Clinical neuroscience research最新文献

Neuroinflammatory processes play a significant role in the pathogenesis of Parkinson’s disease (PD). Epidemiologic, animal, human, and therapeutic studies all support the presence of a neuroinflammatory cascade in disease. This is highlighted by the neurotoxic potential of microglia. In steady-state, microglia serve to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of innate and adaptive immune responses. In neurodegenerative diseases, activated microglia affect neuronal injury and death through production of glutamate, pro-inflammatory factors, reactive oxygen species, quinolinic acid among others and by mobilization of adaptive immune responses and cell chemotaxis leading to transendothelial migration of immunocytes across the blood–brain barrier and perpetuation of neural damage. As disease progresses, inflammatory secretions engage neighboring glial cells, including astrocytes and endothelial cells, resulting in a vicious cycle of autocrine and paracrine amplification of inflammation perpetuating tissue injury. Such pathogenic processes contribute to neurodegeneration in PD. Research from others and our own laboratories seek to harness such inflammatory processes with the singular goal of developing therapeutic interventions that positively affect the tempo and progression of human disease.

Epidemiological twin studies demonstrate that autism spectrum disorders (ASDs) represent genetic disorders. Subsequent analyses indicate that the causes of ASDs include rarer single gene mutations and chromosomal abnormalities, as well as ASDs caused by multiple interacting genes of weak effect. Genome-wide linkage analysis has identified several susceptibility loci for the ASDs, and positional and functional candidate genes have been identified that may represent susceptibility genes for the ASDs. Analysis of additional larger samples, and the use of genome-wide association and high-throughput variant detection will lead to the identification of further genes for ASDs.

All children with autism spectrum disorders have deficits in pragmatic aspects of communication; however, formal language abilities are extremely heterogeneous, ranging from nonverbal to superior linguistic skills. Recent studies have focused on defining different language phenotypes among verbal children. One subtype has been compared to specific language impairment (SLI), a language disorder that is diagnosed on the basis of delays and deficits in language acquisition in the absence of hearing impairment, frank neurological damage or co-morbid psychopathology. Two behavioral studies address the question of whether children with autism and language impairment have specific language deficits that are similar to those found in SLI. These experiments focused on phonological processing in a nonsense word repetition task, and use of grammatical morphology in conversational speech. The findings from these studies are discussed in the context of recent neuroimaging and genetic studies of autism.

This review focuses on a description of two studies that are currently ongoing in the Rubenstein laboratory. The first is the analysis of the Dlx homeobox genes in controlling differentiation of forebrain GABAergic neurons, the principal type of inhibitory neurons. The second is the analysis of mechanisms that control formation of regions of the cerebral cortex; Fgf signaling appears to have a central role in formation of the frontal cortex. We are currently exploring the possibility that both processes contribute to childhood neuropsychiatric disorders.

Some third of parents of children on the autism spectrum report that their toddler’s language regressed, usually insidiously, or stagnated during a prolonged plateau. Regression was associated with loss of sociability, interest in toys, and other behavioral skills, without motor regression. After months or longer, language usually returns, but variably severe autistic features persist. Nonverbal cognitive skills may or may not be affected. Some parents recall some antecedent nonspecific illness or stressor like the absence of a parent, a move, or the birth of a sibling. Occasionally, regression seems temporally related to an epileptic seizure, suggesting an overlap with acquired epileptic aphasia (Landau–Kleffner syndrome—LKS) in which language regression is associated with either clinical seizures or subclinical perisylvian temporo-parietal epileptiform EEG activity. LKS onset peaks at 4–6 years, autistic regression before age 2 years and is infrequently associated with seizures or an epileptiform EEG, except in the rare case of disintegrative disorder, a late global autistic regression which, like LKS, may be associated with electrical status epilepticus in slow wave sleep. Mute or dysfluent children with LKS, autism, or developmental language disorders are unable to decode or have difficulty decoding acoustically presented language (speech). They are at higher risk for epilepsy than fluent children with the typically aberrant language of verbal children with autism. The pathogenesis of language regression remains unknown because autistic toddlers are rarely studied at the time of language regression so that no empirically validated effective treatment has yet been devised.

Structural MRI studies of the brain in autism have yielded inconsistent results until recent years. Studies over the past decade have revealed several exciting new findings and have fostered novel hypotheses about the onset and etiology of this disorder. The most consistent MRI finding in autism is that the brain is enlarged. Studies have suggested that brain overgrowth may be most robust early in development, but increased brain volume has been observed throughout adolescence and early adult life. Retrospective head circumference studies have indicated that the onset of brain enlargement may occur during the latter part of the first year of life and does not appear to be present at birth. Recent studies of infant siblings of children with autism suggest that the onset of the core behavioral features of autism also occur during the latter part of the first year of life and may not be present by 6 months of age. The coincident timing of the onset of brain and behavioral abnormalities in autism suggests that these features may be related. Future longitudinal MRI studies of infant siblings of children with autism will help elucidate this relationship and potentially delineate the pathogenesis of this disorder. Additional findings from structural MRI studies of autism have begun to map patterns of brain overgrowth across cortical lobes and tissue types (gray and white matter). These studies are somewhat inconsistent, but suggest generalized overgrowth affecting both cortical gray and cortical white matter, as well as several subcortical structures. The diffuse network of regions affected has shifted research attention from hypotheses about specific regions and structures to more widespread mechanisms involving neural circuits and diffuse mechanisms at the neuronal level. These findings, their implications for our understanding of the pathogenesis of autism, and future directions for structural MRI studies of autism are discussed.

Autism, as defined by Kanner in 1943, required two features: the abnormal development of social relationships and the obsessive desire for the maintenance of sameness. This definition was applied only to children without dysmorphic features (except macrocephaly) and without profound mental retardation. This definition resulted in a strongly familial disorder. Family members of such cases have not only strictly defined autism but the milder Pervasive Developmental Disorder, Not Otherwise Specified (PDDNOS), and Asperger syndrome as well as milder social dysfunction, obsessional personality characteristics, language and reading disorders, and anxiety and depression. Some of these conditions have come to be called “autism spectrum disorders”. Family members of strictly defined autism cases do not tend to have mental retardation, even when the proband with autism may have marked cognitive impairment and limited language. Another group of children that often meet modern criteria for autism and PDDNOS are those with profound mental retardation (IQ < 35 or 40), children with dysmorphic facial features, specific genetic conditions, such as tuberous sclerosis or Retts syndrome, and children who have suffered certain kinds of severe encephalitis at an early age. These children are etiologically very heterogeneous and need to be considered separately in studies of etiology and mechanism.

Autism is a pervasive developmental condition, characterized by impairments in non-verbal communication, social relationships and stereotypical patterns of behavior. A large body of evidence suggests that several aspects of face processing are impaired in autism, including anomalies in gaze processing, memory for facial identity and recognition of facial expressions of emotion. In search of neural markers of anomalous face processing in autism, much interest has focused on a network of brain regions that are implicated in social cognition and face processing. In this review, we will focus on three such regions, namely the STS for its role in processing gaze and facial movements, the FFA in face detection and identification and the amygdala in processing facial expressions of emotion. Much evidence suggests that a better understanding of the normal development of these specialized regions is essential for discovering the neural bases of face processing anomalies in autism. Thus, we will also examine the available literature on the normal development of face processing. Key unknowns in this research area are the neuro-developmental processes, the role of experience and the interactions among components of the face processing system in shaping each of the specialized regions for processing faces during normal development and in autism.