Epileptic encephalopathies and their relationship to developmental disorders: do spikes cause autism?

Epileptic encephalopathies are progressive clinical and electroencephalographic syndromes where deterioration is thought to be caused by frequent seizures and abundant EEG epileptiform activity. Seizures occur in approximately 10-15% of children with pervasive developmental disorders (PDD) and 8-10% have epileptiform EEG abnormalities without seizures. Thirty percent of children with PDD have regression of social behavior and language at 2-3 years of age. Some authors speculate that the regression is caused by epileptiform activity even in the absence of overt clinical seizures ("autism with epileptic regression") and suggest that elimination of the epileptiform activity, either medically or surgically, should lead to improvement in behavior. This review examines the data showing that interictal epileptiform discharges are associated with transient clinical dysfunction and discusses the implications of these observations for autistic behavioral abnormalities. The results of resective surgery, vagal nerve stimulation, and multiple subpial transaction on children with autism and epileptiform EEG abnormalities are also discussed. I conclude that there is no evidence that interictal discharges per se cause (or contribute to) the complex behavioral phenotype of autism. There is no justification to support the use of anticonvulsant medication or surgery in children with PDD without seizures; that is, there is no evidence that treatment to eliminate EEG spikes will have a therapeutic effect on the behavioral abnormalities of PDD and autism.     

A systems neuroscience approach to autism: biological,cognitive, and clinical perspectives

Autism is a behaviorally defined disorder characterized by a broad constellation of symptoms. Numerous studies directed to the biological substrate demonstrate clear effects of neurodevelopmental differences that will likely point to the etiology, course, and long-term outcomes of the disorder. Consistently replicated research on the neural underpinnings of autism is reviewed. In general, results suggest several main conclusions: First, autism is a heterogeneous disorder and is likely to have multiple possible etiologies; second, structural brain studies have indicated a variety of diffuse anatomical differences, reflective of an early developmental change in the growth or pruning of neural tissue, rather than localized lesions; similarly, neurochemical studies suggest early, neuromodulatory discrepancies rather than gross or localized abnormalities; and finally, there are a number of limitations on studies of brain activity that to date preclude definitive answers to questions of how the brain functions differently in autism. The large number of active research programs investigating the cognitive neuroscience of autism spectrum disorders, in combination with the exciting development of new methodologies and tools in this area, indicates the drama and excitement of work in this area.     

The Implications of Brain Connectivity in the Neuropsychology of Autism

Autism is a neurodevelopmental disorder that has been associated with atypical brain functioning. Functional connectivity MRI (fcMRI) studies examining neural networks in autism have seen an exponential rise over the last decade. Such investigations have led to the characterization of autism as a distributed neural systems disorder. Studies have found widespread cortical underconnectivity, local overconnectivity, and mixed results suggesting disrupted brain connectivity as a potential neural signature of autism. In this review, we summarize the findings of previous fcMRI studies in autism with a detailed examination of their methodology, in order to better understand its potential and to delineate the pitfalls. We also address how a multimodal neuroimaging approach (incorporating different measures of brain connectivity) may help characterize the complex neurobiology of autism at a global level. Finally, we also address the potential of neuroimaging-based markers in assisting neuropsychological assessment of autism. The quest for a neural marker for autism is still ongoing, yet new findings suggest that aberrant brain connectivity may be a promising candidate.     

AEDs and psychotropic drugs in children with autism and epilepsy

The efficacy of antiepileptic drugs (AEDs) and psychotropic medications in children with autism is limited to the treatment of seizures or to specific behaviors such as irritability, impulsivity, hyperactivity, repetitive behaviors, or aggression. The reliability and value of the available data--to determine the efficacy of these medications in autism--are limited by lack of controlled clinical trials, the small number of subjects, the heterogeneity of the population studied, and the brief duration of most drug trials. Indeed, few controlled clinical trials using AEDs in autism, with or without seizures, have been conducted. Because some AEDs also have a positive effect on mood, the benefits that children with autism sometimes obtain from these medications may not be due to the treatment of the abnormal electrical activity or the seizures per se but to an effect on common neuronal systems responsible for both behavior and epilepsy. The relationship between epilepsy and autism, and specifically the effects that abnormal electrical activity may have on the developing brain, may provide some valuable insights into the type of studies that are needed to help us understand the pathophysiology of autism.     

Neural substrates of latent inhibition: the switching model

Latent inhibition (LI) refers to decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. It is a robust phenomenon that has been demonstrated in a variety of classical and instrumental conditioning procedures and in many mammalian species, including humans. The development of LI is considered to reflect decreased associability of, or attention to, stimuli that predict no significant outcome. The fact that LI is considered to be a reflection of attentional processes has become of increasing importance to neuroscientists who see LI as a convenient tool for measuring the effects of drug treatments and lesions on attention. The present article surveys the data on brain systems, which have been studied in regard to their involvement in LI. These are reviewed and discussed separately in sections on noradrenergic, cholinergic, dopaminergic, serotonergic, and septo-hippocampal manipulations. On the basis of these data, it is concluded that the neural substrates of LI include the mesolimbic dopaminergic system, the mesolimbic serotonergic system, and the hippocampus. It is proposed that the preexposed stimulus loses its capacity to affect behavior in conditioning, even though it predicts reinforcement, because the hippocampus inhibits the switching mechanism of the nucleus accumbens via the subiculum-accumbens pathway. This action of the hippocampus is modulated by the mesolimbic serotonergic system via its interactions with the hippocampal or mesolimbic dopaminergic systems, or both.     

Neurobiological Correlates of Autism: A Review of Recent Research

This review paper integrates recent structural and functional imaging, postmortem, animal lesion, and neurochemical research about the pathophysiology of autism. An understanding of the neurobiological correlates of autism is becoming increasingly important as more children are diagnosed with the condition and funding for well-targeted interventions increases. Converging evidence suggests that autism involves abnormalities in brain volume, neurotransmitter systems, and neuronal growth. In addition, evidence firmly links autism with abnormalities in the cerebellum, the medial temporal lobe, and the frontal lobe. Potential implications of these findings and suggestions for future research are reviewed.     

Neurobiological correlates of autism: a review of recent research.

This review paper integrates recent structural and functional imaging, postmortem, animal lesion, and neurochemical research about the pathophysiology of autism. An understanding of the neurobiological correlates of autism is becoming increasingly important as more children are diagnosed with the condition and funding for well-targeted interventions increases. Converging evidence suggests that autism involves abnormalities in brain volume, neurotransmitter systems, and neuronal growth. In addition, evidence firmly links autism with abnormalities in the cerebellum, the medial temporal lobe, and the frontal lobe. Potential implications of these findings and suggestions for future research are reviewed.     

The role of the extrapersonal brain systems in religious activity

The neuropsychology of religious activity in normal and selected clinical populations is reviewed. Religious activity includes beliefs, experiences, and practice. Neuropsychological and functional imaging findings, many of which have derived from studies of experienced meditators, point to a ventral cortical axis for religious behavior, involving primarily the ventromedial temporal and frontal regions. Neuropharmacological studies generally point to dopaminergic activation as the leading neurochemical feature associated with religious activity. The ventral dopaminergic pathways involved in religious behavior most closely align with the action-extrapersonal system in the model of 3-D perceptual-motor interactions proposed by . These pathways are biased toward distant (especially upper) space and also mediate related extrapersonally dominated brain functions such as dreaming and hallucinations. Hyperreligiosity is a major feature of mania, obsessive-compulsive disorder, schizophrenia, temporal-lobe epilepsy and related disorders, in which the ventromedial dopaminergic systems are highly activated and exaggerated attentional or goal-directed behavior toward extrapersonal space occurs. The evolution of religion is linked to an expansion of dopaminergic systems in humans, brought about by changes in diet and other physiological influences.     

Examining neurochemical determinants of inspection time: Development of a biological model

Inspection time (IT), an information-processing correlate of psychometric intelligence, has been extensively studied. Previous research has shown that IT is a reliable correlate of psychometric intelligence across different developmental periods, mirroring developmental trends of fluid intelligence. Despite this extensive previous literature, very little is known about the biological basis of IT. In the present review, we discuss recent results from our laboratories examining the neurochemical determinants of IT. In this review, we outline the significance of several studies in which performance on the IT task is measured before and after modulating key human central nervous system (CNS) neurotransmitters and receptor systems (e.g., cholinergic, serotonergic, noradrenergic, and dopaminergic systems). The results of these studies indicate a primarily cholinergic basis for IT, although other aspects of psychometric intelligence may have serotonergic and dopaminergic determinants in addition to a cholinergic basis. The results are consistent with data reporting cholinergic depletion and impaired IT performance in dementia of the Alzheimer's type (DAT). Speculatively, we propose that compounds that enhance the release of the neurotransmitter acetylcholine (Ach) will improve IT and the variance that IT shares with IQ test performance.     

The neurocognitive basis of autism

The cognitive study of the underlying mental abnormalities in autism has advanced rapidly, while the biological study of the underlying brain abnormalities and of putative genetic mechanisms is lagging somewhat behind. However, the linking of cognitive and biological studies has become a real possibility. Developmental cognitive neuroscience has transformed our understanding of this enigmatic disorder, which was once misguidedly thought to be caused by maternal rejection. The hypothesis of a specific theory of mind deficit was a crucial step in this process. It explains the puzzle of the characteristic social and communication impairments of autism and allows for the fact that they can coexist with good general abilities. This hypothesis has been widely accepted and a start has been made at pinpointing the brain basis of theory of mind. The non-social impairments of autism have now become a major focus for cognitive research. One theory proposes dysfunction in executive processes, in an attempt to explain repetitive behaviour and inflexibility. Another theory proposes weak information integration, in an attempt to explain narrow interests and special talents. Autism research has thus stimulated ideas on important mind-brain systems that may be dedicated to the development of social awareness, executive functions and integrative processing.     

Pharmacological interventions in autism: theoretical and practical issues

Focused on issues of drug treatment in relation to autism. Pharmacological treatment studies in autism are complicated by various factors including a tremendous range of syndrome expression, a lack of robust animal models of the disorder, and various methodological problems. Theories have tended to follow treatments, and various neurochemical systems have been the focus of study. Neurochemical systems potentially implicated include those involving dopamine, norepinephrine, serotonin, and neuropeptides. The dopaminergic system has been the most extensively studied. Treatments developed are effective relative to certain disabling symptoms but "core" problems (e.g., in social relatedness and communication) appear less responsive to medications. The development of new approaches to assessment, including integration of behavioral and pharmacological approaches, is an important research priority.     

Brain development in autism: early overgrowth followed by premature arrest of growth

Due to the relatively late age of clinical diagnosis of autism, the early brain pathology of children with autism has remained largely unstudied. The increased use of retrospective measures such as head circumference, along with a surge of MRI studies of toddlers with autism, have opened a whole new area of research and discovery. Recent studies have now shown that abnormal brain overgrowth occurs during the first 2 years of life in children with autism. By 2-4 years of age, the most deviant overgrowth is in cerebral, cerebellar, and limbic structures that underlie higher-order cognitive, social, emotional, and language functions. Excessive growth is followed by abnormally slow or arrested growth. Deviant brain growth in autism occurs at the very time when the formation of cerebral circuitry is at its most exuberant and vulnerable stage, and it may signal disruption of this process of circuit formation. The resulting aberrant connectivity and dysfunction may lead to the development of autistic behaviors. To discover the causes, neural substrates, early-warning signs and effective treatments of autism, future research should focus on elucidating the neurobiological defects that underlie brain growth abnormalities in autism that appear during these critical first years of life.     

Acquired epileptiform aphasia: a dimensional view of Landau-Kleffner syndrome and the relation to regressive autistic spectrum disorders.

Acquired epileptiform aphasia (AEA) is characterized by deterioration in language in childhood associated with seizures or epileptiform electroencephalographic abnormalities. Despite an extensive literature, discrepancies and contradictions surround its definition and nosological boundaries. This paper reviews current conceptions of AEA and highlights variations in the aphasic disturbance, age of onset, epileptiform EEG abnormalities, temporal course, and long-term outcome. We suggest that AEA, rather than being a discrete entity, is comprised of multiple variants that have in common the features of language regression and epileptiform changes on EEG. Viewed this way, we argue that AEA can be conceptualized on a spectrum with other epileptiform neurocognitive disorders that may share pathophysiological features. The implications of this viewpoint are discussed, with emphasis on parallels between the AEA variants and regressive autistic spectrum disorders.     

Environmental complexity and central nervous system development and function

Environmental restriction or deprivation early in development can induce social, cognitive, affective, and motor abnormalities similar to those associated with autism. Conversely, rearing animals in larger, more complex environments results in enhanced brain structure and function, including increased brain weight, dendritic branching, neurogenesis, gene expression, and improved learning and memory. Moreover, in animal models of CNS insult (e.g., gene deletion), a more complex environment has attenuated or prevented the sequelae of the insult. Of relevance is the prevention of seizures and attenuation of their neuropathological sequelae as a consequence of exposure to a more complex environment. Relatively little attention, however, has been given to the issue of sensitive periods associated with such effects, the relative importance of social versus inanimate stimulation, or the unique contribution of exercise. Our studies have examined the effects of environmental complexity on the development of the restricted, repetitive behavior commonly observed in individuals with autism. In this model, a more complex environment substantially attenuates the development of the spontaneous and persistent stereotypies observed in deer mice reared in standard laboratory cages. Our findings support a sensitive period for such effects and suggest that early enrichment may have persistent neuroprotective effects after the animal is returned to a standard cage environment. Attenuation or prevention of repetitive behavior by environmental complexity was associated with increased neuronal metabolic activity, increased dendritic spine density, and elevated neurotrophin (BDNF) levels in brain regions that are part of cortical-basal ganglia circuitry. These effects were not observed in limbic areas such as the hippocampus.     

Cognitive deficits in developmental disorders

The existence of specific developmental disorders such as dyslexia and autism raises interesting issues about the structure of the normally developing mind. In these disorders distinct cognitive deficits can explain a range of behavioural impairments and have the potential to be linked to specific brain abnormalities. One possibility is that there are specific mechanisms dedicated to particular types of information processing. These mechanisms may function independently of more general information processing systems and may have a distinct anatomical basis in the brain.     

A model for narcolepsy.

A model for narcolepsy is developed on the basis of data obtained from brains collected at post mortem from three patients with narcolepsy. The concentration of dopamine, noradrenaline, and serotonin and their metabolites was measured in many brain regions. The number and affinity of the 3-H-spiperone and 3-H-prazocin binding sites was also measured in many of these regions to characterize the D-2 dopamine and alpha-1-noradrenergic receptors, respectively. Evidence for significantly increased serotonin levels and serotonin turnover was found in many brain regions. Noradrenaline turnover was increased in the frontal cortex. DOPAC/DA was significantly reduced in the striatum. The number of D-2 dopamine receptors, however, was markedly increased in this region. The number of alpha-1-noradrenergic receptors was significantly decreased in the frontal cortex and amygdala. Our neurochemical data demonstrating increased NA and 5-HT turnover suggest that locus coeruleus noradrenergic neurones and raphe serotonergic neurones are overactive in narcolepsy. Current evidence posits that increased activity in these neurones depresses the activity of cholinergic pedunculopontine (PP) REM sleep effector neurones. PP neurones project to and stimulate the dopaminergic substantia nigra compacta neurones. Decreased PP activity in narcolepsy, thus, could lead to pontine cholinergic supersensitivity and could also reduce the firing rates of dopaminergic neurones, as the low striatal ratio of DOPAC/DA suggests. An increase in the number of D-2 dopamine receptors in the striatum may result. The reason for the increased activity of the noradrenergic and serotonergic neurones remains to be determined, but immune inactivation of alpha-1-noradrenergic receptors may be the initiating event. Low alpha-1-noradrenergic receptor numbers may account for the chronic drowsiness of narcolepsy. The repeated entry into sleep, and into REM sleep in particular, may represent a homeostatic response to increase these receptor numbers and, thus, to increase alertness. Some therapeutic implications of this model are presented in the discussion.     

网络成瘾者的大脑异于常人吗?

研究网络成瘾者的大脑是否异于常人的问题有助于对网络成瘾进行定性、诊断和治疗。近年来认知神经科学研究发现, 与正常人相比, 网络成瘾者的大脑主要存在四个方面的异常：①额叶和扣带回多部位存在结构性萎缩和功能退化, 导致其对上网行为的冲动控制出现障碍。②海马功能障碍, 导致其认知功能特别是工作记忆能力下降。③奖赏中枢功能代偿性增强, 可能与其多巴胺系统的功能异常有关。④内囊后肢的神经纤维结构较密、活性较高, 可能与其长时间兴奋性操作键盘、鼠标或游戏手柄有关。目前的研究结果至少说明：网络成瘾者的大脑存在一些功能性的、与物质成瘾者类似的异常, 但这些异常是否由网络成瘾导致, 以及这些异常是结构性的, 还是持久性的, 则还需要进一步的研究来证实。     

Combination pharmacotherapy in alcoholism: a novel treatment approach

Combination pharmacotherapy has proven effective in a number of psychiatric disorders, including depression and schizophrenia. However, compared with other affective disorders, few studies have explored the use of combination therapy in alcoholism, and the majority have been limited to animal models. There is evidence to support a role for combination therapy in alcoholism. For example, several neurochemical systems, including the dopaminergic, serotonergic, and opioidergic, appear to affect alcohol intake. Studies in several different types of alcohol-preferring rats have suggested that coadministration of agents to target more than one of these systems simultaneously may produce beneficial effects on alcohol intake, while avoiding problematic effects, such as alterations in food or water intake. Data from preliminary clinical studies have shown trends toward combination therapy reducing alcohol intake in humans. While such findings are encouraging, they must be explored further in larger, randomized, double-blind trials.     

自闭症谱系障碍的生物基础

自闭症谱系障碍是一组发病于生命早期, 由一系列生理、心理因素引起的神经发育障碍。遗传、脑神经结构、营养素等是自闭症谱系障碍的生物基础的重要来源。个体在孕育早期形成的大脑和机体异常可能是导致自闭症谱系障碍的关键。这种异常在出生后的发育中具体作用于神经活动、脑发育、免疫系统等生理途径。研究者们今后可以尝试横跨不同自闭症谱系障碍亚型、年龄和发育阶段, 开展横向与纵向相结合的大范围研究, 以进一步明确自闭症谱系障碍的生物基础。     

Probing emotion in the developing brain: functional neuroimaging in the assessment of the neural substrates of emotion in normal and disordered children and adolescents

Virtually all developmental neuropsychiatric disorders involve some dysfunction or dysregulation of emotion. Moreover, many psychiatric disorders with adult onset have early subclinical manifestations in children. This essay selectively reviews the literature on the neuroimaging of affect and disorders of affect in children. Some critical definitional and conceptual issues are first addressed, including the distinctions between the perception and production of emotion and between emotional states and traits. Developmental changes in morphometric measures of brain structure are then discussed and the implications of such findings for studies of functional brain activity are considered. Data on functional neuroimaging and childhood depression are then reviewed. While the extant data in this area are meager, they are consistent with studies in adults that have observed decreased left-sided anterolateral prefrontal cortex activation in depression. Studies in children on the recognition of emotion and affective intent in faces using functional magnetic resonance imaging are then reviewed. These findings indicate that the amygdala plays an important role in such affective face processing in children, similar to the patterns of activation observed in adults. Moreover, one study has reported abnormalities in amygdala activation during a task requiring the judgment of affective intent from the eye region of the face in subjects with autism. Some of the methodological complexities of developmental research in this area are discussed, and directions for future research are suggested.