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.     

Perinatal anoxia degrades auditory system function in rats

Little is known about the neural bases of the reduced auditory and cortical processing speeds that have been recorded in language-impaired, autistic, schizophrenic, and other disabled human populations. Although there is strong evidence for genetic contributions to etiologies, epigenetic factors such as perinatal anoxia (PA) have been argued to be contributors, or causal, in a significant proportion of cases. In this article, we explored the consequences of PA on this elementary aspect of auditory behavior and on auditory system function in rats that were briefly perinatally anoxic. PA rats had increased acoustic thresholds and reduced processing efficiencies recorded in an auditory behavioral task. These rats had modestly increased interpeak intervals in their auditory brainstem responses, and substantially longer latencies in poststimulus time histogram responses recorded in the primary auditory cortex. The latter were associated with degraded primary auditory cortex receptive fields and a disrupted tonotopy. These processing deficits are consistent with the parallel behavioral and physiological deficits recorded in children and adults with a history of language-learning impairment and autism.     

Cortical auditory signal processing in poor readers

Magnetoencephalographic responses recorded from auditory cortex evoked by brief and rapidly successive stimuli differed between adults with poor vs. good reading abilities in four important ways. First, the response amplitude evoked by short-duration acoustic stimuli was stronger in the post-stimulus time range of 150-200 ms in poor readers than in normal readers. Second, response amplitude to rapidly successive and brief stimuli that were identical or that differed significantly in frequency were substantially weaker in poor readers compared with controls, for interstimulus intervals of 100 or 200 ms, but not for an interstimulus interval of 500 ms. Third, this neurological deficit closely paralleled subjects' ability to distinguish between and to reconstruct the order of presentation of those stimulus sequences. Fourth, the average distributed response coherence evoked by rapidly successive stimuli was significantly weaker in the beta- and gamma-band frequency ranges (20-60 Hz) in poor readers, compared with controls. These results provide direct electrophysiological evidence supporting the hypothesis that reading disabilities are correlated with the abnormal neural representation of brief and rapidly successive sensory inputs, manifested in this study at the entry level of the cortical auditory/aural speech representational system(s).     

Age-dependent capacity for somatosensory cortex reorganization in chronic spinal cats

Primary somatosensory cortex was mapped in chronic spinal cats that were spinalized (T12) at two weeks and 6 weeks of age. The magnitude of cortical reorganization is age-dependent. In cats spinalized at two weeks, extensive reorganization of the deafferented hindlimb region resulted in a second complete map of intact tactile input from the trunk and forelimb, while in cats transected at 6 weeks of age, trunk afferent input only partially activated the deafferented hindlimb region.     

Variability in hand surface representations in areas 3b and 1 in adult owl and squirrel monkeys

Detailed microelectrode maps of the hand representation were derived in cortical areas 3b and 1 from a series of normal adult owl and squirrel monkeys. While overlap relationships were maintained, and all maps were internally topographic, many map features varied significantly when examined in detail. Variable features of the hand representations among different monkeys included a) the overall shapes and sizes of hand surface representations; b) the actual and proportional areas of representations of different skin surfaces and the cortical magnifications of representations of specific skin surfaces, which commonly varied severalfold in area 3b and manyfold in area 1; c) the topographic relationships among skin surface representations, with skin surfaces that were represented adjacently in some monkeys represented in locations many hundreds of microns apart in others; d) the internal orderliness of representations; e) the completeness of representations of the dorsal hand surfaces; and f) the skin surfaces represented along the borders of the hand representation. Owl monkey maps were, in general, internally more strictly topographic than squirrel monkey maps. In both species, area 3b was more strictly topographic and less variable than was area 1. The degree of individual variability revealed in these experiments is difficult to reconcile with the hypothesis that details of cortical maps are ontogenetically specified during a period in early life. Instead, we propose that differences in the details of cortical map structure are the consequence of individual differences in lifelong use of the hands. This conclusion is consistent with earlier studies of the consequences of peripheral nerve transection and digital amputation, which revealed that cortical maps are dynamically maintained and are alterable as a function of use or nerve injury in these monkeys (Merzenich et al., '83a,b, '84a; Merzenich, '86; Jenkins et al., '84; Jenkins and Merzenich, '87).     

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.     

Cardiac late effects after modern 3D-conformal radiotherapy in breast cancer patients: a retrospective cohort study in Germany (ESCaRa)

Breast Cancer Research and Treatment - Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques...     

Band-pass response properties of rat SI neurons

Rats typically employ 4- to 12-Hz "whisking" movements of their vibrissae during tactile exploration. The intentional sampling of signals in this frequency range suggests that neural processing of tactile information may be differentially engaged in this bandwidth. We examined action potential responses in rat primary somatosensory cortex (SI) to a range of frequencies of vibrissa motion. Single vibrissae were mechanically deflected with 5-s pulse trains at rates /=3 Hz. In contrast with this low-pass feature of the response, several other characteristics of the response revealed bandpass response properties. While average evoked response amplitudes measured 0-35 ms after stimulus onset typically decreased with increasing frequency, the later components of the response (>15 ms post stimulus) were augmented at frequencies between 3 and 10 Hz. Further, during the steady state, both rate and temporal measures of neural activity, measured as total spike rate or vector strength (a measure of temporal fidelity of spike timing across cycles), showed peak signal values at 5-10 Hz. A minimal biophysical network model of SI layer IV, consisting of an excitatory and inhibitory neuron and thalamocortical input, captured the spike rate and vector strength band-pass characteristics. Further analyses in which specific elements were selectively removed from the model suggest that slow inhibitory influences give rise to the band-pass peak in temporal precision, while thalamocortical adaptation can account for the band-pass peak in spike rate. The presence of these band-pass characteristics may be a general property of thalamocortical circuits that lead rodents to target this frequency range with their whisking behavior.     

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)     

Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation

1. Multiple microelectrode maps of the hand representation within and across the borders of cortical area 3b were obtained before, immediately after, or several weeks after a period of behaviorally controlled hand use. Owl monkeys were conditioned in a task that produced cutaneous stimulation of a limited sector of skin on the distal phalanges of one or more fingers. 2. Analysis of microelectrode mapping experiment data revealed that 1) stimulated skin surfaces were represented over expanded cortical areas. 2) Most of the cutaneous receptive fields recorded within these expanded cortical representational zones were unusually small. 3) The internal topography of representation of the stimulated and immediately surrounding skin surfaces differed greatly from that recorded in control experiments. Representational discontinuities emerged in this map region, and "hypercolumn" distances in this map sector were grossly abnormal. 4) Borders between the representations of individual digits and digit segments commonly shifted. 5) The functionally defined rostral border of area 3b shifted farther rostralward, manifesting either an expansion of the cutaneous area 3b fingertip representation into cortical field 3a or an emergence of a cutaneous input zone in the caudal aspect of this normally predominantly deep-receptor representational field. 6) Significant lateralward translocations of the borders between the representations of the hand and face were recorded in all cases. 7) The absolute locations--and in some cases the areas or magnifications--of representations of many skin surfaces not directly involved in the trained behavior also changed significantly. However, the most striking areal, positional, and topographic changes were related to the representations of the behaviorally stimulated skin in every studied monkey. 3. These experiments demonstrate that functional cortical remodeling of the S1 koniocortical field, area 3b, results from behavioral manipulations in normal adult owl monkeys. We hypothesize that these studies manifest operation of the basic adaptive cortical process(es) underlying cortical contributions to perception and learning.