Neural deficits in children with dyslexia ameliorated by behavioral remediation: evidence from functional MRI

Developmental dyslexia, characterized by unexplained difficulty in reading, is associated with behavioral deficits in phonological processing. Functional neuroimaging studies have shown a deficit in the neural mechanisms underlying phonological processing in children and adults with dyslexia. The present study examined whether behavioral remediation ameliorates these dysfunctional neural mechanisms in children with dyslexia. Functional MRI was performed on 20 children with dyslexia (8-12 years old) during phonological processing before and after a remediation program focused on auditory processing and oral language training. Behaviorally, training improved oral language and reading performance. Physiologically, children with dyslexia showed increased activity in multiple brain areas. Increases occurred in left temporo-parietal cortex and left inferior frontal gyrus, bringing brain activation in these regions closer to that seen in normal-reading children. Increased activity was observed also in right-hemisphere frontal and temporal regions and in the anterior cingulate gyrus. Children with dyslexia showed a correlation between the magnitude of increased activation in left temporo-parietal cortex and improvement in oral language ability. These results suggest that a partial remediation of language-processing deficits, resulting in improved reading, ameliorates disrupted function in brain regions associated with phonological processing and produces additional compensatory activation in other brain regions.     

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

Abnormal cortical circuitry and function as well as distortions in the modulatory neurological processes controlling cortical plasticity have been argued to underlie the origin of autism. Here, we chemically distorted those processes using an antidepressant drug-exposure model to generate developmental neurological distortions like those characteristics expressed in autism, and then intensively trained altered young rodents to evaluate the potential for neuroplasticity-driven renormalization. We found that young rats that were injected s.c. with the antidepressant citalopram from postnatal d 1–10 displayed impaired neuronal repetition-rate following capacity in the primary auditory cortex (A1). With a focus on recovering grossly degraded auditory system processing in this model, we showed that targeted temporal processing deficits induced by early-life antidepressant exposure within the A1 were almost completely reversed through implementation of a simple behavioral training strategy (i.e., a modified go/no-go repetition-rate discrimination task). Degraded parvalbumin inhibitory GABAergic neurons and the fast inhibitory actions that they control were also renormalized by training. Importantly, antidepressant-induced degradation of serotonergic and dopaminergic neuromodulatory systems regulating cortical neuroplasticity was sharply reversed. These findings bear important implications for neuroplasticity-based therapeutics in autistic patients.Recently, extensive efforts have been made to understand better the etiology of pervasive developmental disorders (PDDs), such as autism spectrum disorders (ASDs), with an ultimate goal of identifying preventive and more effective treatment strategies. At present, a general consensus from both human and animal studies is that a variety of genetic and environmental factors play an integrated role in the establishment of neurobehavioral abnormalities marking these disorders (1–5). Given the complexity of its origins and of the expressions of neurological abnormalities in ASD, it has been generally concluded that no single drug or therapy can be expected to provide effective treatment for the core and associated symptoms of ASDs (6–9).Interestingly, early behavioral intervention has been associated with significant improvements in intelligence quotient, language acquisition, and adaptive behavior (10). Furthermore, positive outcomes of individuals with an unequivocal history of moderate-severe ASD (11) provide hope that the strong behavioral deficits expressed in the disorder might, on some corrective neurobehavioral path, be reversible. What is that path? A critical question to answer is whether and to what extent the cortical network dysfunction and the subcortical machinery that regulates it, repeatedly described as distorted in humans with autism and in animal models of autism (12–15), can be reversed, either through drug treatment or via behavioral approaches.Cortical circuit miswirings and synaptic malformations are characteristic neuropathological markers for ASDs (14, 16, 17). Recent studies have clearly implicated that early exposure to selective serotonin reuptake inhibitors (SSRIs) could have long-term consequences on neurodevelopment (18). Specifically, rodent studies have shown that perinatal exposure to SSRIs like citalopram (CTM) induce abnormal autistic-like behaviors and cortical network disorganization, including degraded topographic organization and callosal connectivity (19, 20). Exposure to SSRIs also alters speech perception in infants (21). A potential link between prenatal SSRI exposure and subsequent ASDs in children has been indicated recently by studies of Harrington et al. (22). Interestingly, most of these children with ASDs also display deficient auditory temporal processing (23). In addition, a series of auditory behavioral training studies in rodents have shown that auditory cortical network miswirings can potentially be reversed at any postnatal age (24–27). All of these studies prompted us to investigate further whether intensive auditory behavioral training could result in a reversal in auditory system network function and in global forebrain network miswiring in this rat autism (SSRI-exposed) model.     

The topographic organization of corticocollicular projections from physiologically identified loci in the AI,AII, and anterior auditory cortical fields of the cat

The connections of the three auditory fields AI, AII, and the anterior auditory field (AAF) with the inferior colliculus (IC) were studied using anterograde tracing techniques. Microinjections of tracers were placed at physiologically identified loci after these fields had been functionally mapped using microelectrode recording techniques. This methodology ensured that the injections were well within the borders of each cortical field that was studied and enabled the elucidation of the topographies of the projections of AI and AAF onto the IC with respect to their cochleotopicorganizations. The projection of loci in AI to the caudal aspect of the IC was in the form of sheets of terminals in the dorsomedial division of the central nucleus bilaterally and the pericentral nucleus ipsilaterally. The topography of projection with respect to the cochleotopic organization of AI appeared to be in register with the described cochleotopic organization of the central nucleus and the pericentral nucleus. The sheets of labeled terminals in the dorsomedial division of the central nucleus that resulted from the projection of single loci in AI were of the proper orientation to be continuous with the morphological laminae described in the ventrolateral division of the central nucleus. These sheets of corticocollicular terminals also paralleled the dorsomedial aspect of the physiologically defined “isofrequency contours” of the central nucleus. Single injections placed in AAF produced autoradiographic label in the IC that was of the same basic pattern and systematic topography as the labeling recorded with AI injections; however, it was much weaker. The projection from AII was to the lateral (ipsilateral) and medial (bilateral) aspects of the pericentral nucleus.     

Neurophysiological correlates of hand preference in primary motor cortex of adult squirrel monkeys.

Variability in the functional topography of area 4 was examined in adult squirrel monkeys. Conventional intracortical microstimulation techniques were used to derive detailed maps (250 microns interpenetration distances) of distal forelimb movement representations in both hemispheres of six monkeys. Spatial features of these representational maps were then compared to the hand preferred by the individual animals during a motor task requiring skilled digit use. Beyond a few broad generalizations common to all area 4 motor maps, the local mosaic-like topography of individual distal forelimb representations was highly idiosyncratic. Using statistical procedures to determine the independent contributions of individual, side, and movement category to the total variation in motor maps, the results demonstrate statistically significant variation in representational topography among individuals as well as between hemispheres of the same individuals. In the dominant hemisphere (i.e., the hemisphere opposite the preferred hand), the distal forelimb representations generally were greater in number and larger in total area, and displayed a longer total boundary length and a greater index of spatial complexity. Because of the direct relationship between interhemispheric asymmetry and behavioral asymmetry, these studies suggest that a large source of variability found in the topography of motor maps in this and other studies derives from differences in the way particular movements and/or movement combinations are performed by individual animals.     

Representation of the cochlear partition on the superior temporal plane of the macaque monkey

The distribution of best frequencies of neurons and neuron clusters was mapped on the superior temporal plane of the macaque monkey. Primary auditory cortex (A1) comprises a complete and orderly cochlear representation. It is coextensive with a cytoarchitectonic field often referred to as koniocortex. Cochlear apex (low frequency) is represented rostrolaterally within the field and cochlear base (high frequency) caudomedially. A small region of the cochlear partition is found represented in a band of auditory cortex; that is neurons with very similar best frequencies are arrayed both vertically and horizontally. Surrounding A1 4 other fields are found that on both anatomical and physiological grounds stand apart from the primary field. In two of them the data suggest the way in which they are topographically organized. In addition there appear to be auditory areas extending further rostrally on the plane and onto the lateral surface of the superior temporal gyrus.     

Optical imaging and electrophysiology of rat barrel cortex. I. Responses to small single-vibrissa deflections

A study was undertaken to investigate the response of the rodent somatosensory barrel cortex to single-whisker, near-threshold vibrissal stimuli. Cortical responses to controlled whisker deflections were recorded by (i) conventional multi-unit extracellular recording within the cytochrome oxidase rich barrels centers and the interbarrel septa, and (ii) intrinsic signal optical imaging, a technique that provides a spatial view of cortical activation thought to be related to the deoxygenation of hemoglobin in activated areas. Barrel cortex neurons responded weakly to whisker deflections of 0.04 degrees. Their response to a series of small stimuli of increasing amplitude was well-fitted by a logarithmic function. Responses to larger stimuli declined monotonically with distance from the center of the barrel column, and were characterized by greater onset and offset firing rates, by greater post-excitatory reduction of firing to below spontaneous levels, and by shorter response latency. In comparison to measurements taken previously from primary vibrissal afferent fibers, we conclude that cortical cells can respond to activity in a very small fraction of first-order sensory neurons.      

Expansion of the cortical representation of a specific skin field in primary somatosensory cortex by intracortical microstimulation.

Intracortical microstimulation (ICMS) was applied to a single site in the middle cortical layers (III-IV) in the koniocortical somatosensory fields of sodium pentobarbital-anesthetized rats (Sml) and new world monkeys (area 3b). Low-threshold cutaneous receptive fields were defined in the cortical region surrounding the stimulation site prior to and following 2-6 hr of 5 microA ICMS stimulation. ICMS stimulation did not usually affect the receptive field location, size, or responsiveness to tactile stimulation of neurons at the stimulation site. However, the number of cortical neurons surrounding the stimulation site with a receptive field that overlapped with the ICMS-site receptive field increased in all studied animals, resulting in an enlarged cortical representation of a restricted skin region spanning several hundred microns. The mean size of receptive fields changed in some but not all cases. These results provide evidence that the responses of cortical neurons are subject to change by the introduction of locally coincident inputs into a single location, and demonstrate a capacity for representational plasticity in the neocortex in the absence of peripheral stimulation. These experimental observations are consistent with hypotheses that the cerebral cortex comprises radially oriented populations of neurons that share a common input, and that these inputs are shaped by coincident activity (see Edelman, 1978, 1987; Merzenich, 1987; Merzenich et al., 1990; von der Malsburg and Singer, 1988).     

Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study

Normal aging is associated with progressive functional losses in perception, cognition, and memory. Although the root causes of age-related cognitive decline are incompletely understood, psychophysical and neuropsychological evidence suggests that a significant contribution stems from poorer signal-to-noise conditions and down-regulated neuromodulatory system function in older brains. Because the brain retains a lifelong capacity for plasticity and adaptive reorganization, dimensions of negative reorganization should be at least partially reversible through the use of an appropriately designed training program. We report here results from such a training program targeting age-related cognitive decline. Data from a randomized, controlled trial using standardized measures of neuropsychological function as outcomes are presented. Significant improvements in assessments directly related to the training tasks and significant generalization of improvements to nonrelated standardized neuropsychological measures of memory (effect size of 0.25) were documented in the group using the training program. Memory enhancement appeared to be sustained after a 3-month no-contact follow-up period. Matched active control and no-contact control groups showed no significant change in memory function after training or at the 3-month follow-up. This study demonstrates that intensive, plasticity-engaging training can result in an enhancement of cognitive function in normal mature adults.     

Influences of un-modulated acoustic inputs on functional maturation and critical-period plasticity of the primary auditory cortex

Sensory experiences contribute to the development and specialization of signal processing capacities in the mammalian auditory system during a "critical period" of postnatal development. Earlier studies have shown that passive exposure to tonal stimuli during this postnatal epoch induces a large-scale expansion of the representations of those stimuli within the primary auditory cortex (A1) [Zhang LI, Bao S, Merzenich MM (2001) Persistent and specific influences of early acoustic environments on primary auditory cortex. Nat Neurosci 4:1123-1130]. Here, we show that exposing rat pups through the normal critical period epoch and beyond to continuous, un-modulated, moderate-level tones induces no such representational distortion, and in fact disrupts the normal development of frequency response selectivity and tonotopicity all across area A1. The area of cortex responding selectively to continuously exposed sound frequencies was actually reduced, when compared with rats reared in normal environments. Strong exposure-driven plasticity characteristic of the critical period could be induced well beyond the normal end of the critical period, by simply modulating the tonal stimulus. Thus, continuous tone exposure, like continuous noise exposure [Chang EF, Merzenich MM (2003) Environmental noise retards auditory cortical development. Science 300:498-502], ineffectively induces critical period plasticity, and indefinitely blocks the closure of a normally-brief critical period window. These findings again demonstrate the crucial role of temporally structured inputs for inducing the progressive cortical maturational changes that result in the closure of the critical period window.     

Changes in the distributed temporal response properties of SI cortical neurons reflect improvements in performance on a temporally based tactile discrimination task.

1. Temporal response characteristics of neurons were sampled in fine spatial grain throughout the hand representations in cortical areas 3a and 3b in adult owl monkeys. These monkeys had been trained to detect small differences in tactile stimulus frequencies in the range of 20-30 Hz. Stimuli were presented to an invariant, restricted spot on a single digit. 2. The absolute numbers of cortical locations and the cortical area over which neurons showed entrained frequency-following responses to behaviorally important stimuli were significantly greater when stimulation was applied to the trained skin, as compared with stimulation on an adjacent control digit, or at corresponding skin sites in passively stimulated control animals. 3. Representational maps defined with sinusoidal stimuli were not identical to maps defined with just-visible tapping stimuli. Receptive-field/frequency-following response site mismatches were recorded in every trained monkey. Mismatches were less frequently recorded in the representations of control skin surfaces. 4. At cortical locations with entrained responses, neither the absolute firing rates of neurons nor the degree of the entrainment of the response were correlated with behavioral discrimination performance. 5. All area 3b cortical locations with entrained responses evoked by stimulation at trained or untrained skin sites were combined to create population peristimulus time and cycle histograms. In all cases, stimulation of the trained skin resulted in 1) larger-amplitude responses, 2) peak responses earlier in the stimulus cycle, and 3) temporally sharper responses, than did stimulation applied to control skin sites. 6. The sharpening of the response of cortical area 3b neurons relative to the period of the stimulus could be accounted for by a large subpopulation of neurons that had highly coherent responses. 7. Analysis of cycle histograms for area 3b neuron responses revealed that the decreased variance in the representation of each stimulus cycle could account for behaviorally measured frequency discrimination performance. A strong correlation between these temporal response distributions and the discriminative performances for stimuli applied at all studied skin surfaces was even stronger (r = 0.98) if only the rising phases of cycle histogram were considered in the analysis. 8. The responses of neurons in area 3a could not account for measured differences in frequency discrimination performance. 9. These representational changes did not occur in monkeys that were stimulated on the same schedule but were performing an auditory discrimination task during skin stimulation. 10. It is concluded that by behaviorally training adult owl monkeys to discriminate the temporal features of a tactile stimulus, distributed spatial and temporal response properties of cortical neurons are altered.(ABSTRACT TRUNCATED AT 400 WORDS)