcohol during the late stages of pregnancy can affect adult behaviour is by increasing the chances that that person will seek alcohol when an adult (Abate, et al., 2008; Spear and Molina, 2005). This is because preference for an environment containing alcohol can be passed on to the unborn foetus by low to moderate amounts of prenatal alcohol exposure. Thus, though there are well-established genetic variations in susceptibility to alcohol, this particular form of increased risk is due to the mother’s drinking during pregnancy, not to her genes.

Cognitive, emotional and social consequences of FASD/ARND

The various cognitive, behavioural, emotional and social consequences of FASD/ARND are all too clear to those who live with them. The most salient difficulties involve impairments such as attentional disorders similar to attention deficit hyperactivity disorder (ADHD), impaired learning and memory, and a reduced ability to suppress inappropriate impulsive reactions. Some of the most pervasive impairments involve executive function, emotional control and self-regulation, which seem to be intractable features that persist throughout life (Soh, et al., 2015). Mathematical abilities and fine motor co-ordination are also frequently impaired. Given such an extensive list of impairments it is clear that the effects of alcohol on brain development are widely spread throughout the brain.

As the most rigorous scientific studies of the effects of prenatal alcohol on cognition and behaviour are carried out on animals, it is necessary to show that valid comparisons can be made between the behavioural consequences in animals and the symptoms of FASD/ARND in humans. Ways in which this has been done are reviewed in depth by Patten, Fontaine and Christie (2014). They show that impairments of executive function, one of the hallmarks of higher cognitive deficits in FASD/ARND, also occur in experimental animals exposed to alcohol under rigorously controlled experimental conditions. Executive functioning has been broadly defined as the ability to regulate attention and to use appropriate problem-solving abilities. More specifically, it includes such things as the ability to ignore distractions, the ability to suppress automatic but inappropriate reactions, working memory abilities and the capacity to flexibly switch cognitive strategies in response to current goals and conditions. These functions are in part dependent on frontal lobe structures such as the prefrontal cortex. In humans, they can be rigorously measured through standardised tests, such as the Stroop task in which the automatic tendency to read a word such as ‘yellow’ must be suppressed in favour of naming the colour of the ink in which it is printed. All such tests of executive function show it to be impaired in FASD/ARND. Other fundamental capabilities that are known to be impaired, such as fine motor skills, the control of attention, learning and memory and social skills, have also been shown to be impaired in animals that were exposed to alcohol during the early stages of brain development (Chokroborty-Hoque, Alberry and Singh, 2014; Patten, Fontaine and Christie, 2014). It is therefore highly likely that the effects of prenatal alcohol on the behaviour of animals in these experiments are relevant to the effects of FASD/ARND on cognition and behaviour as seen in humans.

Effects of prenatal alcohol on regional brain structure and function

Brain imaging, neurobiological and psychological studies have all been used to identify the specific brain regions affected by FASD/ARND. Neuro-imaging studies in humans have demonstrated reductions in the size of the brain as a whole, and particularly of specific regions of the cerebral cortex such as the prefrontal cortex and regions of the parietal lobe (which are central to executive function and attention), the amygdala (which is central to anxiety and other emotions) and the cerebellum (which plays important roles in cognition and in co-ordinating actions such as those involved in fine motor control) (Guerri, et al., 2009; Riley and McGee, 2005; Soh, et al., 2015). These studies show that it is not only the gross anatomical size of these brain regions that is impaired; they also reveal that their activities as measured by functional neuro-imaging are affected, sometimes being less than that in control groups and sometimes more. Cases where activity of prefrontal regions is greater than normal suggest that people with FASD/ARND often have to work harder to achieve what others can do with much less effort. They have to work harder because they have to take much of the current contextual information into account by conscious voluntary effort. For people unaffected by FASD/ARND, much more of this information is absorbed automatically, thus requiring less voluntary effort.

Overall, it is clear that although regions concerned with higher mental functions are particularly vulnerable, the damage caused by prenatal alcohol is widespread throughout the brain and is not restricted to just a few regions. This is to be expected given that some of the damaging effects occur before the various brain regions are well differentiated. The following section therefore reviews the evidence showing that it is not only the overall architecture of the brain that is affected but also the structure and function of the very components from which it is built, i.e. the individual brain cells.

Effects of prenatal alcohol on the glial cells and pyramidal neurons of the cerebral cortex

Recent studies have clearly implicated glial cells in FASD/ARND as well as in some other neurodevelopmental disorders including Down’s syndrome, Fragile X syndrome and Autism Spectrum Disorders (Guerri, Basinet and Riley, 2009; Guizzetti, et al., 2014). Glial cells guide neuronal growth and are found throughout the whole cortex. Abnormalities of these cells therefore have wide-ranging effects. Although they are not central to moment-by-moment processing of information in the brain, glial cells play a central role in guiding the development, survival and function of pyramidal neurons during the early stages of brain development and beyond. Alterations in glial cell function thus have major consequences for adult brain architecture, connectivity and function. The changes in brain structure and function that are characteristic of FASD/ARND include a greatly reduced number of pyramidal cells in the cerebral cortex and malformation of the corpus callosum, which is the thick band of axonal cables that connects the left and right cortical hemispheres. These are expected consequences of the glial cell malfunctions known to be caused by exposure to alcohol (Guerri, Pascual and Renau-Piqueras, 2001; Guerri, et al., 2009; Guizzetti, et al., 2014).

In both humans and other animals the cerebral cortex is one of the brain regions most affected by FASD, and when exposed to alcohol during prenatal development cortical neurons are subject to an increased rate of pruning or cell death (Guerri, Basinet and Riley, 2009). Furthermore, the surviving neurons have enduring impairments (e.g. Granato, et al., 2003; Miller, et al., 1990). Recent work now clearly shows that exposure to alcohol during the early stages of brain development leads to enduring impairment of the structure and function of the pyramidal neurons of which the cortex is mostly composed (Granato, et al., 2012). This work is important because it helps to explain the particular pattern of cognitive, emotional and social impairments seen in FASD/ARND. It shows that the neuronal mechanisms particularly impaired by early exposure to alcohol include those concerned with regulating neuronal activity so that it is well adapted to the particular needs of the moment. These mechanisms involve synaptic connections that are made on specific parts of pyramidal neurons, i.e. on their apical dendrites. It is those connections in particular that were found to be much reduced in rats exposed to alcohol at a developmental stage equivalent to the third trimester in humans (De Giorgio and Granato, 2015). Those connections play a central role in regulating neuronal activity because they amplify local neuron activities that are relevant in the context of current activity elsewhere in the brain. Inappropriate activities can be suppressed by inhibiting this amplification. Such neuronal mechanisms have been known to cellular neurophysiologists for several years (e.g. Larkum, Zhu and Sakmann, 1999), but their crucial role in the cognitive functions that are impaired by exposure to alcohol during early development are only now becoming clear (Larkum, 2013; Phillips, Clark and Silverstein, 2015). Further understanding of these mechanisms, their role in mental life and their impairments in FASD/ARND may therefore make it possible to design coping and therapeutic strategies that are more effective than those currently available.

Therapeutic strategies in relation to the underlying neuronal bases of FASD/ARND

Since FASD/ARND was first identified there have been several attempts to identify effective interventions that reduce its adverse consequences. These efforts are encouraged by findings showing that affected adults have fewer secondary disabilities if they are diagnosed, and presumably more appropriately treated, early in life (Streissguth, et al., 2004). Although most strategies for managing or ameliorating the consequences of FASD/ARND have not been clearly related to its underlying neuronal bases, a few have been. Wells and colleagues (2012) evaluated the effectiveness of ‘neurocognitive habilitation’, a group therapy intervention adapted for use by foster and adoptive caregivers and their children who were prenatally exposed to alcohol. The therapeutic intervention used combined techniques and interventions developed to treat cases of traumatic brain injury with components of the Alert programme (Williams and Shellenberger, 1996). This programme helps children improve self-regulatory skills by teaching them how to identify their arousal level and how to alter it on the basis of current situational demands. In particular, the intervention sought to teach the children how to identify internal indicators of dysregulation and how to use strategies to improve their self-regulation and emotional control within the context of complex group settings, such as those they have to deal with at home and at school. Wells and colleagues’ (2012) findings provided evidence of the effectiveness of the intervention in improving executive functioning and emotional problem-solving in children with FASD/ARND. Soh and colleagues (2015) have now combined the use of this therapy with brain scans done both before and after the intervention. They also found evidence of the same kind of behavioural improvements as did Wells, et al. (2012), but, in addition, they discovered that the brain regions most enhanced by the treatment were those prefrontal and other cortical regions that support functions such as response inhibition and emotional control, which the intervention sought to improve.

There is also evidence that although there are as yet no therapies that fully overcome the impairments associated with FASD/ARND, they can be ameliorated by an enriched environment involving rich physical, cognitive and social experiences (Kodituwakku, 2010; Peadon, et al., 2009). Animal experiments have recently shown that being raised in an enriched environment can ameliorate some of the deficits produced in mice by early exposure to alcohol. Compared to small non-enriched cages and a basic food supply, enriched cages are larger, with toys of various shapes, sizes and textures, tunnels, nesting material, heavy bedding and access to running wheels and ladders. Being raised in such an enriched environment reduced anxiety and produced long-lasting improvements in learning and memory in mice exposed to alcohol as well as in those that were not (Chokroborty-Hoque, Alberry and Singh, 2014). Social enrichment, i.e. housing ethanol-exposed rats with non-exposed control rats, has been shown to partially reverse some of the adverse effects of early exposure to alcohol in adult rats (Middleton, Varlinskaya and Mooney, 2012). The adverse effects of alcohol and the beneficial effects of social enrichment in those experiments were assessed by behavioural measures such as social investigation (sniffing the other rat’s body), contact behaviour (grooming, crawling over or under the novel rat), play fighting (following, chasing, nape attacks, pinning), and social motivation (a ratio of social preference vs. avoidance of the other rat). The most significant finding was that prenatal ethanol exposure impaired social motivation performance in both male and female rats, and that this impairment was reversed by social enrichment.

Conclusions

It is clear that in our society, exposure to alcohol is one of the major risk factors faced by the human brain during prenatal development. The brain damage caused can have consequences that endure well into adult life. The repercussions for cognition, emotion and social behaviour are clear to all of those who live with them. This damage affects brain function on both large and small scales. On the large scale of brain size and organisation it results in smaller brains with those regions that are concerned with the overall organisation and regulation of neuronal activity and behaviour, such as the prefrontal cortex, being particularly vulnerable. However, the effects of prenatal alcohol are not only limited to these large-scale effects. It is not just the structure of the brain as a whole that is affected; there is also an impact on the structure and function of the neurons from which the neocortex is built, i.e. pyramidal cells and inhibitory interneurons. The various symptoms of FASD/ARND are as expected given the nature of those effects on both the large and the small scales. This leaves little room for doubt concerning the causal role of prenatal exposure to alcohol in producing cognitive impairments in adults. Although there is evidence that these effects can be managed and ameliorated by appropriate strategies, they make life much more difficult for those concerned. By increasing the overall amount of such exposure, the drinking ‘culture’ of societies such as the UK bears a heavy burden of responsibility. In the long term this burden may be lightened by cultural changes that reduce the amount of prenatal exposure to alcohol, e.g. by informing people of the facts and by putting prominent warnings on alcoholic products. In the meantime, society needs to provide support, therapy and understanding for those exceptional people who bear the burden most directly, i.e. affected individuals and those who care for them.