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.

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.

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.

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.

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.

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.

Unintended Consequences of White Noise Therapy for Tinnitus-Otolaryngology's Cobra Effect: A Review.

Importance: Critical to the success of many medical therapeutics is a consideration of the brain's miraculous ability to dynamically rewire itself anatomically and neurochemically on the basis of incoming information. We argue that white noise exposure, a commonly recommended therapy for patients with tinnitus, engages these plastic processes in a way that induces maladaptive changes in the brain that degrade neurological health and compromise cognition. Observations: The pathophysiologic mechanisms commonly associated with hearing loss and tinnitus reflect cortical dedifferentiation and widespread loss of inhibitory tone throughout the central auditory pathway. Importantly, these same changes are also induced by exposure to unstructured noise, even at nontraumatic levels in the adult nervous system. Not by coincidence, the same changes appear in age-related decline of central auditory function, suggesting that both tinnitus and white noise accelerate the aging of the brain. Conclusions and Relevance: Noise exposure therapies offer a seductive short-term solution for relief but, in the long term, undermine the functional and structural integrity of the central auditory system and the brain more generally. Sound therapies using unstructured, random ("white") noise should be avoided as a treatment for tinnitus. Alternative therapeutics that drive positive, adaptive plastic changes are discussed.

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.

Targeting alertness to improve cognition in older adults: A preliminary report of benefits in executive function and skill acquisition.

Efficient self-regulation of alertness declines with age exacerbating normal declines in performance across multiple cognitive domains, including learning and skill acquisition. Previous cognitive intervention studies have shown that it is possible to enhance alertness in patients with acquired brain injury and marked attention impairments, and that this benefit generalizes to improvements in more global cognitive functions. In the current preliminary studies, we sought to test whether this approach, that targets both tonic (over a period of minutes) and phasic (moment-to-moment) alertness, can improve key executive functioning declines in older adults, and enhance the rate of skill acquisition. The results of both Experiments 1 and 2 demonstrate that, compared to active control (AC) training, alertness training significantly enhanced performance in several validated executive function measures. In Experiment 2, alertness training significantly improved skill acquisition compared to AC training in a well-characterized speed of processing (SOP) task, with the largest benefits shown in the most challenging SOP blocks. The results of the current study suggest that targeting intrinsic alertness through cognitive training provides a novel approach to improve executive functions in older adults and may be a useful adjunct treatment to enhance benefits gained in other clinically validated treatments.

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.

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.

Early UCSF contributions to the development of multiple-channel cochlear implants.

The early contributions of the UCSF cochlear implant (CI) research team to the development of multiple-channel cochlear implants from about 1971 through the mid-1980s are briefly summarized. Scientists at UCSF conducted fundamental studies related to device safety, the control of patterned electrical stimulation, and the designs of intracochlear electrode arrays, coders, and implanted multiple-channel electrode drivers. They conducted many original studies documenting parameters of hearing with cochlear implants relevant to next-generation CI designs. On these bases, the UCSF team constructed early models of multichannel devices that were progenitors of the Advanced Bionics' Clarion CI. This article is part of a Special Issue entitled .

Brain plasticity-based therapeutics.

The primary objective of this review article is to summarize how the neuroscience of brain plasticity, exploiting new findings in fundamental, integrative and cognitive neuroscience, is changing the therapeutic landscape for professional communities addressing brain-based disorders and disease. After considering the neurological bases of training-driven neuroplasticity, we shall describe how this neuroscience-guided perspective distinguishes this new approach from (a) the more-behavioral, traditional clinical strategies of professional therapy practitioners, and (b) an even more widely applied pharmaceutical treatment model for neurological and psychiatric treatment domains. With that background, we shall argue that neuroplasticity-based treatments will be an important part of future best-treatment practices in neurological and psychiatric medicine.

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.

Principles of neuroplasticity-based rehabilitation.

The purpose of this review is to summarize how our perspective about the neuroscience of brain plasticity, informed by perceptual, experimental, and cognitive psychology, has led to the designs of a new class of therapeutic tools developed to drive functionally distorted and damaged brains in corrective directions. How does neuroplasticity science inform us about optimal therapeutic program designs? How do we apply that science, using modern technology, to drive neurological changes that address both the neurobehavioral distortions and the resulting behavioral deficits that are expressed in specific neurological and psychiatric disorders? By what strategies can we achieve the strongest and most complete rehabilitative corrections? These are questions that we have extensively explored in our efforts to establish new medical applications of neuroplasticity-based therapeutics. Here, we summarize the state of this rapidly emerging area of translational neuroscience, beginning with an explanation of the scientific premises and strategies, then describing their implementation in therapeutic software to address two human illnesses: the treatment of social cognition deficits in chronic schizophrenia and in autism; and the amelioration of age-related functional decline using strategies designed to delay the onset of--and potentially prevent--Alzheimer's Disease and related causes of dementia in aging.

Accessible online neuroplasticity-targeted training for children with ADHD.

Childhood Attention Deficit Hyperactivity Disorder (ADHD) is a growing mental health concern worldwide. Effective, accessible and low-cost therapeutics for the disorder are urgently needed. Here we introduce a novel internet-based cognitive training intervention: Online Neuroplasticity-based Training for the Remediation of ADHD in Children (ONTRAC). The intervention is deployed in the home setting; it is customized to the cognitive capacities of each child and progressively improves performance in the specific neuro-cognitive domains deficient in ADHD. A feasibility trial of ONTRAC is being conducted in a resource limited clinical setting in New Delhi, India and is an exemplar of hi-tech global psychiatry.

Manipulation of BDNF signaling modifies the experience-dependent plasticity induced by pure tone exposure during the critical period in the primary auditory cortex.

Sensory experience powerfully shapes cortical sensory representations during an early developmental "critical period" of plasticity. In the rat primary auditory cortex (A1), the experience-dependent plasticity is exemplified by significant, long-lasting distortions in frequency representation after mere exposure to repetitive frequencies during the second week of life. In the visual system, the normal unfolding of critical period plasticity is strongly dependent on the elaboration of brain-derived neurotrophic factor (BDNF), which promotes the establishment of inhibition. Here, we tested the hypothesis that BDNF signaling plays a role in the experience-dependent plasticity induced by pure tone exposure during the critical period in the primary auditory cortex. Elvax resin implants filled with either a blocking antibody against BDNF or the BDNF protein were placed on the A1 of rat pups throughout the critical period window. These pups were then exposed to 7 kHz pure tone for 7 consecutive days and their frequency representations were mapped. BDNF blockade completely prevented the shaping of cortical tuning by experience and resulted in poor overall frequency tuning in A1. By contrast, BDNF infusion on the developing A1 amplified the effect of 7 kHz tone exposure compared to control. These results indicate that BDNF signaling participates in the experience-dependent plasticity induced by pure tone exposure during the critical period in A1.