Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders.

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimer's disease, schizophrenia, Sjögren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Reading in a deep orthography: neuromagnetic evidence for dual-mechanisms.

Despite substantial efforts to connect cognitive-linguistic models with appropriate anatomical correlates, the question of which cognitive model best accounts for the neuropsychological and functional neuroimaging evidence remains open. The two most popular models are grounded in conceptually different bases and thus make quasi-distinct predictions in regard to the patterns of activation that should be observed in imaging investigations of linguistic processing. Dual-mechanism models propose that high-frequency regular and irregular words are processed through a lexicon-based word code, which facilitates their processing and pronunciation latencies relative to pseudowords. In contrast, single-mechanism models suggest the same behavioral effects can be explained through semantic mediation without the existence of a lexicon. In most previous studies, words and pronounceable pseudowords were presented in lexical-decision or word reading paradigms, and hemodynamic techniques were utilized to distinguish involved anatomical areas. The results typically indicated that both word classes activated largely congruent tissues, with a magnitude advantage for pseudowords in most or all activated regions. However, since the dual-mechanism model predicts both word types utilize the entire linguistic network, but that certain operations are merely obligatorily involved, these results do not sharply refute nor clearly support the model's main tenets. In the current study, we approach the dual- versus single-mechanism question differently by focusing on the temporal dynamics of MEG imaged neuronal activity, during performance of an oddball version of continuous lexical-decision, to determine whether the onset latency of any cortical language region shows effects of word class that are indicative of preferential versus obligatory processing pathways. The most remarkable aspect of our results indicated that both words and pseudowords initially activate the left posterior fusiform region, but that the spatiotemporal dynamics clearly distinguish the two word classes thereafter. For words, this left fusiform activation was followed by engagement of the left posterior inferior temporal, and subsequently activation reached the left posterior superior temporal region. For pseudowords, this sequential order of left temporal area activations was reversed, as activity proceeded from the left fusiform to the left superior temporal and then the left inferior temporal region. For both classes, this dynamic sequential spread manifested within the first 300 ms of stimulus processing. We contend these results provide strong support for the existence of dual-mechanisms underlying reading in a deep orthographic language (i.e., English).

About the mechanisms of auditory verbal hallucinations: a positron emission tomographic study.

OBJECTIVE: Auditory verbal hallucinations (AVHs) likely result from disorders, as yet unspecified, of the neural mechanisms of language. Here we examine the functional neuroanatomy of single-word reading in patients with and without a history of AVH. METHOD: Eighteen medicated schizophrenia patients (8 with AVH and 10 without AVH) and 12 healthy control subjects were scanned with PET (15)O-water technique under 2 conditions: reading aloud English nouns and passively looking at English nouns without reading them. RESULTS: The contrast between the 2 conditions shows higher activation in Wernicke's area during the reading condition in the patient group and a reversed laterality index for the supplementary motor area in the AVH group. CONCLUSIONS: These findings provide indications about the possible mechanisms of AVH. We suggest that the abnormal laterality of the supplementary motor area activity accounts for the failure to attribute speech generated by one's own brain to one's self and that the activation of Wernicke's area accounts for the perceptual nature (hearing) of the patient's experience.

Classification of adolescent psychotic disorders using linear discriminant analysis.

BACKGROUND: The differential diagnosis between schizophrenia and bipolar disorder during adolescence presents a major clinical problem. Can these two diagnoses be differentiated objectively early in the courses of illness? METHODS: We used linear discrimination analysis (LDA) to classify 28 adolescent subjects into one of three diagnostic categories (healthy, N=8; schizophrenia, N=10; bipolar, N=10) using subsets from a pool of 45 variables as potential predictors (22 neuropsychological test scores and 23 quantitative structural brain measurements). The predictor variables were adjusted for age, gender, race, and psychotropic medication. All possible subsets composed of k=2-12 variables, from the set of 45 variables available, were evaluated using the robust leaving-one-subject-out method. RESULTS: The highest correct classification (96%) of the 3 diagnostic categories was yielded by 9 sets of k=12 predictors, comprising both neuropsychological and brain structural measures. Although each one of these sets misclassified one case, each set correctly classified (100%) at least one group, such that a fully correct diagnosis could be reached by a tree-type decision procedure. CONCLUSIONS: We conclude that LDA with 12 predictor variables can provide correct and robust classification of subjects into the three diagnostic categories above. This robust classification relies upon both neuropsychological and brain structural information. Our results demonstrate that, despite overlapping clinical symptoms, schizophrenia and bipolar disorder can be differentiated early in the course of disease. This finding has two important implications. Firstly, schizophrenia and bipolar disorder are different illnesses. If schizophrenia and bipolar are dissimilar clinical manifestations of the same disease, we would not be able to use non-clinical information to classify ('diagnose') schizophrenia and bipolar disorder. Secondly, if this study's findings are replicated, brain structure (MRI) and brain function (neuropsychological) used together may be useful in the diagnosis of new patients.

Neurocognitive dysfunction in antidepressant-free, non-elderly patients with unipolar depression: alerting and covert orienting of visuospatial attention.

BACKGROUND: Cognition is impaired across various domains in young and middle-age adults with unipolar depression. Performance appears in general worse in effortful tasks requiring executive function and attention. Probing specific cognitive operations in depressed patients, such as alerting and covert orienting of visuospatial attention, can better define and characterize the pathophysiology. METHODS: Nine antidepressant-free, clinically depressed patients and fourteen age-matched healthy subjects performed a Posner task with components of phasic alerting and covert orienting of visuospatial attention. Reaction times were analyzed by repeated-measures ANOVA with DIAGNOSIS as the between-group measure. Visual field (FIELD), stimulus onset asynchrony (SOA), and orienting CUE condition were within-subject, repeated measures. RESULTS: ANOVA showed intact attentional orienting in both groups. There were no FIELD differences across groups nor main effects of DIAGNOSIS. Interactions of DIAGNOSIS with SOA and DIAGNOSIS with CUE condition identified a phasic alerting deficit in the depressed patients. There were no significant effects of time-on-task, suggesting adequate vigilance or sustained attention in both groups. Plotting depressed versus control subjects' reaction time for each task condition (Brinley plot) showed linearity with a slope of 1.6 (i.e., patients were 1.6-fold slower) and a correlation coefficient of 0.98 (accounting for 96% of the overall variance). LIMITATIONS: This study contains a small sample with potential for Type II error. The study addressed depression at the syndrome level. Depressed patients selected on particular symptom dimensions (e.g., anxiety, psychomotor retardation, etc.) could reveal abnormalities in hemisphere asymmetries that were not observed here. CONCLUSIONS: These data highlight that global slowing is a major cognitive deficit in depression and arises across levels of difficulty. Putative specific deficits in depression need adjustment for the large effects of global slowing which can mimic selective impairments in more effortful task conditions.

Cognitive dimensions of orthographic stimuli affect occipitotemporal dynamics.

Previous research documented letter-string specific cortices in the ventral visual stream near the left occipitotemporal junction (i.e., anterior fusiform gyrus). These neural areas potentially code the perceptual elements comprising orthographic stimuli, and thus function as feature detectors in high-level vision. While abundant evidence supports this region's role in detecting isomorphic perceptual features, any influence cognitive dimensions (e.g., the lexicality of letter-strings) may play in modulating this area's processing remains an open question. To investigate this, we examined the spatiotemporal dynamics of high-density magnetoencephalographic signals, recorded as subjects completed a rhyme-judgment task on stimuli varying in the cognitive property of lexicality. Our data demonstrate that the time course of occipitotemporal cortices discriminates cognitive attributes of orthographic stimuli. The dynamics in this brain region may indicate interactive processes unfolding later in the time course, when more anterior fronto-temporal circuits are activated by semantic correlates of real words.

The time and space of lexicality: a neuromagnetic view.

Illuminating the neural mechanisms subserving lexico-semantic processing is requisite to further understanding the neurophysiological basis of the dyslexias. Yet, despite numerous functional neuroimaging experiments, the location and temporal behavior of brain regions mediating word-level language processing remain an area of debate. Such investigations typically utilize the word/pseudoword contrast within hemodynamic measurements, and report several left hemisphere regions that respond more strongly to pseudowords but fail to replicate neural areas unique to real word processing. The present experiment addressed this problem from a different perspective. Mainly, we hypothesized that the time course, but not the neuroanatomy, would show within-subject across-condition disparities. For that purpose, we applied dipole-modeling techniques to high-density magnetoencephalographic recordings of healthy subjects, and utilized excellent spatiotemporal accuracy to demonstrate significant across-condition differences in the time domain, along with indistinguishable neural correlates within-subject. In all participants, both words and pseudowords elicited activity in left perisylvian language areas, with words consistently activating these regions approximately 100 ms earlier than pseudowords. Considerable functional heterogeneity was also observed, and this might underlie the inconsistencies among previous studies. We conclude that the neural distinction in word/pseudoword processing is not in spatial localization, but is better conceptualized as a dynamic difference in processing time.