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

Imaging the Impact of Prenatal Alcohol Exposure on the Structure of the Developing Human Brain

Prenatal alcohol exposure has numerous effects on the developing brain, including damage to selective brain structure. We review structural magnetic resonance imaging (MRI) studies of brain abnormalities in subjects prenatally exposed to alcohol. The most common findings include reduced brain volume and malformations of the corpus callosum. Advanced methods have been able to detect shape, thickness and displacement changes throughout multiple brain regions. The teratogenic effects of alcohol appear to be widespread, affecting almost the entire brain. The only region that appears to be relatively spared is the occipital lobe. More recent studies have linked cognition to the underlying brain structure in alcohol-exposed subjects, and several report patterns in the severity of brain damage as it relates to facial dysmorphology or to extent of alcohol exposure. Future studies exploring relationships between brain structure, cognitive measures, dysmorphology, age, and other variables will be valuable for further comprehending the vast effects of prenatal alcohol exposure and for evaluating possible interventions

Review of Current Neuroimaging Studies of the Effects of Prenatal Drug Exposure: Brain Structure and Function

Neuroimaging tools have provided novel methods for understanding the impact of prenatal drug exposure on brain structure and function and its relation to development and behavior. Information gained from neuroimaging studies allows for the investigation of how prenatal drug exposure alters the typical developmental trajectory. The current prevalence and characteristics of prenatal drug exposure and its implications for vulnerable periods of brain development are reviewed. Structural and functional neuroimaging methods are introduced with examples of how study results from prenatal alcohol, cocaine, marijuana, and tobacco exposure further our understanding of the neurodevelopment impact of prenatal drug exposure. Prenatal drug neuroimaging studies have advanced our understanding of mechanisms and functional deficits associated with prenatal drug exposure. Studies have identified brain circuits associated with the default mode network, inhibitory control, and working memory that show differences in function as a result of prenatal drug exposure. The information gained from studies of prenatal drug exposure on brain structure and function can be used to make connections between animal models and human studies of prenatal drug exposure, identify biomarkers of documented effects of prenatal drug exposure on behavior, and inform prevention and intervention programs for young children

Radiological studies of fetal alcohol spectrum disorders in humans and animal models: an updated comprehensive review

Fetal Alcohol Spectrum Disorders encompass a wide range of birth defects in children born to mothers who consumed alcohol during pregnancy. Typical mental impairments in FASD include difficulties in life adaptation and learning and memory, deficits in attention, visuospatial skills, language and speech disabilities, mood disorders and motor disabilities. Multimodal imaging methods have enabled in vivo studies of the teratogenic effects of alcohol on the central nervous system, giving more insight into the FASD phenotype. This paper offers an up-to-date comprehensive review of radiological findings in the central nervous system in studies of prenatal alcohol exposure in both humans and translational animal models, including Magnetic Resonance Imaging, Computed Tomography, Positron Emission Tomography, Single Photon Emission Tomography and Ultrasonography. (C) 2017 Elsevier Inc. All rights reserved

Striatal Morphological and Functional Alterations Induced by Prenatal Alcohol Exposure

Prenatal alcohol exposure (PAE) is an insidious yet preventable cause of developmental disability. The prenatal stage is a critical period for brain development with the concurrence of high vulnerability to the acute and prolonged effects of PAE. There is substantial evidence from both human observations and laboratory experiments that PAE is a common risk factor that predisposes to an array of postnatal mental disorders, including emotional, cognitive, and motor deficits. Although it is well accepted that PAE causes substantial morbidity, available treatments are limited. One reason is the lack of sufficient understanding about the neuroalterations induced by PAE, and how these changes contribute to PAE-induced mental disorders. Among a number of brain structures that have been explored extensively in PAE, the striatum has attracted great attention in the last 20 years in the field of PAE neurobiology. Interestingly, in animal models, the striatum has been considered as a pivotal switch of brain dysfunction induced by PAE, such as addiction, anxiety, depression, and neurodegeneration. In this review, we focus on recent advances in the understanding of morphological and functional changes in brain regions related to alterations after PAE, in particular the striatum. Because this region is central for behavior, emotion and cognition, there is an urgent need for more studies to uncover the PAE-induced alterations at the circuit, neuronal, synaptic and molecular levels, which will not only improve our understanding of the neuroplasticity induced by PAE, but also provide novel biological targets to treat PAE-related mental disorders with translational significance

A Longitudinal Study of the Long-Term Consequences of Drinking during Pregnancy: Heavy In Utero Alcohol Exposure Disrupts the Normal Processes of Brain Development

Exposure to alcohol in utero can cause birth defects including face and brain abnormalities, and is the most common preventable cause of intellectual disabilities. Here we use structural magnetic resonance imaging (MRI) to measure cortical volume change longitudinally in a cohort of human children and youth with prenatal alcohol exposure (PAE) and a group of unexposed control subjects, demonstrating that the normal processes of brain maturation are disrupted in individuals whose mothers drank heavily during pregnancy. Trajectories of cortical volume change within children and youth with PAE differed from those of unexposed control subjects in posterior brain regions, particularly in the parietal cortex. In these areas, control children appear to show a particularly plastic cortex with a prolonged pattern of cortical volume increases followed by equally vigorous volume loss during adolescence, while the alcohol-exposed participants showed primarily volume loss, demonstrating decreased plasticity. Furthermore, smaller volume changes between scans were associated with lower intelligence and worse facial morphology in both groups, and were related to the amount of PAE during each trimester of pregnancy in the exposed group. This demonstrates that measures of IQ and facial dysmorphology predict, to some degree, the structural brain development that occurs in subsequent years. These results are encouraging in that interventions aimed at altering “experience” over time may improve brain trajectories in individuals with heavy PAE, and possibly other neurodevelopmental disorders

Combined Face-Brain Morphology and Associated Neurocognitive Correlates in Fetal Alcohol Spectrum Disorders

BACKGROUND: Since the 1970s, a range of facial, neurostructural, and neurocognitive adverse effects have been shown to be associated with prenatal alcohol exposure. Typically, these effects are studied individually and not in combination. Our objective is to improve the understanding of the teratogenic effects of prenatal alcohol exposure by simultaneously considering face-brain morphology and neurocognitive measures. METHODS: Participants were categorized as control (n = 47), fetal alcohol syndrome (FAS, n = 22), or heavily exposed (HE) prenatally, but not eligible for a FAS diagnosis (HE, n = 50). Structural brain MRI images and high-resolution 3D facial images were analyzed using dense surface models of features of the face and surface shape of the corpus callosum (CC) and caudate nucleus (CN). Asymmetry of the CN was evaluated for correlations with neurocognitive measures. RESULTS: (i) Facial growth delineations for FAS, HE, and controls are replicated for the CN and the CC. (ii) Concordance of clinical diagnosis and face-based control-FAS discrimination improves when the latter is combined with specific brain regions. In particular, midline facial regions discriminate better when combined with a midsagittal profile of the CC. (iii) A subset of HE individuals was identified with FAS-like CN dysmorphism. The average of this HE subset was FAS-like in its facial dysmorphism. (iv) Right-left asymmetry found in the CNs of controls is not apparent for FAS, is diminished for HE, and correlates with neurocognitive measures in the combined FAS and HE population. CONCLUSIONS: Shape analysis which combines facial regions with the CN, and with the CC, better identify those with FAS. CN asymmetry was reduced for FAS compared to controls and is strongly associated with general cognitive ability, verbal learning, and recall in those with prenatal alcohol exposure. This study further extends the brain-behavior relationships known to be vulnerable to alcohol teratogenesis

The Long-Term Teratogenic Effect of Prenatal Alcohol Exposure on the Somatosensory and Motor Cortex of Rats

The primary goal of this dissertation was to examine the long-term effect of prenatal alcohol exposure (PAE) on the primary somatosensory (SI) and primary motor cortex (MI). For over 30 years, PAE has been shown to produce a triad of symptoms (growth deficits, craniofacial dysmorphologies and central nervous system disruptions) diagnosed as fetal alcohol syndrome (FAS) in children and adults. Since low to moderate levels of prenatal alcohol exposure are less likely to produce FAS symptoms in children, the term “PAE” in this dissertation typically refers to heavy/abusive/chronic levels of prenatal alcohol exposure (in humans this equates to 5+ drinks/per occasion/1+ times per week) administered in a chronic binge-type fashion having a high potential to cause FAS. However, it must be pointed out that the most important factor in studies dealing with PAE in humans or animals is the peak blood alcohol level (BAL) and next are the temporal and spatial parameters dealing with high BALs. It is evident that children with FAS frequently show major deficits in information processing, which is one of the major functions of the sensorimotor system. Two major components of the sensorimotor system are the cortical input to layer IV primary sensory cortex (SI) and output from layers V and VI primary motor cortex (MI). Therefore, the focus of this dissertation is on PAE-related anatomical and physiological deficits in SI and MI that are likely to play a role in the multiple sensorimotor, behavioral, and learning disruptions seen in children with FAS. The similarities in rodent and human cortical organization make rodents excellent models for elucidating the influence of PAE on the sensorimotor system. Of particular note is the highly organized human and rodent sensorimotor system with the sensory input and motor output arranged into structural and functional columns. However, one difference between humans and rodents is that the latter receives its sensory information in layer IV cortex into cell aggregates termed “barrels,” whereas humans have no such specific cortical structures per se. Each barrel in rodent cortex is spatially related to sensory receptors that innervate specific regions of the body surface, thus barrels produce a cortical somatic map. The longest studied and most easily identifiable barrel region is the posterior medial barrel subfield (PMBSF), representing mystacial vibrissae of the rodent. A second highly studied region of the barrel cortex is the forepaw barrel subfield (FBS), representing the forepaw. One hallmark feature of PAE is the behavioral disruptions seen in fine motor control. These deficits may be due to disruptions in both SI and MI. Like SI, MI is also well organized into specific cortical regions associated with eliciting motor responses. Because SI and MI are highly organized, these cortical regions are very useful for studying the effect of prolonged PAE-related sensorimotor disruptions. The primary goal of this dissertation was to examine the long-term consequences of PAE on SI and MI in 6-week-old (juvenile) or 7-month-old (adult) rats. To accomplish this goal, four major experiments were carried out utilizing a binge-type alcohol exposure paradigm on pregnant rat dams followed by an examination of the PAE pups as well as untreated control and nutritional control pups at six weeks and seven months of age. Experiment 1: We tested the hypothesis (Chapter 2) that PAE would reduce the PMBSF area in juvenile and adult rats. Results indicated that PAE significantly reduced the PMBSF area, the total PMBSF barrel area, and interbarrel septa area in PAE juveniles and adult rats. Furthermore, PAE effects were asymmetrical across the PMBSF, as the areas of posterior barrels were less reduced than anterior barrel areas. By combining barrels into lateral-to-medial running “arcs” and calculating the area as a percent difference from respective chowfed (CF) or pairfed (PF) arcs, results suggested a split in the PMBSF between a more reduced anterior region and a less reduced posterior region. The areas of anterior arcs of PMBSF were always more reduced than the areas of posterior arcs. However, a similar asymmetric pattern was not identified in anterior to posterior running rows. Experiment 2: The goal of Experiment 2 (Chapter 2) was to test the hypothesis that the rostrocaudal asymmetry identified in Experiment 1 was due, in part, to differential sensory experience across the mystacial pad. It is well established that numerous peripheral and CNS asymmetries already occur by way of variations in mystacial pad vibrissae lengths, base widths, vibrissae behavior, peripheral innervation patterns, and metabolic activity levels within cortical PMBSF barrels. It was hypothesized that trimming the mystacial pad would eliminate any differences between posterior and anterior vibrissae, in turn affecting the vibrissae cortical barrel representations and subsequent PMBSF asymmetries. To test this hypothesis, unilateral mystacial vibrissae were trimmed in EtOH and CF rats from postnatal day five (PD5) to PD42. EtOH rats sacrificed on PD42 had their individual PMBSF area and individual PMBSF barrel areas measured. These areas were then compared to respective PMBSF and barrel areas of the ipsilateral cortex from a CF group that had also undergone vibrissae trimming, and the percent change was calculated. Results indicated that vibrissae trimming did not affect the asymmetry identified in Chapter 2. Experiment 3: We tested the hypothesis that PAE would significantly reduce the area of the FBS morphology and the area of the peripheral glabrous forepaw (Chapter 3). The FBS morphology and peripheral glabrous forepaw areas were significantly reduced in juvenile rats following PAE. Experiment 4: This experiment was carried out to test the hypothesis that PAE would reduce the physiological/functional forepaw representation and also delay evoked response latency between periphery and SI (Chapter 4). Using carbon-fiber electrodes inserted into layer IV cortex, the physiological forepaw representation was mapped by lightly tapping the forepaw periphery (i.e., digits, or pads) with a dull insect pin and recording forepaw receptive fields in the cortex. PAE significantly reduced the representation of the entire glabrous forepaw surface as well as the physiological forepaw representation. Experiment 5: We tested the hypothesis that PAE would reduce the size of the primary motor cortex (MI), specifically those regions responsible for contralateral vibrissae and forepaw movement (Chapter 5). Results indicated that PAE significantly reduced MI areas for mystacial vibrissae and forepaw motor cortex. Results from Experiments 1 to 5 reinforce the hypothesis that PAE has a long-term effect on the sensorimotor system and provides new information on the effect of PAE on MI. The sensorimotor system is important for processing peripheral information and performing planned motor movements. Therefore, deficits in this system may be among the underlying mechanisms for reported clinical symptoms, such as the disturbances in balance, posture, fine motor control, attention, learning, reaction time, and other information disruptions often identified in children exposed to high levels of alcohol in utero

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Abnormal Cortical Thickness Alterations in Fetal Alcohol Spectrum Disorders and Their Relationships with Facial Dysmorphology

Accumulating evidence from structural brain imaging studies on individuals with fetal alcohol spectrum disorder (FASD) has supported links between prenatal alcohol exposure and brain morphological deficits. Although global and regional volumetric reductions appear relatively robust, the effects of alcohol exposure on cortical thickness and relationships with facial dysmorphology are not yet known. The structural magnetic resonance imaging data from 69 children and adolescents with FASD and 58 nonexposed controls collected from 3 sites were examined using FreeSurfer to detect cortical thickness changes across the entire brain in FASD and their associations with facial dysmorphology. Controlling for brain size, subjects with FASD showed significantly thicker cortices than controls in several frontal, temporal, and parietal regions. Analyses conducted within site further revealed prominent group differences in left inferior frontal cortex within all 3 sites. In addition, increased inferior frontal thickness was significantly correlated with reduced palpebral fissure length. Consistent with previous reports, findings of this study are supportive of regional increases in cortical thickness serving as a biomarker for disrupted brain development in FASD. Furthermore, the significant associations between thickness and dysmorphic measures suggest that the severity of brain anomalies may be reflected by that of the face