Comprehensive analysis suggests simple processes underlying EEG/ERP - demonstration with the go/no-go paradigm in ADHD.

BACKGROUND: Current basic or more advanced methods for analysis of averaged EEG/ERP are based on assumptions on the underlying processes, which are not necessarily precise. NEW METHOD: In this work we present the findings of a method which obviates such assumptions and aims at a comprehensive analysis of the averaged EEG/ERP signal. RESULTS: For the sake of demonstration we chose the established go/no-go paradigm in the context of ADHD. Our analysis method characterized two spatiotemporally distinct neurophysiologic processes which underlie the sampled signal: one which may be related to attention and the other which may be more related to perception. COMPARISON WITH EXISTING METHOD(S): We show how these processes accord with and provide insight on the waveforms reported in the literature. CONCLUSIONS: Finally we suggest that application of our method on averaged EEG/ERP data sampled from other paradigms may point at a similarly parsimonious set of underlying neurophysiologic processes which underlie the signal.

Introducing a novel approach of network oriented analysis of ERPs, demonstrated on adult attention deficit hyperactivity disorder.

OBJECTIVE: Introducing a network-oriented analysis method (brain network activation [BNA]) of event related potential (ERP) activities and evaluating its value in the identification and severity-grading of adult ADHD patients. METHODS: Spatio-temporal interrelations and synchronicity of multi-sited ERP activity peaks were extracted in a group of 13 ADHD patients and 13 control subjects for the No-go stimulus in a Go/No-go task. Participants were scored by cross-validation against the most discriminative ensuing group patterns and scores were correlated to neuropsychological evaluation scores. RESULTS: A distinct frontal-central-parietal pattern in the delta frequency range, dominant at the P3 latency, was unraveled in controls, while central activity in the theta and alpha frequency ranges predominated in the ADHD pattern, involving early ERP components (P1-N1-P2-N2). Cross-validation based on this analysis yielded 92% specificity and 84% sensitivity and individual scores correlated well with behavioral assessments. CONCLUSIONS: These results suggest that the ADHD group was more characterized by the process of exerting attention in the early monitoring stages of the No-go signal while the controls were more characterized by the process of inhibiting the response to that signal. SIGNIFICANCE: The BNA method may provide both diagnostic and drug development tools for use in diverse neurological disorders.

PKCeta enhances cell cycle progression, the expression of G1 cyclins and p21 in MCF-7 cells.

Protein kinase C encodes a family of enzymes implicated in cellular differentiation, growth control and tumor promotion. However, not much is known with respect to the molecular mechanisms that link protein kinase C to cell cycle control. Here we report that the expression of PKCeta in MCF-7 cells, under the control of a tetracycline-responsive inducible promoter, enhanced cell growth and affected the cell cycle at several points. The induced expression of another PKC isoform, PKCdelta, in MCF-7 cells had opposite effects and inhibited their growth. PKCeta expression activated cellular pathways in these cells that resulted in the increased expression of the G1 phase cyclins, cyclin D and cyclin E. Expression of the cyclin-dependent kinase inhibitor p21(WAF1) was also specifically elevated in PKCeta expressing cells, but its overall effects were not inhibitory. Although, the protein levels of the cyclin-dependent kinase inhibitor p27(KIP1) were not altered by the induced expression of PKCeta, the cyclin E associated Cdk2 kinase activity was in correlation with the p27(KIP1) bound to the cyclin E complex and not by p21(WAF1) binding. PKCeta expression enhanced the removal of p27(KIP1) from this complex, and its re-association with the cyclin D/Cdk4 complex. Reduced binding of p27(KIP1) to the cyclin D/Cdk4 complex at early time points of the cell cycle also enhanced the activity of this complex, while at later time points the decrease in bound p21(WAF1) correlated with its increased activity in PKCeta-expressing cells. Thus, PKCeta induces altered expression of several cell cycle functions, which may contribute to its ability to affect cell growth.

Learning in networks of cortical neurons.

The results presented here demonstrate selective learning in a network of real cortical neurons. We focally stimulate the network at a low frequency (0.3-1 Hz) until a desired predefined response is observed 50 +/- 10 msec after a stimulus, at which point the stimulus is stopped for 5 min. Repeated cycles of this procedure ultimately lead to the desired response being directly elicited by the stimulus. By plotting the number of stimuli required to achieve the target response in each cycle, we are able to generate learning curves. Presumably, the repetitive stimulation is driving changes in the circuit, and we are selecting for changes consistent with the predefined desired response. To the best of our knowledge, this is the first time learning of arbitrarily chosen tasks, in networks composed of real cortical neurons, is demonstrated outside of the body.

Expression of PKCeta in NIH-3T3 cells promotes production of the pro-inflammatory cytokine interleukin-6.

Protein kinase C encodes a family of enzymes implicated in cellular differentiation, growth control and tumor promotion. The generation and characterization of NIH-3T3 cells which stably overexpress the PKCeta isoform has been previously described by us. In these cells, overexpression of PKCeta altered the expression of specific cell cycle regulators and promoted differentiation [20]. Since PKC has been implicated in the regulation of gene expression, including that of various cytokines, we examined the production of several cytokines in these cells. We report here that out of the major pro-inflammatory cytokines examined, IL-1alpha, IL-1beta, TNF-alpha and IL-6, only IL-6 was generated and secreted in PKCeta -expressing cells without any additional inducer in serum-supplemented cultures (10% FCS). IL-6 was not detected in the control cell line, transfected with the same vector, but lacking the cDNA coding for PKCeta. Moreover, the production of IL-6 on serum stimulation correlated with the levels of PKCeta expressed in these cells. This implies that factors in the serum activate PKCeta and induce IL-6 production. We have examined several growth factors and cytokines for their ability to induce IL-6 production in our PKCeta-expressing cells. Among the growth factors tested (EGF, PDGF, FGF, insulin, IGF-1 and IL-1), PDGF and FGF were the most potent IL-6 inducers. The effects of FGF and PDGF on IL-6 production were blocked in the presence of PKC inhibitors. We also examined the signaling pathways that mediate production of IL-6 in PKCeta-expressing cells. Using specific inhibitors of the MAPK pathway, we have shown a role for ERK and p38 MAPK in FGF- and serum-stimulated IL-6 production, but only for p38 MAPK in PDGF-stimulated IL-6 production. Our studies provide evidence that PDGF and FGF can serve as upstream regulators of PKCeta and that PKCeta is involved in the expression of IL-6. This suggests that inhibition of PKC may provide a basis for the development of drugs for the treatment of disorders in which IL-6 is pathologically involved.