Exploration of the Impact of Brief Noninvasive Vagal Nerve Stimulation on EEG and Event-Related Potentials.

OBJECTIVES: The primary objective of this study was to explore the impact of noninvasive Vagal Nerve Stimulation (nVNS) on brain electrophysiology, as assessed through spontaneous resting-state EEG and stimulus-driven event-related potentials (ERPs). METHODS: A hand-held transcutaneous stimulator was placed on the neck over the main branch of the left vagus (active condition) or more laterally over neck muscles (sham condition), with two 120-sec long bursts of stimulation applied over a five-minute period. For each of eight neurotypical subjects, prior to stimulation, and then again beginning at 15, 120, and 240 min post-stimulation, ten minutes of background EEG data were collected, along with a series of ERPs-N100 auditory sensory-gating; the N1/P2 loudness dependent auditory evoked responses (LDAER); mismatch negativity; P300a; and P300b. Each subject participated in active and sham stimulation sessions. RESULTS: Brief nVNS had a significant (p < 0.05), and in some cases prolonged (>2 hours), impact on the spontaneous EEG (decreased theta and alpha, and increased beta and gamma), and on sensory gating, LDAER, and P300b evoked responses. Based on prior literature, these specific observations may reflect nVNS-induced modulation of particular neurotransmitter systems including those for GABA (gamma power and frequency); acetylcholine (sensory gating); serotonin (LDAER); and noradrenaline (P300b). CONCLUSIONS: Brief nVNS leads to changes in a sub-set of resting-state and event-related electrophysiologic indices of brain activity. These changes are believed to be mediated by vagal afferent projections to the nucleus of the solitary tract, which in turn regulates several neurotransmitter systems through known direct and indirect neuroanatomic pathways.

The effect of days since last concussion and number of concussions on cognitive functioning in Division I athletes.

OBJECTIVE: Cognitive recovery from sports concussion may be incomplete after resolution of other symptoms. It was hypothesized that independent effects of the number of days since last concussion (Days) and total number of concussions (Number) would predict poorer cognitive functioning. METHODS AND PROCEDURES: Cognition was assessed in an NCAA Division I student-athlete population (n = 87) using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery. In a MANOVA, the five ImPACT Composite scores were dependent variables, with Group (Concussion, Unaffected) as the independent variable and prior number of concussions (Number) and days since last concussion (Days; 68-2495 days) entered as covariates. OUTCOMES AND RESULTS: The hypothesis that Days and Number would each independently affect cognitive functioning (as assessed by ImPACT Composite scores) was only partly supported. A significant, multivariate, main effect of Days (p = 0.01) indicated that more Days predicted better cognitive functioning overall (p = 0.01). Univariate effects emerged such that more Days specifically predicted better visual memory (p = 0.004) and faster reaction times (p = 0.02). A trend toward a Group*Days*Number three-way interaction for reaction time emerged (p = 0.06), such that smaller Number and more Days each predicted slower reaction time. CONCLUSIONS: Cognitive recovery following sports concussion may take far longer than was previously thought, the aetiology of cognitive reductions may be very complex and the ImPACT appears to be sensitive to subtle changes in cognition across time.

Electroconvulsive Therapy Modulates Loudness Dependence of Auditory Evoked Potentials: A Pilot MEG Study.

Electroconvulsive therapy (ECT) remains a critical intervention for treatment-resistant depression (MDD), yet its neurobiological underpinnings are not fully understood. This pilot study utilizes high-resolution magnetoencephalography (MEG) in nine depressed patients receiving right unilateral ECT, to investigate the changes in loudness dependence of auditory evoked potentials (LDAEP), a proposed biomarker of serotonergic activity, following ECT. We hypothesized that ECT would reduce the LDAEP slope, reflecting enhanced serotonergic neurotransmission. Contrary to this, our findings indicated a significant increase in LDAEP post-ECT ( t 8 = 3.17, p = .013). The increase in LDAEP was not associated with changes in depression severity or cognitive performance, as assessed by the Hamilton Depression Rating Scale (HAMD-24) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We discussed potential mechanisms for the observed increase, including ECT's impact on serotonergic, dopaminergic, glutamatergic, and GABAergic receptor activity, neuroplasticity involving brain-derived neurotrophic factor (BDNF), and inflammation modulators such as TNF- alpha . Our results suggest a complex interaction between ECT and these neurobiological systems, rather than a direct reflection of serotonergic neurotransmission.

Quantitative EEG Biomarkers for Mild Traumatic Brain Injury.

PURPOSE: The development of objective biomarkers for mild traumatic brain injury (mTBI) in the chronic period is an important clinical and research goal. Head trauma is known to affect the mechanisms that support the electrophysiological processing of information within and between brain regions, so methods like quantitative EEG may provide viable indices of brain dysfunction associated with even mTBI. METHODS: Resting-state, eyes-closed EEG data were obtained from 71 individuals with military-related mTBI and 82 normal comparison subjects without traumatic brain injury. All mTBI subjects were in the chronic period of injury (>5 months since the time of injury). Quantitative metrics included absolute and relative power in delta, theta, alpha, beta, high beta, and gamma bands, plus a measure of interhemispheric coherence in each band. Data were analyzed using univariate and multivariate methods, the latter coupled to machine learning strategies. RESULTS: Analyses revealed significant (P < 0.05) group level differences in global relative theta power (increased for mTBI patients), global relative alpha power (decreased for mTBI patients), and global beta-band interhemispheric coherence (decreased for mTBI patients). Single variables were limited in their ability to predict group membership (e.g., mTBI vs. control) for individual subjects, each with a predictive accuracy that was below 60%. In contrast, the combination of a multivariate approach with machine learning methods yielded a composite metric that provided an overall predictive accuracy of 75% for correct classification of individual subjects as coming from control versus mTBI groups. CONCLUSIONS: This study indicates that quantitative EEG methods may be useful in the identification, classification, and tracking of individual subjects with mTBI.

Spatio-temporal reconstruction of bilateral auditory steady-state responses using MEG beamformers.

A rapidly growing number of neuromagnetic studies focus on the analysis of auditory steady-state responses (ASSR) in relation to a diverse array of factors including age, selective attention, and presence of psychopathology. The objectives of these studies require accurate spatio-temporal estimation of the underlying neural generators, a challenging task due to the relatively low signal strength and high correlation between bilateral auditory cortical sources. This paper evaluates the performance of two beamforming schemes that can potentially overcome such difficulties: 1) the linearly constrained minimum variance beamformer with partial sensor coverage (LCMV-PSC), and 2) the multiple constrained minimum-variance beamformer with coherent source region suppression (MCMV-CSRS). Simulation experiments are conducted to assess the impact of source parameters on the reconstruction accuracy. The results indicate that the LCMV-PSC method is prone to localization errors that essentially occur along medio-lateral directions, increase with source depth, and are associated to amplitude and phase distortions of the estimated time courses of activity. Comparatively, the MCMV-CSRS method exhibits precise localization and minimal amplitude and phase distortion for a broad range of relative interferer's positions within the suppression region. The results from the numerical experiments are validated on real magnetoencephalographic (MEG) data collected from a 40-Hz ASSR paradigm.

Diminished auditory sensory gating during active auditory verbal hallucinations.

Auditory sensory gating, assessed in a paired-click paradigm, indicates the extent to which incoming stimuli are filtered, or "gated", in auditory cortex. Gating is typically computed as the ratio of the peak amplitude of the event related potential (ERP) to a second click (S2) divided by the peak amplitude of the ERP to a first click (S1). Higher gating ratios are purportedly indicative of incomplete suppression of S2 and considered to represent sensory processing dysfunction. In schizophrenia, hallucination severity is positively correlated with gating ratios, and it was hypothesized that a failure of sensory control processes early in auditory sensation (gating) may represent a larger system failure within the auditory data stream; resulting in auditory verbal hallucinations (AVH). EEG data were collected while patients (N=12) with treatment-resistant AVH pressed a button to indicate the beginning (AVH-on) and end (AVH-off) of each AVH during a paired click protocol. For each participant, separate gating ratios were computed for the P50, N100, and P200 components for each of the AVH-off and AVH-on states. AVH trait severity was assessed using the Psychotic Symptoms Rating Scales AVH Total score (PSYRATS). The results of a mixed model ANOVA revealed an overall effect for AVH state, such that gating ratios were significantly higher during the AVH-on state than during AVH-off for all three components. PSYRATS score was significantly and negatively correlated with N100 gating ratio only in the AVH-off state. These findings link onset of AVH with a failure of an empirically-defined auditory inhibition system, auditory sensory gating, and pave the way for a sensory gating model of AVH.

Reduced auditory M100 asymmetry in schizophrenia and dyslexia: applying a developmental instability approach to assess atypical brain asymmetry.

Although atypical structural and functional superior temporal gyrus (STG) asymmetries are frequently observed in patients with schizophrenia and individuals with dyslexia, their significance is unclear. One possibility is that atypical asymmetries reflect a general risk factor that can be seen across multiple neurodevelopmental conditions--a risk factor whose origins are best understood in the context of Developmental Instability (DI) theory. DI measures (minor physical anomalies (MPAs) and fluctuating asymmetries (FAs)) reflect perturbation of the genetic plan. The present study sought to assess whether the presence of peripheral indices of DI predicts anomalous functional auditory cortex asymmetry in schizophrenia patients and dyslexia subjects. The location of the auditory M100 response was used as a measure of functional STG asymmetry, as it has been reported that in controls (but not in subjects with schizophrenia or dyslexia) the M100 source location in the right hemisphere is shifted anterior to that seen for the left hemisphere. Whole-brain auditory evoked magnetic field data were successfully recorded from 14 male schizophrenia patients, 21 male subjects with dyslexia, and 16 normal male control subjects. MPA and FA measures were also obtained. Replicating previous studies, both schizophrenia and dyslexia groups showed less M100 asymmetry than did controls. Schizophrenia and dyslexia subjects also had higher MPA scores than normal controls. Although neither total MPA nor FA measures predicted M100 asymmetry, analyses on individual MPA items revealed a relationship between high palate and M100 asymmetry. Findings suggest that M100 positional asymmetry is not a diagnostically specific feature in several neurodevelopmental conditions. Continued research examining DI and brain asymmetry relationships is warranted.

Reconstruction of fetal cardiac vectors from multichannel fMCG data using recursively applied and projected multiple signal classification.

Previous attempts at unequivocal specification of signal strength in fetal magnetocardiographic (fMCG) recordings have used an equivalent current dipole (ECD) to estimate the cardiac vector at the peak of the averaged QRS complex. However, even though the magnitude of fetal cardiac currents are anticipated to be relatively stable, ECD-based estimates of signal strength show substantial and unrealistic variation when comparing results from different time windows of the same recording session. The present study highlights the limitations of the ECD model, and proposes a new methodology for fetal cardiac source reconstruction. The proposed strategy relies on recursive subspace projections to estimate multiple dipoles that account for the distributed myocardial currents. The dipoles are reconstructed from spatio-temporal fMCG data, and are subsequently used to derive estimators of the cardiac vector over the entire QRS. The new method is evaluated with respect to simulated data derived from a model of ventricular depolarization, which was designed to account for the complexity of the fetal cardiac source configuration on the QRS interval. The results show that the present methodology overcomes the drawbacks of conventional ECD fitting, by providing robust estimators of the cardiac vector. Additional evaluation with real fMCG data show fetal cardiac vectors whose morphology closely resembles that obtained in adult MCG.

Relations Between Nonverbal and Verbal Social Cognitive Skills and Complex Social Behavior in Children and Adolescents with Autism.

Although there is an extensive literature on domains of social skill deficits in individuals with Autism Spectrum Disorders (ASD), little research has examined the relation between specific social cognitive skills and complex social behaviors in daily functioning. This was the aim of the present study. Participants were 37 (26 male and 11 female) children and adolescents aged 6-18 years diagnosed with ASD. To determine the amount of variance in parent-rated complex social behavior accounted for by the linear combination of five directly-assessed social cognitive variables (i.e., adult and child facial and vocal affect recognition and social judgment) after controlling for general intellectual ability, a hierarchical regression analysis was performed. The linear combination of variables accounted for 35.4 % of the variance in parent-rated complex social behavior. Vocal affect recognition in adult voices showed the strongest association with complex social behavior in ASD. Results suggest that assessment and training in vocal affective comprehension should be an important component of social skills interventions for individuals with ASD.

Adolescent Self-reported Alcohol/other Drug Use Consequences: Moderators of Self and Parent Agreement.

While the reliability of assessment instruments designed for use with adults is well established, much less is known about the adequacy of these instruments for adolescent substance abusers. As part of a comprehensive intake evaluation, the Inventory of Drug Use Consequences (InDUC) was administered both to forty adolescents assigned to a probationary substance abuse treatment program and to one of their parents. The correlation was statistically significant between Parent and Adolescent InDUC score(s), but the interrater reliability was relatively low. IQ scores and level of substance use were considered as moderator variables, but neither showed a significant effect. History of head injury, however, significantly moderated this relationship; those adolescents reporting no history of head injury showed little correspondence with Parent InDUC Score(s), whereas those adolescents with a history of head injury showed significant correlations with parent InDUC scores. This suggests that a history of head injury may affect the way in which adolescents perceive substance-related consequences.

A preliminary evaluation of Fast ForWord-Language as an adjuvant treatment in language intervention.

PURPOSE: Fast ForWord-Language (FFW-L) is designed to enhance children's processing of auditory-verbal signals and, thus, their ability to learn language. As a preliminary evaluation of this claim, we examined the effects of a 5-week course of FFW-L as an adjuvant treatment with a subsequent 5-week conventional narrative-based language intervention (NBLI) that targeted narrative comprehension and production and grammatical output. METHOD: Twenty-three children 6-8 years of age with language impairments were assigned randomly to 1 of 3 intervention sequences: (a) FFW-L/NBLI, (b) NBLI/FFW-L, or (c) wait/NBLI. We predicted that after both treatment periods, the FFW-L/NBLI group would show greater gains on measures of narrative ability, conversational grammar, and nonword repetition than the other groups. RESULTS: After the first 5-week study period, the intervention groups, taken together (i.e., FFW-L/NBLI and NBLI/FFW-L), significantly outperformed the no-treatment wait/NBLI group on 2 narrative measures. At the final test period, all 3 groups displayed significant time-related effects on measures of narrative ability, but there were no statistically significant between-groups effects of intervention sequence. CONCLUSIONS: This preliminary study provides no evidence to support the claim that FFW-L enhances children's response to a conventional language intervention.

N400 responses of children with primary language disorder: intervention effects.

Event-related brain potentials were examined in 6 to 8-year-old children with primary language disorder before and after a 5-week narrative-based language intervention. Participants listened to sentences ending with semantically congruous or incongruous words. By comparison with typical controls, the children with primary language disorder exhibited no pretreatment differences in their N400 responses to congruous and incongruous sentence-final words. After intervention, the typical incongruous-congruous difference was observable owing to a dramatic reduction in the amplitude of the N400 response to congruous words. These characteristic changes in brain responses may reflect a positive effect of the language intervention on the lexical-semantic processing skills in children with language impairment.

Laminar variation in threshold for detection of electrical excitation of striate cortex by macaques.

Macaques were trained to signal their detection of electrical stimulation applied by a movable microelectrode to perifoveal striate cortex. Trains of < or =100 cathodal, 0.2-ms, constant current pulses were delivered at 50 or 100 Hz. The minimum current that could be reliably detected was measured at successive depths along radial electrode penetrations through the cortex. The lowest detection thresholds were routinely encountered when the stimulation was applied to layer 3, particularly just at the juncture between layers 3 and 4A. On the average, there was a twofold variation in threshold along the penetrations, with the highest intracortical thresholds being in layers 4C and 6. Variations as high as 20-fold were obtained in some individual penetrations, whereas relatively little change was observed in others. The minimum detectable current was 1 muA at a site in layer 3, i.e., 10-100 times lower than that for surface stimulation. Because macaques, as do human subjects, find electrical stimulation of striate cortex to be highly similar at all loci (a phosphene in the human case), it is puzzling as to how such uniformity of effect evolves from the exceedingly intricate circuitry available to the effective stimuli. It is hypothesized that the stimulus captures the most excitable elements, which then suppress other functional moieties, producing only the luminance of the phosphene. Lowest thresholds presumably are encountered when the electrode lies among these excitable elements that can, with higher currents, be stimulated directly from some distance or indirectly by the horizontal bands of myelinated axons, the stria of Baillarger.

Psychophysics of electrical stimulation of striate cortex in macaques.

Macaques indicated their detection of onset or alteration of 0.2-ms pulses applied in various configurations through electrodes implanted in striate cortex. When microelectrodes were introduced and left in place, the threshold for detection of 100-Hz pulses nearly doubled within 24 h. However, for chronically implanted platinum-alloy macroelectrodes detection thresholds usually remained stable for many months, independently of location within striate cortex or its immediately subjacent white matter. Thresholds were unaffected by the visual conditions, such as light versus darkness, or movement of the eyes; but in one animal blind after acute glaucoma thresholds for loci in striate cortex were permanently decreased by about 50%. Learning to respond to electrical stimulation of the optic tract produced no tendency to respond to such stimulation of striate cortex. Onset of stimulation at a given locus could be detected even in the face of continuous supraliminal stimulation at four surrounding loci on a 3-mm radius. The surround stimulation did alter the threshold of the central locus, but such stimuli could not summate if they were subliminal by some 10%. Cessation of stimulation that had been continuing for 1 min to 1 h could be detected if it were being applied at a level 20-75% above that needed for detection of stimulus onset. Continuous stimulation had a pronounced "priming" effect, in that modulation of frequency or intensity of such stimulation by as little as 5% could be detected (e.g., 20 microA in a background of 500 microA, or <2-ms interpulse interval with pulses at 50 Hz). Using pulses inserted in various phase relations to ongoing pulses at 2-5 Hz, it could be determined that stimulus pulses were surrounded by a strong facilitatory period for about 30 ms, which was then replaced by refractoriness. Given the congruence of macaque and human visual anatomy and psychophysics, these results further encourage efforts to develop a cortical prosthesis for the blind.

N400-like magnetoencephalography responses modulated by semantic context, word frequency, and lexical class in sentences.

Words have been found to elicit a negative potential at the scalp peaking at approximately 400 ms that is strongly modulated by semantic context. The current study used whole-head magnetoencephalography (MEG) as male subjects read sentences ending with semantically congruous or incongruous words. Compared with congruous words, sentence-terminal incongruous words consistently evoked a large magnetic field over the left hemisphere, peaking at approximately 450 ms. Source modeling at this latency with conventional equivalent current dipoles (ECDs) placed the N400 m generator in or near the left superior temporal sulcus. A distributed solution constrained to the cortical surface suggested a sequence of differential activation, beginning in Wernicke's area at approximately 250 ms, spreading to anterior temporal sites at approximately 270 ms, to Broca's area by approximately 300 ms, to dorsolateral prefrontal cortices by approximately 320 ms, and to anterior orbital and frontopolar cortices by approximately 370 ms. Differential activity was exclusively left-sided until >370 ms, and then involved right anterior temporal and orbital cortices. At the peak of the N400 m, activation in the left hemisphere was estimated to be widespread in the anterior temporal, perisylvian, orbital, frontopolar, and dorsolateral prefrontal cortices. In the right hemisphere, the orbital, as well as, weakly, the right anterior temporal cortices were activated. Similar but weaker field patterns were evoked by intermediate words in the sentences, especially to low-frequency words occurring in early sentence positions where there is little preceding context. The locations of the N400 m sources identified with the distributed solution correspond well with those previously demonstrated with direct intracranial recordings, and suggested by functional magnetic resonance imaging (fMRI). These results help identify a distributed cortical network that supports online semantic processing.

Fluctuating asymmetry and the human brain.

Adaptive development requires the organism to resist genetic and environmental stresses that disrupt the genetic plan for growth, a buffering capacity termed developmental stability. Developmental instability is revealed by fluctuating asymmetry (FA), which has been demonstrated in many species to reflect phenotypic and genetic quality. We report (1) that a measure of developmental instability based on body FA predicts deviation from typical brain asymmetry, (2) that a combined measure of atypical brain asymmetry and body FA correlated negatively with the area of the corpus callosum, especially the portion connecting the left and right planum temporale, and (3) that this combined measure also predicted atypical asymmetry of the size of the somatosensory representation of the two hands, as determined from magnetic source imaging.