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.     

Acute and chronic effects of cocaine on the spontaneous behavior of pigeons

The present experiment examined the effects of acute and daily cocaine on spontaneous behavior patterns of pigeons. After determining the acute effects of a range of doses, 9 pigeons were divided into three groups that received one of three doses of cocaine daily, either 1.0, 3.0, or 10.0 mg/kg cocaine. Measures were taken of spontaneous locomotion, pecking, preening, and emesis. Under daily administration, cocaine induced consistent and substantial enhancements of its locomotor effects in all 9 pigeons, consistent with the phenomenon of locomotor sensitization. The maximum locomotor output did not differ according to the size of the daily dose. Locomotion was not elevated following tests of the saline vehicle, suggesting the effect was due to cocaine, not to a change in baseline or reactivity to the injection procedure. Cocaine dose‐dependently decreased preening when given acutely, and those effects were not altered by repeated cocaine administration. Pecking occurred at very low rates and was unresponsive to cocaine treatment. Cocaine‐induced emesis showed a dose‐dependent increase under initial tests with cocaine, and those effects were attenuated following daily exposure. In a final condition, cocaine was replaced with daily saline for 30 days to assess the persistence cocaine‐related increases in locomotion. Approximately half of the pigeons continued to show enhanced effects even after 30 days without cocaine, so although persistence was obtained, it showed marked intersubject variability. The data indicate that the effects of repeated cocaine administration on the behavior of pigeons shows parallels with many effects commonly reported with rodents (i.e., increased locomotion following repeated treatment, decrease in preening or grooming, persistence following drug withdrawal).     

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.     

Environmental factors associated with a spectrum of neurodevelopmental deficits

A number of environmental agents have been shown to demonstrate neurotoxic effects either in human or laboratory animal studies. Critical windows of vulnerability to the effects of these agents occur both pre- and postnatally. The nervous system is relatively unique in that different parts are responsible for different functional domains, and these develop at different times (e.g., motor control, sensory, intelligence and attention). In addition, the many cell types in the brain have different windows of vulnerability with varying sensitivities to environmental agents. This review focuses on two environmental agents, lead and methylmercury, to illustrate the neurobehavioral and cognitive effects that can result from early life exposures. Special attention is paid to distinguishing between the effects detected following episodes of poisoning and those detected following lower dose exposures. Perinatal and childhood exposure to high doses of lead results in encephalopathy and convulsions. Lower-dose lead exposures have been associated with impairment in intellectual function and attention. At high levels of prenatal exposure, methylmercury produces mental retardation, cerebral palsy and visual and auditory deficits in children of exposed mothers. At lower levels of methylmercury exposure, the effects in children have been more subtle. Other environmental neurotoxicants that have been shown to produce developmental neurotoxicity include polychlorinated biphenyls (PCBs), dioxins, pesticides, ionizing radiation, environmental tobacco smoke, and maternal use of alcohol, tobacco, marijuana and cocaine. Exposure to environmental agents with neurotoxic effects can result in a spectrum of adverse outcomes from severe mental retardation and disability to more subtle changes in function depending on the timing and dose of the chemical agent.     

Neurobiology of Cocaine-Induced Organic Brain Impairment: Contributions from Functional Neuroimaging

The present review is directed at imparting the current knowledge regarding functional neuroimaging as a tool for enhancing the understanding of cerebrophysiologic and neurobehavioral consequences of stimulant abuse. Stimulants like cocaine are capable of inducing clinically significant neurocognitive impairment through direct action on the brain, and indirectly through other organs that influence cerebral physiology. Neurochemical dysregulation including profound effects on the serotonergic and dopaminergic systems have substantial physiological and neurobehavioral consequences. Brain hemorrhages, transient ischemic attacks, strokes, and seizures frequently follow cocaine use. The residual cerebropathologic consequences of cocaine are seen only in significant or pronounced brain events when structural neuroimaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) are employed. However, recent research with newer functional neuroimaging techniques such as single photon emission, positron emission tomography, and quantitative electroencephalography have revealed high rates of significant alteration in brain function among cocaine users, with negative structural imaging studies. These findings are often associated with impairment on neuropsychological evaluation, also in the absence of positive findings on CT and MRI. Both cerebral metabolic and hypoperfusion anomalies are seen, especially in anterior and temporal brain regions. Observed changes can persist for months, and for some patients, may represent a permanent change in brain functioning.     

Children's intellectual and emotional-behavioral adjustment at 4 years as a function of cocaine exposure,maternal characteristics,and environmental risk

The authors examined 223 children at age 4 years for the effects of prenatal cocaine exposure, exposure to other substances, maternal and environmental risk factors, and neonatal medical problems on IQ, externalizing problems, and internalizing problems. Regression analyses showed that maternal verbal IQ and low environmental risk predicted child IQ. Cocaine exposure negatively predicted children's overall IQ and verbal reasoning scores, but only for boys. Cocaine exposure also predicted poorer short-term memory. Maternal harsh discipline, maternal depressive symptoms, and increased environmental risk predicted externalizing problems. In contrast, only maternal depressive symptoms predicted internalizing problems. These findings indicate that early exposure to substances is largely unrelated to subsequent IQ or adjustment, particularly for girls.     

Centrally elicited aggressive behavior: A model system for the study of episodic neurobehavioral pathologies?

Studies in which the predatory-like attack of a cat upon a rat has been elicited by electrical brain stimulation have been briefly reviewed with an emphasis on the question of where within the central nervous system such brain stimulation is producing its behaviorally meaningful effects. Two opposing but by no means mutually exclusive views are considered. The first is that brain stimulation elicits this behavior pattern primarily because it affects a specific motivated behavior system that is organized discretely in the midbrain and pons. The second is that forebrain neural activity is modulated in behaviorally significant ways by brainstem stimulation, which elicits predatory-like aggressive behavior in the cat. The possibility that further research on the altered state of central nervous system activity, induced by brain stimulation which elicits aggressive behavior in the cat, may lead to a further understanding of the altered states of central nervous system activity that underlie the aggressive dyscontrol syndrome and other episodic state disorders is discussed.     

Modulatory role of serotonin in neural information processing: implications for human psychopathology.

Investigation of the role of 5-hydroxytryptophan (5-HT), which functions as a modulator in the central nervous system, across behavioral contexts suggests that a general principle of transmitter function may be derived that is independent of specific behaviors and specific neural loci. A functional principle of 5-HT action in neural information processing in the central nervous system is proposed. Extremes deviations in 5-HT activity result in biases in information processing that may have direct effects on behavior. Such biases may predispose to pathological conditions such as violent suicide and aggression.     

Ratio size and cocaine concentration effects on oral cocaine-reinforced behavior.

Monkeys were given a choice between cocaine solutions and water under concurrent fixed-ratio reinforcement schedules. The operant response was spout contact. Six rhesus monkeys served as subjects. The cocaine concentration was varied from 0.0125 to 0.8 mg/ml, and the fixed-ratio value was varied from 8 to 128. Cocaine maintained higher response rates than did water over a wide range of conditions. Response rate and number of cocaine deliveries per session were inverted U-shaped functions of concentration. These functions were shifted to the right as the fixed ratio was increased. The number of cocaine deliveries was more persistent as fixed-ratio value was increased when the unit dose was larger rather than smaller. Cocaine consumption was analyzed as a function of unit price (fixed-ratio value divided by cocaine concentration), and unit price accounted for between 77% and 92% of the variance in cocaine consumption for individual monkeys. The current data support the claim that a drug's reinforcing effects increase directly with dose and underscore the need to gather parametric data when examining the effects of experimental manipulations on a drug-reinforced baseline.     

Functional brain imaging of childhood clinical disorders with PET and SPECT

During the first years of life, the human brain undergoes repetitive modifications in its anatomical, functional and synaptic construction to reach the complex functional organization of the adult central nervous system. Over the last decade, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have provided further insight into these maturation processes. This article reviews clinical and research applications of PET and SPECT in childhood disorders, with an emphasis on the specific contribution of these techniques in improving our knowledge about the pathophysiology of the developing brain.     

Developmental neuroimaging of children using magnetic resonance techniques

Cognitive and motor development in children remain fascinating processes that are uniquely human. Progress has been made in recent years in elucidating the prenatal process of human brain development. In addition, much information exists regarding the behavioral aspects of postnatal human development. However, little is known about the relationship between anatomic postnatal central nervous system development and the accretion of functional milestones observed in children from the neonatal period through adolescence. Recently, powerful qualitative and quantitative magnetic resonance techniques have been developed that will permit detailed inquiry into the connection between the developing brain and the developing mind. In this review, first, the steps of prenatal and postnatal brain development are reviewed briefly. Subsequently, recent magnetic resonance imaging data related to human brain development during the fetal, neonatal, and later childhood periods are presented. Finally, functional magnetic resonance imaging (fMRI) is discussed. Specific examples of its usefulness are provided. Magnetic resonance imaging techniques such as quantitative MRI, volumetric MRI, diffusion tensor imaging, and functional magnetic resonance imaging (fMRI) when combined with neurologic and neuropsychologic evaluation, will provide new insights into the cognitive development of children. MRDD Research Reviews 6:68-80, 2000.     

Delusions and hallucinations of cocaine abusers and paranoid schizophrenics: a comparative study

We compared delusions and hallucinations of 100 cocaine abusers and 100 paranoid schizophrenic subjects admitted to an East Texas state psychiatric hospital. Subjects in both groups feared that individuals or organized groups might harm them in some way, but delusions of the paranoid schizophrenic subjects were more often bizarre than those of the cocaine abuse subjects. "Cocaine bugs" (parasitosis) were more often found in the cocaine abuse subjects. Command hallucinations were found in both groups, but the commands of the schizophrenic group more often related to harming or killing others. Cocaine abusers had a greater frequency of visual hallucinations (47 to 7), distinguished by shadows, flashing lights ("snow lights"), objects moving and bugs crawling on the arm. Finally, the most distinguishing characteristics were identity delusions, possession delusions, grandiose delusions (other than identities and possessions), and delusions that their families were imposters (Capgras Syndrome) reported by paranoid schizophrenics. No such delusions were reported by the cocaine abusers.     

Physically Transcendent Awareness: A Comparison of the Phenomenology of Consciousness Before Birth and After Death

Veridical evidence of a physically transcendent source of consciousness comes from both extremes of the life span when central nervous system functioning is compromised, suggesting that some form of personhood can exist independently of known cellular processes associated with the body. In pre- and perinatal accounts, veridical memories have surfaced of events in the first two trimesters, long before the central nervous system is fully functional, continuing through the third trimester, when measurable brain activity begins, until just after birth. In the empirically verifiable out-of-body phase of near-death experience (NDE) accounts, a source of consciousness has been shown to record events when measurable metabolic processes, including brain activity, have ceased altogether. These two states have similar phenomenologies, suggesting that a physically transcendent source representing individual consciousness predates physical life at the moment of conception and survives it after death, and that its maturity and functioning do not directly reflect the level of central nervous system functioning in the body.     

Functional effects of neural grafting in the mammalian central nervous system

Grafts of fetal and nonfetal brain tissues have been successfully implanted into the mammalian central nervous system (CNS). The functional effects of neural grafting in the CNS of rodents and nonhuman primates in a variety of situations are reviewed. Research areas discussed included the effects of dopamine-rich grafts in animal models of Parkinson's disease and acetylcholine-rich grafts in animals with lesions of the cholinergic pathways to the neocortex and hippocampus. Graft effects also are examined in aged animals and genetic mutants. In addition, the effects of neural grafts on circadian rhythmicity, reproductive functions, and conditioned taste aversion are discussed. The beneficial functional effects of neural grafts and the possible mechanisms and implications for these effects are discussed, including the possibility that the CNS exhibits a regional biochemical specificity that influences the outcome of neural graft procedures.     

PRENATAL COCAINE EXPOSURE AND NEONATAL CONDITION

Infants who are prenatally exposed to cocaine have an increased risk of suffering neonatal medical complications. We hypothesized that this effect is mediated by the relation between cocaine use and prenatal medical risk of the mother, birth weight, and intrapartum risk, that would lead to increased neonatal complications. This study used structural equation modeling to assess the direct and indirect effects of prenatal cocaine exposure on neonatal medical risk in a sample of 337 neonates. Prenatal cocaine exposure had a significant indirect, but not direct effect on neonatal medical risk. Several paths contributed to this indirect effect. The strongest was via cocaine's impact on birth weight, and birth weight's effect on neonatal medical risk. The paths through prenatal risk and intrapartum risk also contributed to the total indirect effect. These results suggest that the observed relation between prenatal cocaine exposure and neonatal medical complications is mediated by prenatal and intrapartum risk factors.     

Strain-dependent interactions between MK-801 and cocaine on retention of C57BL/6 and DBA/2 mice tested in a one-trial inhibitory avoidance task: involvement of dopaminergic mechanisms

Two sets of experiments were carried out with C57BL/6 (C57) and DBA/2 (DBA) mice tested in a one-trial inhibitory avoidance task. In the first set C57 and DBA mice were injected posttraining with saline or with the D1 DA receptor antagonist SCH 23390 and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Cocaine enhanced retention in the C57 strain and impaired it in the DBA strain, and MK-801 potentiated the effects of cocaine in both strains. Furthermore, pretreatment with SCH 23390 completely antagonized the potentiation of the effects of cocaine exerted by MK-801. In the second set of experiments mice belonging to these same two strains were injected posttraining with vehicle or with the D2 DA receptor antagonist (-)-sulpiride and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Pretreatment with the D2 DA receptor antagonist completely antagonized in both strains the potentiation of the effect of cocaine exerted by MK-801. The results of the present research show that the noncompetitive NMDA receptor antagonist MK-801 enhances the effect of cocaine on retention performance in C57 and DBA mice and that dopaminergic mechanisms are involved in this potentiation.     

Prenatal cocaine exposure and infants' preference for novelty and distractibility

The authors used the Fagan Test of Infant Intelligence (J. F. Fagan, L. T. Singer, J. E. Montie, & P. A. Shepherd, 1986) to examine preferences for novelty and to evaluate several indicators of attention (off- and on-task indexes and durations) in 6- and 9-month-old infants who had been prenatally exposed to cigarette smoke only or to cocaine plus other substances. The infants were matched for socioeconomic status. The authors found no group differences in preference for novelty, but the off-task distractibility index and duration were affected by exposure history and showed effects of dosage at the 9-month test time. Infants exposed to cocaine had a higher off-task index and a shorter average off-task look duration than did infants in the other groups. The authors interpreted this pattern of behavior as an indicator of distractibility or stimulation seeking. There were no group differences in measures involving on-task looks or duration at either test time. Correlations between the off-task look index and duration and teratogen use produced moderate correlations at 9 months of age. The authors calculated partial correlations between teratogen exposure and the off-task index at each trimester. Cocaine use during the 1st and 2nd trimesters was significantly correlated with the off-task index at 9 months of age, even when the authors controlled for neonatal measures (e.g., gestational age, birth weight) and during the 1st trimester when they controlled for alcohol and cigarette exposure.     

Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models

Developmental differences in hypothalamic–pituitary–adrenal (HPA) axis responsiveness to stressors and ongoing development of glucocorticoid-sensitive brain regions in adolescence suggest that similar to the neonatal period of ontogeny, adolescence may also be a sensitive period for programming effects of stressors on the central nervous system. Although research on this period of life is scarce compared to early life and adulthood, the available research indicates that effects of stress exposure during adolescence differ from, and may be longer-lasting than, effects of the same stress exposure in adulthood. Research progress in animal models in this field is reviewed including HPA function and the enduring effects of stress exposures in adolescence on sensitivity to drugs of abuse, learning and memory, and emotional behaviour in adulthood. The effects of adolescent stress depend on a number of factors, including the age, gender, the duration of stress exposure, the type of stressor, and the time between stress exposure and testing.     

Sensorimotor development in cocaine-exposed infants

This study investigated the effects of prenatal cocaine exposure on infant sensorimotor development. One hundred and sixty-seven12-month-olds (74 cocaine-exposed and 93 unexposed) were assessed using the Bayley Scales of Infant Development (BSID). Ninety-seven had previously been evaluated on the Movement Assessment of Infants and the Test of Sensory Functions in Infants at age 4 months. On the BSID, the cocaine-exposed infants performed less well on the Mental portion and were more frequently rated as behaviorally suspect. Cocaine-exposed infants also performed less well at four months on the motor and sensory measures. Early motor performance predicted 12 month BSID mental, motor and behavioral outcomes. Cocaine exposure had an effect independent from confounders on general cognitive and specific motor and behavioral outcomes.     

Correlating brain metabolism with stereotypic and locomotor behavior

Many studies have shown that developmental cocaine exposure alters brain function and behavior; the present study examined the relationship between brain metabolism and behavioral responses to drug challenge. SKF 82958, a selective D1 dopamine agonist, was administered to preweaning cocaine-exposed (50 mg/kg/day) rats and controls at 60 days of age. Deoxyglucose was administered 30 min later, during the peak behavioral response, to measure brain functional activity Pearson product-moment correlations of behavior (locomotor activity and Stereotypic behavior) with rates of glucose metabolism in components of the nigrostriatal and mesolimbic circuits were analyzed. The analysis revealed that under saline-challenge conditions in control animals, rates of metabolism in mesolimbic regions are positively correlated to rates of locomotor activity, whereas in cocaine-treated rats, these correlations were absent. Following SKF challenge, a different pattern was seen; locomotor activity or Stereotypic behavior was not correlated with mesolimbic or nigrostriatal metabolism, respectively,in controls but was positively correlatedin cocaine-treatedrats. Therefore, cocaine exposure during development enhances the coupling of metabolism in components of the mesolimbic and nigrostriatal dopamine systems with the behavioral output associated with these systems under drug-challenge conditions. This may be due to loss of inhibitory influences within the mesolimbic and nigrostriatal systems. Thus, the correlation of behavior and cerebral glucose metabolism provides a unique way of examining the effect of developmental cocaine exposure.