The ontogenesis of language impairment in autism: a neuropsychological perspective.

Autistic Disorder (AD) is a phenotypically heterogeneous condition characterized by impairments in social interaction, communication, and the presence of repetitive behavior and restricted interests. It is a model syndrome to investigate neural interaction and integration at the nexus of language and social cognition. This paper considers the problems of language acquisition in AD from an evolutionary and ontogenetic context. Following a review of normal language development during the formative years of brain development, we examine what is known about infant linguistic and nonlinguistic precursors of language acquisition in AD and examine how anomalies of several processes relate to language abnormalities manifest by the early elementary school years. Population heterogeneity and practical limitations inherent to the study of children currently limit a comprehensive understanding of the significance of specific neurological abnormalities in relation to observed deficits. However, convergent evidence implicates anomalies of a widely distributed neural network, involving superior temporal sulcus, superior temporal gyrus, supramarginal gyrus, insula, inferior frontal gyrus, hippocampus, amygdala and cerebellum. These anomalies reflect the cumulative effects of genetic, epigenetic and environmental influences. Neuropsychological studies of language in AD provide an important means to define the phenotypic variation resulting from alterations in neural architecture. By mapping broad relationships between key symptoms, neuropsychological impairment and neural substrate, information derived from these studies enable a level of analysis that bridges the gap between the genome and the syndrome. Further study of children during the critical first 2 years of life using behavioral, electrophysiological, and functional neuroimaging methods is essential.

Regression in autistic spectrum disorders.

A significant proportion of children diagnosed with Autistic Spectrum Disorder experience a developmental regression characterized by a loss of previously-acquired skills. This may involve a loss of speech or social responsitivity, but often entails both. This paper critically reviews the phenomena of regression in autistic spectrum disorders, highlighting the characteristics of regression, age of onset, temporal course, and long-term outcome. Important considerations for diagnosis are discussed and multiple etiological factors currently hypothesized to underlie the phenomenon are reviewed. It is argued that regressive autistic spectrum disorders can be conceptualized on a spectrum with other regressive disorders that may share common pathophysiological features. The implications of this viewpoint are discussed.

Speech perceived through a damaged temporal window: lessons from word deafness and aphasia.

Word deafness is an intriguing neurological syndrome characterized by severe difficulties in the ability to understand or reproduce spoken language with otherwise intact speech production and nonauditory language comprehension. The disorder is of significant theoretical importance because it putatively supports the modularity of speech recognition from more central language computational networks. However, the specificity and functional locus of the processing disturbances resulting in word deafness remains unclear. This article discusses the nature and potential treatment of word deafness, with particular reference to a detailed case study (neuropsychological, neuroimaging, and event-related potential) of an adult case of Landau-Kleffner syndrome. The findings in this case suggested temporal lobe pathophysiology involving cortical mechanisms concerned with temporal processing of rapid frequency changes in sound. We propose that these deficits may impede the analysis of linguistically important transitional frequency cues in speech and account for the profound difficulties in understanding and producing speech. The implications of these findings for approaches to the treatment of word deafness are discussed.

Activation of human auditory cortex during speech perception: effects of monaural, binaural, and dichotic presentation.

We used a rapid event-related functional magnetic resonance imaging (fMRI) paradigm to compare cortical activation to speech tokens presented monaurally to each ear, binaurally, and dichotically. Two forms of dichotic conditions were examined: one presented consonant-vowel (CV) syllables simultaneously to each ear while the other paired a CV syllable with a non-speech stimulus (band-limited noise). Right-handed adults were asked to differentially respond to serially presented target and distractor CV syllables. Activations were localized with reference to anatomic segmentation algorithms that allowed us to distinguish between activity in primary (PAC) and non-primary auditory cortex (NPAC). Monaural CV syllables presented to the right ear (CVR) produced highly asymmetric activations in left PAC and NPAC. A similar but reduced left hemisphere (LH) bias was evident in binaural presentation, when monaural syllables were paired with contra-aural noise, and in dichotic CV-CV presentations. However, LH activation was two times larger to CVR than any other condition, while RH activation to CVR was insubstantial. By contrast, a small rightward asymmetry in PAC activation was observed from monaural left ear (CVL) presentation. In all conditions except CVL, magnitude of response favored left PAC and NPAC. CV processing across different listening conditions disclosed complex interactions in activation. Our results confirm the superiority of left NPAC in speech processing and suggest comparable left lateralization in PAC. The findings suggest that monaural CV presentation may be more useful than previously anticipated. The paradigm developed here may hold some promise in investigations where abnormal hemispheric balance of speech processing is suspected.

Attention-deficit/hyperactivity disorder: a neuropsychological perspective towards DSM-V.

Neuropsychological methods and techniques have much to offer in the evaluation of the individual suspected as having Attention-Deficit/Hyperactivity Disorder (ADHD). After a review of the historical evolution of the ADHD concept, incidence and prevalence, and DSM-IV criteria for diagnosis, especially as regards omission related to gender differences, and other associated cultural, familial, socioenvironmental, and subject influences, this paper describes a number of dilemmas and obstacles encountered in clinical practice. Included are the confounds associated with the wide range of possible comorbidities, the insufficiency of current DSM-IV criteria, the emergence of subtype differentiation and its impact on diagnosis and treatment. The complex relationship between neuropsychological constructs and ADHD, and obstacles to valid assessment are also addressed. The complexities associated with a thorough ADHD evaluation are viewed within an impressive and expansive existing scientific framework and recommendations are made for future directions.

Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis.

Multiple theories of Attention-Deficit/Hyper-activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.

On pure word deafness, temporal processing, and the left hemisphere.

Pure word deafness (PWD) is a rare neurological syndrome characterized by severe difficulties in understanding and reproducing spoken language, with sparing of written language comprehension and speech production. The pathognomonic disturbance of auditory comprehension appears to be associated with a breakdown in processes involved in mapping auditory input to lexical representations of words, but the functional locus of this disturbance and the localization of the responsible lesion have long been disputed. We report here on a woman with PWD resulting from a circumscribed unilateral infarct involving the left superior temporal lobe who demonstrated significant problems processing transitional spectrotemporal cues in both speech and nonspeech sounds. On speech discrimination tasks, she exhibited poor differentiation of stop consonant-vowel syllables distinguished by voicing onset and brief formant frequency transitions. Isolated formant transitions could be reliably discriminated only at very long durations (> 200 ms). By contrast, click fusion threshold, which depends on millisecond-level resolution of brief auditory events, was normal. These results suggest that the problems with speech analysis in this case were not secondary to general constraints on auditory temporal resolution. Rather, they point to a disturbance of left hemisphere auditory mechanisms that preferentially analyze rapid spectrotemporal variations in frequency. The findings have important implications for our conceptualization of PWD and its subtypes.

The effect of genetic differences and ovarian failure: intact cognitive function in adult women with premature ovarian failure versus turner syndrome.

Premature ovarian failure (POF) is generally defined as amenorrhea, hypoestrogenism, and elevated gonadotropins occurring in a woman before the age of 40 yr. Usually, the etiology is unknown. Turner syndrome (TS, monosomy X), also associated with ovarian failure, has a characteristic neurocognitive profile. TS females, as a group, have specific deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function, and attentional abilities. Observed deficits in TS could be due to endocrine (estrogen deficiency) or genetic factors. If early estrogen deficiency contributes to the cognitive deficits in TS, women with POF would also be at risk for similar findings. The objective of this work was to examine the specific cognitive profile in women with POF and compare it with women with TS and normal female controls. We compared two unique populations (women with POF vs. TS), both with earlier estrogen deficiency. The TS group only had a major genetic deficiency, absence of all or part of one X chromosome. We evaluated the cognitive performance of estrogen-repleted women with POF (n = 89), compared with verbal IQ- and socioeconomic status-matched females with TS (n = 94) and controls (n = 96). Performance by the POF population was similar to that of controls and differed from the TS population. In contrast, TS adults had relative difficulty with measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attention, and executive function. These deficits are apparent in TS women, despite apparently adequate estrogen treatment. The cognitive phenotypes of women with POF and normal controls are similar and differ from women with TS, indicating that prior estrogen deficiency does not have a major impact on cognitive function in adult females. The genetic deficiencies of women with TS most likely account for their specific cognitive phenotype.

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.