Publications

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    ABSTRACT: Background: People with schizophrenia show social impairments that are related to functional outcomes. Here we tested the hypothesis that social interaction impairments in schizophrenia are related to alterations in the predictions of others’ behavior, and explored their underlying neurobiological mechanisms. Methods: Twenty patients with schizophrenia and 25 well-matched controls underwent EEG recording. Participants played as proposers in the repeated version of the Ultimatum Game believing that they were playing with another human or with a computer. The power of oscillatory brain activity was obtained by means of the wavelet transform. We performed a trial-by-trial correlation between the oscillatory activity and the risk of the offer. Results: Control subjects adapted their offers when playing with computers and tended to maintain their offers when playing with humans, as such revealing learning and bargaining strategies, respectively. People with schizophrenia presented the opposite pattern of behavior in both games. During the anticipation of others’ responses, the power of alpha oscillations correlated with the risk of the offers made, in a different way in both games. Schizophrenia patients presented a greater correlation in computer games than that in human games; control subjects showed the opposite pattern. The alpha activity correlated with positive symptoms. Conclusions: Our results reveal an alteration in social interaction in schizophrenia that is related to oscillatory brain activity, suggesting maladjustment of expectation when patients face social and non-social agents. This alteration is related to psychotic symptoms and could guide further therapies addressed for improving social functioning.
    Biological psychiatry 02/2015; · 8.93 Impact Factor
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    ABSTRACT: Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.
    PLoS ONE 02/2015; 10(2). · 3.53 Impact Factor
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    ABSTRACT: Intra-individual variability of response times (RTisv) is considered as potential endophe-notype for attentional deficit/hyperactivity disorder (ADHD). Traditional methods for esti-mating RTisv lose information regarding response times (RTs) distribution along the task, with eventual effects on statistical power. Ex-Gaussian analysis captures the dynamic nature of RTisv, estimating normal and exponential components for RT distribution, with specific phenomenological correlates. Here, we applied ex-Gaussian analysis to explore whether intra-individual variability of RTs agrees with criteria proposed by Gottesman and Gould for endophenotypes. Specifically, we evaluated if normal and/or exponential com-ponents of RTs may (a) present the stair-like distribution expected for endophenotypes (ADHD > siblings > typically developing children (TD) without familiar history of ADHD) and (b) represent a phenotypic correlate for previously described genetic risk variants. This is a pilot study including 55 subjects (20 ADHD-discordant sibling-pairs and 15 TD children), all aged between 8 and 13 years. Participants resolved a visual Go/Nogo with 10% Nogo probability. Ex-Gaussian distributions were fitted to individual RT data and compared among the three samples. In order to test whether intra-individual variability may represent a cor-relate for previously described genetic risk variants, VNTRs at DRD4 and SLC6A3 were identified in all sibling-pairs following standard protocols. Groups were compared adjust-ing independent general linear models for the exponential and normal components from the ex-Gaussian analysis. Identified trends were confirmed by the non-parametric Jonckheere– Terpstra test. Stair-like distributions were observed for µ (p = 0.036) and σ (p = 0.009). An additional "DRD4-genotype" × "clinical status" interaction was present for τ (p = 0.014) reflecting a possible severity factor. Thus, normal and exponential RTisv components are suitable as ADHD endophenotypes.
    Frontiers in Psychiatry 01/2015; 5(197).
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    ABSTRACT: Solving demanding tasks requires fast and flexible coordination among different brain areas. Everyday examples of this are the social dilemmas in which goals tend to clash, requiring one to weigh alternative courses of action in limited time. In spite of this fact, there are few studies that directly address the dynamics of flexible brain network integration during social interaction. To study the preceding, we carried out EEG recordings while subjects played a repeated version of the Ultimatum Game in both human (social) and computer (non-social) conditions. We found phase synchrony (inter-site-phase-clustering) modulation in alpha band that was specific to the human condition and independent of power modulation. The strength and patterns of the inter-site-phase-clustering of the cortical networks were also modulated, and these modulations were mainly in frontal and parietal regions. Moreover, changes in the individuals' alpha network structure correlated with the risk of the offers made only in social conditions. This correlation was independent of changes in power and inter-site-phase-clustering strength. Our results indicate that, when subjects believe they are participating in a social interaction, a specific modulation of functional cortical networks in alpha band takes place, suggesting that phase synchrony of alpha oscillations could serve as a mechanism by which different brain areas flexibly interact in order to adapt ongoing behavior in socially demanding contexts.
    PLoS ONE 10/2014; 9(10):e109829. · 3.53 Impact Factor
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    ABSTRACT: A cardinal symptom of attention deficit and hyperactivity disorder (ADHD) is a general distractibility where children and adults shift their attentional focus to stimuli that are irrelevant to the ongoing behavior. This has been attributed to a deficit in dopaminergic signaling in cortico-striatal networks that regulate goal-directed behavior. Furthermore, recent imaging evidence points to an impairment of large scale, antagonistic brain networks that normally contribute to attentional engagement and disengagement, such as the task-positive networks and the default mode network (DMN). Related networks are the ventral attentional network (VAN) involved in attentional shifting, and the salience network (SN) related to task expectancy. Here we discuss the tonic-phasic dynamics of catecholaminergic signaling in the brain, and attempt to provide a link between this and the activities of the large-scale cortical networks that regulate behavior. More specifically, we propose that a disbalance of tonic catecholamine levels during task performance produces an emphasis of phasic signaling and increased excitability of the VAN, yielding distractibility symptoms. Likewise, immaturity of the SN may relate to abnormal tonic signaling and an incapacity to build up a proper executive system during task performance. We discuss different lines of evidence including pharmacology, brain imaging and electrophysiology, that are consistent with our proposal. Finally, restoring the pharmacodynamics of catecholaminergic signaling seems crucial to alleviate ADHD symptoms; however, the possibility is open to explore cognitive rehabilitation strategies to top-down modulate network dynamics compensating the pharmacological deficits.
    Frontiers in Psychology 03/2014; 5:183. · 2.80 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: During social bargain, one has to both figure out the others' intentions and behave strategically in such a way that the others' behaviors will be consistent with one's expectations. To understand the neurobiological mechanisms underlying these behaviors, we used electroencephalography while subjects played as proposers in a repeated Ultimatum Game. We found that subjects adapted their offers in order to obtain more acceptances in the last round and that this adaptation correlated negatively with prefrontal theta oscillations. People with higher prefrontal theta activity related to a rejection did not adapt their offers along the game to maximize their earning. Moreover, between-subject variation in posterior theta oscillations correlated positively with how individual theta activity influenced the change of offer after a rejection, reflecting a process of behavioral adaptation to the others' demands. Interestingly, people adapted better their offers when they knew that they where playing against a computer, although the behavioral adaptation did not correlate with prefrontal theta oscillation. Behavioral changes between human and computer games correlated with prefrontal theta activity, suggesting that low adaptation in human games could be a strategy. Taken together, these results provide evidence for specific roles of prefrontal and posterior theta oscillations in social bargaining.
    Social Cognitive and Affective Neuroscience 02/2014; · 5.04 Impact Factor
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    ABSTRACT: The capacity to inhibit prepotent and automatic responses is crucial for proper cognitive and social development, and inhibitory impairments have been considered to be key for some neuropsychiatric conditions. One of the most used paradigms to analyze inhibitory processes is the Go-Nogo task (GNG). This task has been widely used in psychophysical and cognitive EEG studies, and more recently in paradigms using fMRI. However, a technical limitation is that the time resolution of fMRI is poorer than that of the EEG technique. In order to compensate for these temporal constraints, it has become common practice in the fMRI field to use longer inter-stimulus intervals (ISI) than those used in EEG protocols. Despite the noticeable temporal differences between these two techniques, it is currently assumed that both approaches assess similar inhibitory processes. We performed an EEG study using a GNG task with both short ISI (fast-condition, FC, as in EEG protocols) and long ISI (slow-condition, SC, as in fMRI protocols). We found that in the FC there was a stronger Nogo-N2 effect than in the SC. Moreover, in the FC, but not in the SC, the number of preceding Go trials correlated positively with the Nogo-P3 amplitude and with the Go trial reaction time; and negatively with commission errors. In addition, we found significant topographical differences for the Go-P3 elicited in FC and SC, which is interpreted in terms of different neurotransmitter dynamics. Taken together, our results provide evidence that frequency of stimulus presentation in the GNG task strongly modulates the behavioral response and the evoked EEG activity. Therefore, it is likely that short-ISI EEG protocols and long-ISI fMRI protocols do not assess equivalent inhibitory processes.
    PLoS ONE 01/2014; 9(1):e87232. · 3.53 Impact Factor
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    ABSTRACT: The capacity for language is arguably the most remarkable innovation of the human brain. A relatively recent interpretation prescribes that part of the language-related circuits were co-opted from circuitry involved in hand control-the mirror neuron system (MNS), involved both in the perception and in the execution of voluntary grasping actions. A less radical view is that in early humans, communication was opportunistic and multimodal, using signs, vocalizations or whatever means available to transmit social information. However, one point that is not yet clear under either perspective is how learned communication acquired a semantic property thereby allowing us to name objects and eventually describe our surrounding environment. Here we suggest a scenario involving both manual gestures and learned vocalizations that led to the development of a primitive form of conventionalized reference. This proposal is based on comparative evidence gathered from other species and on neurolinguistic evidence in humans, which points to a crucial role for vocal learning in the early development of language. Firstly, the capacity to direct the attention of others to a common object may have been crucial for developing a consensual referential system. Pointing, which is a ritualized grasping gesture, may have been crucial to this end. Vocalizations also served to generate joint attention among conversants, especially when combined with gaze direction. Another contributing element was the development of pantomimic actions resembling events or animals. In conjunction with this mimicry, the development of plastic neural circuits that support complex, learned vocalizations was probably a significant factor in the evolution of conventionalized semantics in our species. Thus, vocal imitations of sounds, as in onomatopoeias (words whose sound resembles their meaning), are possibly supported by mirror system circuits, and may have been relevant in the acquisition of early meanings.
    Frontiers in Human Neuroscience 01/2014; 8:605. · 2.90 Impact Factor
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    Francisco Aboitiz, Francisco Zamorano
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    ABSTRACT: The anatomical organization of the mammalian neocortex stands out among vertebrates for its laminar and columnar arrangement, featuring vertically oriented, excitatory pyramidal neurons. The evolutionary origin of this structure is discussed here in relation to the brain organization of other amniotes, i.e., the sauropsids (reptiles and birds). Specifically, we address the developmental modifications that had to take place to generate the neocortex, and to what extent these modifications were shared by other amniote lineages or can be considered unique to mammals. In this article, we propose a hypothesis that combines the control of proliferation in neural progenitor pools with the specification of regional morphogenetic gradients, yielding different anatomical results by virtue of the differential modulation of these processes in each lineage. Thus, there is a highly conserved genetic and developmental battery that becomes modulated in different directions according to specific selective pressures. In the case of early mammals, ecological conditions like nocturnal habits and reproductive strategies are considered to have played a key role in the selection of the particular brain patterning mechanisms that led to the origin of the neocortex.
    Frontiers in Neuroanatomy 11/2013; 7:38. · 4.18 Impact Factor
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    Pablo Billeke, Francisco Aboitiz
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    ABSTRACT: Social cognition consists of several skills which allow us to interact with other humans. These skills include social stimuli processing, drawing inferences about others' mental states, and engaging in social interactions. In recent years, there has been growing evidence of social cognitive impairments in patients with schizophrenia. Apparently, these impairments are separable from general neurocognitive impairments, such as attention, memory, and executive functioning. Moreover, social cognition seems to be a main determinant of functional outcome and could be used as a guide to elaborate new pharmacological and psychological treatments. However, most of these studies focus on individual mechanisms and observational perspectives; only few of them study schizophrenic patients during interactive situations. We first review evidences of social cognitive impairments both in social stimuli processing and in mental state attribution. We focus on the relationship between these functions and both general cognitive impairments and functional outcome. We next review recent game theory approaches to the study of how social engagement occurs in schizophrenic patients. The advantage of using game theory is that game-oriented tasks can assess social decision making in an interactive everyday situation model. Finally, we review proposed theoretical models used to explain social alterations and their underlying biological mechanisms. Based on interactive studies, we propose a framework which takes into account the dynamic nature of social processes. Thus, understanding social skills as a result of dynamical systems could facilitate the development of both basic research and clinical applications oriented to psychiatric populations.
    Frontiers in Psychiatry 02/2013; 4:4.
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    Enzo Brunetti, Pedro E Maldonado, Francisco Aboitiz
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    ABSTRACT: During monitoring of the discourse, the detection of the relevance of incoming lexical information could be critical for its incorporation to update mental representations in memory. Because, in these situations, the relevance for lexical information is defined by abstract rules that are maintained in memory, a central aspect to elucidate is how an abstract level of knowledge maintained in mind mediates the detection of the lower-level semantic information. In the present study, we propose that neuronal oscillations participate in the detection of relevant lexical information, based on "kept in mind" rules deriving from more abstract semantic information. We tested our hypothesis using an experimental paradigm that restricted the detection of relevance to inferences based on explicit information, thus controlling for ambiguities derived from implicit aspects. We used a categorization task, in which the semantic relevance was previously defined based on the congruency between a kept in mind category (abstract knowledge), and the lexical semantic information presented. Our results show that during the detection of the relevant lexical information, phase synchronization of neuronal oscillations selectively increases in delta and theta frequency bands during the interval of semantic analysis. These increments occurred irrespective of the semantic category maintained in memory, had a temporal profile specific for each subject, and were mainly induced, as they had no effect on the evoked mean global field power. Also, recruitment of an increased number of pairs of electrodes was a robust observation during the detection of semantic contingent words. These results are consistent with the notion that the detection of relevant lexical information based on a particular semantic rule, could be mediated by increasing the global phase synchronization of neuronal oscillations, which may contribute to the recruitment of an extended number of cortical regions.
    Frontiers in Psychology 01/2013; 4:308. · 2.80 Impact Factor
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    ABSTRACT: Visual spatial orienting of attention towards exogenous cues has been one of the attentional functions considered to be spared in ADHD. Here we present a design in which 60 (30 ADHD) children, age: 10.9±1.4, were asked to covertly orient their attention to one or two (out of four) cued locations, and search for a target stimulus in one of these locations, while recording behavioral responses and EEG/ERP. In all conditions, ADHD children showed delayed reaction times and poorer behavioral performance. They also exhibited larger cue-elicited P2 but reduced CNV in the preparation stage. Larger amplitude of CNV predicted better performance in the task. Target-elicited N1 and selection negativity were also reduced in the ADHD group compared to non-ADHD. Groups also differed in the early and late P3 time-windows. The present results suggest that exogenous orienting of attention could be dysfunctional in ADHD under certain conditions. This limitation is not necessarily caused by an impairment of the orienting process itself, but instead by a difficulty in maintaining the relevant information acquired during the early preparation stage through the target processing stage, when it is really needed.
    Brain research 11/2012; · 2.83 Impact Factor
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    ABSTRACT: In social interactions, the perception of how risky our decisions are depends on how we anticipate other people's behaviors. We used electroencephalography to study the neurobiology of perception of social risk, in subjects playing the role of proposers in an iterated ultimatum game in pairs. Based on statistical modeling, we used the previous behaviors of both players to separate high-risk [HR] offers from low-risk [LR] offers. The HR offers present higher rejec-tion probability and higher entropy (variability of possible outcome) than the LR offers. Rejections of LR offers elicited both a stronger mediofrontal negativity and a higher prefrontal theta activity than rejections of HR offers. Moreover, prior to feedback, HR offers gen-erated a drop in alpha activity in an extended network. Interestingly, trial-by-trial variation in alpha activity in the medial prefrontal, pos-terior temporal, and inferior pariental cortex was specifically modu-lated by risk and, together with theta activity in the prefrontal and posterior cingulate cortex, predicted the proposer's subsequent be-havior. Our results provide evidence that alpha and theta oscil-lations are sensitive to social risk and underlie a fine-tuning regulation of social decisions.
    Cerebral Cortex 11/2012; · 8.31 Impact Factor
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    Revista medica de Chile 11/2012; 140(11):1409-1416. · 0.37 Impact Factor
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    ABSTRACT: Background: The assessment of Attentional Deficit Hyperactivity Disorder (ADHD) among ethnic groups may reveal environmental or cultural variables that influence the appearance of this disorder. Aim: To assess the presence and characteristics of ADHD in two communities of the inland Arica valleys (Azapa and Lluta), where the Aymara population predominates. Material and Methods: Startingfrom a screening based on the Conner's test, we evaluated 79 children aged 8 to 13 years. Sixty children were of Aymara origin and 19 children were of non-Aymara origin. Twenty Aymara and 9 non-Aymara children had ADHD. They were compared with a group of patients from Santiago, Chile (110 children) that were previously assessed. Results: Patientsfrom Azapa/Lluta displayed similar characteristics to those from Santiago. However the former had significantly less psychiatric comorbidities than the latter. On the other hand, the non-Aymara subgroup of Azapa/ Lluta displayed an increased rate of comorbidities and was exclusively of the combined subtype, although their sample size is too small to draw strong conclusions. Conclusions: Although we cannot dismiss biological variables, the importance of family values and the respect to authorities may be protective factors for ADHD, associated to Aymara culture. Our findings suggest that the clinical characteristics of ADHD are not uniform among ethnic groups and cultures. The relative contribution of environmental and genetic factors in this variability remain to be determined.
    Revista medica de Chile 11/2012; 140(11):1409-16. · 0.37 Impact Factor
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    Francisco Aboitiz, Tomas Ossandon, Francisco Zamorano, Pablo Billeke
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    ABSTRACT: Background: Worldwide diversity of alleles of D4 receptor gene (DRD4), linked to attention deficit hyperactivity disorder (ADHD), is mostly the result of length and single nucleotide polymorphisms in a 48-bp tandem repeat (VNTR). Alleles containing from two (2R) to eleven (11R) repeats have been identified. The most common are 4R, 7R and 2R. Aim: To study the association of ADHD risk with DRD4 genotypes in Chilean students. Subjects and Methods: ADHD risk data were obtained through the abbreviated Conner's Scale for School Teachers in 66 Aymara children (11 cases and 55 controls), 91 Rapa-Nui children (60 cases ad 31 controls) and 96 children from a mixed urban population from Santiago (51 cases and 45 controls). DNA extracted from saliva was amplified by polymerase chain reaction (PCR) to genotype the DRD4 VNTR. Results: The distribution of DRD4 alleles reveals that, beneath the 4R allele, 7R exhibits the second highest frequencies in Aymara and Santiago children. In Polynesian children, 2R ranks after 4R. A statistically significant association between ADHD risk and 2R/4R genotype was identified in Polynesian children (p < 0.05; odds ratio = 3.7). Conclusions: Different DRD4 genotypes are associated with ADHDphenotype in Chilean populations, probably as a consequence of their initial colonization history.
    Revista medica de Chile 10/2012; 140(10):1276-81. · 0.37 Impact Factor
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    Revista medica de Chile 10/2012; 140(10):1276-1281. · 0.37 Impact Factor
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    ABSTRACT: En este artículo discutimos investigaciones recientes relacionadas a los mecanismos neurobiológicos subyacientes al Trastorno por Déficit Atencional e Hiperactividad, (TDAH) en particular la dinámica de señalización dopaminérgica y la llamada red por defecto, que consiste en patrones de actividad que se generan durante el reposo. Ambos tipos de fenómenos han sido asociados al TDAH, y aquí proponemos una relación entre ambas dinámicas, y cómo ésta puede estar afectada enel TDAH. Palabras clave: TDAH, Dopamina, Red por Defecto. SUMMARY In this article we discuss recent findings on the neurobiological mechanisms underlying Attentional Deficit Hyperactivity Disorder (ADHD); specifically the dynamics of dopaminergic signaling and the default mode network, consisting of activity patterns generated during the resting state. Both phenomena have been related to ADHD, and we propose here a relationship between both dynamics, and how this can be affected in ADHD.
    Revista Medica Clínica las Condes. 09/2012; 23(5-23):559-565.
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    ABSTRACT: Behavioral variability may be an ADHD key feature. Currently used ex-Gaussian/Fast Fourier Transform analyses characterize general distribution and oscillatory/rhythmic components of performance but are unable to demonstrate slow cumulative changes over entire tasks. Objective: To explore how performance of ADHD children and unaffected sibs gradually evolves in relation to genetic variants linked to ADHD. Method: A total of 40 kids (20 ADHD-discordant sib pairs) between 8 and 13 years resolved a visual Go/NoGo with 10% NoGo probability. Variable number tandem repeats (VNTRs) at DRD4 and SLC6A3 were identified following standard protocols. Performance changes were assessed by linear/logistic mixed-effect models. Results: Models exploring SLC6A3 effects demonstrated less accentuated increments of response time (RT) (p = .046) and cumulative increments in the correct responses to NoGo (p = .00027) in 10R/10R participants. Models for DRD4 showed faster decline of correct responses to Go (p = .0078) in 2R/7R carriers. Conclusion: Dynamical analysis of attention/inhibition measures may unravel new correlates to DRD4 and SLC6A3 variants.
    Journal of Attention Disorders 08/2012; · 2.40 Impact Factor

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