Reduced auditory steady state responses in autism spectrum disorder.

BACKGROUND: Auditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40 Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD (Mol Autism. 2011;2:11, Biol Psychiatry. 2007;62:192-197). METHODS: Using a 1.5 s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40 Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls. RESULTS: The ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1 s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40 Hz from 0.5 to 1.5 s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40 Hz from 0.64-0.82 s for right A1 and 1.04-1.22 s for left A1. LIMITATIONS: In this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore, it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD. CONCLUSION: Overall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing.

Oscillatory networks of high-level mental alignment: A perspective-taking MEG study.

Mentally imagining another's perspective is a high-level social process, reliant on manipulating internal representations of the self in an embodied manner. Recently Wang et al. (2016) showed that theta-band (3-7 Hz) brain oscillations within the right temporo-parietal junction (rTPJ) and brain regions coding for motor/body schema contribute to the process of perspective-taking. Using a similar paradigm, we set out to unravel the extended functional brain network in detail. Increasing the angle between self and other perspective was accompanied by longer reaction times and increases in theta power within rTPJ, right lateral prefrontal cortex (PFC) and right anterior cingulate cortex (ACC). Using Granger-causality, we showed that lateral PFC and ACC exert top-down influence over rTPJ, indicative of executive control processes required for managing conflicts between self and other perspectives. Finally, we quantified patterns of whole-brain phase coupling in relation to the rTPJ. Results suggest that rTPJ increases its theta-band phase synchrony with brain regions involved in mentalizing and regions coding for motor/body schema; whilst decreasing synchrony to visual regions. Implications for neurocognitive models are discussed, and it is proposed that rTPJ acts as a 'hub' to route bottom-up visual information to internal representations of the self during perspective-taking, co-ordinated by theta-band oscillations.

Brain oscillations and connectivity in autism spectrum disorders (ASD): new approaches to methodology, measurement and modelling.

Although atypical social behaviour remains a key characterisation of ASD, the presence of sensory and perceptual abnormalities has been given a more central role in recent classification changes. An understanding of the origins of such aberrations could thus prove a fruitful focus for ASD research. Early neurocognitive models of ASD suggested that the study of high frequency activity in the brain as a measure of cortical connectivity might provide the key to understanding the neural correlates of sensory and perceptual deviations in ASD. As our review shows, the findings from subsequent research have been inconsistent, with a lack of agreement about the nature of any high frequency disturbances in ASD brains. Based on the application of new techniques using more sophisticated measures of brain synchronisation, direction of information flow, and invoking the coupling between high and low frequency bands, we propose a framework which could reconcile apparently conflicting findings in this area and would be consistent both with emerging neurocognitive models of autism and with the heterogeneity of the condition.

MR imaging features of amyloid-related imaging abnormalities.

BACKGROUND AND PURPOSE: AD is one of the few leading causes of death without a disease-modifying drug; however, hopeful agents are in various phases of development. MR imaging abnormalities, collectively referred to as amyloid-related imaging abnormalities, have been reported for several agents that target cerebral Aß burden. ARIA includes ARIA-E, parenchymal or sulcal hyperintensities on FLAIR indicative of parenchymal edema or sulcal effusions, and ARIA-H, hypointense regions on gradient recalled-echo/T2* indicative of hemosiderin deposition. This report describes imaging characteristics of ARIA-E and ARIA-H identified during studies of bapineuzumab, a humanized monoclonal antibody against Aß. MATERIALS AND METHODS: Two neuroradiologists with knowledge of imaging changes reflective of ARIA reviewed MR imaging scans from 210 bapineuzumab-treated patients derived from 3 phase 2 studies. Each central reader interpreted the studies independently, and discrepancies were resolved by consensus. The inter-reader κ was 0.76, with 94% agreement between neuroradiologists regarding the presence or absence of ARIA-E in individual patients. RESULTS: Thirty-six patients were identified with incident ARIA-E (17.1%, 36/210) and 26 with incident ARIA-H (12.4%, 26/210); of those with incident ARIA-H, 24 had incident microhemorrhages and 2 had incident large superficial hemosiderin deposits. CONCLUSIONS: In 49% of cases of ARIA-E, there was the associated appearance of ARIA-H. In treated patients without ARIA-E, the risk for incident blood products was 4%. This association between ARIA-E and ARIA-H may suggest a common pathophysiologic mechanism. Familiarity with ARIA should permit radiologists and clinicians to recognize and communicate ARIA findings more reliably for optimal patient management.

Semantic and phonological task-set priming and stimulus processing investigated using magnetoencephalography (MEG).

In this study the neural substrates of semantic and phonological task priming and task performance were investigated using single word task-primes. Magnetoencephalography (MEG) data were analysed using Synthetic Aperture Magnetometry (SAM) to determine the spatiotemporal and spectral characteristics of cortical responses. Comparisons were made between the task-prime conditions for evidence of differential effects as a function of the nature of the task being primed, and between the task-prime and the task performance responses for evidence of parallels in activation associated with preparation for and completion of a specific task. Differential priming effects were found. Left middle temporal and inferior frontal voxels showed a statistically significant power decrease associated with the semantic task-prime, and a power increase associated with the phonological task-prime, within beta and gamma frequency bands respectively. Similarities between the task-related differential effects associated with task-prime presentation and those associated with target stimulus presentation were also found. For example, within the semantic task condition, left superior frontal and middle temporal regions showed a significant power decrease within both task-prime and target epochs; within the phonological task condition there were significant parietal and cerebellar power decreases within both types of epoch. In addition there was evidence within the priming epochs of dissociable patterns of activity which could be interpreted as indices of de-activation of task-irrelevant networks. Following a phonological task-prime, significant power increases were observed in those inferior frontal and middle temporal regions in which significant power decreases were associated with semantic task priming and performance.

Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement.

BACKGROUND: Factors that modify risk related to APOE variants have been examined primarily in unrelated patients and controls, but seldom in family-based studies. Stroke, vascular risk factors, estrogen replacement therapy (ERT), head injury (HI), and smoking have been reported to influence risk of sporadic but not familial Alzheimer disease (AD). OBJECTIVES: To examine the potential relationship between these risk factors and APOE, the authors used a family study design in a population in which the APOE-epsilon4 variant is strongly associated with risk of AD. METHODS: Latino families primarily from the Caribbean Islands in which two or more living relatives had dementia were identified in the New York City metropolitan area, the Dominican Republic, and Puerto Rico. A total of 1,498 participants from 350 families underwent a clinical interview, medical and neurologic examinations, neuropsychological testing, and APOE genotyping. Diagnosis was made by consensus using research criteria for AD. RESULTS: APOE-epsilon4 was associated with a nearly twofold increased risk of AD. A history of stroke was also associated with a fourfold increased risk. A statistical interaction between APOE-epsilon4 and stroke was observed. Women with an APOE-epsilon4 who took ERT did not have an increased risk of AD, but in women with a history of stroke ERT was a deleterious effect modifier. CONCLUSIONS: APOE-epsilon4 and stroke independently increase risk of familial Alzheimer disease (AD) among Latinos, and may interact to further increase AD risk. Among women, the risk of AD associated with APOE-epsilon4 may be attenuated by a history of ERT.

Late-onset frontotemporal dementia associated with progressive supranuclear palsy/argyrophilic grain disease/Alzheimer's disease pathology.

Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer's disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized by apathy, emotional blunting, disinhibition, and impairment in executive functioning despite relatively preserved memory and visuospatial abilities. Cognitive deficits are known to occur in PSP; however, overt clinical FTD without parkinsonism or supranuclear gaze palsy associated with PSP pathology has rarely been documented. We report an elderly patient with the typical clinical, neuropsychometric, and neuroimaging features of FTD who had autopsy findings most consistent with PSP plus AGD and AD in limbic structures. We suggest that PSP with or without coexisting AD and AGD be included in the differential diagnosis of patients presenting with FTD.

Acute febrile neutrophilic vasculitis of the skin of young Shar-Pei dogs.

Three young Shar-Pei dogs were presented for signs of an acute widespread dermatopathy associated with fever and malaise. Cutaneous lesions initially consisted of multifocal areas of skin discolouration (haemorrhagic papules, macules or plaques) or oedema, preferentially affecting the head and limbs. In some locations, pus-filled bullae were evident also. Cutaneous lesions exuded seropurulent liquid and, in time, usually progressed to full thickness necrosis and ulceration. Lesions were so widespread and severe that one of the dogs was euthanased because its owners could not afford the reconstructive surgery required to close the skin deficits left at the completion of otherwise successful therapy. Histological examination of representative biopsies showed neutrophilic dermatitis and vasculitis, which ultimately resulted in ischaemic necrosis of skin. Therapy with immunosuppressive doses of corticosteroids, and in one case cyclophosphamide, resulted in prompt amelioration of the underlying inflammatory process, although regions of skin deprived of their blood supply eventually became necrotic and sloughed. Healing occurred through granulation, contraction and epithelialisation. The physical findings in these three dogs were so similar that it is likely all suffered from the same breed-related syndrome, an immune-mediated vasculitis precipitated by some event, such as vaccination or an undetected infection. Whatever the inciting cause, it was most likely a one-off event, as the two surviving dogs were readily weaned off immunosuppressive medication without relapse.

A double-dissociation of English past-tense production revealed by event-related potentials and low-resolution electromagnetic tomography (LORETA).

OBJECTIVES: Evidence of systematic double-dissociations of neural activity associated with the generation of regular and irregular past tense in healthy individuals may prove decisive in distinguishing between single- and dual-route models of morphological processing, because the former (connectionist models of morphological processing) have only been able to simulate double-dissociations of past-tense morphology as low-probability phenomena. METHODS: Twenty-eight channel event-related potentials (ERPs) were recorded in response to past-tense production and subsequently analyzed using a 3-stage strategy. RESULTS: A data-driven algorithm temporally segmented the ERPs into 16 distinct epochs of stable field configuration (microstates). A space-oriented brain electric field analysis determined that one of those epochs, 288-321 ms after the verb stem presentation, showed significant differences between the regular and irregular verb conditions. As a further test of these results, a novel source localization technique that computes 3-dimensional distribution of cortical current density in the Talairach brain atlas--low-resolution electromagnetic tomography--found in the above microstate more activity for regulars in the right prefrontal and right temporal areas and for irregulars in the left temporal areas and the anterior cingulate cortex, which can be taken as evidence of systematic double-dissociation. CONCLUSIONS: The present results achieved with a source localization technique provide evidence of a two-way compartmentalization of neural activity corresponding to regular and irregular past tense, thus corroborating the dual-mechanism character of verb morphology.

Mapping dissociations in verb morphology.

Substantial behavioural and neuropsychological evidence has been amassed to support the dual-route model of morphological processing, which distinguishes between a rule-based system for regular items (walk-walked, call-called) and an associative system for the irregular items (go-went). Some neural-network models attempt to explain the neuropsychological and brain-mapping dissociations in terms of single-system associative processing. We show that there are problems in the accounts of homogeneous networks in the light of recent brain-mapping evidence of systematic double-dissociation. We also examine the superior capabilities of more internally differentiated connectionist models, which, under certain conditions, display systematic double-dissociations. It appears that the more differentiation models show, the more easily they account for dissociation patterns, yet without implementing symbolic computations.

Differences in working memory involvement in analytical and creative tasks: an ERP study.

If, as suggested, creative (insight) problem solving is less systematic and employs less planning than analytical problem solving, the former requires substantially less working memory (WM) than the latter. Subjects simultaneously solved problems and counted auditory stimuli (concurrent WM task), in response to which ERPs were recorded. Counting disrupted analytical, but not creative performance. Peak and time-window average P300 were more frontal during analytical problem solving as compared to insight or counting tones only (control). A PCA extracted two factors in the P3 range, one frontal and one broad left-lateralized, which distinguished analytical from creative problem solving. The findings indicate distinct processing pathways for the two types of tasks with more WM involvement in analytical tasks.

Trait and state EEG indices of information processing in developmental dyslexia.

L asymmetry in beta activity in the dyslexic group, again in both tasks. Theta activity did discriminate between the two tasks in the dyslexic group. In the phonological task, task-related frontal theta in the dyslexic group was significantly different from the control group, with the former showing an increase in amplitude and the latter a decrease. In the visual task, there was no significant difference between the dyslexic and the control group, with both showing a task-related decrease in amplitude. The inter-task variations in EEG response in the dyslexic group paralleling variations in task performance are interpreted in terms of the varying engagement of a frontally-based attentional system. Inter-task consistencies of EEG response despite variations in performance are interpreted in terms of the continued application of a specific cognitive strategy.

Opposite patterns of P300 asymmetry in schizophrenia are syndrome related.

In schizophrenia reduction of the P300 amplitude is a robust statistical finding but with inconsistent evidence of symptom correlates and of lateral asymmetry. Here relations were examined with active and withdrawn syndromes which in other cognitive and electrophysiological measurement modalities have been associated with opposite functional asymmetries. A standard oddball detection task was used to elicit auditory evoked potentials from dextral DSM-IV schizophrenic patients. On clinical ratings blind to the psychophysiology, eight were classified as withdrawn and 12 had a predominance of active syndrome features. Both patient groups had congruent P300 maxima at Pz or P4, attesting to their application to the detection task. Syndromes were differentiated by opposite asymmetries in P300, N200-P300 and N100 amplitudes at the posterior temporal sites: a reduction in P300 and N200-P300 amplitudes on the left in the active patients, and a reduction on the right in the withdrawn patients, with the opposite asymmetries in N100 amplitudes. The syndrome-related asymmetries in P300, also manifested in earlier attentional (N100) components are interpreted in terms of thalamo-cortical arousal systems having generalised, internalised influences, rather than in terms of later cognitive processes underpinning the P300. The findings endorse a syndromal approach to laterality research in schizophrenia.

Psychophysiological correlates of dynamic imagery.

Brain Electrical Activity Maps were recorded from 20 subjects whilst performing: (a) the Vandenberg & Kuse Mental Rotation Test (MRT) and: (b) the Isaac, Marks & Russell Vividness of Movement Imagery Questionnaire (VMIQ), and under control conditions. Subjects were classified as good or poor imagers, first on the basis of their VMIQ scores, and secondly on their MRT scores. Alpha, beta 1 and beta 2 at different cortical regions were compared between groups and between task performance and control conditions. During MRT significant reductions in alpha amplitude were found over both right and left parietal areas and over the left frontal region. In beta 1 non-significant trends in the same direction were observed in the same regions found to be significant in alpha. Non-significant trends in beta 2 were observed over the right parietal and frontal regions. No differences in amplitude at any frequency band were found between good and poor VMIQ scorers but subjects with high MRT scores showed greater alpha amplitude at many sites in the parietal, parieto-occipital and frontal areas than subjects with low MRT scores. During VMIQ testing the VMIQ high imagers showed a non-significant trend towards higher alpha amplitude at frontal regions and some scattered parietal and occipital sites and significantly higher levels of beta 2 in the left frontal region. However, no differences were found between imagery and control conditions. The results confirm the involvement of motor as well as spatial processes in dynamic imagery.

Auditory event-related potentials, dichotic listening performance and handedness as indices of lateralisation in dyslexic and normal readers.

Evidence suggests that children with developmental dyslexia have poor phonological processing skills, are less likely to show lateralised activation during the processing of verbal information than children with normal reading ability and tend towards the left of the handedness continuum. The present study investigated this relationship between cerebral lateralisation and reading ability in children with and without dyslexia, directly using a dichotic listening paradigm with contemporaneous recording of auditory evoked potentials and indirectly using measures of hand preference and hand skill. The two groups were significantly different on a phonemic awareness task, particularly with reference to rime rather than phoneme onset. The two groups performed equally well on the dichotic listening task. However, normal readers produced significantly greater N100 amplitudes in the left temporal region during dichotic listening than the dyslexics who displayed approximately equivalent levels of amplitude bilaterally. In terms of hand preference the dyslexics were significantly less right-hand preferent than the controls, although the groups did not differ on a measure of right/left hand skill. The AEP lateralisation indices and the hand preference scores were significantly related to phonemic awareness performance. The different patterns of AEP activity produced by the two groups of children during the dichotic listening task and the differences in hand preference may be related to abnormal cerebral lateralisation of language functions. The failure of the dichotic listening task to discriminate between the two groups in spite of evidence of differences in cortical activation suggests that the processing difficulties which may be indexed by these differences in cortical activation affect the reading process at a later stage than that tapped by dichotic listening.

Paranoid-nonparanoid differences--psychophysiological parallels.

It was predicted that the psychological differences between paranoids and nonparanoids would be parallelled by differences in psychophysiological responses to stimuli varying along both informational and motivational dimensions. Skin conductance and heart rate responses to stimuli in a guessing task were measured in a group of paranoid patients and compared with those from non-paranoid and non-patient controls. A group of nonschizophrenic patients on phenothiazine medication served as drug-matched controls. Skin conductance level, response frequency and amplitude data are reported; heart rate response changes were examined by means of times series analysis and reported as first and second deceleration and first and second acceleration components. It was predicted that paranoid patients would show a greater increase in skin conductance measures with cognitive demand, and an increase in acceleratory components of the heart rate to increases in motivational variables. The normal pattern of greater electrodermal responding to the negative stimuli than the positive, and greater heart rate acceleration to the positive stimuli but not the negative (Fowles, 1980) was predicted to be reversed in schizophrenic patients, and possibly more marked in paranoids. Cognitive manipulations showed the predicted increase in electrodermal and heart rate responding in normal controls. The paranoid subjects showed a similar increase as a function of task demands, but there was no significant difference between the other groups. Motivational manipulations produced increased skin conductance responding and increases in heart rate acceleration components in normal controls, this was not parallelled in the patient groups. All subject groups failed to show greater electrodermal activity to negative than to positive stimuli. Normal controls showed significant heart rate acceleration to positive as compared to negative stimuli, this pattern was reversed in paranoid patients.

Individual differences in electrodermal and electroencephalographic asymmetries.

In a continuing investigation of the relationship between differential hemispheric activation and electrodermal asymmetry, comparisons were made between the electroencephalographic asymmetries and electrodermal asymmetries exhibited by subjects carrying out particular tasks. Bilateral skin conductance responses and 28 channels of EEG data allowing the production of topographical maps were collected from 8 female and 8 male right-handed subjects during the performance of two tasks, one verbal and one visuospatial. The tasks were selected with the aim of differentially activating the hemispheres to investigate whether parallel changes in the direction of electroencephalographic and electrodermal asymmetries would occur. EEG asymmetries were compared in female and male subjects. Previous research has indicated that males tend to show stronger EEG asymmetry than females, and that this is emphasised in verbal tasks. This was confirmed by the present study. Comparison with electrodermal activity revealed a weak relationship between the two measures, with some parallels between task-related variations in the beta 2 waveband and skin conductance responses. No parallels between alpha activity or skin conductance level were demonstrated. If the subjects are regrouped according to degree of electrodermal asymmetries, then some closer parallels with electroencephalographic asymmetries are revealed with more marked electrodermal asymmetry paralleling more marked electroencephalographic asymmetry. Variations in electrodermal asymmetry appear to be related to greater activity on the hand contralateral to the hemisphere showing smaller amplitude EEG activity, generally in the beta waveband. In discussing cortical control of electrodermal activity, these findings are discussed in terms of both the contralateral excitatory and the contralateral inhibitory models.