Smaller P3 Research Articles

Auditory event-related potentials and cognitive function of preterm children at five years of age

Objective In our previous study, auditory event-related potentials (AERPs) in preterm 1-year-old children had a positive deflection at 150–350 ms that correlated positively with their 2-year neurodevelopmental outcome. In a study of the same subjects at age 5, our aim was to assess AERPs and their relationship to neuropsychological test results. Methods Preterm small (SGA, n = 13), appropriate for gestational age (AGA, n = 15), and control ( n = 13) children were assessed with an Easy paradigm presenting a large frequency change accompanied with occasional novel sounds, and a Challenging paradigm presenting small frequency and duration changes with a rapid rate. The preterm children underwent neurocognitive tests. Results Easy paradigm. The P1 response to frequency deviant was smaller and MMN larger in the preterm than in the control children. Challenging paradigm. The P1 response to standard, frequency, and duration deviants was smaller in the preterm than in the control children. The N2 response to frequency deviant was larger in the preterm than in the control children. AGA and SGA children had similar AERPs. The P1, N2, and MMN amplitudes correlated with verbal IQ and NEPSY language subtests. Conclusions Small P1 response(s) appears to be typical for preterm children. Significance Small P1 response in preterm children may suggest altered primary auditory processing.

Abnormalities of auditory event-related potentials in students with high scores on the Schizotypal Personality Questionnaire

Some auditory event-related potential (ERP) abnormalities characterize both patients with schizophrenia and subjects with schizotypal personality disorder. It was therefore hypothesized that subjects from the community with schizotypal traits might also present ERP abnormalities. In this study, we compared auditory ERP latencies and amplitudes in 13 subjects with high (H-SPQ) and 12 subjects with low (L-SPQ) scores on the Schizotypal Personality Questionnaire (SPQ), selected from 198 Tunisian students. Auditory ERPs were recorded at Fz, Cz, and Pz, with a standard oddball paradigm. Smaller P300 amplitudes and delayed P300 latencies were found in H-SPQ compared with L-SPQ participants. Confirming previous reports, our results suggest that reduced P300 amplitudes and delayed P300 latencies may be considered as vulnerability markers of the schizophrenia spectrum in nonclinical subjects from the community.

The Fetal Variant of the Circle of Willis and Its Influence on the Cerebral Collateral Circulation

In a fetal-type posterior circle of Willis (FTP) there is an embryonic derivation of the posterior cerebral artery (PCA) from the internal carotid artery (ICA). Besides the fact that a larger area is thus dependent on the ICA, leptomeningeal vessels cannot develop between the anterior and posterior circulation. The tentorium namely prevents cerebellar vessels from connecting to the PCA territory. Therefore patients with an FTP could be more prone to develop vascular insufficiency. An overview of the literature is given. We propose to define a partial FTP, in which a small P1 segment between the basilar artery and the postcommunicating part of the PCA is present, and a full FTP, in which the P1 segment is absent. Whether a full FTP is a risk factor for stroke should be subject of further investigation.

The Repeat Domain of the Melanosomal Matrix Protein PMEL17/GP100 Is Required for the Formation of Organellar Fibers

Over 125 pigmentation-related genes have been identified to date. Of those, PMEL17/GP100 has been widely studied as a melanoma-specific antigen as well as a protein required for the formation of fibrils in melanosomes. PMEL17 is synthesized, glycosylated, processed, and delivered to melanosomes, allowing them to mature from amorphous round vesicles to elongated fibrillar structures. In contrast to other melanosomal proteins such as TYR and TYRP1, the processing and sorting of PMEL17 is highly complex. Monoclonal antibody HMB45 is commonly used for melanoma detection, but has the added advantage that it specifically reacts with sialylated PMEL17 in the fibrillar matrix in melanosomes. In this study, we generated mutant forms of PMEL17 to clarify the subdomain of PMEL17 required for formation of the fibrillar matrix, a process critical to pigmentation. The internal proline/serine/threonine-rich repeat domain (called the RPT domain) of PMEL17 undergoes variable proteolytic cleavage. Deletion of the RPT domain abolished its recognition by HMB45 and its capacity to form fibrils. Truncation of the C-terminal domain did not significantly affect the processing or trafficking of PMEL17, but, in contrast, deletion of the N-terminal domain abrogated both. We conclude that the RPT domain is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles.

State regulation and response inhibition in children with ADHD and children with early‐ and continuously treated phenylketonuria: An event‐related potential comparison

The presentation rate of stimuli plays an important role in explaining the performance inefficiency in children with ADHD. In general, children with ADHD have been found to perform more poorly in conditions of relatively slow event rates as compared with fast and moderate event rates. The state regulation hypothesis states that these children have problems in correcting their energetic state necessary to counteract a performance decrement, which requires extra effort allocation. In this study, we investigated state regulation in children with ADHD and used children with early- and continuously treated phenylketonuria (PKU) as a clinical contrast group. We measured the parietal P3 during a Go/No-Go task that incorporated a condition with a fast and a slow presentation rate. We were able to show that children with ADHD, relative to controls, responded more slowly and more variably in the slow condition only, which was accompanied by a smaller P3, suggesting less effort allocation. In contrast, the children with PKU did not show a state regulation deficit. The PKU group showed prolonged stimulus evaluation processing, as indexed by P3 latency, compared to controls and children with ADHD. In addition, they made more errors of commission than the controls and the ADHD group. Our electrophysiological data support the state regulation hypothesis of ADHD. Only the children with PKU had more problems in inhibiting pre-potent responding than controls, which is in accord with the prefrontal dysfunction hypothesis of PKU.

The Wisconsin Card Sort Test and P300 responses to novel auditory stimuli in schizophrenic patients

The authors studied the relationship between performance on the Wisconsin Card Sort Test (WCST) and P300 activity in schizophrenics and normal controls. Fourteen male predominantly medicated schizophrenics and matched non-ill controls were administered the WCST and tests of temporal lobe (delayed verbal and spatial memory) and general intellectual functioning (Shipley). Patients were rated with negative and positive symptom scales extracted from the Brief Psychiatric Rating Scale. Subjects performed a tone discrimination task requiring identification of rare targets in both a standard oddball paradigm and a three-stimulus paradigm that included rare novel sounds. Reference independent data from 16 scalp electrodes yielded Global Field Power (GFP), from which P300 latency was determined. P300 amplitude measures included amplitude at this identified latency as well as amplitude integrated over a 100 ms time window centered over it. These amplitude measures were examined at six selected electrode locations. Schizophrenics produced smaller P300 responses that tended to be slower, but there were no group differences in the relationships between neuropsychological performance and P300 responses. Across diagnostic groups percent perseverative errors predicted lower integrated and peak P300 amplitude during the novel but not the standard oddball paradigm. The effect on integrated P300 amplitude was localized to anterior leads after novel stimuli. Negative symptoms predicted lower WCST performance, lower integrated P300 amplitude, and smaller GFP after novel stimuli. Positive symptoms predicted reduced overall GFP and specific but inconsistent reductions in parietal P300 amplitude. The results suggest relationships between dorsolateral prefrontal competence, P300 activity in response to stimulus novelty, and negative symptoms in schizophrenic patients, paralleling findings obtained from blood flow and other measures of brain activity.

Emotional states and informational brain processing in drug addicts free of drugs: An ERPs study

ObjectiveTo analyze brain event-related responses in heroin-dependent patients under different emotional conditions, in order to determine the influence of specific emotional loading on information processing in drug addicts.MethodsFifteen male heroin-dependent patients, matched to 11 male healthy individuals, were exposed to emotion-triggering slides designed to elicit neutral, pleasant or unpleasant emotions, while ERPs were obtained by means of an auditory oddball paradigm. Evoked potential analysis consisted of measuring the amplitude, latency, and topographic distribution (mapped from 19 scalp sites) of the early and late latency component waveforms.ResultsBoth groups showed large-amplitude, long-latency, and positive-polarity responses to odd stimuli under all emotional conditions. A within-group comparison between the three emotional conditions showed that the control group had smaller P300 amplitudes under pleasant stimulation; drug addicts showed no differences between all three emotional conditions. Between-group analysis revealed smaller P300 amplitudes in drug addicts than in controls, both for unpleasant and neutral emotional conditions, but this was only significant for some electrode sites. Brain electrical activity mapping at P300 showed that high activation is less spread in the brain areas of drug addicts than in controls for unpleasant and neutral emotional conditions.ConclusionDrug addicts have deficits in extracting relevant information from sensory stimuli under different emotional conditions, particularly under unpleasant and neutral stimulation. Decreased P300 in controls under pleasant stimulation is interpreted as a result of an attentional bias mechanism that directs attentional resources to environmental stimuli of positive emotional valence, in contrast to drug addicts where there is no such effect.

Processing capacity in children and adolescents with pervasive developmental disorders.

This study sought to investigate whether the abnormally small P3 amplitudes observed in pervasive developmental disorder (PDD) are related to differences in processing capacity. PDD children and adolescents and their control groups participated in the study. Visual probe stimuli were presented during an auditory task with two levels of difficulty. Event-related potentials (ERP) were measured from 62 electrodes during task performance. All groups showed amplitude increases to auditory stimuli with increasing task load. Controls showed expected smaller P3 amplitudes to visual probes, whereas PDD subjects did not. The results suggest that autistic subjects show abnormal capacity allocation. Some of these abnormalities may dissolve over time, while others remain into adolescence.

ERP evidence of impaired central nervous system function in virally suppressed HIV patients on antiretroviral therapy

Objective To examine the effects of human immunodeficiency virus (HIV) on central nervous system (CNS) function in patients receiving antiretroviral therapy (ART) who have suppressed viral loads. Methods Event-related brain potentials (ERPs) were recorded from 15 virally suppressed HIV patients and 15 age-, sex-, and education-matched controls while they performed a 3-stimulus auditory oddball task. The amplitude and latency of the P3a, P3b, and early auditory components were examined in HIV patients and controls. Results Virally suppressed HIV patients on ART were more depressed than controls, as determined by the Beck Depression Inventory (BDI). After controlling for the effects of depression, HIV patients had smaller P2, P3a, and P3b amplitudes and longer P3a and P3b latency than control subjects. BDI scores correlated positively with N1 latency in HIV patients and negatively with P3b amplitude in all subjects. Conclusions These electrophysiological results suggest that, even in the absence of detectable levels of HIV in the peripheral blood, viral replication persists in the CNS and continues to cause disease in HIV patients on ART.

Mn K-edge XANES of hexagonal manganites RMnO3 (R=Sc,Y)

Abstract Mn K-edge X-ray absorption near-edge spectra (XANES) and magnetic studies for ferroelectromagnetic compounds RMnO3 (R=Sc,Y) are reported. ScMnO3 shows stronger d–p hybridization with a triangular antiferromagnetic (AF) order of T N =133 K and a spin reorientation T sr =23 K , as compared to T N =74 K for YMnO3. The identical main threshold edge energy of 6545 eV indicates Mn3+ character. Small pre-edge features with energy separation P2–P1 of 2.27 eV for ScMnO3 and 2.72 eV for YMnO3 is from the 1s–3d dipole transition, which is weakly allowed through the hybridization of Mn 4p with 3d states of neighboring Mn atoms. The larger P1 peak is corresponding to transition into empty e↓′ and e↓″ minority states, and the smaller P2 peak is into leftover e↓′ states.

Crystal Structure of Earthworm Fibrinolytic Enzyme Component A: Revealing the Structural Determinants of its Dual Fibrinolytic Activity

Earthworm fibrinolytic enzyme component A (EFEa) from Eisenia fetida is a strong fibrinolytic enzyme that not only directly degrades fibrin, but also activates plasminogen. Proteolytic assays further revealed that it cleaved behind various P1 residue types. The crystal structure of EFEa was determined using the MIR method and refined to 2.3 Å resolution. The enzyme, showing the overall polypeptide fold of chymotrypsin-like serine proteases, possesses essential S1 specificity determinants characteristic of elastase. However, the β strand at the west rim of the S1 specificity pocket is significantly elongated by a unique four-residue insertion (Ser-Ser-Gly-Leu) after Val217, which not only provides additional substrate hydrogen binding sites for distal P residues, but also causes extension of the S1 pocket at the south rim. The S2 subsite of the enzyme was partially occluded by the bulky side-chain of residue Tyr99. Structure-based inhibitor modeling demonstrated that EFEa's S1 specificity pocket was preferable for elastase-specific small hydrophobic P1 residues, while its accommodation of long and/or bulky P1 residues was also feasible if enhanced binding of the substrate and induced fit of the S1 pocket were achieved. EFEa is thereby endowed with relatively broad substrate specificity, including the dual fibrinolysis. The presence of Tyr99 at the S2 subsite indicates a preference for P2-Gly, while an induced fit of Tyr99 was also suggested for accommodation of bigger P2 residues. This structure is the first reported for an earthworm fibrinolytic enzyme component and serine protease originating from annelid worms.

P300 subcomponents and clinical symptoms in schizophrenia

A small P300 component of the auditory event-related potential has been found to predict poor clinical outcome with a higher amount of thought disorders in schizophrenia and has been proposed as a marker for an underlying neurodevelopmental disorder with prominent thought disorders, early age of onset, prominent negative symptoms and positive family history. The present study was designed to confirm our previous findings with subcomponent analysis. Using dipole source analysis a temporo-basal (TB) P300 as well as a temporo-superior (TS) P300 and LP potential were separated. Fifty patients with schizophrenia (DSM-IV) were included in the study. Late auditory event-related P300 potentials were recorded to infrequent auditory stimuli after treatment psychopathology and family history were assessed. The TB-P300 amplitudes were significantly negatively correlated with thought disorders remaining after treatment and were positively correlated with age of onset. Illness duration was significantly correlated to TB-P300 and TS-P300 amplitudes in the group of patients with late onset. No significant correlations were found with negative symptoms. Family history did not show significant effects on P300. A smaller P300 in patients with more thought disorder remaining after stabilization on medication and an earlier age of onset support the hypothesis that P300 characterizes schizophrenic patients with an underlying neurodevelopmental disorder with specific clinical symptom clusters. On the other hand, diminished P300 with illness duration in the group of patients with later age of onset supports an underlying neurodegenerative progressive process in this subgroup of patients.

What the structure of a calcium pump tells us about its mechanism.

The report of the crystal structure of the Ca(2+)-ATPase of skeletal muscle sarcoplasmic reticulum in its Ca(2+)-bound form [Toyoshima, Nakasako and Ogawa (2000) Nature (London) 405, 647-655] provides an opportunity to interpret much kinetic and mutagenic data on the ATPase in structural terms. There are no large channels leading from the cytoplasmic surface to the pair of high-affinity Ca(2+) binding sites within the transmembrane region. One possible access pathway involves the charged residues in transmembrane alpha-helix M1, with a Ca(2+) ion passing through the first site to reach the second site. The Ca(2+)-ATPase also contains a pair of binding sites for Ca(2+) that are exposed to the lumen. In the four-site model for transport, phosphorylation of the ATPase leads to transfer of the two bound Ca(2+) ions from the cytoplasmic to the lumenal pair of sites. In the alternating four-site model for transport, phosphorylation leads to release of the bound Ca(2+) ions directly from the cytoplasmic pair of sites, linked to closure of the pair of lumenal binding sites. The lumenal pair of sites could involve a cluster of conserved acidic residues in the loop between M1 and M2. Since there is no obvious pathway from the high-affinity sites to the lumenal surface of the membrane, transport of Ca(2+) ions must involve a significant change in the packing of the transmembrane alpha-helices. The link between the phosphorylation domain and the pair of high-affinity Ca(2+) binding sites is probably provided by two small helices, P1 and P2, in the phosphorylation domain, which contact the loop between transmembrane alpha-helices M6 and M7.

What the structure of a calcium pump tells us about its mechanism

The report of the crystal structure of the Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum in its Ca2+-bound form [Toyoshima, Nakasako and Ogawa (2000) Nature (London) 405, 647–655] provides an opportunity to interpret much kinetic and mutagenic data on the ATPase in structural terms. There are no large channels leading from the cytoplasmic surface to the pair of high-affinity Ca2+ binding sites within the transmembrane region. One possible access pathway involves the charged residues in transmembrane α-helix M1, with a Ca2+ ion passing through the first site to reach the second site. The Ca2+-ATPase also contains a pair of binding sites for Ca2+ that are exposed to the lumen. In the four-site model for transport, phosphorylation of the ATPase leads to transfer of the two bound Ca2+ ions from the cytoplasmic to the lumenal pair of sites. In the alternating four-site model for transport, phosphorylation leads to release of the bound Ca2+ ions directly from the cytoplasmic pair of sites, linked to closure of the pair of lumenal binding sites. The lumenal pair of sites could involve a cluster of conserved acidic residues in the loop between M1 and M2. Since there is no obvious pathway from the high-affinity sites to the lumenal surface of the membrane, transport of Ca2+ ions must involve a significant change in the packing of the transmembrane α-helices. The link between the phosphorylation domain and the pair of high-affinity Ca2+ binding sites is probably provided by two small helices, P1 and P2, in the phosphorylation domain, which contact the loop between transmembrane α-helices M6 and M7.

Structural basis for the binding of an immunodominant peptide from myelin basic protein in different registers by two HLA-DR2 proteins

Susceptibility to multiple sclerosis (MS) is associated with certain MHC class II haplotypes, in particular HLA-DR2. Two DR β chains, DRB1∗1501 and DRB5∗0101, are co-expressed in the HLA-DR2 haplotype, resulting in the formation of two functional cell surface heterodimers, HLA-DR2a (DRA∗0101, DRB5∗0101) and HLA-DR2b (DRA∗0101, DRB1∗1501). Both isotypes can present an immunodominant peptide of myelin basic protein (MBP 84–102) to MBP-specific T cells from MS patients. We have determined the crystal structure of HLA-DR2a complexed with MBP 86–105 to 1.9 Å resolution. A comparison of this structure with that of HLA-DR2b complexed with MBP 85–99, reported previously, reveals that the peptide register is shifted by three residues, such that the MBP peptide is bound in strikingly different conformations by the two MHC molecules. This shift in binding register is attributable to a large P1 pocket in DR2a, which accommodates Phe92, in conjunction with a relatively shallow P4 pocket, which is occupied by Ile95. In DR2b, by contrast, the small P1 pocket accommodates Val89, while the deep P4 pocket is filled by Phe92. In both complexes, however, the C-terminal half of the peptide is positioned higher in the binding groove than in other MHC class II/peptide structures. As a result of the register shift, different side-chains of the MBP peptide are displayed for interaction with T cell receptors in the DR2a and DR2b complexes. These results demonstrate that MHC molecules can impose different alignments and conformations on the same bound peptide as a consequence of topological differences in their peptide-binding sites, thereby creating distinct T cell epitopes.

Fusion of small peroxisomal vesicles in vitro reconstructs an early step in the in vivo multistep peroxisome assembly pathway of Yarrowia lipolytica.

We have identified and purified six subforms of peroxisomes, designated P1 to P6, from the yeast, Yarrowia lipolytica. An analysis of trafficking of peroxisomal proteins in vivo suggests the existence of a multistep peroxisome assembly pathway in Y. lipolytica. This pathway operates by conversion of peroxisomal subforms in the direction P1, P2-->P3-->P4-->P5-->P6 and involves the import of various peroxisomal proteins into distinct vesicular intermediates. We have also reconstituted in vitro the fusion of the earliest intermediates in the pathway, small peroxisomal vesicles P1 and P2. Their fusion leads to the formation of a larger and more dense peroxisomal vesicle, P3. Fusion of P1 and P2 in vitro requires cytosol and ATP hydrolysis and is inhibited by antibodies to two membrane-associated ATPases of the AAA family, Pex1p and Pex6p. We provide evidence that the fusion in vitro of P1 and P2 peroxisomes reconstructs an actual early step in the peroxisome assembly pathway operating in vivo in Y. lipolytica.

P300 topography differs in schizophrenia and manic psychosis

Background: Overall and left temporal scalp area reductions of P300 have been demonstrated in schizophrenia. P300 amplitude and topography in psychotic affective disorder, a crucial comparison in assessing the specificity of P300 abnormalities to schizophrenia, are not well studied. Methods: P300 was recorded from 35 schizophrenic, 20 psychotic manic, and 30 control subjects. All were right-handed men. Results: P300 was reduced in both psychotic groups relative to control subjects. Anteroposterior P300 topography differed between patient groups, with schizophrenic subjects showing posterior reduction and bipolar subjects showing anterior reduction. Schizophrenic subjects showed an abnormal asymmetry, with smaller P300 over the left temporal scalp site than the right. Both bipolar and control subjects showed a left greater than right asymmetry. Conclusions: Widespread auditory P300 reductions were present in schizophrenia and bipolar disorder with psychosis, but subtle topographic differences were present in the two diseases. Although unequivocal knowledge of neural generators cannot be derived from topography alone, differences in topography imply different generator configurations. Based on previous studies, the posterior P300 reductions in schizophrenia may reflect abnormalities of a generator located in the left superior temporal gyrus. The frontal reductions in bipolar psychosis may reflect abnormalities in a hypothetical frontal generator, consonant with reports of altered frontal lobe function in mania.

440 Loudness dependence of auditory evoked N1/p2 component as predictor of clinical response to serotonin agonists in patients with affective disorders

A small P300 component of the auditory event-related potential has been found to predict poor clinical outcome with a higher amount of thought disorders in schizophrenia and has been proposed as a marker for an underlying neurodevelopmental disorder with prominent thought disorders, early age of onset, prominent negative symptoms and positive family history. The present study was designed to confirm our previous findings with subcomponent analysis. Using dipole source analysis a temporo-basal (TB) P300 as well as a temporo-superior (TS) P300 and LP potential were separated. Fifty patients with schizophrenia (DSM-IV) were included in the study. Late auditory event-related P300 potentials were recorded to infrequent auditory stimuli after treatment psychopathology and family history were assessed. The TB-P300 amplitudes were significantly negatively correlated with thought disorders remaining after treatment and were positively correlated with age of onset. Illness duration was significantly correlated to TB-P300 and TS-P300 amplitudes in the group of patients with late onset. No significant correlations were found with negative symptoms. Family history did not show significant effects on P300. A smaller P300 in patients with more thought disorder remaining after stabilization on medication and an earlier age of onset support the hypothesis that P300 characterizes schizophrenic patients with an underlying neurodevelopmental disorder with specific clinical symptom clusters. On the other hand, diminished P300 with illness duration in the group of patients with later age of onset supports an underlying neurodegenerative progressive process in this subgroup of patients.

Stimulus context determines P3a and P3b

P300 differences for target (.10), nontarget (.10), and standard tones (.80) were assessed using a three-stimulus oddball paradigm in which participants responded only to the target (n = 12). Target/standard (easy or difficult) and nontarget/standard (large or small) pitch differences were manipulated orthogonally. In all conditions, target tones elicited a parietal P300, which was affected only by the target/standard discrimination ease. Nontarget in the easy/large and difficult/small conditions elicited a parietal but smaller P300 than the target but in the easy/small condition elicited similar ERPs to the standard. However, nontarget stimuli in the difficult/large condition elicited an anterior maximum and earlier P300 (P3a) component. The findings suggest that target P300s are not influenced by the nontarget stimulus configuration, whereas the nontarget P300 outcomes are determined directly by the stimulus context. The theoretical implications are discussed.

Fast and Slow Reaction times and Associated Erps in Patients with Schizophrenia and Controls

A number of studies have examined across-trial averaged late component Event Related Potentials (EPR) and Reaction Times (RT) in response to multiple target stimuli. In this study, within-trial relatively fast and slow sub averages are additionally examined, in 20 patients with schizophrenia and 20 age and sex matched controls. A conventional auditory oddball paradigm. Across-trial ERP average analysis showed smaller N200 amplitude and delayed latency (but larger P200 amplitude) in patients with schizophrenia compared with controls. Within-trial ERP analysis revealed a number of additional findings. Controls showed distinctive differences in fast compared with slow ERP sub averages (smaller P200 amplitude, increased N200/P300 amplitudes and earlier latencies). The schizophrenic group on the other hand, showed relatively similar fast versus slow subaverages (no differences in P200 amplitude and N200 latency). In addition, between-group (within-trial) analyses highlighted significant differences in earlier stages of processing (compared with across-trial averages) in both fast and slow subaverages (increased N100 amplitude in controls). The complementary within-trial (compared with across-trial) data are interpreted with respect to a possible disturbance in inhibitory function in patients with schizophrenia.