Estimating biological accuracy of DSM for attention deficit/hyperactivity disorder based on multivariate analysis for small samples.

OBJECTIVE: To estimate whether the "Diagnostic and Statistical Manual of Mental Disorders" (DSM) is biologically accurate for the diagnosis of Attention Deficit/ Hyperactivity Disorder (ADHD) using a biological-based classifier built by a special method of multivariate analysis of a large dataset of a small sample (much more variables than subjects), holding neurophysiological, behavioral, and psychological variables. METHODS: Twenty typically developing boys and 19 boys diagnosed with ADHD, aged 10-13 years, were examined using the Attentional Network Test (ANT) with recordings of event-related potentials (ERPs). From 774 variables, a reduced number of latent variables (LVs) were extracted with a clustering of variables method (CLV), for further reclassification of subjects using the k-means method. This approach allowed a multivariate analysis to be applied to a significantly larger number of variables than the number of cases. RESULTS: From datasets including ERPs from the mid-frontal, mid-parietal, right frontal, and central scalp areas, we found 82% of agreement between DSM and biological-based classifications. The kappa index between DSM and behavioral/psychological/neurophysiological data was 0.75, which is regarded as a "substantial level of agreement". DISCUSSION: The CLV is a useful method for multivariate analysis of datasets with much less subjects than variables. In this study, a correlation is found between the biological-based classifier and the DSM outputs for the classification of subjects as either ADHD or not. This result suggests that DSM clinically describes a biological condition, supporting its validity for ADHD diagnostics.

Visuospatial information processing load and the ratio between parietal cue and target P3 amplitudes in the Attentional Network Test.

In ERP studies of cognitive processes during attentional tasks, the cue signals containing information about the target can increase the amplitude of the parietal cue P3 in relation to the 'neutral' temporal cue, and reduce the subsequent target P3 when this information is valid, i.e. corresponds to the target's attributes. The present study compared the cue-to-target P3 ratios in neutral and visuospatial cueing, in order to estimate the contribution of valid visuospatial information from the cue to target stages of the task performance, in terms of cognitive load. The P3 characteristics were also correlated with the results of individuals' performance of the visuospatial tasks, in order to estimate the relationship of the observed ERP with spatial reasoning. In 20 typically developing boys, aged 10-13 years (11.3±0.86), the intelligence quotient (I.Q.) was estimated by the Block Design and Vocabulary subtests from the WISC-III. The subjects performed the Attentional Network Test (ANT) accompanied by EEG recording. The cued two-choice task had three equiprobable cue conditions: No cue, with no information about the target; Neutral (temporal) cue, with an asterisk in the center of the visual field, predicting the target onset; and Spatial cues, with an asterisk in the upper or lower hemifield, predicting the onset and corresponding location of the target. The ERPs were estimated for the mid-frontal (Fz) and mid-parietal (Pz) scalp derivations. In the Pz, the Neutral cue P3 had a lower amplitude than the Spatial cue P3; whereas for the target ERPs, the P3 of the Neutral cue condition was larger than that of the Spatial cue condition. However, the sums of the magnitudes of the cue and target P3 were equal in the spatial and neutral cueing, probably indicating that in both cases the equivalent information processing load is included in either the cue or the target reaction, respectively. Meantime, in the Fz, the analog ERP components for both the cue and target stimuli did not depend on the cue condition. The results show that, in the parietal site, the spatial cue P3 reflects the processing of visuospatial information regarding the target position. This contributes to the subsequent "decision-making", thus reducing the information processing load on the target response, which is probably reflected in the lower P3. This finding is consistent with the positive correlation of parietal cue P3 with the individual's ability to perform spatial tasks as scored by the Block Design subtest.

Electrophysiological Correlates of Morphological Neuroplasticity in Human Callosal Dysgenesis.

In search for the functional counterpart of the alternative Probst and sigmoid bundles, considered as morphological evidence of neuroplasticity in callosal dysgenesis, electroencephalographic (EEG) coherence analysis was combined with high resolution and diffusion tensor magnetic resonance imaging. Data of two patients with callosal agenesis, plus two with typical partial dysgenesis with a remnant genu, and one atypical patient with a substantially reduced genu were compared to those of fifteen neurotypic controls. The interhemispheric EEG coherence between homologous nontemporal brain regions corresponded to absence or partial presence of callosal connections. A generalized coherence reduction was observed in complete acallosal patients, as well as coherence preservation in the anterior areas of the two patients with a remnant genu. jThe sigmoid bundles found in three patients with partial dysgenesis correlated with augmented EEG coherence between anterior regions of one hemisphere and posterior regions of the other. These heterologous (crossed) interhemispheric connections were asymmetric in both imaging and EEG patterns, with predominance of the right-anterior-to-left-posterior connections over the mirror ones. The Probst bundles correlated with higher intrahemispheric long-distance coherence in all patients. The significant correlations observed for the delta, theta and alpha bands indicate that these alternative pathways are functional, although the neuropsychological nature of this function is still unknown.

Reduced interhemispheric connectivity in childhood autism detected by electroencephalographic photic driving coherence.

The EEG coherence among 14 scalp points during intermittent photic stimulation at 11 fixed frequencies of 3-24 Hz was studied in 14 boys with autism, aged 6-14 years, with relatively intact verbal and intellectual functions, and 19 normally developing boys. The number of interhemispheric coherent connections pertaining to the 20 highest connections of each individual was significantly lower in autistic patients than in the control group at all the EEG beta frequencies corresponding to those of stimulation. The coefficient of coherence values between homologous occipital, parietal and central areas at the same frequencies were also lower in the autistic group in both mono- and bipolar montages due to a deficit in reactive photic driving increase. No differences between the groups were observed in the spontaneous EEG.

Diaphorase-positive neurons in the cingulate cortex of human fetuses during the second half of gestation.

In this work, the time course of appearance, distribution and morphology of diaphorase-positive neurons were studied in the developing cingulate cortex of the human brain during the second half of gestation. Five human fetuses at 18, 20, 25, 30 and 35 weeks postovulatory (wpo) were examined. The brain tissue was reacted by an indirect histochemistry protocol for detection of NADPH-diaphorase activity. Labeled neurons were identified at the microscope and documented photographically or by computer-aided charts. We have found that heavily labeled neurons (type I) first appear in the subplate (SP) between 20 and 25 wpo, and in the cortical plate (CP) between 25 and 35 wpo. By 35 wpo, CP neurons were both type I and type II (lightly labeled neurons). In addition, we observed 4 different morphological types among subplate neurons, very similar to callosally-projecting subplate cells (as described previously by our group). We concluded that medial nitridergic neurons of humans appear prenatally according to the usual gradient of cortical maturation -- first in the subplate and later in the cortical plate. Also, we suggest that some of the diaphorase-positive neurons in the transient subplate could possibly be callosal.

Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: functional outcome related to neuroprotection in the striatum.

Human umbilical cord blood mononuclear cells (HUCB) have been shown to have a therapeutic role in different models of central nervous system (CNS) damage, including stroke. We evaluated the possible therapeutic potential of HUCB in P7 rats submitted to the Rice-Vannucci model of neonatal hypoxic-ischemic (HI) brain damage. Our results demonstrated that intraperitoneal transplantation of HUCB, 3 h after the HI insult, resulted in better performance in two developmental sensorimotor reflexes, in the first week after the injury. We also showed a neuroprotective effect in the striatum, and a decrease in the number of activated microglial cells in the cerebral cortex of treated animals. We suggest that HUCB transplantation might rescue striatal neurons from cell death after a neonatal HI injury resulting in better functional recovery.

EEG photic driving: right-hemisphere reactivity deficit in childhood autism. A pilot study.

In 14 autistic boys, aged 6-14 years, free of drug treatment, with relatively intact verbal functions and without severe or moderate mental retardation (I.Q. 91.4+/-22.8), intermittent photic stimulation at 11 fixed frequencies of 3-24 Hz revealed latent deficiency of the right hemisphere in the photic driving reactivity, predominantly at the fast alpha and beta frequencies of stimulation. The left-side prevalence was observed: 1) in the total number of driving peaks evaluated for the first four harmonics in the EEG spectra of 14 cortical areas and 2) in the driving amplitude in the spectra of the 2 occipital areas. As compared to 21 normally developing boys matched on age who did not show interhemispheric asymmetry in the driving reactivity, the autistic patients had significantly lower driving characteristics only in the right hemisphere. There were no significant differences between the autistic and control groups in the spontaneous EEG spectra of the occipital areas in the resting state.

Immune allergic response in Asperger syndrome.

Asperger's syndrome is a subgroup of autism characterized by social deficits without language delay, and high cognitive performance. The biological nature of autism is still unknown but there are controversial evidence associating an immune imbalance and autism. Clinical findings, including atopic family history, serum IgE levels as well as cutaneous tests showed that incidence of atopy was higher in the Asperger group compared to the healthy controls. These findings suggest that atopy is frequent in this subgroup of autism implying that allergic inflammation might be an important feature in Asperger syndrome.

Cortical radial glial cells in human fetuses: depth-correlated transformation into astrocytes.

In the human brain, the transformation of radial glial cells (RGC) into astrocytes has been studied only rarely. In this work, we were interested in studying the morphologic aspects underlying this transformation during the fetal/perinatal period, particularly emphasizing the region-specific glial fiber anatomy in the medial cortex. We have used carbocyanine dyes (DiI/DiA) to identify the RGC transitional forms and glial fiber morphology. Immunocytochemical markers such as vimentin and glial fibrillary acidic protein (GFAP) were also employed to label the radial cells of glial lineage and to reveal the early pattern of astrocyte distribution. Neuronal markers such as neuronal-specific nuclear protein (NeuN) and microtubule-associated protein (MAP-2) were employed to discern whether or not these radial cells could, in fact, be neurons or neuronal precursors. The main findings concern the beginning of RGC transformation showing loss of the ventricular fixation in most cases, followed by transitional figures and the appearance of mature astrocytes. In addition, diverse fiber morphology related to depth within the cortical mantle was clearly demonstrated. We concluded that during the fetal/perinatal period the cerebral cortex is undergoing the final stages of radial neuronal migration, followed by involution of RGC ventricular processes and transformation into astrocytes. None of the transitional or other radial glia were positive for neuronal markers. Furthermore, the differential morphology of RGC fibers according to depth suggests that factors may act locally in the subplate and could have a role in the process of cortical RGC transformation and astrocyte localization. The early pattern of astrocyte distribution is bilaminar, sparing the cortical plate. Few astrocytes (GFAP+) in the upper band could be found with radial processes at anytime. This suggests that astrocytes in the marginal zone could be derived from different precursors than those that differentiate from RGCs during this period.