A Fragile Balance: Perturbation of GABA Mediated Circuit in Prefrontal Cortex Generates High Intraindividual Performance Variability Pierre Pouget1,2*, Nicolas Wattiez1,2, Sophie Rivaud-Pe´ choux1,2, Bertrand Gaymard1,2,3 1 Inserm U975, Movement disorders and basal ganglia, Hoˆ pital de la Salpeˆtrie`re, Paris, France, 2 Universite´ Pierre & Marie Curie-Paris 6, CNRS UMR 7225, Centre de Recherche – Institut du Cerveau et de la Moelle – CR-ICM, UMR S975, Paris, France, 3 AP-HP, Hoˆ pital de la Salpeˆtrie`re, Service d’Explorations Fonctionnelles Neurologiques, Paris, France Abstract High intraindividual performance variability is one of the most robust findings to emerge in cognitive-experimental research of attention deficit hyperactivity disorder (ADHD). Evidences from studies incorporating structural or functional human brain mapping methods indicate that this increased intraindividual variability is not simply a sequel of general brain dysfunction, but is likely related to the functioning of neural circuits that engage the prefrontal cortex, particularly the dorsolateral areas (dlPFC). In order to examine further the anatomical and pharmacological substrate responsible for this high intraindividual variability disorder, we injected GABAA antagonist (bicuculline) or GABAA agonist (muscimol) in the dlPFC of monkeys performing a reflexive oculomotor task. Here we show that, whereas GABAA agonist injection induced no or minimal impairments, injection of GABAA antagonist dramatically increased the intraindividual variability of saccade response time and of saccade spatial accuracy (amplitude and direction). Overall, this study demonstrates that the balance between excitatory/inhibitory activities in the dlPFC is fragile but crucial, since local micro-injection of GABAA antagonist can induce marked behavioural effects. It also reveals that higher cognitive areas such as the dlPFC are markedly capable to influence the productions and metrics of reflexive movements. Altogether, this study provides promising perspectives for the development of new therapeutic strategies for the treatment of diseases in which high intravariability disorders are a prominent feature. Citation: Pouget P, Wattiez N, Rivaud-Pe´choux S, Gaymard B (2009) A Fragile Balance: Perturbation of GABA Mediated Circuit in Prefrontal Cortex Generates High Intraindividual Performance Variability. PLoS ONE 4(4): e5208. doi:10.1371/journal.pone.0005208 Editor: Georges Chapouthier, L’universite´ Pierre et Marie Curie, France Received February 10, 2009; Accepted March 9, 2009; Published April 21, 2009 Copyright: 2009 Pouget et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Institut de Recherche Servier: the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: pierre.pouget@upmc.fr Introduction Significant and reliable differences in the speed and the variability of responses have been documented between ADHD and typically developing children (TDC) across a wide variety of neuropsychological tasks [1,2]. Increased variability, that is hypothesized to reflect underlying unstable attentional resources, is seen in tasks requiring continual responses to rapid stimuli as well as basic reaction time (RT) tasks [3]. Children with ADHD display are often found to respond more slowly and less accurately than the typically developing peers. However and importantly, response variability correlates more strongly and reliably with ratings of ADHD symptoms than commission errors or other outcome measures [4]. Evidences from studies incorporating structural or functional human brain mapping methods indicate that this intraindividual variability may not simply be a sequel of general brain dysfunction, but may likely be related to the functioning of neural circuits that, among other brain areas, engage the prefrontal cortex, particularly the dorsolateral areas (dlPFC) [5,6–14]. In order to examine further the anatomical and pharmacological substrate of this high intraindividual variability disorder, we injected a GABAA antagonist (bicuculline) or a GABAA agonist (muscimol) in the dlPFC of monkeys performing a reflexive oculomotor task (see supplementary information). Here, we show that specific and focal perturbation of GABA-mediated circuit in the dlPFC is capable to generate high intraindividual performance variability. Results As shown in Figure 1, in a representative injected site within the dlPFC, the variability of simple RTs dramatically increased after GABAA antagonist injection (Figure 1A), but not after GABAA agonist injection (Figure 1B). This result was confirmed across all injected sites (100%; 15/15 and 11/11sites; respectively 9 and 6 for monkey A and 6 and 5 for monkey B). Statistically and compared to pre-injection periods, GABAA antagonist but not GABAA agonist injections significantly increased RT variability (Figure 2A and 2B) (U(15,11) = 152, p,0.001; and U(15,11) = 11, p.0.05). Similar effects were observed when complete control experiments or saline injections were compared to GABAA injections (see Text S1). This effect was bilateral in both monkeys (see Figure S2 and Text S1). Injection of GABAA antagonist did also affect important metric properties of the movements, since variability of both saccade gain and direction were markedly affected (see Text S1 and Figure S3, S4). Specificity of dlPFC PLoS ONE | www.plosone.org 1 April 2009 | Volume 4 | Issue 4 | e5208