General Alertness Research Articles

Task-irrelevant valence-preferred colors boost visual search for a singleton-shape target

Some studies have suggested that emotion-associated features might influence attentional capture. However, demonstrating valence-dependent distractor interference has proven challenging, possibly due to the neglect of individuals’ color–valence preferences in standard, averaged reaction-time (RT) measures. To address this, we investigated valence-driven attentional-capture using an association phase in which emotionally neutral vs. positive-feedback photographs were paired with two alternative target colors, red vs. green. This was followed by a test phase requiring participants to search for a pop-out shape target in the presence or absence of an emotion-associated color. In Experiments 1 and 2, this color could only appear in a distractor, while in Experiment 3, it appeared in the target. Analyzing the standard, averaged RT measures, we found no significant valence association or valence-modulated attentional capture. However, correlational analyses revealed a positive relationship between individual participants’ color–valence preference during the association phase and their valence-based effect during the test phase. Moreover, most individuals favored red over green in the association phase, leading to marked color-related asymmetries in the average measures. Crucially, the presence of the valence-preferred color anywhere in the test display facilitated RTs. This effect persisted even when the color appeared in one of the distractors (Experiments 1 and 2), at variance with this distractor capturing attention. These findings suggest that task-irrelevant valence-preferred color signals were registered pre-attentively and boosted performance, likely by raising the general (non-spatial) alertness level. However, these signals were likely kept out of attentional-priority computation to prevent inadvertent attentional capture.

The ALARM Theory of Consciousness: A Two-Level Theory of Phenomenal Consciousness

The scientific investigation of consciousness generates new findings at a rapid pace. We argue that we need a novel theoretical framework, which we call the ALARM theory of consciousness, in order to account for all central observations. According to this theory, we need to distinguish two levels of consciousness, namely basic arousal and general alertness. Basic arousal functions as a specific alarm system, keeping a biological organism alive under sudden intense threats, and general alertness enables flexible learning and behavioural strategies. This two-level theory of consciousness helps us to account for (i) recent discoveries of subcortical brain activities with a central role of thalamic processes, (ii) observations of differences in the behavioural repertoire of non-human animals indicating two types of conscious experiences. Furthermore, the framework enables us (iii) to unify the neural evidence for the relevance of subcortical processes, on the one hand, and of cortico-cortical loops, on the other, and finally (iv) to clarify the evolutionary and actual functional role of conscious experiences.

Photo-elicited conversations about meetings with a therapy dog as a tool for communication in dementia care: An observational study.

It is well-known that people with dementia living in residential care facilities spend most of their time not engaged in meaningful activities. Being involved in activities can improve their quality of life. Animal-assisted therapy is an activity that can evoke engagement and joy. Another way to create engagement and promote communication between people with dementia and caregivers is to use photos. In this observational study, the researchers combined animal-assisted therapy and photobooks in order to explore whether photos of people with dementia who were engaged in animal-assisted therapy could be used as a tool for communication in dementia care. Ten persons (4 men and 6 women; aged 72-92) with dementia were video recorded during photo-elicited conversations with a dog handler/assistant nurse. The recordings were conducted in two residential care facilities in Sweden during 2017-2018. Each participant was video recorded 2-4 times. The recordings were analysed using The Observed Emotion Rating Scale and The Observational Measurement of Engagement-OME Modified. In addition, the video recordings were interpreted from a hermeneutic perspective. The findings showed that the most frequently observed effects were pleasure and general alertness, and the participants were observed to be attentive most of the time. The most common attitude during the conversations was 'somewhat positive'. The hermeneutic interpretations were grouped into four themes: Conveys a structure for the conversation with an inherent beginning and ending; An opportunity to recognise oneself and recall a sense of belonging; Awakens emotions and creates fellowship and Entails confirmation and revitalises their identity. Photobooks can be used by caregivers as a tool for meaningful and joyful communication with people with dementia, even those with severe dementia.

Implicit-explicit gradient of nondual awareness or consciousness as such.

Consciousness is multi-dimensional but is most often portrayed with a two-dimensional (2D) map that has global levels or states on one axis and phenomenal contents on the other. On this map, awareness is conflated either with general alertness or with phenomenal content. This contributes to ongoing difficulties in the scientific understanding of consciousness. Previously, I have proposed that consciousness as such or nondual awareness—a basic non-conceptual, non-propositional awareness in itself free of subject-object fragmentation—is a unique kind that cannot be adequately specified by this 2D map of states and contents. Here, I propose an implicit–explicit gradient of nondual awareness to be added as the z-axis to the existing 2D map of consciousness. This gradient informs about the degree to which nondual awareness is manifest in any experience, independent of the specifics of global state or local content. Alternatively, within the multi-dimensional state space model of consciousness, nondual awareness can be specified by several vectors, each representing one of its properties. In the first part, I outline nondual awareness or consciousness as such in terms of its phenomenal description, its function and its neural correlates. In the second part, I explore the implicit–explicit gradient of nondual awareness and how including it as an additional axis clarifies certain features of everyday dualistic experiences and is especially relevant for understanding the unitary and nondual experiences accessed via different contemplative methods, mind-altering substances or spontaneously.

Human-Machine Interfaces for Handover from Automated Driving Systems: A Literature Review

New automated driving systems are constantly being developed and integrated into vehicles. At the current state of technology, these features still require drivers to monitor performance and resume control when required by the systems. To cue drivers to take control, a takeover request (TOR) is presented with auditory, visual, and haptic cues. To characterize current TOR practices, a literature review was conducted to review types of human-machine interfaces (HMI’s) and their associated message presentation. Twenty-six articles were identified after searching keywords across journal articles and conference proceedings. HMIs and message types were identified and classified. Results indicated that TORs are more commonly used as general alerts to gain driver attention to driving tasks, rather than to request drivers to engage in a specific action or explain context of the TOR. Literature suggests that future systems may focus more on not only alerting drivers but providing additional context to those alerts.

Dissociating cholinergic influence on alertness and temporal attention in primates in a simple reaction time paradigm.

The ability to promptly respond to behaviourally relevant events depends on both general alertness and phasic changes in attentional state driven by temporal expectations. Using a variable foreperiod simple reaction time (RT) task in four adult male rhesus macaques, we investigated the role of the cholinergic system in alertness and temporal expectation. Foreperiod effects on RT reflect temporal expectation, while alertness is quantified as overall response speed. We measured these RT parameters under vehicle treatment and systemic administration of the muscarinic receptor antagonist scopolamine. We also investigated whether and to what extent the effects of scopolamine were reversed by donepezil, a cholinesterase inhibitor widely used for the treatment of dementia. In the control condition, RT showed a continuous decrease as the foreperiod duration increased, which clearly indicated the effect of temporal expectation on RT. This foreperiod effect was mainly detectable on the faster tail of the RT distribution and was eliminated by scopolamine. Furthermore, scopolamine treatment slowed down the average RT. Donepezil treatment was efficient on the slower tail of the RT distribution and improved scopolamine-induced impairments only on the average RT reflecting a general beneficial effect on alertness without any improvement in temporal expectation. The present results highlight the role of the cholinergic system in temporal expectation and alertness in primates and help delineate the efficacy and scope of donepezil and other cholinomimetic agents as cognitive enhancers in present and future clinical practice.

A Moan of Pleasure Should Be Breathy: The Effect of Voice Quality on the Meaning of Human Nonverbal Vocalizations

Prosodic features, such as intonation and voice intensity, have a well-documented role in communicating emotion, but less is known about the role of laryngeal voice quality in speech and particularly in nonverbal vocalizations such as laughs and moans. Potentially, however, variations in voice quality between tense and breathy may convey rich information about the speaker’s physiological and affective state. In this study breathiness was manipulated in synthetic human nonverbal vocalizations by adjusting the relative strength of upper harmonics and aspiration noise. In experiment 1 (28 prototypes × 3 manipulations = 84 sounds), otherwise identical vocalizations with tense versus breathy voice quality were associated with higher arousal (general alertness), higher dominance, and lower valence (unpleasant states). Ratings on discrete emotions in experiment 2 (56 × 3 = 168 sounds) confirmed that breathiness was reliably associated with positive emotions, particularly in ambiguous vocalizations (gasps and moans). The spectral centroid did not fully account for the effect of manipulation, confirming that the perceived change in voice quality was more specific than a general shift in timbral brightness. Breathiness is thus involved in communicating emotion with nonverbal vocalizations, possibly due to changes in low-level auditory salience and perceived vocal effort.

Acute psychological stress promotes general alertness and attentional control processes: An ERP study.

The current study investigated the influence of acute psychological stress on selective attention processes. After an acute stressor or a control condition, 20 participants performed an arrow-based version of the Eriksen flanker task, while ERPs (N1, N2, P3), reaction times, accuracy, subjective stress, and electrocardiogram signal were measured. Results showed elevated self-report stress, negative affect, state anxiety, heart rate, and reduced high-frequency heart rate variability in the stress block than in the control block, indicating that the flanker task was performed in a stressful situation. In the flanker task, faster response and larger flanker effect of accuracy were observed for the stress block relative to the control block, indicating increased arousal level and improved conflict detection under stress. Event-related potentials locked to target stimuli in the flanker task revealed that (a) frontal N1 was amplified in the stress block than in the control block, indicating elevated vigilance level under stress; (b) frontal N2 was increased in the stress block than in the control block for both congruent and incongruent trials, indicating more intensive attention control under stress; and (c) Increased P3 in the stress block than in the control block may reflect more allocation of neural resources as a consequence of improved attentional control under stress. These findings suggest that acute psychological stress increases general alertness and promotes attentional control in selective attention processes.

Creative Music Therapy in an Acute Care Setting for Older Patients with Delirium and Dementia

Background/Aims: The acute hospital ward can be unfamiliar and stressful for older patients with impaired cognition, rendering them prone to agitation and resistive to care. Extant literature shows that music therapy can enhance engagement and mood, thereby ameliorating agitated behaviours. This pilot study evaluates the impact of a creative music therapy (CMT) programme on mood and engagement in older patients with delirium and/or dementia (PtDD) in an acute care setting. We hypothesize that CMT improves engagement and pleasure in these patients. Methods: Twenty-five PtDD (age 86.5 ± 5.7 years, MMSE 6/30 ± 5.4) were observed for 90 min (30 min before, 30 min during, and 30 min after music therapy) on 3 consecutive days: day 1 (control condition without music) and days 2 and 3 (with CMT). Music interventions included music improvisation such as spontaneous music making and playing familiar songs of patient's choice. The main outcome measures were mood and engagement assessed with the Menorah Park Engagement Scale (MPES) and Observed Emotion Rating Scale (OERS). Results: Wilcoxon signed-rank test showed a statistically significant positive change in constructive and passive engagement (Z = 3.383, p = 0.01) in MPES and pleasure and general alertness (Z = 3.188,p = 0.01) in OERS during CMT. The average pleasure ratings of days 2 and 3 were higher than those of day 1 (Z = 2.466, p = 0.014). Negative engagement (Z = 2.582, p = 0.01) and affect (Z = 2.004, p = 0.045) were both lower during CMT compared to no music. Conclusion: These results suggest that CMT holds much promise to improve mood and engagement of PtDD in an acute hospital setting. CMT can also be scheduled into the patients' daily routines or incorporated into other areas of care to increase patient compliance and cooperation.

Revisiting organizational interpretation and three types of uncertainty

Purpose– The aim of this paper is to move toward a holistic model of organizational interpretation under uncertainty. This paper makes a series of novel conceptual propositions regarding the associations between state, effect and response uncertainty and the organizational interpretation process.Design/methodology/approach– This conceptual paper extends existing conceptual work by distinguishing between general and issue-specific scanning and linking the interpretation process to three different types of perceived uncertainty: state, effect and response uncertainty.Findings– It is proposed that environmental scanning leads to lower state and effect uncertainty, i.e. less uncertainty regarding the estimation of probabilities of events occurring in the external environment of the organization and of their consequences. It is further proposed that scanning leads to higher levels of perceived control over events and that the actual interpretation of events, in opportunity/threat terms, drives irregular issue-specific scanning and organizational reactions to such events.Research limitations/implications– The paper suggests a way to test links between organizational interpretation and uncertainty that might help explain and untangle some of the conflicting empirical results found in the extant literature. The paper illustrates how the literature could benefit from re-conceptualizing the perceived environmental uncertainty construct to take into account different types of uncertainty.Practical implications– For practitioners, this paper emphasizes the importance of environmental scanning and how scanning practices can lead to general alertness, to more positive event interpretations and how interpretations form responses to opportunities in the environment.Originality/value– This paper extends on existing work by linking the interpretation process to three different types of uncertainty (state, effect and response uncertainty) with several novel and testable propositions. The paper also differentiates clearly general (regular) scanning from issue-specific (irregular) scanning. Finally, the paper provides a unifying view, piecing together in one picture elements that have so far been dispersed in the literature.

Time course of EEG oscillations during repeated listening of a well-known aria.

While previous studies have analyzed mean neurophysiological responses to musical stimuli, the current study aimed to identify specific time courses of electroencephalography (EEG) oscillations, which are associated with dynamic changes in the acoustic features of the musical stimulus. In addition, we were interested in whether these time courses change during a repeated presentation of the same musical piece. A total of 16 subjects repeatedly listened to the well-known aria “Nessun dorma,” sung by Paul Potts, while continuous 128-channel EEG and heart rate, as well as electrodermal responses, were recorded. The time courses for the EEG oscillations were calculated using a time resolution of 1 second for several frequency bands, on the basis of individual alpha-peak frequencies (theta, low alpha-1, low alpha-2, upper alpha, and beta). For all frequency bands, we identified a more or less continuous increase in power relative to a baseline period, indicating strong event-related synchronization (ERS) during music listening. The ERS time courses, however, did not correlate strongly with the time courses of the acoustic features of the aria. In addition, we did not observe changes in EEG oscillations after repeated presentation of the same musical piece. Aside from this distinctive feature, we identified a remarkable variability in EEG oscillations, both within and between the repeated presentations of the aria. We interpret the continuous increase in ERS observed in all frequency bands during music listening as an indicator of a particular neurophysiological and psychological state evoked by music listening. We suggest that this state is characterized by increased internal attention (accompanied by reduced external attention), increased inhibition of brain networks not involved in the generation of this internal state, the maintenance of a particular level of general alertness, and a type of brain state that can be described as “mind wandering.” The overall state can be categorized as a psychological process that may be seen as a “drawing in” to the musical piece. However, this state is not stable and varies considerably throughout the music listening session and across subjects. Most important, however, is the finding that the neurophysiological activations occurring during music listening are dynamic and not stationary.

Everyday Waltzes for Active Ageing, Evaluating a Creative Movement Programme in Nursing Homes

Singapore has started the process of integrating health and social care to promote holistic longterm care. This effort is taking many forms. One example is: Agency for Integrated Care and National Arts Council funded an initiative to integrate art activities into nursing homes. In early 2013, a pilot tested three curricula, of which one showed significantly greater benefit to nursing home residents, such as improved memory and confidence in avoiding falls. This study aims to gather further evidence of the effectiveness of a Creative Movement curriculum on improving well-being and quality of life of nursing home residents who are wheelchair bound or ambulant but require supervision most of the time. The programme curriculum consists of 12 onehour sessions where participants follow dancer-facilitators to connect everyday actions into creative movements to enhance mobility, sensory experience and imagination. The study involves a total of 80 nursing home residents from two homes, with 40 participating in the programme and 40 as a comparator group. Physical and mental health was assessed by nursing home staff preand post-pilot using: a localised version of the Abbreviated Mental Test Score (AMTS), Geriatric Depression Scale (GDS-15), Modified Barthel Index (MBI), and a modified version of the Falls Efficacy Scale (FES). Programme participants' emotional well-being were assessed at 4 sessions using a modified version of the Observed Emotion Rating Scale (OES). Post-pilot, short-answer questions captured residents’ and staffs’ perceptions about the programme. The programme delivery ended in early November 2014. AMTS, GDS, FES, and MBI scores will be analysed by comparing preand post-programme scores between the programme and 15th International Conference on Integrated Care, Edinburgh, UK, March 25-27, 2015 1 International Journal of Integrated Care – Volume 15, 27 May – URN:NBN:NL:UI:10-1-117090– http://www.ijic.org/ comparator groups. OES scores will be analysed by aggregating durations of each affect state (Pleasure, Anger, Anxiety/Fear, Sadness or General Alertness) exhibited by all participants across sessions. Short-answer responses will serve to further inform future curriculum modifications. This study will more precisely indicate the potential impact this Creative Movement curriculum can have on Singapore's nursing home residents' quality of life and serves as an example of integrating social components into a traditionally health-focused service.

Noradrenergic and cholinergic effects on speed and sensitivity measures of phasic alerting.

An intense but task-irrelevant auditory accessory stimulus that is presented almost simultaneously with a visual imperative stimulus can reduce reaction times (RTs) to that stimulus. The information-processing locus and neural underpinnings underlying this phasic alerting effect are still poorly understood. The authors investigated a possible noradrenergic or cholinergic basis of the accessory stimulus effect in a double-blind pharmacological study (N = 18), in which healthy participants received a single dose of clonidine (an α2-adrenergic agonist), scopolamine (a muscarinic antagonist), and placebo in separate test sessions. A backward-masking procedure was used to examine, for the first time, the effect of accessory stimuli on perceptual sensitivity. The authors found that accessory stimuli enhanced perceptual sensitivity and decreased RTs to target stimuli, consistent with a recent hypothesis that phasic alerting speeds up stimulus encoding. In contrast to the authors' expectations, clonidine increased the accessory stimulus effect, a finding that seems at odds with earlier proposals that phasic alerting effects are mediated by a phasic noradrenergic response. Furthermore, the accessory stimulus effect was modulated to a similar extent by clonidine and scopolamine, suggesting that the effect of clonidine was not specific to the noradrenergic system. The results instead suggest that clonidine and scopolamine decrease general alertness and that these drug-related reductions in alertness yield room for compensatory performance improvements by phasic alerting.

EPA-1578 - Modifications of human brain activity due to transcranial direct current stimulation (tdcs) in patients with nicotine dependence

Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate human brain responses and has been used successfully in the treatment of depression. In this study tDCS was used as an add-on to psychotherapeutic interventions for the treatment of nicotine dependence. The goal of this study is to investigate modifications of brain activity before and after tDCS therapy. The study is based on a sample of 32 smokers, 22 to 65 years; participants were divided into a placebo group and a verum group. Each participated in fMRI measurements before and after treatment (tDCS plus psychotherapy). During the fMRI sessions, pictures with or without a connection to smoking were presented in a pseudo-randomised order, in order to assess craving-related responses. The results indicate cue-related brain activations, mainly within the basal ganglia, in the thalamus, the occipital cortex and the cuneus. The verum group showed an increased activation of the frontal cortex which is possibly related to a reinforcement of the brain's control function. The placebo group demonstrated reduced responses in the thalamus, the parahippocampal gyrus and the occipital cerebral cortex after tDCS, which may be related to changes of general attention and alertness.

Foot massage versus quiet presence on agitation and mood in people with dementia: A randomised controlled trial

BackgroundThere is increasing interest in using complementary and alternative treatments to manage behavioural and psychological symptoms of dementia such as agitation, aggression and depressed mood. ObjectiveTo compare the effect of foot massage (intervention) and quiet presence (control) on agitation and mood in people with dementia. DesignA randomised controlled trial using a within-subjects, crossover design. SettingsFive long-term care facilities in Brisbane, Australia. The primary outcome was the Cohen-Mansfield Agitation Inventory (CMAI) and the secondary outcome was the Observed Emotion Rating Scale (OERS). The screening and data collection research assistants, families, and care staff were blinded to participant allocation. ParticipantsParticipants of the study were 55 long-term care residents aged 74–103 years (mean age 86.5), with moderate to severe dementia and a history of agitated behaviour according to the Pittsburgh Agitation Scale. A computer-program randomised participants to 10-min foot massage (intervention) or quiet presence (control), every weekday for 3 weeks. ResultsA carry-over effect was identified in the data, and so the data was treated as a parallel groups RCT. The mean total CMAI increased in both groups (reflecting an increase in agitation) with this increase greater in the quiet presence group than the foot massage group (p=0.03). There was a trend towards a difference on OERS General Alertness, with a positive change in alertness for participants in the foot massage group (indicating reduced alertness) and a negative change for participants in the quiet presence group (indicating increased alertness) (F(1,51)=3.88, p=0.05, partial ή2=0.07). ConclusionsThe findings highlight the need for further research on the specific conditions under which massage might promote relaxation and improve mood for people with dementia. The unfamiliar research assistants and variations in usual activity may have contributed to the increase in agitation and this needs further research. Trial registrationACTRN12612000658819.

Odor naming and interpretation performance in 881 schizophrenia subjects: association with clinical parameters

BackgroundOlfactory function tests are sensitive tools for assessing sensory-cognitive processing in schizophrenia. However, associations of central olfactory measures with clinical outcome parameters have not been simultaneously studied in large samples of schizophrenia patients.MethodsIn the framework of the comprehensive phenotyping of the GRAS (Göttingen Research Association for Schizophrenia) cohort, we modified and extended existing odor naming (active memory retrieval) and interpretation (attribute assignment) tasks to evaluate them in 881 schizophrenia patients and 102 healthy controls matched for age, gender and smoking behavior. Associations with emotional processing, neuropsychological test performance and disease outcome were studied.ResultsSchizophrenia patients underperformed controls in both olfactory tasks. Odor naming deficits were primarily associated with compromised cognition, interpretation deficits with positive symptom severity and general alertness. Contrasting schizophrenia extreme performers of odor interpretation (best versus worst percentile; N=88 each) and healthy individuals (N=102) underscores the obvious relationship between impaired odor interpretation and psychopathology, cognitive dysfunctioning, and emotional processing (all p<0.004).ConclusionsThe strong association of performance in higher olfactory measures, odor naming and interpretation, with lead symptoms of schizophrenia and determinants of disease severity highlights their clinical and scientific significance. Based on the results obtained here in an exploratory fashion in a large patient sample, the development of an easy-to-use clinical test with improved psychometric properties may be encouraged.

Auditory event-related brain potentials for an early discrimination between normal and pathological brain aging.

The brain as a system with gradually decreasing resources maximizes its chances by reorganizing neural networks to ensure efficient performance. Auditory event-related potentials were recorded in 28 healthy volunteers comprising 14 young and 14 elderly subjects in auditory discrimination motor task (low frequency tone – right hand movement and high frequency tone – left hand movement). The amplitudes of the sensory event-related potential components (N1, P2) were more pronounced with increasing age for either tone and this effect for P2 amplitude was more pronounced in the frontal region. The latency relationship of N1 between the groups was tone-dependent, while that of P2 was tone-independent with a prominent delay in the elderly group over all brain regions. The amplitudes of the cognitive components (N2, P3) diminished with increasing age and the hemispheric asymmetry of N2 (but not for P3) reduced with increasing age. Prolonged N2 latency with increasing age was widespread for either tone while between-group difference in P3 latency was tone-dependent. High frequency tone stimulation and movement requirements lead to P3 delay in the elderly group. The amplitude difference of the sensory components between the age groups could be due to a general greater alertness, less expressed habituation, or decline in the ability to retreat attentional resources from the stimuli in the elderly group. With aging, a neural circuit reorganization of the brain activity affects the cognitive processes. The approach used in this study is useful for an early discrimination between normal and pathological brain aging for early treatment of cognitive alterations and dementia.

FDA safety alerts: Getting the response right!

The Food and Drug Administration (FDA) has issued more than 350 safety alerts for drugs and biological products, since January 2008. Approximately 12% (40) of these alerts were regarding medications indicated for the treatment of neurologic or psychiatric disorders. FDA safety alerts are intended to improve patient safety by providing the medical community with timely new safety data and actionable information that may impact treatment choices by both healthcare providers and patients. Communication of the safety alert to health care professionals also generally provides a summary of the data that serves as the basis for the alert, although often unpublished and not accessible for in depth review by decision makers. Health care providers and institutions are expected to orchestrate a response to these alerts that is in the best interest of delivering safe care to patients. Responses may range from dissemination of new information, policy development, or changes in selection or use of a drug or medication class. As mental health care delivery systems vary widely in size, patient population, infrastructure and financing, and resources (personnel and technology), responses to safety alerts may also vary to same degree. We were interested in identifying commonalities for failures and successes, in the experiences of clinical pharmacy specialists in mental health settings responding to safety alerts.

In Vitro Screening for Drug-Induced Depression and/or Suicidal Adverse Effects: A New Toxicogenomic Assay Based on CE-SSCP Analysis of HTR2C mRNA Editing in SH-SY5Y Cells

Many drugs in clinical trials, or already on the market, can have psychiatric side effects, independently of their therapeutic indication (e.g., Acomplia, Taranabant, and Roaccutane). There is currently no in vitro or in vivo approved test for the detection/prediction of such adverse effects, and the Food and Drugs Administration (FDA) can only issue general alerts on specific therapeutic classes. The development of a screening assay is therefore of real interest. The anti-viral and anti-tumor action of human interferon-alpha (hIFNα) is associated with a variety of neuropsychiatric side effects, including major depression, suicidal ideation and suicide. RNA editing of the serotonin 2C receptor (HTR2C) by adenosine deaminases acting on RNA (ADARs) is a post-transcriptional modification, the regulation of which is altered in depressed suicide victims. In this study, we show that in the SH-SY5Y neuroblastoma cell line, hIFNα specifically activates the ADAR1a isoform and thereby modifies the HTR2C mRNA editing profile. As this hIFNα-induced altered profile partly overlaps with that observed in the brain of depressed suicide victims, we investigated whether it could be used as a signature to identify drugs with depression and/or suicidal side effects. By means of the Biocortech proprietary screening assay, which allows the relative quantification of all the edited HTR2C isoforms in a sample, we blind-tested the effect of 50 marketed molecules on HTR2C mRNA editing in SH-SY5Y cells and identified 17 compounds with an IFN-like editing profile. This new toxicogenomic assay can identify compounds with potential psychiatric adverse events with a positive predictive value of 90%.

No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample

Noradrenergic neurotransmission influences executive functions, attentional performance, and general alertness, involving neuronal networks affected in attention deficit/hyperactivity disorder (ADHD). The norepinephrine transporter facilitates the reuptake of norepinephrine and dopamine in the prefrontal cortex and represents the main target of atomoxetine, an effective drug in the treatment of ADHD. Due to its influence on catecholaminergic signaling, variants of the coding gene (SLC6A2) have been widely investigated in ADHD. Several previous studies report an association between single nucleotide polymorphisms located in SLC6A2 and ADHD; however, the findings are inconsistent. The variant A-3081T (rs28386840) has been shown to have major influence on the expression levels of SLC6A2 due to sequence alteration at a repressor binding site, with the T-allele being associated with ADHD. We tested this potential association of A-3081T in a German family-based ADHD sample of 235 children from 162 families, which has a power >99% based on the previously reported odds ratios. There was no evidence for an overtransmission of the risk allele T (transmission rate: 48.5%, P=0.55). We conclude that A-3081T is not a major risk variant in our ADHD sample, though SLC6A2 remains an interesting candidate gene in ADHD, especially for the inattentive subtype.