|Year : 2014 | Volume
| Issue : 5 | Page : 1-5
Impact of alcohol on the developing brain
Pronob Kumar Dalal, Sujita Kumar Kar
Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Web Publication||19-Dec-2014|
Sujita Kumar Kar
Department of Psychiatry, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Dalal PK, Kar SK. Impact of alcohol on the developing brain. Int J Nutr Pharmacol Neurol Dis 2014;4, Suppl S1:1-5
| Introduction|| |
Ethanol is the consumable form of alcohol. It is reported that nearly 2.5 million deaths worldwide occur because of alcohol, every year. , The use of alcohol is increasing globally. A national household survey attempted to estimate the burden of different substances of abuse including alcohol in India and found that the prevalence (current) of alcohol abuse in India is ∼21%. , As per the World Health Organization (WHO) report, 2011, the prevalence of alcohol use disorder among the above-15-year-old population is 3.47% in males and 0.42% in females.  Alcohol has a significant adverse impact on different organ systems by alteration of the normal physiological functions and homeostasis of the body.  It also has substantial impact on the nervous system (cerebral cortex, subcortical group of nuclei, cranial and spinal nerves, cerebellum, and spinal cord).  The effect of alcohol on the nervous system is dependent on many factors like: Age of onset, quantity, frequency, duration of alcohol use, gender, general health condition, and genetic configuration of the individual. ,
Development of the brain
The development of the brain in a fetus is a complex process. In the early fetal life, brain development follows a sequence of events like - formation of the neural plate, neural crest, and neural tube. This is followed by complex modulation of the neural tube to form the brain vesicles, which expand and undergo intricate modifications to form the brain, spinal cord, and other related neural elements. At the cellular level of the brain, development advances through neurogenesis, neuronal migration, neuronal maturation, synapse formation, pruning, and myelination. 
The development of the brain continues after birth in early childhood. However, following this neuronal regeneration, multiplication gets restricted to specific areas of the brain, although myelination continues till adolescence. Besides this, any insult to the brain is followed by a natural healing process and repair by the glial cells. The growth and development of the brain is mediated by certain neurotrophic growth factors. Many factors influence brain development in the prenatal period, which can be genetic, environmental or nutritional. 
The complex interplay of these factors leads to growth and development of the brain. Deterioration of brain development results, if there is any deficiency or negative effect of any of the factors, in the critical stages of development. , The most critical periods of brain development are during the last trimester of pregnancy and in the first three years following birth. 
The brain development of the child during the prenatal period (as in the fetus) and infancy, is more strongly influenced by the environmental factor than by any other factors. , Maximum cognitive development occurs during adolescence.  An individual's ability to take decisions, abstract reasoning, and social cognition takes shape during this critical phase of development. 
Chronic stress has a negative impact on brain development (especially the hippocampus), as the neuronal survival is reduced due to inadequate expression of the neurotrophic factors.  The factors that negatively effect the growth and development of the brain are - Environmental factors (Lipid peroxidation - mediated by toxins, alcohol,  and environmental neurotoxins), , Nutritional factors (decreased nerve growth factors - nutritional, toxin-mediated (alcohol), , Metabolic disturbances - (diabetes,  homocystinemia, , and stress), ,, and Genetic factors (Decreased nerve growth factors). , Many nutritional factors that affect brain development are - protein, certain fats, folic acid, vitamin A, choline, and many other micronutrients (iron, selenium, zinc, copper). 
Impact of alcohol on the developing brain
Alcohol has neurotoxic effects, which can be explained though several mechanisms.  Chronic use of alcohol induces neuronal damage by: Oxidation, microglial activation, and neuronal inflammation. ,,
Alcohol-induced neurodegeneration is mediated through oxidative stress and proinflammatory mediators.  Ethanol induces the hepatic CYP 450 enzyme system and facilitates the production of reactive oxygen species and nitrous oxide, which in turn produces neuronal injury. ,
Experience from animal studies
Alcohol has a significant negative impact on the brain. Experiment on animal models revealed that alcohol binge drinking leads to significant structural and functional changes, particularly in the areas of the prefrontal cortex and hippocampus.  Shabanov et al., in their experiment on alcoholized rats, in gestation and feeding period, found that alcohol affects the serotonergic and dopaminergic systems of the fetal rat brain resulting in the under-activity of these systems.  In another animal study, it was found that alcohol reduces the mass of the cerebral cortex in a periadolescent mouse in comparison to adult mouse, whereas, the length of the corpus callosum is affected more in an adult mouse in comparison to a periadolescent mouse.  Alcohol (ethanol) has a toxic effect on the cerebellum as the Purkinje cells and granule cells of the cerebellum are sensitive to ethanol.  The growth of the Bergmann glia, which coordinates the development of these cerebellar cells, is mediated by the liver X receptors.  Therefore, activation of the liver X receptors helps in the protection of cerebellar Purkinje and granular cells.  Research is going on to find pharmaceutical agents that will facilitate the expression of the liver X receptor in order to protect the cerebellum from the toxic effects of alcohol.  On the other hand, as alcohol causes a significant adverse impact on the liver, the expression of the liver X receptors may be hampered, leading to loss of protection of the cerebellar Bergmann glia. In animal studies, it was found that the hippocampal mass gets reduced on exposure to alcohol prenatally, as a result of which, there occurs impairment of memory.  Maternal alcohol use affects the fetal brain growth and it causes neuronal loss from specific areas of the brain like the cerebellum, hippocampus, corpus callosum, thalamus, olfactory bulb, and optic nerve as proved by the animal studies.  In experimental animals, prenatal alcohol exposure leads to hypermethylation in certain brain regions like the prefrontal cortex and hippocampus.  Tiwari et al., in their study on the effect of alcohol (ethanol) on the different neurotransmitter pathways in the mouse brain found that: 
- The levels of glutamate and aspartate were reduced in the cerebral cortex following acute exposure to alcohol
- Astroglial metabolism remained unaffected to the acute exposure of alcohol in naïve mice
- Acute exposure also differentially decreased the excitatory and inhibitory activity in the different cortical regions
- The Tri Carboxylic Acid (TCA) cycle and neurotransmitter cycles associated with GABAergic and Glutaminergic neurons were diminished across the cortical and sub-cortical regions.
In a recent study on experimental animals (rats), it was found that prenatal exposure to alcohol resulted in a disproportionate increase in the cholesterol content in the brain during adulthood and the brain phospholipid-cholesterol ratio had also increased (by 1.3 fold).  Chronic binge drinking in adolescent rats led to impairment in neuronal differentiation and decreased neuronal survival in the hippocampus.  In chronic adolescent rat binge drinkers, there was a decrease in the brain-derived neurotrophic factor (BDNF) activity during the withdrawal period, which impaired the process of neuronal growth and differentiation. 
Experience from human studies
Prenatal exposure to alcohol has adverse consequences on the brain, which usually gets manifested in the form of a learning disability, hyperactivity or disruptive behavior, and seems to be due to acetyl choline deficiency.  The executive function is an important cortical function responsible for task performance, reasoning, analysis, and abstraction. Substantial exposure to alcohol during the prenatal period results in impairment of the executive function. , Prenatal exposure to alcohol leads to a decreased volume of basal ganglia in adolescents.  Among the different nuclei of basal ganglia, the caudate nucleus is affected the most.  The white matter of the cerebellum is more vulnerable to be affected in prenatal exposure to alcohol.  Among the cerebral cortical structures, the parietal lobes are disproportionately more affected than the temporal and occipital lobes. 
Prenatal exposure to alcohol has a toxic effect on the corpus callosum, which leads to thinning and even agenesis of the corpus callosum.  As the corpus callosum is responsible for attention processing, verbal memory, executive functioning, and several other cognitive functions, degeneration of it results in impairment of these cognitive functions.  Alcohol exposure also leads to a disproportionate loss of the mass of the cerebellum. 
During adolescence, females are more susceptible to the neurotoxic side effects of alcohol in comparison to males and show comparatively more impairment in the spatial working memory. , Use of alcohol in adults' leads to impairment in the spatial working memory, learning, spatial skills, and executive functioning, and again females are more vulnerable to the neurotoxic effects of alcohol. ,,, The frontoparietal cortex responsible for the working memory develops earlier in females than in males. , In studies on adolescents with alcohol use disorder, it is found that the domains of attention and verbal and visual retention are significantly impaired in comparison to adolescents without alcohol use disorder. ,, During adolescence, an expansion of the white fibers occurs due to the process of myelination, which is helpful in cognitive processing, and any toxic insult that affects this process leads to improper cognitive development. ,,, Studies also suggest that the degree of cortical involvement depends on the age of onset of alcohol use.  Those having onset of alcohol use during their adolescence have more cortical white matter involvement, than those who have a later age of onset of alcohol use.  Alcohol also affects the expression of microRNA (miRNA) in the prefrontal cortex of humans as well as animal models, thereby attributing to the neuroinflammation and dysregulation of neurotransmission.  The impact of alcohol on the adolescent brain is more than that in adults, giving rise to resilient cognitive deficits. 
In adults, chronic use of alcohol leads to development of degenerative changes in the brain resulting in cortical atrophy and development of features of dementia, which usually manifest in the form of difficulty in task performance, inattentiveness, and impairment of memory. , Alcohol-induced dementia is usually a reversible condition.  The degenerative changes following chronic alcohol abuse are a result of direct alcohol-induced neurotoxicity, oxidative stress, due to alcohol use-related nutritional deficiency or a combination of the above factors.  Alcohol is a known cause of vasculopathy and is a potential vascular risk factor of dementia.  The ethanol-induced process of neurodegeneration results in loss of cortical and subcortical brain matter and compensatory dilatation of the ventricular system.  The cholinergic system of the brain, which is responsible for the cognitive function, is highly sensitive to the effects of alcohol (ethanol). , Long-term ethanol use causes leakage of the blood-brain barrier and activation of microglial cells in the brain. 
A preliminary study to assess the acute impact of alcohol on a healthy adult brain was conducted by Weber et al.  In this study 11 healthy male volunteers were subjected to alcohol consumption in a measured amount followed by a series of post-consumption assessments (Resting state blood oxygen level dependent (rsBOLD) magnetic resonance imaging (MRI) scans). Before each rsBOLD scan, pointed-resolved spectroscopy (PRESS) and H-MRS (magnetic resonance spectroscopy) scans were done.  It was found that the functional connectivity of the default mode network (DMN) and temporal fractal properties, which were responsible for personal identity and social behavior, were significantly affected.  Di Guio et al., in their study on cortical morphology in children with fetal alcohol spectrum disorders, found that there was a decrease in complexity of the cortical folding resulting in a reduced buried cortical surface.  The cortical fold opening was believed to be the strongest anatomical correlate of prenatal alcohol intake.  Adolescent intermittent binge ethanol (AIE) exposure led to structural changes in the brain during adulthood, as found in the study of Coleman et al.  This study has revealed that there was an increase in the volume of certain brain areas (Orbitofrontal cortex, Cerebellum, Thalamus, Internal capsule, and genu of the corpus callosum) without any change in the total brain volume.  AIE exposure also leads to increased expression of certain extracellular matrix proteins like, Brevican, Neurocan, Tenascin-C, and HABP, and also results in loss of flexibility in behavior.  In a study on the effect of alcohol on the electrophysiological activities of adult brain, Lee et al., found that alcohol caused deficient coupling of the theta-phase gamma amplitude and predicted that this cross-frequency coupling could be a useful tool to study the effects of alcohol on the brain.  It was found that exposure to alcohol during the second trimester of pregnancy could adversely affect the spatial learning in juvenile rats.  López-Caneda and Yun, et al., in their study attempted to see the correlation between impulsive behavior and alcohol use in adolescents and young adults.  In this study it was found that loss of inhibitory control was an important risk factor of alcohol use and alcohol use further impaired an individual's ability to control the impulses, ultimately resulting in a vicious cycle of alcohol-use disorder. 
| Conclusion|| |
Alcohol affects the brain during all stages of development. No organ in the body is resistant to the toxic effects of alcohol. Alcohol-induced effects may be reversible or irreversible. Extensive research in this area (both in experimental animals and human subjects) are suggestive of the significant adverse effect of alcohol on the developing brain.
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