Specificity and sensitivity of visual evoked potentials in the diagnosis of schizophrenia: rethinking VEPs.

Alterations of the visual evoked potential (VEP) component P1 at the occipital region represent the most extended functional references of early visual dysfunctions in schizophrenia (SZ). However, P1 deficits are not reliable enough to be accepted as standard susceptibility markers for use in clinical psychiatry. We have previously reported a novel approach combining a standard checkerboard pattern-reversal stimulus, spectral resolution VEP, source detection techniques and statistical procedures which allowed the correct classification of all patients as SZ compared to controls. Here, we applied the same statistical approach but to a single surface VEP - in contrast to the complex EEG source analyses in our previous report. P1 and N1 amplitude differences among spectral resolution VEPs from a POz-F3 bipolar montage were computed for each component. The resulting F-values were then Z-transformed. Individual comparisons of each component of P1 and N1 showed that in 72% of patients, their individual Z-score deviated from the normal distribution of controls for at least one of the two components. Crossvalidation against the distribution in the SZ-group improved the detection rate to 93%. In all, six patients were misclassified. Clinical validation yielded striking positive (78.13%) and negative (92.69%) predictive values. The here presented procedure offers a potential clinical screening method for increased susceptibility to SZ which should then be followed by high density electrode array and source detection analyses. The most important aspect of this work is represented by the fact that this diagnostic technique is low-cost and involves equipment that is feasible to use in typical community clinics.

Basic visual dysfunction allows classification of patients with schizophrenia with exceptional accuracy.

Basic visual dysfunctions are commonly reported in schizophrenia; however their value as diagnostic tools remains uncertain. This study reports a novel electrophysiological approach using checkerboard visual evoked potentials (VEP). Sources of spectral resolution VEP-components C1, P1 and N1 were estimated by LORETA, and the band-effects (BSE) on these estimated sources were explored in each subject. BSEs were Z-transformed for each component and relationships with clinical variables were assessed. Clinical effects were evaluated by ROC-curves and predictive values. Forty-eight patients with schizophrenia (SZ) and 55 healthy controls participated in the study. For each of the 48 patients, the three VEP components were localized to both dorsal and ventral brain areas and also deviated from a normal distribution. P1 and N1 deviations were independent of treatment, illness chronicity or gender. Results from LORETA also suggest that deficits in thalamus, posterior cingulum, precuneus, superior parietal and medial occipitotemporal areas were associated with symptom severity. While positive symptoms were more strongly related to sensory processing deficits (P1), negative symptoms were more strongly related to perceptual processing dysfunction (N1). Clinical validation revealed positive and negative predictive values for correctly classifying SZ of 100% and 77%, respectively. Classification in an additional independent sample of 30 SZ corroborated these results. In summary, this novel approach revealed basic visual dysfunctions in all patients with schizophrenia, suggesting these visual dysfunctions represent a promising candidate as a biomarker for schizophrenia.

BET differences among simultaneous evoked frequency band responses during early-stage visual processing distinguish schizophrenia from healthy subjects.

In this work, we attempt to extend to the schizophrenia's research the evidence that different frequency bands may emerge from different sources during early-stage visual processing, in a mental state-specific manner, while subjects are passively viewing a visual stimulus. We applied standard pattern reversal stimulation (checker-board), a task with low cognitive demands, coupled to a dense EEG recording system to estimate the neural correlates of the evoked theta, alpha, beta, beta1, and gamma frequency band responses by means of brain electrical tomography (BET). After filtering the evoked activity using different band-passes, a very different picture about the current sources during P100 will emerge. The results showed notable differences between the two groups. In healthy subjects we localized the significances in the anterior cingulate, caudate nucleus, thalamus, precuneous region, and superior parietal that were more active for gamma band. In patients with schizophrenia differences occupy the hippocampus, parahippocampus, thalamus, midbrain, precuneus, and superior parietal regions. Most areas were more active for gamma band except precuneous and superior parietal region more active for theta and alpha frequency band. These sets of regions, in both groups, reflect events that are parallel to and partly independent of the P100 component, while in the schizophrenia, these regions have been previous linked to the major symptoms of the disease. We concluded that this result provides important evidence indicating that the proposed method is able to differentiate electrophysiological patterns in healthy subjects from those in patients with schizophrenia.

From genes to brain oscillations: is the visual pathway the epigenetic clue to schizophrenia?

Molecular data and gene expression data and recently mitochondrial genes and possible epigenetic regulation by non-coding genes is revolutionizing our views on schizophrenia. Genes and epigenetic mechanisms are triggered by cell-cell interaction and by external stimuli. A number of recent clinical and molecular observations indicate that epigenetic factors may be operational in the origin of the illness. Based on the molecular insights, gene expression profiles and epigenetic regulation of gene, we went back to the neurophysiology (brain oscillations) and found a putative role of the visual experiences (i.e. visual stimuli) as epigenetic factor. The functional evidences provided here, establish a direct link between the striate and extrastriate unimodal visual cortex and the neurobiology of the schizophrenia. This result support the hypothesis that 'visual experience' has a potential role as epigenetic factor and contribute to trigger and/or to maintain the progression of the schizophrenia. In this case, candidate genes sensible for the visual 'insult' may be located within the visual cortex including associative areas, while the integrity of the visual pathway before reaching the primary visual cortex is preserved. The same effect can be perceived if target genes are localised within the visual pathway, which actually, is more sensitive for 'insult' during the early life than the cortex per se. If this process affects gene expression at these sites a stably sensory specific 'insult', i.e. distorted visual information, is entering the visual system and expanded to fronto-temporo-parietal multimodal areas even from early maturation periods. The difference in the timing of postnatal neuroanatomical events between such areas and the primary visual cortex in humans (with the formers reaching the same development landmarks later in life than the latter) is 'optimal' to establish an abnormal 'cell- communication' mediated by the visual system that may further interfere with the local physiology. In this context the strategy to search target genes need to be rearrangement and redirected to visual-related genes. Otherwise, psychophysics studies combining functional neuroimage, and electrophysiology are strongly recommended, for the search of epigenetic clues that will allow to carrier gene association studies in schizophrenia.

Dynamic event-related potentials and rapid source analysis reveals an intermittent short-lasting dysfrontality in schizophrenia.

Neuroimaging studies have identified regional brain dysfunctions in schizophrenia, but their dynamic consequences remain unclear. This study reports electrophysiological evaluation of medicated schizophrenic patients during performance of the Wisconsin Card Sorting Test. Using event-related potentials (ERPs), averaged after passing through several band pass filters, and source analysis with variable-resolution brain electrical tomography, cerebral sources were visualized at every latency point of the evoked potential. ERPs which differed from the control group were elicited principally in frontal, central, and parietal regions, within the delta and theta frequency ranges. Significant differences emerged at three different latencies (S1, S2, S3) in frontal/midline areas and at the anterior temporal electrode site T3 for slow potentials. The left occipitoparietal region showed significant differences within the alpha and beta 2 ranges, respectively. Medial fronto-orbital area and anterior cingulate cortex contributed to the development of the frontal ERPs and the lateral inferior frontal area to the temporal (T(3)) evoked-potential, while the precuneus/medial region generated the posterior activity recorded on the scalp. The significant intervals S1 and S3 were synchronous between the medial frontal and lateral inferior frontal region, while in the S2 interval the medial frontal areas were parallel with the precuneus/medial occipitotemporal region. A simultaneous functional imbalance between frontal subregions and posterior areas was uncovered. Here, we show for the first time an intermittent functional deficiency of specific brain areas during task-directed mentation in schizophrenia, which by its brevity is not accessible by neuroimaging methods measuring hemodynamic activity.

Abnormal functional asymmetry in occipital areas may prevent frontotemporal regions from achieving functional laterality during the WCST performance in patients with schizophrenia.

There is much evidence of frontotemporal lateralized abnormalities in schizophrenia. However, the relationship has not yet been examined between performance on the Wisconsin Card Sorting Test, with supposed anterior left dominance and event-related potential (ERP) asymmetry. ERPs recorded at homologous bilateral sites were compared using statistical permutation methods. Patients had an unexpected abnormal lateralization over occipital regions, preceding slow anterior potentials. This indicates a defect in early stages of information processing, which may contribute to prevent further hemispheric lateralization during performance.

Induced oscillations and the distributed cortical sources during the Wisconsin card sorting test performance in schizophrenic patients: new clues to neural connectivity.

Prefrontal dysfunction has been associated with schizophrenia. Activation during Wisconsin card sorting test (WCST) is a common approach used in functional neuroimaging to address this failure. Equally, current knowledge states that oscillations are basic forms of cells-assembly communications during mental activity. Promising results were revealed in a previous study assessing healthy subjects, WCST and oscillations. However, those previous studies failed to meet the functional integration of the network during the WCST in schizophrenics, based on the induced oscillations and their distributed cortical sources. In this research, we utilized the brain electrical tomography (variable-resolution brain electromagnetic tomography) technique to accomplish this goal. Task specific delta, theta, alpha and beta-2 oscillations were induced and simultaneously synchronized over large extensions of cortex, encompassing prefrontal, temporal and posterior regions as in healthy subjects. Every frequency had a well-defined network involving a variable number of areas and sharing some of them. Oscillations at 11.5, 5.0 and 30 Hz seem to reflect an abnormal increase or decrease, being located at supplementary motor area (SMA), left occipitotemporal region (OT), and right frontotemporal subregions (RFT), respectively. Three cortical areas appeared to be critical, that may lead to difficulties either in coordinating/sequencing the input/output of the prefrontal networks-SMA, and retention of information in memory-RFT, both preceded or paralleled by a deficient visual information processing-OT.