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.

Regions with different evoked frequency band responses during early-stage visual processing distinguish mild Alzheimer dementia from mild cognitive impairment and normal aging.

Although diagnostic procedures have been developed for detection of mild cognitive impairment (MCI) and mild Alzheimer dementia (AD), more valid noninvasive tools are needed. In this work, we apply a procedure based on the evidences that different evoked frequency band responses may emerge from different sources during early-stage visual processing in a mental state-specific manner, while subjects were passively viewing a visual stimulus. In this case, spatial differences should arise across mental conditions such as mild Alzheimer dementia, mild cognitive impairment, and normal aging. With the use of EEG source image we found three different neural patterns in aged individuals: (1) left hippocampus and midbrain in mild AD, (2) left lateral orbitofrontal gyrus, left nucleus accumbens, caudate nucleus, thalamus, posterior cinguli, right precuneous, right superior parietal lobe in MCI, and (3) right lateral-medial orbitofrontal gyrus, caudate nucleus, thalamus, right lateral occipitotemporal gyrus in elderly controls. Although preliminary, these results show remarkably robust differences that distinguish between an age-matched control group, a group with MCI, and a group with mild AD. Because the method applied in this work differentiates among clinical entities with varying severity of cognitive decline, it may eventually serve as an electrophysiological marker in the early detection of neurodegeneration.

Obesity-specific circuits in the human brain: exploration by dynamic Brain Self-Reference (dynBSR).

In the last decade many efforts have been made in order to identify brain regions that may be abnormal in obese subjects. Most of the lines of research have examined links between brain circuits, behavioral processing, and overweight. We introduce here a novel analysis to the brain mapping, 'dynamic Brain Self-Reference' (dynBSR), based on the electrical response evoked during passively viewing a simple stimulus. Hypothetically, it should be possible to monitor both task-related networks and task-irrelevant networks during a mental state with low cognitive demand, as shown previously by others using fMRI and establishing the latter as the neural correlates of an 'inherent' brain activation pattern. However, this fact has been usually ignored. Our results showed that a distinct set of interconnected brain regions including, frontal areas (middle, inferior, orbitofrontal, and dorsolateral), dorsal/ventral striatum, thalamus, superior temporal region, insula cortex, post-central gyrus, left supramarginal gyrus, and parietal regions, whose activities seem to be tonically maintained, displays cohesive functional state in obesity during passively viewing a simple stimulus. This organized network is maintained in a dynamic equilibrium with the transient activation of the right supramarginal gyrus. These brain areas have been previously implicated in the regulation of taste, reward, and behavioral processing and most of them have also structural abnormalities regarding normal-weight subjects. Although exploratory, the most important result here is that the evaluation of the visual-evoked responses with dynBSR provides a foundation for investigating the brain circuits in obesity, and becomes the first attempt, to our knowledge, to imply task-irrelevant networks in these individuals.

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.

[Interictal EEG coherence in patients with partial temporal lobe epilepsy]. / Coherencia cerebral interictal en pacientes con epilepsia parcial del lóbulo temporal.

AIMS: The purpose of this research was to study the spatio-temporal characteristics of the correlation that exists between two simultaneous EEG signals (coherence) in the interictal period in patients with partial epilepsy that is presumably symptomatic of the temporal lobe (ILAE). PATIENTS AND METHODS: A study of 13 patients, aged between 17-60 years, was conducted (53% females). A digital EEG was performed on each patient using the 10/20 system of electrode location. 24 artifact-free segments were selected from the recording made in a rest-waking state with the patient's eyes closed. Fourier's transformation was employed to obtain cross spectrum matrices, which were then used to calculate the intrahemispheric (Cohintra) and interhemispheric (Cohinter) coherences expressed by the Z transformation. These values were ordered by regions considering the known anatomical connections. RESULTS: In both the overall and the individual analyses, we found greater alterations of the Cohintra and the Cohinter in the temporal regions, and there was a predominance of the left hemisphere. The individual analysis of coherence, unlike the visual interpretation of the EEG recording, showed significant alterations in all the patients in the sample. CONCLUSIONS: Incorporating this type of tool would enable us to reach a more accurate topographic diagnosis in cases of epilepsy of unknown aetiology. At the same time the possible means of medical and surgical treatment available would be widened.

Coherencia cerebral interictal en pacientes con epilepsia parcial del lóbulo temporal / Interictal eeg coherence in patients with partial temporal lobe epilepsy

Aims. The purpose of this research was to study the spatio-temporal characteristics of the correlation that exists between two simultaneous EEG signals (coherence) in the interictal period in patients with partial epilepsy that is presumably symptomatic of the temporal lobe (ILAE). Patients and methods. A study of 13 patients, aged between 17-60 years, was conducted (53% females). A digital EEG was performed on each patient using the 10/20 system of electrode location. 24 artifact-free segments were selected from the recording made in a rest-waking state with the patient’s eyes closed. Fourier’s transformation was employed to obtain cross spectrum matrices, which were then used to calculate the intrahemispheric (Cohintra) and interhemispheric (Cohinter) coherences expressed by the Z transformation. These values were ordered by regions considering the known anatomical connections. Results. In both the overall and the individual analyses, we found greater alterations of the Cohintra and the Cohinter in the temporal regions, and there was a predominance of the left hemisphere. The individual analysis of coherence, unlike the visual interpretation of the EEG recording, showed significant alterations in all the patients in the sample. Conclusions. Incorporating this type of tool would enable us to reach a more accurate topographic diagnosis in cases of epilepsy of unknown aetiology. At the same time the possible means of medical and surgical treatment available would be widened (AU)

Objetivo. Estudiar las características espacio-temporales de la correlación que existe entre dos señales simultáneas del EEG (coherencia) en el período interictal en pacientes con epilepsia parcial presumiblemente sintomática del lóbulo temporal (ILAE). Pacientes y métodos. Se estudiaron 13 pacientes (53% del sexo femenino), con edades de 17-60 años. A cada paciente se le realizó un EEG digital, utilizando el sistema 10/20 de colocación de electrodos. Del trazado en vigilia con ojos cerrados, se seleccionaron 24 segmentos, libres de artefactos. Mediante la transformada de Fourier, se obtuvieron matrices de espectros cruzados, con las que se calcularon la coherencias intrahemisféricas (Cohintra) e interhemisféricas (Cohinter), expresadas mediante la transformación Z. Estos valores se ordenaron por regiones considerando las conexiones anatómicas conocidas. Resultados. Tanto en el análisis global como individual encontramos mayores alteraciones de la Cohintra y la Cohinter en las regiones temporales, y predominó el hemisferio izquierdo. El análisis individual de la coherencia, a diferencia de la interpretación visual del EEG, evidenció alteraciones significativas en todos los pacientes de la muestra. Conclusiones. La incorporación de este tipo de herramienta permitiría un diagnóstico topográfico más preciso en las epilepsias cuya etiología se desconoce, y ampliaría las posibilidades de tratamiento médico y quirúrgico (AU)

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.

Human adrenal cells express tumor necrosis factor-alpha messenger ribonucleic acid: evidence for paracrine control of adrenal function.

Tumor necrosis factor (TNF) is gaining increasing importance in clinical medicine. It plays a role in the interaction of the immune system with the hypothalamic-pituitary-adrenal axis. In the present study various morphological methods, including immunohistochemistry, electron microscopy, and in situ hybridization were applied to characterize the localization and distribution of TNF in the human adrenal gland. Double immunostaining revealed an astonishing degree of intermingling of steroid-producing cells and chromaffin cells. Macrophages could be found in all regions of the adrenal gland, but particularly in the transition zone of cortex and medulla. The steroid-producing cells of the inner zone of the cortex express major histocompatibility complex class II molecules. On the ultrastructural level, immune cells, steroid cells, and catecholamine-producing cells were found in direct contact. The combination of immunohistochemistry and in situ hybridization was optimally suited to define the exact cellular source of TNF in the human adrenal. TNF is produced in macrophages, but above all in 17 alpha-hydroxylase-positive cells (steroid-producing cells) in the zona reticularis and medulla. No signal was found in chromaffin cells. TNF may induce major histocompatibility complex class II in human adrenal gland in a paracrine or autocrine manner. It is concluded that TNF may have an important role in normal human adrenal physiology.

IL-1 is expressed in human adrenal gland in vivo. Possible role in a local immune-adrenal axis.

IL-1 is an important mediator in the dialogue between the immune system and the hypothalamo-pituitary-adrenal axis. A direct influence of IL-1 upon adrenal steroidogenesis has been demonstrated in experimental animals. We therefore designed a study to see if IL-1 is expressed within the normal human adrenal gland. The combination of in situ hybridization and specific immunostaining to IL-1 beta was eminently suited to demonstrate both mRNA and protein production. The specific immunostaining of the different cells combined with in situ hybridization (IL-1) allowed us to identify the exact cellular source of IL-1. IL-1 mRNA occurred in the zona reticularis in 17 alpha-hydroxylase positive steroid cells surrounding the adrenomedullary cells. Some CD68+ macrophages in this zona showed a positive signal. A weak signal was seen to IL-1 mRNA in few chromaffin cells, while IL-1-like immunoreactivity was more frequent. We conclude that in the normal situation in man IL-1 is mainly expressed in specialized cortical cells. The occurrence of the major glucocorticoid inducing factor in the normal human adrenal gland itself provides evidence for an autocrine or paracrine reaction under physiological conditions.

Macrophages within the human adrenal gland.

There is increasing evidence for an immune-adrenal interaction in which macrophages may play an important role. However, few data are available with respect to a human intra-adrenal macrophage system. In this study, we have investigated the density, distribution and phenotype of human adrenal macrophages using monoclonal antibodies. Macrophages are localized in all zones of the adrenal gland. These cells exhibit the phenotype of the phagocytotic macrophage compartment (CD11c+, KiM8+). At the ultrastructural level, macrophages are frequently attached to the endothelial wall, but also lie in direct contact with cortical and chromaffin cells. This investigation reveals the cellular basis for the possible role of macrophages in the local immune-neuroendocrine axis.

Interleukin-6 messenger ribonucleic acid expression in human adrenal gland in vivo: new clue to a paracrine or autocrine regulation of adrenal function.

Interleukin-6 (IL-6) is an important mediator in the interaction of the hypothalamo-pituitary-adrenal axis with the immune system. Recently, a direct influence of IL-6 on adrenal steroidogenesis has been demonstrated. Therefore, we designed a study to determine whether IL-6 is expressed within the normal human adrenal gland. The combination of in situ hybridization and specific immunostaining was eminently suited to identify the cell types producing IL-6. IL-6 messenger ribonucleic acid occurred in the inner zone of the adrenal cortex in anti-17 alpha-hydroxylase-positive steroid cells. Also, CD68-positive macrophages in the zona reticularis showed a positive signal. No reaction was seen in chromaffin cells. We conclude that under normal conditions, IL-6 is expressed in specialized adrenocortical cells. Therefore, IL-6 may play an important role as a paracrine or autocrine factor in a local immune-adrenal interaction.

Intimate contact of chromaffin and cortical cells within the human adrenal gland forms the cellular basis for important intraadrenal interactions.

A new role for the adrenal medulla as a regulator of adrenocortical function has been postulated. However, there has been no idea as to how such a cellular interaction within the human adrenal gland could take place. In this study we were able to demonstrate with the help of specific immunostaining of cortical and chromaffin cells, respectively, that the two endocrine systems are interwoven with each other to an astonishing degree. Protrusions, clusters, islets, and single cortical cells were made visible by immunostaining with an antibody against 17 alpha-hydroxylase cytochrome P450 enzyme. They occurred diffusely within the entire adrenal medulla, providing ample contact zones for paracrine interactions. Specific immunostaining for the neuroendocrine protein chromogranin-A identified the occurrence of chromaffin cells within all three zones of the human adrenal cortex, including the zona glomerulosa. In an ultrastructural analysis, cortical and chromaffin cells were found in all zones in direct apposition, providing the possibility for direct intercellular exchange. The close morphological colocalization of cortical and chromaffin cells revealed in this study may constitute the basis for the growing evidence of relevant intraadrenal paracrine mechanisms within the human adrenal gland.