Structural,Metabolic, and Functional Brain Abnormalities as a Result of Prenatal Exposure to Drugs of Abuse: Evidence from Neuroimaging

Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse.     

Functional Neuroimaging in the Examination of Effects of Prenatal Alcohol Exposure

Functional neuroimaging offers the opportunity to understand the effect of prenatal alcohol exposure on the activities of the brain as well as providing a window into the relationship between neural activation and the behavioral outcomes that have been described in affected individuals. Several different methodologies have been used to examine the neurophysiological signal changes associated with different brain functions in prenatally exposed individuals and those diagnosed with fetal alcohol syndrome (FAS) or other fetal alcohol spectrum disorders (FASD). These include electroencephalography (EEG), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI). These studies demonstrate that it is feasible to use these technologies with this clinical population and that the damage to the central nervous system associated with prenatal alcohol exposure has widespread functional implications; however, currently, the literature in these areas is limited and unsystematic. Functional MRI with this clinical population has just begun to explore the implications of prenatal alcohol exposure with the first paper published in 2005. Other methodologies are similarly limited in scope. Nonetheless, these functional neuroimaging studies suggest that prenatal alcohol exposure, or a diagnosis of FAS, may lead to restrictions in neural efficiency or a global decrement in processing resources.     

Fetal alcohol syndrome and the developing socio-emotional brain

Fetal alcohol syndrome (FAS) is currently recognized as the most common known cause of mental retardation, affecting from 1 to 7 per 1000 live-born infants. Individuals with FAS suffer from changes in brain structure, cognitive impairments, and behavior problems. Researchers investigating neuropsychological functioning have identified deficits in learning, memory, executive functioning, hyperactivity, impulsivity, and poor communication and social skills in individuals with FAS and fetal alcohol effects (FAE). Investigators using autopsy and brain imaging methods have identified microcephaly and structural abnormalities in various regions of the brain (including the basal ganglia, corpus callosum, cerebellum, and hippocampus) that may account for the neuropsychological deficits. Results of studies using newer brain imaging and analytic techniques have indicated specific alterations (i.e., displacements in the corpus callosum, increased gray matter density in the perisylvian regions, altered gray matter asymmetry, and disproportionate reductions in the frontal lobes) in the brains of individuals prenatally exposed to alcohol, and their relations with brain function. Future research, including using animal models, could help inform our knowledge of brain-behavior relations in the context of prenatal alcohol exposure, and assist with early identification and intervention.     

Formula: see text]Substance exposure in utero and developmental consequences in adolescence: A systematic review

Background: The impacts of maternal substance use have been observed in both research and clinical experience. Several studies have shown that preschool children are at heightened risk of developing various cognitive, behavioral, and socioemotional difficulties. Most knowledge has been generated concerning alcohol consumption during pregnancy and the postnatal effects thereof. Less is known about substance use other than alcohol (for instance, opiates, marijuana, and cocaine) during pregnancy and the long-term developmental consequences. Objective: The aims of this review are to identify relevant published data on adolescents who have been exposed in utero to alcohol and/or other substances and to examine developmental consequences across functions and mental health at this point in life. Methods: PubMed, Embase, and PsychInfo were searched for publications during the period of 1980-2011 and titles and abstracts selected according to prespecified broad criteria. Results: Twenty-five studies fulfilled all of the specific requirements and were included in this review. Most research covered prenatal alcohol exposure. Other substances, however, included cocaine, marijuana, opiates, and poly-substances. Results showed that prenatal exposure to alcohol has long-term cognitive, behavioral, social, and emotional developmental consequences depending on amount and timing of exposure in utero. Less evidence exists for long-term consequences of exposure in utero to other substances than alcohol. However, recent brain-imaging studies have provided important evidence of serious effects of other substance exposure on the developing brain and recent follow-up studies have found an association with deficits in language, attention, areas of cognitive performance and delinquent behavior in adolescence.     

Fetal Alcohol Spectrum Disorders: Neuropsychological and Behavioral Features

Heavy prenatal alcohol exposure can cause alterations to the developing brain. The resulting neurobehavioral deficits seen following this exposure are wide-ranging and potentially devastating and, therefore, are of significant concern to individuals, families, communities, and society. These effects occur on a continuum, and qualitatively similar neuropsychological and behavioral features are seen across the spectrum of effect. The term fetal alcohol spectrum disorders (FASD) has been used to emphasize the continuous nature of the outcomes of prenatal alcohol exposure, with fetal alcohol syndrome (FAS) representing one point on the spectrum. This paper will provide a comprehensive review of the neuropsychological and behavioral effects of heavy prenatal alcohol exposure, including a discussion of the emerging neurobehavioral profile. Supporting studies of lower levels of exposure, brain-behavior associations, and animal model systems will be included when appropriate.     

Alcohol and social behavior II: the helpful drunkard

Can alcohol make people more helpful, and if so, how? We hypothesized that alcohol would increase helping when, if the person were sober, the helping response would be under high inhibitory conflict--that is, when it would be affected by strong instigating and inhibiting pressures. Alcohol's damage to inhibitory processing should then allow instigating pressures to have more influence on the response, increasing helping. We expected that under low inhibitory conflict, when either or both of these response pressures would be weak under sobriety, alcohol would have little effect on helping. In two experiments we examined this reasoning. In Study 1, a mild dose of alcohol increased helping among high-conflict subjects pressured to help with a task they did not like, but did not increase helping among low-conflict subjects who either liked the task or were weakly pressured to help. In Study 2, a somewhat stronger dose of alcohol increased helping among all high-conflict subjects pressured to help with an undesirable task, yet again had no effect among low-conflict subjects weakly pressured to help. These studies provided an experimental demonstration of the role of inhibitory response conflict in mediating alcohol's social effects, and show that this process generalizes to prosocial behavior. Additional evidence from both experiments helped to rule out alternative explanations concerning drinking expectancies, alcohol's ability to enhance mood, and its ability to make the task more bearable.     

Using Eyeblink Classical Conditioning as a Test of the Functional Consequences of Exposure of the Developing Cerebellum to Alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Using eyeblink classical conditioning as a test of the functional consequences of exposure of the developing cerebellum to alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Flicker fusion frequency and organic syndrome in alcoholics

Flicker fusion frequencies of 48 healthy controls and of 35 alcoholics were measured to detect possible associations between flicker fusion and signs of nonspecific brain damage, the aim of the study. FFF was statistically significantly lower in patients addicted to alcohol than in healthy subjects. Lower flicker fusion frequencies were associated with the severeness of organic psychosis as rated psychopathologically. The hypothesis that addiction to alcohol is a sign of diffuse, nonspecific, organic brain damage was discussed.     

Priming across modalities and priming across category levels: extending the domain of preserved function in amnesia

Amnesia is considered to reflect the effects of damage to a specific brain system required for elaboration, consolidation, and conscious recollection. The study of amnesia is therefore a useful approach for establishing dissociations of function and for understanding the normal organization of memory functions. Amnesic patients and two control groups were tested in two studies of priming. In the first experiment, as measured by a word completion test, all groups exhibited significant priming effects that were greater within a modality than across modalities. The amnesic patients exhibited normal priming effects both within and across modalities, despite severe impairment in recall. In the second experiment, all groups exhibited significant and equivalent priming of category exemplars when category labels were presented and subjects were asked to produce the first exemplars that came to mind. The results extend the domain in which preserved priming effects can be observed in amnesia and they suggest that features of priming observed in normal subjects describe a capacity that is independent of the brain system damaged in amnesia.     

The Effects of Tobacco Smoke and Nicotine on Cognition and the Brain

Tobacco smoke consists of thousands of compounds including nicotine. Many constituents have known toxicity to the brain, cardiovascular, and pulmonary systems. Nicotine, on the other hand, by virtue of its short-term actions on the cholinergic system, has positive effects on certain cognitive domains including working memory and executive function and may be, under certain conditions, neuroprotective. In this paper, we review recent literature, laboratory and epidemiologic, that describes the components of mainstream and sidestream tobacco smoke, including heavy metals and their toxicity, the effect of medicinal nicotine on the brain, and studies of the relationship between smoking and (1) preclinical brain changes including silent brain infarcts; white matter hyperintensities, and atrophy; (2) single measures of cognition; (3) cognitive decline over repeated measures; and (4) dementia. In most studies, exposure to smoke is associated with increased risk for negative preclinical and cognitive outcomes in younger people as well as in older adults. Potential mechanisms for smoke’s harmful effects include oxidative stress, inflammation, and atherosclerotic processes. Recent evidence implicates medicinal nicotine as potentially harmful to both neurodevelopment in children and to catalyzing processes underlying neuropathology in Alzheimer’s Disease. The reviewed evidence suggests caution with the use of medicinal nicotine in pregnant mothers and older adults at risk for certain neurological disease. Directions for future research in this area include the assessment of comorbidities (alcohol consumption, depression) that could confound the association between smoking and neurocognitive outcomes, the use of more specific measures of smoking behavior and cognition, the use of biomarkers to index exposure to smoke, and the assessment of cognition-related genotypes to better understand the role of interactions between smoking/nicotine and variation in genotype in determining susceptibility to the neurotoxic effects of smoking and the putative beneficial effects of medicinal nicotine.     

Diminished effect of age and education on neuropsychological test performances of older children with learning disabilities

Previous research has shown that age and education have a significant effect on neuropsychological test scores among normals, but that these effects are sharply diminished, or perhaps totally obliterated, among adults with brain damage and children with brain damage. These findings would have their major practical clinical significance in limiting the use of age and/or education adjustments of raw scores for subjects with brain damage, especially if the adjustments were based on data derived from the study of normal subjects. The present investigation studied the effects of age and education on the Neuropsychological Deficit Scale (NDS) for Older Children scores of children with learning disabilities, aged 9 through 14 years. No significant effects among age and education variables and NDS scores were found. In fact, younger and older subgroups as well as lower- and higher-educated subgroups earned mean NDS scores that were not significantly different. It appears that the neuropsychological consequences of learning disabilities override the effects of age and education in the 9- through 14-year age range.     

The Impact of Motor Activity and Inactivity on the Brain: Implications for the Prevention and Treatment of Nervous- System Disorders

ABSTRACT— Since Donald Hebb's pioneering observations in the 1940s, much research has focused on the effects of variations in physical activity and environmental complexity on behavioral performance and brain structure. Beneficial effects on brain health have been linked to physical fitness, skilled training, and exposure to complex environments, though in rodents these effects may be negated by sudden changes in social structure. Such manipulations can alleviate the deficits associated with several nervous-system disorders and aging. But how increased activity produces its beneficial effects is still not fully understood. How does unskilled physical activity (e.g., repetitive exercise) compare to training in skilled activities or exposure to complex environments? In injury states, is task-specific training a better rehabilitative strategy than general exercise? How do changes in motor activity affect specific brain regions, and can the intensity and timing of therapeutic movement be adjusted to produce optimal outcomes? Are the beneficial effects of motor enrichment banked over periods of inactivity and can they be called upon with booster training to treat a later neurological disorder? Are there circumstances in which increased activity is harmful? Enrichment of physical activity shows promise as an easy and healthful means for improving or restoring brain function, and questions like these are now being investigated so that the full potential of increased activity may be harnessed.     

Alcohol-related amnesia and dementia: animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment

Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol-related neurological disorders, alcohol-associated dementia and Wernicke-Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models--from repeated and chronic ethanol exposure to thiamine deficiency--is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone.     

The Effects of Prenatal Alcohol Exposure on Behavior: Rodent and Primate Studies

The use of alcohol by women during pregnancy is a continuing problem. In this review the behavioral effects of prenatal alcohol from animal models are described and related to studies of children and adults with FASD. Studies with monkeys and rodents show that prenatal alcohol exposure adversely affects neonatal orienting, attention and motor maturity, as well as activity level, executive function, response inhibition, and sensory processing later in life. The primate moderate dose behavioral findings fill an important gap between human correlational data and rodent mechanistic research. These animal findings are directly translatable to human findings. Moreover, primate studies that manipulated prenatal alcohol exposure and prenatal stress independently show that prenatal stress exacerbates prenatal alcohol-induced behavioral impairments, underscoring the need to consider stress-induced effects in fetal alcohol research. Studies in rodents and primates show long-term effects of prenatal and developmental alcohol exposure on dopamine system functioning, which could underpin the behavioral effects.     

Alcohol-induced state-dependent learning: Differentiating stimulus and storage hypotheses

State-dependent effects of alcohol have been demonstrated in animals and man. Most studies have used tasks for which accurate performance typically requires that stimulus input was adequately stored initially and that the items were retrieved at the time of testing. Thus an alcohol-induced decrement in performance could be due to impaired storage, impaired retrieval, or both. The purpose of this experiment was to distinguish between stimulus and storage hypotheses of state-dependent learning (SDL). Sixteen subjects were used in a 2×2 design in which the task involved the learning and recall of a 19-item ‘route’ map. During initial learning, all subjects were sober. Immediately after learning, half the subjects were given a moderate dose of alcohol. Twenty-four hours later, all subjects were tested for recall under the same or different conditions. Greater retention was found for those subjects whose drug states were the same in memory storage/consolidation and retrieval. Thus an alcohol state effective during the memory consolidation interval following acquisition appears to be a sufficient condition for producing SDL. In this context, SDL might be better termed state-dependent memory storage and retrieval. The implications of these results for the aetiology and treatment of alcohol dependence are discussed.     

Sex differences in the alcohol deprivation effect in rats

Few studies have investigated the relationship between early onset of alcohol drinking and relapse in adulthood, which may be larger in females, as revealed by studies using rats as subjects. The present study assesses the alcohol deprivation effect (ADE) in adult rats of both sexes that began alcohol consumption during preadolescence or adolescence. Female and male Wistar rats received free-choice access to water, 5, 10 and 20% (v/v) ethanol solutions during the ethanol exposures. The effects of age and sex on ADE in adult rats were assessed after repeated periods of abstinence. The results showed that female but not male rats increased ethanol intake after the second and third deprivation (showing ADE), irrespective of the onset-age of alcohol drinking.     

Fetal Alcohol Spectrum Disorders: An Overview

When fetal alcohol syndrome (FAS) was initially described, diagnosis was based upon physical parameters including facial anomalies and growth retardation, with evidence of developmental delay or mental deficiency. Forty years of research has shown that FAS lies towards the extreme end of what are now termed fetal alcohol spectrum disorders (FASD). The most profound effects of prenatal alcohol exposure are on the developing brain and the cognitive and behavioral effects that ensue. Alcohol exposure affects brain development via numerous pathways at all stages from neurogenesis to myelination. For example, the same processes that give rise to the facial characteristics of FAS also cause abnormal brain development. Behaviors as diverse as executive functioning to motor control are affected. This special issue of Neuropsychology Review addresses these changes in brain and behavior highlighting the relationship between the two. A diagnostic goal is to recognize FAS as a disorder of brain rather than one of physical characteristics.     

Memory and brain volume in adults prenatally exposed to alcohol

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n=26; Alcohol-related Neurodevelopmental Disorder, n=36; and Dysmorphic, n=30) were imaged using structural MRI with brain volume calculated for multiple regions of interest. Memory was measured using the Verbal Selective Reminding Memory Test and its nonverbal counterpart, the Nonverbal Selective Reminding Memory Test, which each yielding measures of learning and recall. For both Verbal and Nonverbal Recall and Slope, linear trends were observed demonstrating a spectrum of deficits associated with prenatal alcohol exposure. Dysmorphic individuals performed significantly poorer than unexposed controls on 5 of 6 memory outcomes. Alcohol-exposed individuals demonstrated significantly lower total brain volume than controls, as well as lower volume in a number of specific regions including hippocampus. Mediation analyses indicated that memory performance associated with effects of prenatal alcohol exposure was mediated from dysmorphic severity through hippocampal volume, particularly right hippocampus. These results indicate that the association between the physical effects of prenatal alcohol exposure and deficits in memory are mediated by volumetric reduction in specific brain regions.     

The relationship between viewing US-produced television programs and intentions to drink alcohol among a group of Norwegian adolescents

The aim of this study was to examine the influence of exposure to US-produced television programs and family rules prohibiting alcohol use on the development of normative beliefs, expectancies, and intentions to drink alcohol in the next 12 months among a group of Norwegian adolescents who reported that they had not previously consumed alcohol. Data were collected via a survey administered to 622 eighth and ninth graders enrolled at ten junior highs in southeastern Norway. To examine these relationships we tested the fit of a structural equation model which was based on the Theory of Planned Behavior (Ajzen, 1988). Data from the non-drinkers (n= 392, 63% of the respondents) were used. To control for the influence of peer drinking on behavioral intentions, our model was tested under two group conditions: (1) those subjects reporting that they have no friends who drink alcohol and (2) those subjects reporting that they have one or more friends who drink. The findings indicate that the influence of TV exposure was a significant predictor (directly) of normative beliefs, expectancies (indirectly) and intentions to drink (both directly and indirectly) only for those subjects who reported having no friends who drink. For the group with non-drinking friends, family rules constrain intentions only indirectly by influencing normative beliefs. For those with friends who drink, however, family rules have a direct (inverse) effect on intentions. It is concluded that exposure to US-produced television programs functions as a limited knowledge source only for those subjects who had little or no personal experience with alcohol while the presence of family rules have limited impact on behavioral intentions.