Associations between rapid auditory processing of speech sounds and specific verbal communication skills in autism.

Introduction: The ability to rapidly process speech sounds is integral not only for processing other's speech, but also for auditory processing of one's own speech, which allows for maintenance of speech accuracy. Deficits in rapid auditory processing have been demonstrated in autistic individuals, particularly those with language impairment. We examined rapid auditory processing for speech sounds in relation to performance on a battery of verbal communication measures to determine which aspects of verbal communication were associated with cortical auditory processing in a sample of individuals with autism. Methods: Participants were 57 children and adolescents (40 male and 17 female) ages 5-18 who were diagnosed with an Autism Spectrum Disorder (ASD). Rapid auditory processing of speech sounds was measured via a magnetoencephalographic (MEG) index of the quality of the auditory evoked response to the second of two differing speech sounds ("Ga" / "Da") presented in rapid succession. Verbal communication abilities were assessed on standardized clinical measures of overall expressive and receptive language, vocabulary, articulation, and phonological processing. Associations between cortical measures of left- and right-hemisphere rapid auditory processing and verbal communication measures were examined. Results: Rapid auditory processing of speech sounds was significantly associated with speech articulation bilaterally (r = 0.463, p = 0.001 for left hemisphere and r = 0.328, p = 0.020 for right hemisphere). In addition, rapid auditory processing in the left hemisphere was significantly associated with overall expressive language abilities (r = 0.354, p = 0.013); expressive (r = 0.384, p = 0.005) vocabulary; and phonological memory (r = 0.325, p = 0.024). Phonological memory was found to mediate the relationship between rapid cortical processing and receptive language. Discussion: These results demonstrate that impaired rapid auditory processing for speech sounds is associated with dysfunction in verbal communication in ASD. The data also indicate that intact rapid auditory processing may be necessary for even basic communication skills that support speech production, such as phonological memory and articulatory control.

Language Abilities are Associated with Both Verbal and Nonverbal Intelligence in Children on the Autism Spectrum.

Intellectual abilities factor into levels of functioning used to characterize autism. Language difficulties are highly prevalent in autism and may impact performance on measures of intellectual abilities. As such, nonverbal tests are often prioritized in classifying intelligence in those with language difficulties and autism. However, the relationship between language abilities and intellectual performance is not well characterized, and the superiority of tests with nonverbal instructions is not well established. The current study evaluates verbal and nonverbal intellectual abilities in the context of language abilities in autism and the potential benefit of tests with nonverbal instructions. Participants were 55 children and adolescents on the autism spectrum who underwent a neuropsychological evaluation as part of a study examining language functioning in autism. Correlation analyses were performed to examine relations between expressive and receptive language abilities. Language abilities (CELF-4) were significantly correlated with all measures of both verbal (WISC-IV VCI) and nonverbal intelligence scores (WISC-IV PRI and Leiter-R). There were no significant differences between nonverbal intelligence measures with verbal or nonverbal instructions. We further discuss the role of assessment of language abilities in interpreting results of intelligence testing in populations with higher prevalence of language difficulties.

Magnetoencephalography for Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are leading causes of sustained physical, cognitive, emotional, and behavioral deficits in the general population, active-duty military personnel, and veterans. However, the underlying pathophysiology of mTBI/PTSD and the mechanisms that support functional recovery for some, but not all individuals is not fully understood. Conventional MR imaging and computed tomography are generally negative in mTBI and PTSD, so there is interest in the development of alternative evaluative strategies. Of particular note are magnetoencephalography (MEG) -based methods, with mounting evidence that MEG can provide sensitive biomarkers for abnormalities in mTBI and PTSD.

Addition of ketamine to standard-of-care countermeasures for acute organophosphate poisoning improves neurobiological outcomes.

Rats poisoned with sarin enter into ahyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an anticonvulsant, death can be avoided in many animals, with the long-term consequences of poisoning partly ameliorated, especially when countermeasures are made available immediately after exposure. However, when anticonvulsant measures are delayed by as little as 30 min, clinical, neurological, cognitive, and psychiatric abnormalities may persist long after the initial exposure. This study sought to determine if the addition of the NMDA receptor antagonist Ketamine to human standard-of-care countermeasures consisting of two rescue medications (2-PAM and atropine) and an anti-convulsant (Midazolam), would afford protection against persistent neurobiological compromise. Rats were exposed to sarin (105 µg/kg via subcutaneous injection), and treated 1 min later with 2-PAM and Atropine Methyl Nitrate (IM) to minimize mortality. One of four anti-convulsant protocols was then initiated at 50 min postsarin:Midazolam alone (MDZ, a single injection (IM) at 0.66 mg/kg); Ketamine alone (KET, a series of five injections (IM) of Ketamine at 7.5 mg/kg, 90 min apart); Midazolam + low dose Ketamine (MDZ + lowKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential doses of ketamine (IM) at 2.5 mg/kg, starting at the time of Midazolam dosing and then 90 min apart); Midazolam + high dose Ketamine (MDZ + highKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential injections of 7.5 mg/kg Ketamine (IM), starting at the time of Midazolam dosing and then 90 min apart). Animals were preassigned to groups culled at post-exposure Days 1, 7 or 30, for histopathology. For all surviving animals, EEG activity was monitored through skull electrodes for 24-h beginning immediately after sarin exposure. Surviving animals also underwent 24-h EEG monitoring on Days 6, 13, and/or 29, post-sarin. Memory assessment using the Morris Water Maze was performed on Days 1, 4, 7, 14 and 30. Following sarin exposure, 85% of surviving animals demonstrated status epilepticus within 20 min. Each of the anti-convulsant protocols was sufficient to stop convulsions within 1 h of anti-convulsant administration, but all of the animals still showed signs of electrographic status for an additional 2-12 h, without substantial differentiation between treatment groups. However, for post-sarin hours 13-24, the MDZ + highKET group showed significantly less severe EEG abnormalities than the MDZ and KET groups (Mood's Median Test, p < 0.005). At one month post-exposure, 90% of animals that had received Midazolam alone still showed evidence of some epileptiform activity. In contrast, 90% of animals that had received Midazolam + high dose Ketamine combination therapy had EEG profiles that were within normal limits. This difference in EEG outcomes was highly significant (Mood's Median Test, p < 0.001). Likewise, on the water maze, the majority of animals that had received Midazolam combined with either high or low dose Ketamine therapy returned to near baseline levels of mnemonic performance within 2 weeks, whereas the majority of the animals that had received midazolam alone or ketamine alone demonstrated persistent and significant memory impairments even at one month postexposure (Mood's Median Test, p < 0.005). With respect to neuronal necrosis, animals in the MDZ + highKET group showed significantly less overall damage than animals in other treatment groups (Mood's Median Test, p < 0.001). Of special note were findings in the hippocampus, where only 12% of animals in the MDZ + highKET group showed evidence of necrosis on H&E staining, whereas 100% of animals in the KET group, 70% of animals in the MDZ group, and 40% of animals in the MDZ + lowKET group showed evidence of hippocampal necrosis. Overall, the data demonstrate that Ketamine augmentation of an atropine, 2PAM, and Midazolam standard-ofcare for sarin exposure provides clinically-relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of the anti-convulsant countermeasures is delayed by 50 min.

Functional MRI Evaluation of Multiple Neural Networks Underlying Auditory Verbal Hallucinations in Schizophrenia Spectrum Disorders.

Functional MRI studies have identified a distributed set of brain activations to be associated with auditory verbal hallucinations (AVH). However, very little is known about how activated brain regions may be linked together into AVH-generating networks. Fifteen volunteers with schizophrenia or schizoaffective disorder pressed buttons to indicate onset and offset of AVH during fMRI scanning. When a general linear model was used to compare blood oxygenation level dependence signals during periods in which subjects indicated that they were versus were not experiencing AVH ("AVH-on" versus "AVH-off"), it revealed AVH-related activity in bilateral inferior frontal and superior temporal regions; the right middle temporal gyrus; and the left insula, supramarginal gyrus, inferior parietal lobule, and extranuclear white matter. In an effort to identify AVH-related networks, the raw data were also processed using independent component analyses (ICAs). Four ICA components were spatially consistent with an a priori network framework based upon published meta-analyses of imaging correlates of AVH. Of these four components, only a network involving bilateral auditory cortices and posterior receptive language areas was significantly and positively correlated to the pattern of AVH-on versus AVH-off. The ICA also identified two additional networks (occipital-temporal and medial prefrontal), not fully matching the meta-analysis framework, but nevertheless containing nodes reported as active in some studies of AVH. Both networks showed significant AVH-related profiles, but both were most active during AVH-off periods. Overall, the data suggest that AVH generation requires specific and selective activation of auditory cortical and posterior language regions, perhaps coupled to a release of indirect influence by occipital and medial frontal structures.

Audiometric Profiles in Autism Spectrum Disorders: Does Subclinical Hearing Loss Impact Communication?

Rates of hearing impairment in individuals with Autism Spectrum Disorders (ASD) are higher than those reported in the general population. Although ASD is not caused by hearing impairment, it may exacerbate symptomatology. Participants with ASD (N = 60) and typically developing peers (N = 16) aged 5-18 years underwent a comprehensive audiological screening (pure tone audiometry, uncomfortable loudness level, tympanometry, acoustic reflexes, distortion product otoacoustic emissions, and auditory brainstem response) and assessment of communication abilities (expressive/receptive language, articulation, phonological awareness, and vocal affect recognition). Incidence of abnormal findings on at least one measure of audiological functioning was higher for the ASD group (55%) than controls (14.9%) or the general population estimate (6%). The presence of sound sensitivity was also considerably higher for the ASD group (37%) compared with controls (0%) or general population estimates (8-15%). When participants with ASD were dichotomized into groups with and without evidence of clinical audiological abnormality, no significant differences were identified on measures of communication; however, results of correlational analyses indicated that variability in hearing thresholds at middle range frequencies (2000 Hz) was significantly related to performance on all measures of speech articulation and language after correction for multiple comparisons (r = -0.48 to r = -0.53, P < 0.0045). These findings suggest that dichotomized classification of clinical audiology may not be sufficient to understand the role of subclinical hearing loss in ASD symptomatology and that treatment studies for mild/subclinical hearing loss in this population may be worthwhile.

Deficits in auditory processing contribute to impairments in vocal affect recognition in autism spectrum disorders: A MEG study.

OBJECTIVE: The primary aim of this study was to examine whether there is an association between magnetoencephalography-based (MEG) indices of basic cortical auditory processing and vocal affect recognition (VAR) ability in individuals with autism spectrum disorder (ASD). METHOD: MEG data were collected from 25 children/adolescents with ASD and 12 control participants using a paired-tone paradigm to measure quality of auditory physiology, sensory gating, and rapid auditory processing. Group differences were examined in auditory processing and vocal affect recognition ability. The relationship between differences in auditory processing and vocal affect recognition deficits was examined in the ASD group. RESULTS: Replicating prior studies, participants with ASD showed longer M1n latencies and impaired rapid processing compared with control participants. These variables were significantly related to VAR, with the linear combination of auditory processing variables accounting for approximately 30% of the variability after controlling for age and language skills in participants with ASD. CONCLUSIONS: VAR deficits in ASD are typically interpreted as part of a core, higher order dysfunction of the "social brain"; however, these results suggest they also may reflect basic deficits in auditory processing that compromise the extraction of socially relevant cues from the auditory environment. As such, they also suggest that therapeutic targeting of sensory dysfunction in ASD may have additional positive implications for other functional deficits.

The role of magnetoencephalography in "nonlesional" epilepsy.

The surgical management of neocortical epilepsy is challenging because many patients are without obvious structural lesions, or lesions are small and easily overlooked during routine clinical interpretation of magnetic resonance imaging (MRI) data. Even when functional imaging data suggest focal epileptiform pathology, in the absence of a concordant structural lesion, invasive monitoring is often required to confirm that an appropriate surgical target has been identified. This study sought to determine the extent to which knowledge of magnetoencephalography (MEG) data can augment the MRI-based detection of structural brain lesions. MRI and whole-head MEG data were obtained from 40 patients with neocortical epilepsy. As a result of MEG data, 29 cases were sent for MRI reevaluation. In seven of these cases, MEG-guided review led to specification of now clear, but previously unidentified, lesions. There were two additional cases for which follow-up high-resolution imaging did not confirm structural abnormalities. In patients with neocortical epilepsy, MEG is a useful adjunct to MRI for the identification of structural lesions.

Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI.

OBJECTIVE: To determine to what extent magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG) can provide objective evidence of brain injury in adult patients with persistent (>1 year) postconcussive symptoms following mild blunt head trauma. DESIGN: A retrospective and blind review of imaging data with respect to the presence of specific somatic, psychiatric, and cognitive complaints. SETTING/PARTICIPANTS: Thirty complete data sets (with MRI, SPECT, MEG, and neuropsychological testing results) were collected between 1994 and 2000 from the MEG programs at the Albuquerque VAMC and the University of Utah. MAIN OUTCOME MEASURES: MRI data were evaluated for focal and diffuse structural abnormalities, SPECT data for regions of hypoperfusion, and resting MEG data for abnormal dipolar slow wave activity (DSWA) and epileptiform transients. RESULTS: Structural MRI was abnormal for 4 patients. SPECT showed regions of hypoperfusion in 12 patients, while MEG showed abnormal activity in 19 patients. None of the imaging methods produced findings statistically associated with postconcussive psychiatric symptoms. A significant association was found between basal ganglia hypoperfusion and postconcussive headaches. For patients with cognitive complaints, abnormalities were more likely to be detected by MEG (86%) than either SPECT (40%) or MRI (18%) (P<.01). MEG also revealed significant (P<.01) associations between temporal lobe DSWA and memory problems, parietal DSWA and attention problems, and frontal DSWA and problems in executive function. CONCLUSIONS: Functional brain imaging data collected in a resting state can provide objective evidence of brain injury in mild blunt head trauma patients with persistent postconcussive somatic and/or cognitive symptoms. MEG proved to be particularly informative for patients with cognitive symptoms.

Developmental instability and the neural dynamics of the speed-intelligence relationship.

Two of the most securely established findings in the biology of intelligence are the relationship between reaction time (RT) and intelligence, and the heritability of intelligence. To investigate why RT may related to intelligence, researchers have used a variety of techniques to subdivide RT into cognitive and motor components. In the current study, magnetoencephalographic (MEG) dipole latencies were used to examine the speed and timing of specific brain processing stages engaged during visually cued simple and choice reaction time tasks. Simple and choice reaction time and timing of MEG sources were considered in relation to fluid intelligence (as measured by the Raven's Advanced Progressive Matrices, RAPM). To address heritability of intelligence, developmental instability (DI) was assessed, measured here as fluctuating asymmetry. DI represents the degree to which an organism is susceptible to developmental stress arising from both environmental and genomic sources. Analyses showed that choice, but not simple reaction time was negatively correlated with RAPM score. MEG revealed a set of complex relationships between the timing of regional brain activations and psychometric intelligence. The neural component associated with integration of sensory and motor information was most associated with RAPM compared to other components. Higher values of fluctuating asymmetry predicted reduced psychometric intelligence, a result suggesting that some part of the variance of the heritability of intelligence reflects DI. Fluctuating asymmetry was significantly and negatively correlated with timing during all components of task completion. These observations suggest that fluid intelligence is primarily related to speed during processing associated with decision time, while fluctuating asymmetry predicted slower processing across all stages of information processing.

Distinguishing between moving and stationary sources using EEG/MEG measurements with an application to epilepsy.

Performances of electroencephalography (EEG) and magnetoencephalography (MEG) source estimation methods depend on the validity of the assumed model. In many cases, the model structure is related to physical information. We discuss a number of statistical selection methods to distinguish between two possible models using least-squares estimation and assuming a spherical head model. The first model has a single moving source whereas the second has two stationary sources; these may result in similar EEG/MEG measurements. The need to decide between such models occurs for example in Jacksonian seizures (e.g., epilepsy) or in intralobular activities, where a model with either two stationary dipole sources or a single moving dipole source may be possible. We also show that all of the selection methods discussed choose the correct model with probability one when the number of trials goes to infinity. Finally we present numerical examples and compare the performances of the methods by varying parameters such as the signal-to-noise ratio, source depth, and separation of sources, and also apply the methods to real MEG data for epilepsy.

Magnetoencephalographically directed review of high-spatial-resolution surface-coil MR images improves lesion detection in patients with extratemporal epilepsy.

PURPOSE: To determine whether (a) interictal magnetoencephalographic (MEG) epileptiform activity corresponds to anatomic abnormalities at magnetic resonance (MR) imaging, (b) high-spatial-resolution MR imaging depicts lesions in regions without MEG spike activity, (c) MEG-directed review of high-spatial-resolution MR images enables detection of abnormalities not apparent on conventional MR images, and (d) MEG information results in a greater number of diagnosed lesions at re-review of conventional MR images. MATERIALS AND METHODS: Twenty patients with neocortical epilepsy were evaluated with MEG, conventional brain MR imaging with a head coil, and high-spatial-resolution MR imaging with either a surface coil (n = 17) or a high-spatial-resolution birdcage coil (n = 3). Abnormal MEG foci were compared with corresponding anatomic areas on conventional and high-spatial-resolution MR images to determine the presence (concordance) or absence (discordance) of anatomic lesions corresponding to foci of abnormal MEG activity. RESULTS: Forty-four epileptiform MEG foci were identified. Twelve foci (27%) were concordant with an anatomic abnormality at high-spatial-resolution MR imaging, and 32 foci (73%) were discordant. Results of high-spatial-resolution MR imaging were normal in eight patients, and 23 lesions were detected in the remaining 12 patients. Twelve lesions (52%) were concordant with abnormal MEG epileptiform activity, and 11 (48%) were discordant (ie, there was normal MEG activity in the region of the anatomic abnormality). At retrospective reevaluation of conventional MR images with MEG guidance, four occult gray matter migration lesions that had initially been missed were observed. An additional patient with MEG-concordant postoperative gliosis was readily identified with high-spatial-resolution MR images but not with conventional MR images. CONCLUSION: Review of MEG-localized epileptiform areas on high-spatial-resolution MR images enables detection of epileptogenic neocortical lesions, some of which are occult on conventional MR images.

Abnormal stimulus-response intensity functions in posttraumatic stress disorder: an electrophysiological investigation.

OBJECTIVE: The purpose of this study was to explore the relationship between combat-related posttraumatic stress disorder (PTSD) and specific augmentation versus reduction patterns for the N100 and P200 components of auditory event-related potentials evoked by tones of increasing intensity. METHOD: Event-related potentials of subjects with PTSD (N=36), subjects with no psychopathology (N=20), subjects with major depression but no PTSD (N=10), and subjects with a history of chronic alcohol abuse but no PTSD (N=8) were recorded. Brain responses were evoked by a 2000-Hz tone presented in intensity blocks of 65, 72.5, 80, 87.5, and 95 dB (SPL). RESULTS: Evoked data from five PTSD subjects were of poor quality and excluded from further analyses. For all but one subject with no psychopathology and for all subjects with a history of alcohol abuse or major depression (but no PTSD), the Cz amplitude of the P200 response component showed augmentation as a nearly linear function of tone intensity. As a group, subjects with PTSD showed no such increase in P200 response magnitude. Examination of the data from individual subjects with PTSD showed that 42% exhibited augmentation patterns similar to those seen for subjects in the comparison groups. However, 58% showed evidence of P200 reduction, with the response to the loudest tone being smaller than responses to tones of intermediate intensity. CONCLUSIONS: The data suggest that there is a significant subgroup of patients with combat-related PTSD who enter into a state of protective inhibition at relatively low stimulus intensities. It is hypothesized that this is an appropriate adaptive mechanism for these subjects rather than an indication of a core neurobiological abnormality.