László Tombor

Drug Effect Prediction by Polypharmacology-Based Interaction Profiling

Most drugs exert their effects via multitarget interactions, as hypothesized by polypharmacology. While these multitarget interactions are responsible for the clinical effect profiles of drugs, current methods have failed to uncover the complex relationships between them. Here, we introduce an approach which is able to relate complex drug-protein interaction profiles with effect profiles. Structural data and registered effect profiles of all small-molecule drugs were collected, and interactions to a series of nontarget protein binding sites of each drug were calculated. Statistical analyses confirmed a close relationship between the studied 177 major effect categories and interaction profiles of ca. 1200 FDA-approved small-molecule drugs. On the basis of this relationship, the effect profiles of drugs were revealed in their entirety, and hitherto uncovered effects could be predicted in a systematic manner. Our results show that the prediction power is independent of the composition of the protein set used for interaction profile generation.

Are patients with schizophrenia rational maximizers? Evidence from an ultimatum game study

Schizophrenia is associated with impaired social cognition and community functioning. Social decision-making strategies of healthy controls and patients with schizophrenia were compared by using the ultimatum game (UG). In this game two players have to split a sum of money. The proposer offers a portion to the responder, who decides to either accept or reject the offer. Rejection results in no income to either of the parties. Unfair proposals are frequently rejected by nonclinical individuals, a phenomenon described as altruistic punishment. Patients and controls participated in a series of UG interactions as responders in a computerized test setting. We also tested the effect of the proposers facial expression on decision-making. Our results indicate that patients with schizophrenia accepted unfair offers at a significantly higher rate than did healthy controls. In contrast, at fair proposals, the acceptance rate was lower in patients compared with controls. At higher offers, the proposers facial expression (positive/negative) significantly influenced the acceptance rate (positive facial expression increased the likelihood of acceptance) in the control group. This effect was not observed in the patient group. These results suggest that schizophrenia patients are impaired in socioeconomic interactions requiring emotion recognition and decision-making, which may result in unstable behavioral strategies.

Virtual Affinity Fingerprints for Target Fishing: A New Application of Drug Profile Matching

We recently introduced Drug Profile Matching (DPM), a novel virtual affinity fingerprinting bioactivity prediction method. DPM is based on the docking profiles of ca. 1200 FDA-approved small-molecule drugs against a set of nontarget proteins and creates bioactivity predictions based on this pattern. The effectiveness of this approach was previously demonstrated for therapeutic effect prediction of drug molecules. In the current work, we investigated the applicability of DPM for target fishing, i.e. for the prediction of biological targets for compounds. Predictions were made for 77 targets, and their accuracy was measured by Receiver Operating Characteristic (ROC) analysis. Robustness was tested by a rigorous 10-fold cross-validation procedure. This procedure identified targets (N = 45) with high reliability based on DPM performance. These 45 categories were used in a subsequent study which aimed at predicting the off-target profiles of currently approved FDA drugs. In this data set, 79% of the known drug-target interactions were correctly predicted by DPM, and additionally 1074 new drug-target interactions were suggested. We focused our further investigation on the suggested interactions of antipsychotic molecules and confirmed several interactions by a review of the literature.

Experimental Confirmation of New Drug–Target Interactions Predicted by Drug Profile Matching

We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.

Electrophysiological indices of aberrant error-processing in adults with ADHD: a new region of interest

Deficits in error-processing are postulated in core symptoms of ADHD. Our goal was to investigate the neurophysiological basis of abnormal error-processing and adaptive adjustments in ADHD, and examine whether error-related alterations extend beyond traditional Regions of Interest (ROIs), particularly to those involved in adaptive adjustments, such as the Salience Network system. We obtained event-related potentials (ERPs) during a Go/NoGo task from 22 adult-ADHD patients and 29 matched healthy controls using a high-density 256-electrode array. Error-related ERPs with error-negativity (ERN) and error-positivity (Pe) served as probes of error-processing. In ADHD patients both ERN and Pe were significantly reduced, and the reduction was associated with core psychopathological symptoms. The ERP-attenuation was prominent not only at traditional ROI-electrodes but across many other brain areas, with a distinctive subset of group-differences and symptom-correlations manifested at temporo-parietal sites, with right-lateralization. Source-localization uncovered two neural-sources for the error-related ERPs: one in the cingulate cortex near midline, which was present in both groups; and one in the right insular cortex, which was present only in the control group. The neural patterns of impairments may be the result of coexisting deficits in the dorsal midline error-processing brain network involved in “error-processing proper” and the right-lateralized temporo-parietal salience network involved in the evaluation of significance of the error-signals. Our source-localization findings potentially identify a missing link between the previously reported structural change, i.e., reduced insular volume, and the well-established behavioral deficits in ADHD.

Altered response-preparation in patients with adult ADHD: A high-density ERP study

Aberrations in early-developing bottom-up processes, such as stimulus-driven response preparation, are thought to play a critical role in the onset of ADHD, and in its persistence over time. Electrophysiology offers a unique tool to gain insight into response preparation, since response preparation has been associated with distinctive ERP changes, including negative potential-shifts which occur predominantly over frontal brain areas. We examined response-preceding negative potential shifts (RPNS) as a probe of response-preparation in adult ADHD patients by obtaining high-density event-related potentials from 33 ADHD and 29 matched healthy subjects during a Go/Nogo task using a 128-channel BioSemi recording-system. Compared to controls, ADHD patients showed enhancement of the RPNS in fronto-central brain regions in the Go condition during correct responses. This change was associated with poor performance in the Stroop incongruency-task: the greater the enhancement, the higher the proportion of errors. Moreover, the ERP-enhancement showed association with the severity of ADHD-symptoms; and with heightened response-variability. Thus, ADHD patients demonstrate neurophysiological alterations in response-preparation and response-preceding brain activity, suggestive of excessive activation of prefrontal neural circuits. Given the correlation with neuropsychological and psychopathological measures, these changes may constitute a pathway for core symptoms of ADHD, including premature and impaired response-preparation and motor-hyperactivity.

Decreased resting gamma activity in adult attention deficit/hyperactivity disorder

Abstract Objectives: To delineate task-free gamma activity in adult ADHD and healthy control subjects based on high-density EEG recordings. Relationship of gamma activity with symptom severity was also examined, since gamma activity is considered to be an index of network functions in the brain that underlie higher-order cognitive processes. Methods: Spontaneous EEG was recorded in adult ADHD subjects (N = 42; 25 methylphenidate-naïve and 17 on methylphenidate treatment) and controls (N = 59) with eyes open. EEG absolute power gamma was investigated in the gamma1 (30.25–39 Hz) and gamma2 (39.25–48 Hz) frequency bands. Results: Gamma1 and gamma2 activity was diminished in ADHD compared with healthy control subjects. The difference between ADHD and controls was the most pronounced in the right centroparietal region for both gamma1 and gamma2. Inverse associations were found between gamma1 and gamma2 activity and ADHD symptoms in centroparietal scalp regions. Conclusions: Gamma activity is reduced in adult ADHD, and the reduction has a predominantly right centroparietal distribution. Our findings are consistent with childhood ADHD literature with respect to diminished posterior gamma activity in patients, which may reflect altered dorsal attention network functions. Gamma abnormalities might provide a link between neurophysiological functioning and neuropsychological deficiencies, thereby offering an opportunity to investigate the neurobiological mechanisms that underlie the clinical symptoms of ADHD.

Pszichiátriai tünetekkel jelentkező neuroszifilisz négyéves utánkövetése

Absztrakt: A szerzők pszichiatriai tunetekkel jaro neuroszifiliszes esetet kozolnek. Az idősodő ferfit zavart, kritikatlan viselkedes, maniform allapot es megaloman teveszmek miatt vettuk fel az első alkalommal. Felvetelkor jobb centralis facialis paresis, tremor es parkinsonismus volt eszlelhető. Akut kepalkoto es rutin laborvizsgalatok a tudatzavart egyertelműen magyarazo elterest nem igazoltak. A pszichiatriai kezeles hatasara a delirium megszűnt. Ezutan antipszichotikummal kezelt maniform allapot dominalta a kepet, majd gyors kognitiv leepulest es a motoros tunetek progressziojat eszleltuk. A koponya-MRI-vizsgalat corticalis es hippocampusatrophiat, feherallomanyi hiperintenzitasokat talalt. A liquorban pleocytosist, emelkedett osszfeherjeszintet talaltunk; a neuroszifilisz diagnozisat szerologiai vizsgalatokkal tamasztottuk ala. Penicillinkezelest kovetően a kognitiv tunetek enyhultek, a pszichiatriai tunetek remisszioba kerultek. Negy evvel a diagnozist kovetően a kognitiv hanyatlas fokozatos progre...

EPA-0645 – Neural correlates of impairments in conflict monitoring in ADHD: an event related potential (ERP) study

Introduction Major symptoms evidenced by patients with Attention Deficit Hyperactivity Disorder (ADHD) have been linked to deficiencies in cognitive control, especially when conflicts in information processing occur. Objective We wanted to define neural correlates of impairments in conflict monitoring in ADHD using the ERP technique. Unlike previous ERP studies that focused on brain potentials following incorrect responses in ADHD, we investigated a brain potential, the N2, which reflects conflict monitoring before a correct response. Method Participants were 33 adult ADHD subjects, and 29 matched healthy controls. We recorded 128-channel EEGs for ERP responses during a Go/NoGo Task with a prepotent GO response, where subjects had to withhold response to repeated stimuli. Results Using age and gender as covariates in the analyses, subjects with ADHD evidenced significantly larger N2 amplitudes than healthy controls. The extent of N2 enhancement showed a significant association with the number of errors in the incongruent condition of the Stroop Task. With regard to scalp topography, the differences were manifested over the frontal areas, with the most pronounced difference appearing at the midline areas. Conclusions Patients with ADHD evidence a marked enhancement in N2 amplitude in a Go/NoGo task with prepotent response tendency. The fact that N2 enhancement is directly related to incongruent errors in the Stroop task suggests that behavioral deficits in conflict processing in ADHD may be underlied, at least partially, by the ‘hyperreactivity’ of neurobiological processes that generate this brain potential. Supported by the Hungarian Scientific Research Fund (OTKA), Grant NN103325

EPA-0649 – Response inhibition in attention deficit hyperactivity disorder (ADHD): the influence of emotional-valence on the P300 brain potential

Introduction Emerging evidence suggests that disturbances in emotional processing in ADHD may interfere with executive functioning, and account for impairments in life functioning. Objective To investigate whether patients with ADHD evidence deficits in processing emotionally-valenced inputs, and to delineate the neurobiological correlates of these deficits. Methods Using event-related potentials from 128-channels, we tested 33 adult ADHD subjects and 29 individually-matched healthy controls (HC) in a cognitive control task of response inhibition. The task was performed by presenting valenced pictures (positive/negative/neutral) of the International Affective Picture System. The pictures were shown in random sequence, and repeated occasionally. Participants were asked to respond to each stimulus, and to withhold response for the repetition. Results With regard to behavioral measures, ADHD subjects showed more commission and omission errors. In terms of ERPs, both groups displayed a pronounced P300 component for all emotional valences in the frontal regions in the NoGo vs. the Go condition (‘NoGo P300’). However, compared to HCs, ADHD subjects showed a significant P300 reduction for negative, but no reduction for positive, or neutral stimuli. Conclusions Regarding the frontal NoGo P300, HCs were able to overcome the intrusion of negative emotion, and showed the same waveform when presented with negative as they showed with positive or neutral stimuli. By contrast, while ADHD subjects did not differ from HCs regarding positive and neutral inputs, they exhibited a pronounced P300 reduction for negative pictures, which may constitute a neurobiological correlate of emotional dysregulation. Supported by the Hungarian Scientific Research Fund (OTKA), Grant NN103325