Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway.

During developmental critical periods (CPs), early-life stress (ELS) induces cognitive deficits and alters neural circuitry in regions underlying learning, memory, and attention. Mechanisms underlying critical period plasticity are shared by sensory cortices and these higher neural regions, suggesting that sensory processing may also be vulnerable to ELS. In particular, the perception and auditory cortical (ACx) encoding of temporally-varying sounds both mature gradually, even into adolescence, providing an extended postnatal window of susceptibility. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. In both male and female animals, ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in auditory cortex, the auditory periphery, and auditory brainstem. ELS thus degrades the fidelity of sensory representations available to higher regions, and could contribute to well-known ELS-induced problems with cognition.SIGNIFICANCE STATEMENT In children and animal models, early-life stress (ELS) leads to deficits in cognition, including problems with learning, memory, and attention. Such problems could arise in part from a low-fidelity representation of sensory information available to higher-level neural regions. Here, we demonstrate that ELS degrades sensory responses to rapid variations in sound at multiple levels of the auditory pathway, and concurrently impairs perception of these rapidly-varying sounds. As these sound variations are intrinsic to speech, ELS may thus pose a challenge to communication and cognition through impaired sensory encoding.

Late maturation of backward masking in auditory cortex.

Speech perception relies on the accurate resolution of brief, successive sounds that change rapidly over time. Deficits in the perception of such sounds, indicated by a reduced ability to detect signals during auditory backward masking, strongly relate to language processing difficulties in children. Backward masking during normal development has a longer maturational trajectory than many other auditory percepts, implicating the involvement of central auditory neural mechanisms with protracted developmental time courses. Despite the importance of this percept, its neural correlates are not well described at any developmental stage. We therefore measured auditory cortical responses to masked signals in juvenile and adult Mongolian gerbils and quantified the detection ability of individual neurons and neural populations in a manner comparable with psychoacoustic measurements. Perceptually, auditory backward masking manifests as higher thresholds for detection of a short signal followed by a masker than for the same signal in silence. Cortical masking was driven by a combination of suppressed responses to the signal and a reduced dynamic range available for signal detection in the presence of the masker. Both coding elements contributed to greater masked threshold shifts in juveniles compared with adults, but signal-evoked firing suppression was more pronounced in juveniles. Neural threshold shifts were a better match to human psychophysical threshold shifts when quantified with a longer temporal window that included the response to the delayed masker, suggesting that temporally selective listening may contribute to age-related differences in backward masking. NEW & NOTEWORTHY In children, auditory detection of backward masked signals is immature well into adolescence, and detection deficits correlate with problems in speech processing. Our auditory cortical recordings reveal immature backward masking in adolescent animals that mirrors the prolonged development seen in children. This is driven by both signal-evoked suppression and dynamic range reduction. An extended window of analysis suggests that differences in temporally focused listening may contribute to late maturing thresholds for backward masked signals.

Brief Stimulus Exposure Fully Remediates Temporal Processing Deficits Induced by Early Hearing Loss.

In childhood, partial hearing loss can produce prolonged deficits in speech perception and temporal processing. However, early therapeutic interventions targeting temporal processing may improve later speech-related outcomes. Gap detection is a measure of auditory temporal resolution that relies on the auditory cortex (ACx), and early auditory deprivation alters intrinsic and synaptic properties in the ACx. Thus, early deprivation should induce deficits in gap detection, which should be reflected in ACx gap sensitivity. We tested whether earplugging-induced, early transient auditory deprivation in male and female Mongolian gerbils caused correlated deficits in behavioral and cortical gap detection, and whether these could be rescued by a novel therapeutic approach: brief exposure to gaps in background noise. Two weeks after earplug removal, animals that had been earplugged from hearing onset throughout auditory critical periods displayed impaired behavioral gap detection thresholds (GDTs), but this deficit was fully reversed by three 1 h sessions of exposure to gaps in noise. In parallel, after earplugging, cortical GDTs increased because fewer cells were sensitive to short gaps, and gap exposure normalized this pattern. Furthermore, in deprived animals, both first-spike latency and first-spike latency jitter increased, while spontaneous and evoked firing rates decreased, suggesting that deprivation causes a wider range of perceptual problems than measured here. These cortical changes all returned to control levels after gap exposure. Thus, brief stimulus exposure, perhaps in a salient context such as the unfamiliar placement into a testing apparatus, rescued impaired gap detection and may have potential as a remediation tool for general auditory processing deficits.SIGNIFICANCE STATEMENT Hearing loss in early childhood leads to impairments in auditory perception and language processing that can last well beyond the restoration of hearing sensitivity. Perceptual deficits can be improved by training, or by acoustic enrichment in animal models, but both approaches involve extended time and effort. Here, we used a novel remediation technique, brief periods of auditory stimulus exposure, to fully remediate cortical and perceptual deficits in gap detection induced by early transient hearing loss. This technique also improved multiple cortical response properties. Rescue by this efficient exposure regime may have potential as a therapeutic tool to remediate general auditory processing deficits in children with perceptual challenges arising from early hearing loss.

Utility of Green's Word Memory Test Free Recall Subtest as a Measure of Verbal Memory: Initial Evidence from a Temporal Lobe Epilepsy Clinical Sample.

This study investigated the Word Memory Test (WMT) Free Recall (FR) subtest as a conventional memory measure. Nineteen participants with pharmacoresistant left temporal lobe epilepsy (LTLE) and 16 with right temporal lobe epilepsy (RTLE) completed the WMT, Rey Auditory Verbal Learning Test (RAVLT), and Wechsler Memory Scale-Fourth Edition Logical Memory (LM) subtest during presurgical evaluation. LTLE participants performed significantly worse on FR subtest (p < .05, [Formula: see text]) and RAVLT Trial 7 (p < .01, [Formula: see text]), but not on LM subtest. Age was a significant covariate for FR (p < .01, [Formula: see text]). Logistic regression revealed FR plus age and RAVLT age-adjusted T-scores both yielded 77.1% classification accuracy and respective diagnostic odds ratios of 11.36 and 11.84. Receiver operating characteristic curves to classify seizure laterality found that RAVLT and FR were significant (area under the curve [AUC] = 0.82 and 0.74), whereas LM was nonsignificant (AUC = 0.67). Cut scores and positive/negative predictive values were established for improved clinical classification.

Clinical utility of the Wechsler Memory Scale--Fourth Edition (WMS-IV) in predicting laterality of temporal lobe epilepsy among surgical candidates.

This study evaluated the accuracy of the Wechsler Memory Scale--Fourth Edition (WMS-IV) in identifying functional cognitive deficits associated with seizure laterality in localization-related temporal lobe epilepsy (TLE) relative to a previously established measure, the Rey Auditory Verbal Learning Test (RAVLT). Emerging WMS-IV studies have highlighted psychometric improvements that may enhance its ability to identify lateralized memory deficits. Data from 57 patients with video-EEG-confirmed unilateral TLE who were administered the WMS-IV and RAVLT as part of a comprehensive presurgical neuropsychological evaluation for temporal resection were retrospectively reviewed. We examined the predictive accuracy of the WMS-IV not only in terms of verbal versus visual composite scores but also using individual subtests. A series of hierarchal logistic regression models were developed, including the RAVLT, WMS-IV delayed subtests (Logical Memory, Verbal Paired Associates, Designs, Visual Reproduction), and a WMS-IV verbal-visual memory difference score. Analyses showed that the RAVLT significantly predicted laterality with overall classification rates of 69.6% to 70.2%, whereas neither the individual WMS-IV subtests nor the verbal-visual memory difference score accounted for additional significant variance. Similar to previous versions of the WMS, findings cast doubt as to whether the WMS-IV offers significant incremental validity in discriminating seizure laterality in TLE beyond what can be obtained from the RAVLT.

Verbal fluency patterns in mild cognitive impairment and Alzheimer's disease.

BACKGROUND/AIMS: Verbal fluency patterns can assist in differential diagnosis during neuropsychological assessment and identify individuals at risk for developing Alzheimer's disease (AD). While evidence suggests that subjects with AD perform worse on category fluency than letter fluency tasks, the pattern in mild cognitive impairment (MCI) is less well known. METHODS: Performance on the Controlled Oral Word Association Test (COWAT) and Animal fluency was compared in control, amnestic MCI, non-amnestic MCI, and AD groups. The sample included 136 participants matched for age, education, and gender. RESULTS: Both MCI groups performed similarly with a category > letter fluency pattern rather than a category < letter fluency pattern typically observed in AD. The pattern in MCI, albeit relatively more impaired than in controls, was more similar to healthy controls who exhibited a category > letter fluency pattern. CONCLUSION: MCI using a category < letter fluency pattern may not represent AD; however, future research requires longitudinal studies of pattern analysis.

Assessing reliable change using the repeatable battery for the assessment of neuropsychological status (RBANS) for patients with Parkinson's Disease undergoing deep brain stimulation (DBS) surgery.

Parkinson's disease (PD) is progressive neurological disease characterized by resting tremor, rigidity, akinesia, postural instability and cognitive changes. The symptoms of PD are debilitating and often become unsatisfactorily treated by medication. Deep brain stimulation (DBS) is an effective treatment to significantly reduce the cardinal motor symptoms of PD. However, the neuropsychological effects of this treatment are less clear. This study examined pre- to post-DBS scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) using Reliable Change Indices (RCIs) derived from 20 patients with PD who were medically managed, and then compared to 20 patients with PD treated with DBS and medication. When using group statistical analyses and false discovery rate correction, no significant differences between or within groups were evident at baseline or at follow-up. However, when using the RCIs more patients in the DBS group exhibited reliable change in RBANS scores than did the Med Tx group. Although preliminary, these RCIs provide clinicians and researchers a foundational tool for assessing the effects of interventions (e.g., DBS) independent of the effects of PD and measurement error when using the RBANS.

Cognitive change on the repeatable battery of neuropsychological status (RBANS) in Parkinson's disease with and without bilateral subthalamic nucleus deep brain stimulation surgery.

Cognitive change following bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery in those with Parkinson's disease (PD) has led to equivocal results. The current study applied a standardized regression-based (SRB) method based on 20 medically managed PD patients and 20 STN DBS PD surgical patients who were administered the Repeatable Battery of Neuropsychological Status (RBANS). Of the medically managed PD participants, 94% remained stable compared to 73% of the DBS group. In the DBS group cognitive change was noted on the Total scale and the Immediate Memory Index. A secondary analysis also revealed reliable change on several subtest scores. Although preliminary, the current study provides change parameters for post DBS surgery on this brief battery.

Does the arousal system contribute to near death experience?

The neurophysiologic basis of near death experience (NDE) is unknown. Clinical observations suggest that REM state intrusion contributes to NDE. Support for the hypothesis follows five lines of evidence: REM intrusion during wakefulness is a frequent normal occurrence, REM intrusion underlies other clinical conditions, NDE elements can be explained by REM intrusion, cardiorespiratory afferents evoke REM intrusion, and persons with an NDE may have an arousal system predisposing to REM intrusion. To investigate a predisposition to REM intrusion, the life-time prevalence of REM intrusion was studied in 55 NDE subjects and compared with that in age/gender-matched control subjects. Sleep paralysis as well as sleep-related visual and auditory hallucinations were substantially more common in subjects with an NDE. These findings anticipate that under circumstances of peril, an NDE is more likely in those with previous REM intrusion. REM intrusion could promote subjective aspects of NDE and often associated syncope. Suppression of an activated locus ceruleus could be central to an arousal system predisposed to REM intrusion and NDE.

Factors leading patients to discontinue multiple sclerosis therapies.

OBJECTIVES: To determine the percentages of patients who discontinued treatment with the multiple sclerosis medications intramuscular interferon beta-1a (IFN-beta-1a; Avonex-Biogen), interferon beta-1b (IFN-beta-1b; Betaseron-Berlex), and glatiramer acetate (Copaxone-Teva) and to determine the factors that led to discontinuation of the medications. DESIGN: Cross-sectional study. SETTING: University-based neurology clinic. PATIENTS: 108 patients with multiple sclerosis who were prescribed intramuscular interferon beta-1a, subcutaneous interferon beta-1b, or subcutaneous glatiramer acetate. INTERVENTION: Telephone survey. MAIN OUTCOME MEASURES: Discontinuation percentages and the factors that contributed to discontinuation. RESULTS: There was no significant difference between the percentages of patients who discontinued and did not restart treatment with the products (interferon beta-1b, 41%; intramuscular interferon beta-1a, 34%; and glatiramer acetate, 28%). Four main reasons for medication discontinuation emerged: adverse effects (52%), physician-documented disease progression (40%), patient perception of drug ineffectiveness (20%), and cost (4%). No statistical differences were identified among the three agents for any of the reasons for discontinuation. CONCLUSION: Patient education on adverse effects and realistic patient expectations may be potential areas of study to improve discontinuation percentages with these agents.

Neurodegenerative memory disorders: a potential role of environmental toxins.

The hypothesis that neurotoxins may play a role in neurodegenerative disorders remains an elusive one, given that epidemiologic studies often provide conflicting results. Although these conflicting results may result from methodological differences within and between studies, the complexity of chemical disruption of the central nervous system cannot be ignored in attempts to evaluate this hypothesis in different neurodegenerative disorders. Spencer provides a detailed review of the complex processes involved in defining the neurotoxic potential of naturally occurring and synthetic agents. Even concepts such as exposure and dose, as often reported in studies attempting to evaluate the risk imparted by a potential compound, can be deceptive. For example, although dose reflects "that amount of chemical transferred to the exposed subject", factors such as time and concentration in the organism, the ability to access the central nervous system, and how a compound reaches the central nervous system (routes of administration) or secondarily affects other organ systems leading to central nervous system disruption are clearly important to the concept of neurotoxic risk in neurodegenerative disorders. These factors would appear to explain the observed disagreements between studies using animal or neuronal models of neurotoxicity and population-based studies in humans. The importance of these factors and how a potential neurotoxin is investigated are clearly seen in the data on AD and aluminum. In contrast, the impact of MTPT on the central nervous system is more direct and compelling. Added complexity in the study of neurotoxins in human neurodegeneration is derived from data showing that agents may have additive, potentiating, synergistic, or antagonistic effects. Therefore, data from studies evaluating EMF risks could be readily confounded by the presence or absence of heavy metals (eg, arc welding). Other factors that may conceal neurotoxic causes for a given disorder focus on additional features such as genetic predispositions, physiologic changes that occur in aging, and even nutritional status that can support or hinder the affect of a given agent on the central nervous system. Finally, many studies that investigate exposure risk do not readily incorporate the five criteria proposed by Schaumburg for establishing causation. For example, if we apply Schaumburg's first criterion, epidemiologic studies often determines the presence of an agent through history, yet they cannot readily confirm exposure based on environmental or clinical chemical analyses to fulfill this criterion for causation. Additional limitations in research design along with the populations and methods that are sued to study neurotoxins in human neurodegenerative disorders often fail to meet other criteria such as linking the severity and onset with duration and exposure level. Therefore, although studies of agents such as MTPT provide compelling models of neurotoxins and neurodegeneration in humans, disorders such as ALS, PD, and particularly AD will require additional effort if research is to determine the contribution (presence or absence) of neurotoxins to these neurologic disorders.

Developmental venous anomaly in association with neuromigrational anomalies.

This report describes a male neonate with unusual neuroradiologic findings at birth. The patient's subsequent clinical course and the evolution of his findings on serial magnetic resonance imaging and magnetic resonance venograms are consistent with a developmental venous anomaly. The case underscores the association of developmental venous anomalies with neuromigrational disorders such as polymicrogyria and nonschizencephalic clefts. It also emphasizes the importance of recognizing this problem for prognostication and treatment.