Environmental noise degrades hippocampus-related learning and memory.

The neural mechanisms underlying the impacts of noise on nonauditory function, particularly learning and memory, remain largely unknown. Here, we demonstrate that rats exposed postnatally (between postnatal days 9 and 56) to structured noise delivered at a sound pressure level of ∼65 dB displayed significantly degraded hippocampus-related learning and memory abilities. Noise exposure also suppressed the induction of hippocampal long-term potentiation (LTP). In parallel, the total or phosphorylated levels of certain LTP-related key signaling molecules in the synapses of the hippocampus were down-regulated. However, no significant changes in stress-related processes were found for the noise-exposed rats. These results in a rodent model indicate that even moderate-level noise with little effect on stress status can substantially impair hippocampus-related learning and memory by altering the plasticity of synaptic transmission. They support the importance of more thoroughly defining the unappreciated hazards of moderately loud noise in modern human environments.

A randomized clinical trial of plasticity-based cognitive training in mild traumatic brain injury.

Clinical practice guidelines support cognitive rehabilitation for people with a history of mild traumatic brain injury (mTBI) and cognitive impairment, but no class I randomized clinical trials have evaluated the efficacy of self-administered computerized cognitive training. The goal of this study was to evaluate the efficacy of a self-administered computerized plasticity-based cognitive training programmes in primarily military/veteran participants with a history of mTBI and cognitive impairment. A multisite randomized double-blind clinical trial of a behavioural intervention with an active control was conducted from September 2013 to February 2017 including assessments at baseline, post-training, and after a 3-month follow-up period. Participants self-administered cognitive training (experimental and active control) programmes at home, remotely supervised by a healthcare coach, with an intended training schedule of 5 days per week, 1 h per day, for 13 weeks. Participants (149 contacted, 83 intent-to-treat) were confirmed to have a history of mTBI (mean of 7.2 years post-injury) through medical history/clinician interview and persistent cognitive impairment through neuropsychological testing and/or quantitative participant reported measure. The experimental intervention was a brain plasticity-based computerized cognitive training programme targeting speed/accuracy of information processing, and the active control was composed of computer games. The primary cognitive function measure was a composite of nine standardized neuropsychological assessments, and the primary directly observed functional measure a timed instrumental activities of daily living assessment. Secondary outcome measures included participant-reported assessments of cognitive and mental health. The treatment group showed an improvement in the composite cognitive measure significantly larger than that of the active control group at both the post-training [+6.9 points, confidence interval (CI) +1.0 to +12.7, P = 0.025, d = 0.555] and the follow-up visit (+7.4 points, CI +0.6 to +14.3, P = 0.039, d = 0.591). Both large and small cognitive function improvements were seen twice as frequently in the treatment group than in the active control group. No significant between-group effects were seen on other measures, including the directly-observed functional and symptom measures. Statistically equivalent improvements in both groups were seen in depressive and cognitive symptoms.

Reversal of Age-Related Changes in Cortical Sound-Azimuth Selectivity with Training.

The compromised abilities to understand speech and localize sounds are two hallmark deficits in aged individuals. Earlier studies have shown that age-related deficits in cortical neural timing, which is clearly associated with speech perception, can be partially reversed with auditory training. However, whether training can reverse aged-related cortical changes in the domain of spatial processing has never been studied. In this study, we examined cortical spatial processing in ~21-month-old rats that were trained on a sound-azimuth discrimination task. We found that animals that experienced 1 month of training displayed sharper cortical sound-azimuth tuning when compared to the age-matched untrained controls. This training-induced remodeling in spatial tuning was paralleled by increases of cortical parvalbumin-labeled inhibitory interneurons. However, no measurable changes in cortical spatial processing were recorded in age-matched animals that were passively exposed to training sounds with no task demands. These results that demonstrate the effects of training on cortical spatial domain processing in the rodent model further support the notion that age-related changes in central neural process are, due to their plastic nature, reversible. Moreover, the results offer the encouraging possibility that behavioral training might be used to attenuate declines in auditory perception, which are commonly observed in older individuals.

Auditory Training Reverses Lead (Pb)-Toxicity-Induced Changes in Sound-Azimuth Selectivity of Cortical Neurons.

Lead (Pb) causes significant adverse effects on the developing brain, resulting in cognitive and learning disabilities in children. The process by which lead produces these negative changes is largely unknown. The fact that children with these syndromes also show deficits in central auditory processing, however, indicates a speculative but disturbing relationship between lead-exposure, impaired auditory processing, and behavioral dysfunction. Here we studied in rats the changes in cortical spatial tuning impacted by early lead-exposure and their potential restoration to normal by auditory training. We found animals that were exposed to lead early in life displayed significant behavioral impairments compared with naïve controls while conducting the sound-azimuth discrimination task. Lead-exposure also degraded the sound-azimuth selectivity of neurons in the primary auditory cortex. Subsequent sound-azimuth discrimination training, however, restored to nearly normal the lead-degraded cortical azimuth selectivity. This reversal of cortical spatial fidelity was paralleled by changes in cortical expression of certain excitatory and inhibitory neurotransmitter receptor subunits. These results in a rodent model demonstrate the persisting neurotoxic effects of early lead-exposure on behavioral and cortical neuronal processing of spatial information of sound. They also indicate that attention-demanding auditory training may remediate lead-induced cortical neurological deficits even after these deficits have occurred.

Positive impacts of early auditory training on cortical processing at an older age.

Progressive negative behavioral changes in normal aging are paralleled by a complex series of physical and functional declines expressed in the cerebral cortex. In studies conducted in the auditory domain, these degrading physical and functional cortical changes have been shown to be broadly reversed by intensive progressive training that improves the spectral and temporal resolution of acoustic inputs and suppresses behavioral distractors. Here we found older rats that were intensively trained on an attentionally demanding modulation-rate recognition task in young adulthood substantially retained training-driven improvements in temporal rate discrimination abilities over a subsequent 18-mo epoch-that is, forward into their older age. In parallel, this young-adult auditory training enduringly enhanced temporal and spectral information processing in their primary auditory cortices (A1). Substantially greater numbers of parvalbumin- and somatostatin-labeled inhibitory neurons (closer to the numbers recorded in young vigorous adults) were recorded in the A1 and hippocampus in old trained versus untrained age-matched rats. These results show that a simple form of training in young adulthood in this rat model enduringly delays the otherwise expected deterioration of the physical status and functional operations of the auditory nervous system, with evident training impacts generalized to the hippocampus.

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.

Perceptual Training Restores Impaired Cortical Temporal Processing Due to Lead Exposure.

Low-level lead exposure is a risk factor for cognitive and learning disabilities in children and has been specifically associated with deficits in auditory temporal processing that impair aural language and reading abilities. Here, we show that rats exposed to low levels of lead in early life display a significant behavioral impairment in an auditory temporal rate discrimination task. Lead exposure also results in a degradation of the neuronal repetition-rate following capacity and response synchronization in primary auditory cortex. A modified go/no-go repetition-rate discrimination task applied in adult animals for ∼50 days nearly restores to normal these lead-induced deficits in cortical temporal fidelity. Cortical expressions of parvalbumin, brain-derived neurotrophic factor, and NMDA receptor subunits NR2a and NR2b, which are down-regulated in lead-exposed animals, are also partially reversed with training. These studies in an animal model identify the primary auditory cortex as a novel target for low-level lead exposure and demonstrate that perceptual training can ameliorate lead-induced deficits in cortical discrimination between sound sequences.

Brains on video games.

The popular press is replete with stories about the effects of video and computer games on the brain. Sensationalist headlines claiming that video games 'damage the brain' or 'boost brain power' do not do justice to the complexities and limitations of the studies involved, and create a confusing overall picture about the effects of gaming on the brain. Here, six experts in the field shed light on our current understanding of the positive and negative ways in which playing video games can affect cognition and behaviour, and explain how this knowledge can be harnessed for educational and rehabilitation purposes. As research in this area is still in its early days, the contributors of this Viewpoint also discuss several issues and challenges that should be addressed to move the field forward.

Environmental acoustic enrichment promotes recovery from developmentally degraded auditory cortical processing.

It has previously been shown that environmental enrichment can enhance structural plasticity in the brain and thereby improve cognitive and behavioral function. In this study, we reared developmentally noise-exposed rats in an acoustic-enriched environment for ∼4 weeks to investigate whether or not enrichment could restore developmentally degraded behavioral and neuronal processing of sound frequency. We found that noise-exposed rats had significantly elevated sound frequency discrimination thresholds compared with age-matched naive rats. Environmental acoustic enrichment nearly restored to normal the behavioral deficit resulting from early disrupted acoustic inputs. Signs of both degraded frequency selectivity of neurons as measured by the bandwidth of frequency tuning curves and decreased long-term potentiation of field potentials recorded in the primary auditory cortex of these noise-exposed rats also were reversed partially. The observed behavioral and physiological effects induced by enrichment were accompanied by recovery of cortical expressions of certain NMDA and GABAA receptor subunits and brain-derived neurotrophic factor. These studies in a rodent model show that environmental acoustic enrichment promotes recovery from early noise-induced auditory cortical dysfunction and indicate a therapeutic potential of this noninvasive approach for normalizing neurological function from pathologies that cause hearing and associated language impairments in older children and adults.

Neocortical correlates of vibrotactile detection in humans.

This study examined the cortical representation of vibrotactile detection in humans using event-related fMRI paired with psychophysics. Suprathreshold vibrotactile stimulation activated several areas, including primary (SI) and second somatosensory cortices (SII/PV). For threshold-level stimuli, poststimulus activity in contralateral and ipsilateral SII/PV was the best correlate of detection success. In these areas, evoked signals on hit trials were significantly greater than on missed trials in all participants, and the relative activity level across stimulation amplitudes matched perceptual performance. Activity in the anterior insula and superior temporal gyrus also correlated with hits and misses, suggesting that a "ventral stream" of somatosensory representations may play a crucial role in detection. In contrast, poststimulus activity in Area SI was not well correlated with perception and showed an overall negative response profile for threshold-level stimulation. A different correlate of detection success was, however, observed in SI. Activity in this representation immediately before stimulus onset predicted performance, a finding that was unique to SI. These findings emphasize the potential role of SII/PV in detection, the importance of state dynamics in SI for perception, and the possibility that changes in the temporal and spatial pattern of SI activity may be essential to the optimal representation of threshold-level stimuli for detection.

A synaptic memory trace for cortical receptive field plasticity.

Receptive fields of sensory cortical neurons are plastic, changing in response to alterations of neural activity or sensory experience. In this way, cortical representations of the sensory environment can incorporate new information about the world, depending on the relevance or value of particular stimuli. Neuromodulation is required for cortical plasticity, but it is uncertain how subcortical neuromodulatory systems, such as the cholinergic nucleus basalis, interact with and refine cortical circuits. Here we determine the dynamics of synaptic receptive field plasticity in the adult primary auditory cortex (also known as AI) using in vivo whole-cell recording. Pairing sensory stimulation with nucleus basalis activation shifted the preferred stimuli of cortical neurons by inducing a rapid reduction of synaptic inhibition within seconds, which was followed by a large increase in excitation, both specific to the paired stimulus. Although nucleus basalis was stimulated only for a few minutes, reorganization of synaptic tuning curves progressed for hours thereafter: inhibition slowly increased in an activity-dependent manner to rebalance the persistent enhancement of excitation, leading to a retuned receptive field with new preference for the paired stimulus. This restricted period of disinhibition may be a fundamental mechanism for receptive field plasticity, and could serve as a memory trace for stimuli or episodes that have acquired new behavioural significance.

Successive-signal biasing for a learned sound sequence.

Adult rats were trained to detect the occurrence of a two-element sound sequence in a background of nine other nontarget sound pairs. Training resulted in a modest, enduring, static expansion of the cortical areas of representation of both target stimulus sounds. More importantly, once the initial stimulus A in the target A-B sequence was presented, the cortical "map" changed dynamically, specifically to exaggerate further the representation of the "anticipated" stimulus B. If B occurred, it was represented over a larger cortical area by more strongly excited, more coordinated, and more selectively responding neurons. This biasing peaked at the expected time of B onset with respect to A onset. No dynamic biasing of responses was recorded for any sound presented in a nontarget pair. Responses to nontarget frequencies flanking the representation of B were reduced in area and in response strength only after the presentation of A at the expected time of B onset. This study shows that cortical areas are not representationally static but, to the contrary, can be biased moment by moment in time as a function of behavioral context.

Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant training.

Cognitive decline is a virtually universal aspect of the aging process. However, its neurophysiological basis remains poorly understood. We describe here more than 20 age-related cortical processing deficits in the primary auditory cortex of aging versus young rats that appear to be strongly contributed to by altered cortical inhibition. Consistent with these changes, we recorded in old rats a decrease in parvalbumin-labeled inhibitory cortical neurons. Furthermore, old rats were slower to master a simple behavior, with learning progressions marked by more false-positive responses. We then examined the effect of intensive auditory training on the primary auditory cortex in these aged rats by using an oddball discrimination task. Following training, we found a nearly complete reversal of the majority of previously observed functional and structural cortical impairments. These findings suggest that age-related cognitive decline is a tightly regulated plastic process, and demonstrate that most of these age-related changes are, by their fundamental nature, reversible.

Natural restoration of critical period plasticity in the juvenile and adult primary auditory cortex.

Since its first description >40 years ago, the neurological "critical period" has been predominantly described as an early, plastic postnatal brain development stage that rather abruptly advances to an aplastic or less plastic "adult" stage. Here, we show that chronic exposure of juvenile or adult rats to moderate-level acoustic noise results in a broad reversal of maturational changes that mark the infant-to-adult progression in the primary auditory cortex. In time, noise exposure reinstates critical period plasticity. Cortical changes resulting from noise exposure are again reversed to reestablish a physically and functionally normal adult cortex, by returning animals to natural acoustic environments. These studies show that at least some of neurological changes believed to mark the transition from the infantile to the mature (adult) stage are, by their nature, reversible.

Enduring effects of early structured noise exposure on temporal modulation in the primary auditory cortex.

Studies have shown that acoustic experiences significantly contribute to the functional shaping of the structural organization and signal processing capacities of the mammalian auditory system during postnatal development. Here, we show how an early epoch of exposure to structured noise influences temporal processing in the rat primary auditory cortex documented immediately after exposure and again in adulthood. Pups were continuously exposed to broadband-pulsed noise across the critical period for auditory system development. Immediately after cessation of exposure at postnatal day approximately 35 (P35) or approximately 55 days later (i.e., P90) in other rats, the temporal modulation-transfer functions of cortical neurons were documented. We found that pulsed noise exposure at a low modulation rate significantly decreased cortical responses to repetitive stimuli presented across a range of higher modulation rates. The highest temporal rate at which temporal modulation-transfer function was at half of its maximum was reduced when compared with naïve rats. Low-rate pulsed noise exposure also decreased cortical response synchronization at higher stimulus rates, as shown by vector strength and Rayleigh statistic measures. These postexposure changes endured into adulthood. These findings bear significant implications for the role of early sound experiences as contributors to the ontogeny of human auditory and language-related abilities and impairments.

Online Social Cognition Training in Schizophrenia: A Double-Blind, Randomized, Controlled Multi-Site Clinical Trial.

Social cognition (SC), the mental operations underlying social functioning, are impaired in schizophrenia. Their direct link to functional outcome and illness status have made them an important therapeutic target. However, no effective treatment for these deficits is currently applied as a standard of care. To address this need, we have developed SocialVille-an online, plasticity-based training program that targets SC deficits in schizophrenia. Here we report the outcomes of a double-blind, controlled, randomized, multi-site clinical trial of SocialVille. Outpatients with schizophrenia were randomized to complete 40 sessions of either SocialVille (N = 55 completers) or active control (computer games; N = 53 completers) from home. The a priori co-primary outcome measures were a social cognitive composite and a functional capacity outcome (UCSD Performance-based Skills Assessment [UPSA-2]). Secondary outcomes included a virtual functional capacity measure (VRFCAT), social functioning, quality of life, and motivation. Linear mixed models revealed a group × time interaction favoring the treatment group for the social cognitive composite (b = 2.81; P < .001) but not for the UPSA-2 measure. Analysis of secondary outcome measures showed significant group × time effects favoring the treatment group on SC and social functioning, on the virtual functional capacity measure and a motivation subscale, although these latter findings were nonsignificant with FDR correction. These results provide support for the efficacy of a remote, plasticity-based social cognitive training program in improving SC and social functioning in schizophrenia. Such treatments may serve as a cost-effective adjunct to existing psychosocial treatments. Trial Registration: NCT02246426.

Experience-dependent adult cortical plasticity requires cognitive association between sensation and reward.

We tested the involvement of cognition in adult experience-dependent neuroplasticity using primate cortical implants. In a prior study, learning an operant sensory discrimination increased cortical excitability and target selectivity. Here, the prior task was separated into three behavioral phases. First, naive animals were exposed to stimulus-reward pairings from the prior study. These yoked animals did not have to discriminate to be rewarded and did not learn the discrimination. The plasticity observed in the prior study did not occur. Second, the animals were classically conditioned to discriminate the same stimuli in a simplified format. Learning was accompanied by increased sensory response strength and an increased range of sensory inputs eliciting responses. The third study recreated the original operant discrimination, and selectivity for task targets increased. These studies demonstrate that cognitive association between sensory stimuli and reinforcers accompanies adult experience-dependent cortical plasticity and suggest that selectivity in representation and action are linked.

Topography and synaptic shaping of direction selectivity in primary auditory cortex.

The direction of frequency-modulated (FM) sweeps is an important temporal cue in animal and human communication. FM direction-selective neurons are found in the primary auditory cortex (A1), but their topography and the mechanisms underlying their selectivity remain largely unknown. Here we report that in the rat A1, direction selectivity is topographically ordered in parallel with characteristic frequency (CF): low CF neurons preferred upward sweeps, whereas high CF neurons preferred downward sweeps. The asymmetry of 'inhibitory sidebands', suppressive regions flanking the tonal receptive field (TRF) of the spike response, also co-varied with CF. In vivo whole-cell recordings showed that the direction selectivity already present in the synaptic inputs was enhanced by cortical synaptic inhibition, which suppressed the synaptic excitation of the non-preferred direction more than that of the preferred. The excitatory and inhibitory synaptic TRFs had identical spectral tuning, but with inhibition delayed relative to excitation. The spectral asymmetry of the synaptic TRFs co-varied with CF, as had direction selectivity and sideband asymmetry, and thus suggested a synaptic mechanism for the shaping of FM direction selectivity and its topographic ordering.

Home-Based, Adaptive Cognitive Training for Cognitively Normal Older adults: Initial Efficacy Trial.

OBJECTIVES: We examined whether a home-based, adaptive cognitive training (CT) program would lead to cognitive performance changes on a neuropsychological test battery in cognitively normal older adults. METHOD: Sixty-eight older adults (age = 70.0, SD = 3.74) were randomly assigned to either CT or an active control group (AC, casual computer games). Participants were instructed to train on their assigned programs for 42 min per day, 5 days per week, over 10 weeks (35 hr of total program usage). Participants completed tests of processing speed, working memory, and executive control before and after 10 weeks of training. RESULTS: Training groups did not differ in performance before training. After training, CT participants out-performed AC participants in the overall cognitive composite score, driven by processing speed and working memory domains. DISCUSSION: Our results show that a limited dose of home-based CT can drive cognitive improvements as measured with neuropsychological test battery, suggesting potential cognitive health maintenance implications for cognitively normal older adults.

Biases in processing of mood-congruent facial expressions in depression.

Cognitive models of depression suggest that depressed individuals exhibit a tendency to attribute negative meaning to neutral stimuli, and enhanced processing of mood-congruent stimuli. However, evidence thus far has been inconsistent. In this study, we sought to identify both differential interpretation of neutral information as well as emotion processing biases associated with depression. Fifty adult participants completed standardized mood-related questionnaires, a novel immediate mood scale questionnaire (IMS-12), and a novel task, Emotion Matcher, in which they were required to indicate whether pairs of emotional faces show the same expression or not. We found that overall success rate and reaction time on the Emotion Matcher task did not differ as a function of severity of depression. However, more depressed participants had significantly worse performance when presented with sad-neutral face pairs, as well as increased reaction times to happy-happy pairs. In addition, accuracy of the sad-neutral pairs was found to be significantly associated with depression severity in a regression model. Our study provides partial support for the mood-congruent hypothesis, revealing only a potential bias in interpretation of sad and neutral expressions, but not a general deficit in processing of facial expressions. The potential of such bias in serving as a predictor for depression should be further examined in future studies.