Publications by authors named "Thomas Boraud"

59 Publications

Economic behaviours among non-human primates.

Philos Trans R Soc Lond B Biol Sci 2021 Mar 11;376(1819):20190676. Epub 2021 Jan 11.

CNRS, UMR 5293, IMN, 33000 Bordeaux, France.

Do we have any valid reasons to affirm that non-human primates display economic behaviour in a sufficiently rich and precise sense of the phrase? To address this question, we have to develop a set of criteria to assess the vast array of experimental studies and field observations on individual cognitive and behavioural competences as well as the collective organization of non-human primates. We review a sample of these studies and assess how they answer to the following four main challenges. (i) Do we see any economic organization or institutions emerge among groups of non-human primates? (ii) Are the cognitive abilities, and often biases, that have been evidenced as underlying typical economic decision-making among humans, also present among non-human primates? (iii) Can we draw positive lessons from performance comparisons among primate species, humans and non-humans but also across non-human primate species, as elicited by canonical game-theoretical experimental paradigms, especially as far as economic cooperation and coordination are concerned? And (iv) in which way should we improve models and paradigms to obtain more ecological data and conclusions? Articles discussed in this paper most often bring about positive answers and promising perspectives to support the existence and prevalence of economic behaviours among non-human primates. This article is part of the theme issue 'Existence and prevalence of economic behaviours among non-human primates'.
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http://dx.doi.org/10.1098/rstb.2019.0676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815433PMC
March 2021

What is the true discharge rate and pattern of the striatal projection neurons in Parkinson's disease and Dystonia?

Elife 2020 08 19;9. Epub 2020 Aug 19.

University of Bordeaux, UMR 5293, IMN, Bordeaux, France.

Dopamine and striatal dysfunctions play a key role in the pathophysiology of Parkinson's disease (PD) and Dystonia, but our understanding of the changes in the discharge rate and pattern of striatal projection neurons (SPNs) remains limited. Here, we recorded and examined multi-unit signals from the striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. Contrary to earlier human findings, we found no drastic changes in the spontaneous discharge of the well-isolated and stationary SPNs of the PD patients compared to the dystonic patients or to the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations, indicating no SPN subpopulation-specific (D1 or D2 SPNs) discharge alterations in the pathological state. Our results imply that small to moderate changes in spontaneous SPN discharge related to PD and Dystonia are likely amplified by basal ganglia downstream structures.
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http://dx.doi.org/10.7554/eLife.57445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462612PMC
August 2020

Optimizing Treatment in Undertreated Late-Stage Parkinsonism: A Pragmatic Randomized Trial.

J Parkinsons Dis 2020 ;10(3):1171-1184

UCL Queen Square Institute of Neurology, University College London, Royal Free Campus, Rowland Hill Street, London, UK.

Background: Treatment of patients with late-stage parkinsonism is often sub-optimal.

Objective: To test the effectiveness of recommendations by a movement disorder specialist with expertise in late-stage parkinsonism.

Methods: Ninety-one patients with late-stage parkinsonism considered undertreated were included in apragmatic a pragmatic multi-center randomized-controlled trial with six-month follow-up. The intervention group received a letter with treatment recommendations to their primary clinician based on an extensive clinical assessment. Controls received care as usual. The primary outcome was the Unified Parkinson Disease Rating Scale (UPDRS)part-II (Activities of Daily Living). Other outcomes included quality-of-life (PDQ-8), mental health (UPDRS-I), motor function (UPDRS-III), treatment complications (UPDRS-IV), cognition (Mini-mental-state-examination), non-motor symptoms (Non-Motor-Symptoms-scale), health status (EQ-5D-5L) and levodopa-equivalent-daily-dose (LEDD). We also assessed adherence to recommendations. In addition to intention-to-treat analyses, a per-protocol analysis was conducted.

Results: Sample size calculation required 288 patients, but only 91 patients could be included. Treating physicians followed recommendations fully in 16 (28%) and partially in 21 (36%) patients. The intention-to-treat analysis showed no difference in primary outcome (between-group difference = -1.2, p = 0.45), but there was greater improvement for PDQ-8 in the intervention group (between-group difference = -3.7, p = 0.02). The per-protocol analysis confirmed these findings, and showed less deterioration in UPDRS-part I, greater improvement on UPDRS-total score and greater increase in LEDD in the intervention group.

Conclusions: The findings suggest that therapeutic gains may be reached even in this vulnerable group of patients with late-stage parkinsonism, but also emphasize that specialist recommendations need to be accompanied by better strategies to implement these to further improve outcomes.
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http://dx.doi.org/10.3233/JPD-202033DOI Listing
January 2020

In vivo electrophysiological validation of DREADD-based modulation of pallidal neurons in the non-human primate.

Eur J Neurosci 2020 Apr 19. Epub 2020 Apr 19.

Institut des Maladies Neurodégénératives (IMN), UMR 5293, Université de Bordeaux, Bordeaux, France.

Designer receptors exclusively activated by designer drugs (DREADDs) are widely used in rodents to manipulate neuronal activity and establish causal links between structure and function. Their utilization in non-human primates (NHPs) is, however, limited and their efficacy still debated. Here, we recorded and examined the neuronal activity in the hM4Di DREADD-transduced and hM4Di DREADD-free GPe of two anesthetized animals following local intra-GPe microinjection of clozapine-N-oxide (CNO). Our results revealed that the neuronal activity of the well-isolated units recorded in the hM4Di DREADD-transduced GPe exhibited diverse patterns in timing and polarity (increase/decrease) of firing rate modulations following CNO injection. Nevertheless, significant decreases in activity were more frequent (and more pronounced) than significant increases in activity during CNO injection (6/18 vs. 3/18 units) and were exclusive after CNO Injection (8/18 units). In contrast, only one of the 8 well-isolated units recorded in hM4Di DREADD-free GPe exhibited a significant increase in activity after CNO injection. Overall, the number of units exhibiting a significant period-related decrease following CNO injection was significantly larger in hM4Di DREADD-transduced GPe than in the hM4Di DREADD-free GPe (8/18 [44.4%] vs. 0/8 [0%]). Moreover, postmortem histochemical analysis revealed that hM4Di DREADDs were expressed at high level in the GPe neurons located in the vicinity of the viral vector injection sites. Our results therefore show in vivo hM4Di DREADD-based inhibition of pallidal neurons in the NHP model and reinforce the view that DREADD technology can be effective in NHPs.
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http://dx.doi.org/10.1111/ejn.14746DOI Listing
April 2020

Publisher Correction: The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

Nat Commun 2020 Apr 16;11(1):1930. Epub 2020 Apr 16.

Université de Bordeaux, Institut des Maladies Neurodégénératives, 33076, Bordeaux, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-15947-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162959PMC
April 2020

The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

Nat Commun 2020 03 26;11(1):1570. Epub 2020 Mar 26.

Université de Bordeaux, Institut des Maladies Neurodégénératives, 33076, Bordeaux, France.

The dynamical properties of cortico-basal ganglia (CBG) circuits are dramatically altered following the loss of dopamine in Parkinson's disease (PD). The neural circuit dysfunctions associated with PD include spike-rate alteration concomitant with excessive oscillatory spike-synchronization in the beta frequency range (12-30 Hz). Which neuronal circuits orchestrate and propagate these abnormal neural dynamics in CBG remains unknown. In this work, we combine in vivo electrophysiological recordings with advanced optogenetic manipulations in normal and 6-OHDA rats to shed light on the mechanistic principle underlying circuit dysfunction in PD. Our results show that abnormal neural dynamics present in a rat model of PD do not rely on cortical or subthalamic nucleus activity but critically dependent on globus pallidus (GP) integrity. Our findings highlight the pivotal role played by the GP which operates as a hub nucleus capable of orchestrating firing rate and synchronization changes across CBG circuits both in normal and pathological conditions.
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http://dx.doi.org/10.1038/s41467-020-15352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099038PMC
March 2020

An asymmetry of treatment between lotteries involving gains and losses in rhesus monkeys.

Sci Rep 2019 07 18;9(1):10441. Epub 2019 Jul 18.

Institut des Maladies Neurodégénératives, Université de Bordeaux, 33000, Bordeaux, France.

Decision-making in humans is known to be subject to several biases. For instance, when facing bets, humans demonstrate some asymmetry concerning their preference for the riskiest option depending on whether stakes involve potential gains or potential losses. They are indeed risk-averse for bets involving gains but risk seeking for bets involving losses. They also exhibit a distorted perception of probabilities. It is not clear whether non-human primates exhibit the same biases. Setting up a protocol that allowed two rhesus monkeys to make choices between lotteries involving either gains or losses, we demonstrated that rhesus monkeys facing bets exhibited an asymmetry in the treatment of gains and losses comparable with that of humans.
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http://dx.doi.org/10.1038/s41598-019-46975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639334PMC
July 2019

A Computational Model of Dual Competition between the Basal Ganglia and the Cortex.

eNeuro 2018 Nov-Dec;5(6). Epub 2019 Jan 4.

INRIA Bordeaux Sud-Ouest, Talence 33405, France.

We propose a model that includes interactions between the cortex, the basal ganglia (BG), and the thalamus based on a dual competition. We hypothesize that the striatum, the subthalamic nucleus (STN), the internal globus pallidus (GPi), the thalamus, and the cortex are involved in closed feedback loops through the hyperdirect and direct pathways. These loops support a competition process that results in the ability of BG to make a cognitive decision followed by a motor one. Considering lateral cortical interactions, another competition takes place inside the cortex allowing the latter to make a cognitive and a motor decision. We show how this dual competition endows the model with two regimes. One is driven by reinforcement learning and the other by Hebbian learning. The final decision is made according to a combination of these two mechanisms with a gradual transfer from the former to the latter. We confirmed these theoretical results on primates () using a novel paradigm predicted by the model.
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http://dx.doi.org/10.1523/ENEURO.0339-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325557PMC
March 2019

Do newspapers preferentially cover biomedical studies involving national scientists?

Public Underst Sci 2019 Feb 29;28(2):191-200. Epub 2018 Oct 29.

University of Bordeaux, France.

News value theory rates geographical proximity as an important factor in the process of issue selection by journalists. But does this apply to science journalism? Previous observational studies investigating whether newspapers preferentially cover scientific studies involving national scientists have generated conflicting answers. Here we used a database of 123 biomedical studies, 113 of them involving at least one research team working in eight countries (Australia, Canada, France, Ireland, Japan, New Zealand, the United Kingdom, and the United States). We compiled all the newspaper articles covering these 123 studies and published in English, French, and Japanese languages. In all eight countries, we found that newspapers preferentially covered studies involving a national team. Moreover, these "national" studies on average gave rise to a larger number of newspaper articles than "foreign" studies. Finally, our study resolves the conflict with previous conclusions by providing an alternative interpretation of published observations.
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http://dx.doi.org/10.1177/0963662518809804DOI Listing
February 2019

Naftazone in advanced Parkinson's disease: An acute L-DOPA challenge randomized controlled trial.

Parkinsonism Relat Disord 2019 03 4;60:51-56. Epub 2018 Oct 4.

Clinical Investigation Center CIC-1436, Departments of Clinical Pharmacology and Neurosciences, University Hospital of Toulouse, INSERM, University of Toulouse 3, Toulouse, France; F-CRIN, UMS 015, Toulouse, France.

Introduction: There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study.

Methods: We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population.

Results: Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ± 3.4 versus 6.7 ± 4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated.

Conclusions: This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration.
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http://dx.doi.org/10.1016/j.parkreldis.2018.10.005DOI Listing
March 2019

A natural history of skills.

Prog Neurobiol 2018 12 29;171:114-124. Epub 2018 Aug 29.

University of Bordeaux, UMR 5293, IMN, 33000 Bordeaux, France; INRIA Bordeaux Sud-Ouest, 33405 Talence, France; LaBRI, University of Bordeaux, IPB, CNRS, UMR 5800, 33405 Talence, France.

The dorsal pallium (a.k.a. cortex in mammals) makes a loop circuit with the basal ganglia and the thalamus known to control and adapt behavior but the who's who of the functional roles of these structures is still debated. Influenced by the Triune brain theory that was proposed in the early sixties, many current theories propose a hierarchical organization on the top of which stands the cortex to which the subcortical structures are subordinated. In particular, habits formation has been proposed to reflect a switch from conscious on-line control of behavior by the cortex, to a fully automated subcortical control. In this review, we propose to revalue the function of the network in light of the current experimental evidence concerning the anatomy and physiology of the basal ganglia-cortical circuits in vertebrates. We briefly review the current theories and show that they could be encompassed in a broader framework of skill learning and performance. Then, after reminding the state of the art concerning the anatomical architecture of the network and the underlying dynamic processes, we summarize the evolution of the anatomical and physiological substrate of skill learning and performance among vertebrates. We then review experimental evidence supporting for the hypothesis that the development of automatized skills relies on the BG teaching cortical circuits and is actually a late feature linked with the development of a specialized cortex or pallium that evolved in parallel in different taxa. We finally propose a minimal computational framework where this hypothesis can be explicitly implemented and tested.
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http://dx.doi.org/10.1016/j.pneurobio.2018.08.003DOI Listing
December 2018

Social decision making in autism: On the impact of mirror neurons, motor control, and imitative behaviors.

CNS Neurosci Ther 2018 08 2;24(8):669-676. Epub 2018 Jul 2.

Department of Prevention and Health Psychology, SRH Mobile University, Riedlingen, Germany.

The Mirror Neuron System (MNS) plays a crucial role in action perception and imitative behavior, which is suggested to be impaired in Autism Spectrum Disorders (ASDs). In this review, we discuss the plausibility and empirical evidence of a neural interaction between the MNS, action perception, empathy, imitative behavior, and their impact on social decision making in ASDs. To date, there is no consensus regarding a particular theory in ASDs and its underlying mechanisms. Some theories have completely focused on social difficulties, others have emphasized sensory aspects. Based on the current studies, we suggest a multilayer neural network model including the MNS on a first layer and transforming this information to a higher layer network responsible for reasoning. Future studies with ASD participants combining behavioral tasks with neuroimaging methods and transcranial brain stimulation as well as computational modeling can help validate and complement this suggested model. Moreover, we propose applying the behavioral paradigms, and the neurophysiological markers mentioned in this review article for evaluating psychiatric treatment approaches in ASDs. The investigation of modulating effects of different treatment approaches on the neurophysiological markers of the MNS can help find specific subgroups of ASDs patients and support tailored psychiatric interventions.
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http://dx.doi.org/10.1111/cns.13001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055683PMC
August 2018

Alterations in Functional Cortical Hierarchy in Hemiparkinsonian Rats.

J Neurosci 2017 08 7;37(32):7669-7681. Epub 2017 Jul 7.

Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam Neuroscience, 1081 BT Amsterdam, The Netherlands,

Parkinson's disease and experimentally induced hemiparkinsonism are characterized by increased beta synchronization between cortical and subcortical areas. This change in beta connectivity might reflect either a symmetric increase in interareal influences or asymmetric changes in directed influences among brain areas. We assessed patterns of functional and directed connectivity within and between striatum and six cortical sites in each hemisphere of the hemiparkinsonian rat model. LFPs were recorded in resting and walking states, before and after unilateral 6-hydroxydopamine lesion. The hemiparkinsonian state was characterized by increased oscillatory activity in the 20-40 Hz range in resting and walking states, and increased interhemispheric coupling (phase lag index) that was more widespread at rest than during walking. Spectral Granger-causality analysis revealed that the change in symmetric functional connectivity comprised profound reorganization of hierarchical organization and directed influence patterns. First, in the lesioned hemisphere, the more anterior, nonprimary motor areas located at the top of the cortical hierarchy (i.e., receiving many directed influences) tended to increase their directed influence onto the posterior primary motor and somatosensory areas. This enhanced influence of "higher" areas may be related to the loss of motor control due to the 6-OHDA lesion. Second, the drive from the nonlesioned toward the lesioned hemisphere (in particular to striatum) increased, most prominently during walking. The nature of these adaptations (disturbed signaling or compensation) is discussed. The present study demonstrates that hemiparkinsonism is associated with a profound reorganization of the hierarchical organization of directed influence patterns among brain areas, perhaps reflecting compensatory processes. Parkinson's disease classically first becomes manifest in one hemibody before affecting both sides, suggesting that degeneration is asymmetrical. Our results suggest that asymmetrical degeneration of the dopaminergic system induces an increased drive from the nonlesioned toward the lesioned hemisphere and a profound reorganization of functional cortical hierarchical organization, leading to a stronger directed influence of hierarchically higher placed cortical areas over primary motor and somatosensory cortices. These changes may represent a compensatory mechanism for loss of motor control as a consequence of dopamine depletion.
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http://dx.doi.org/10.1523/JNEUROSCI.3257-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596647PMC
August 2017

Low statistical power in biomedical science: a review of three human research domains.

R Soc Open Sci 2017 Feb 1;4(2):160254. Epub 2017 Feb 1.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.

Studies with low statistical power increase the likelihood that a statistically significant finding represents a false positive result. We conducted a review of meta-analyses of studies investigating the association of biological, environmental or cognitive parameters with neurological, psychiatric and somatic diseases, excluding treatment studies, in order to estimate the average statistical power across these domains. Taking the effect size indicated by a meta-analysis as the best estimate of the likely true effect size, and assuming a threshold for declaring statistical significance of 5%, we found that approximately 50% of studies have statistical power in the 0-10% or 11-20% range, well below the minimum of 80% that is often considered conventional. Studies with low statistical power appear to be common in the biomedical sciences, at least in the specific subject areas captured by our search strategy. However, we also observe evidence that this depends in part on research methodology, with candidate gene studies showing very low average power and studies using cognitive/behavioural measures showing high average power. This warrants further investigation.
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http://dx.doi.org/10.1098/rsos.160254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367316PMC
February 2017

Poor replication validity of biomedical association studies reported by newspapers.

PLoS One 2017 21;12(2):e0172650. Epub 2017 Feb 21.

Institute of Neurodegenerative Diseases, CNRS UMR5293 at Université de Bordeaux, Bordeaux, France.

Objective: To investigate the replication validity of biomedical association studies covered by newspapers.

Methods: We used a database of 4723 primary studies included in 306 meta-analysis articles. These studies associated a risk factor with a disease in three biomedical domains, psychiatry, neurology and four somatic diseases. They were classified into a lifestyle category (e.g. smoking) and a non-lifestyle category (e.g. genetic risk). Using the database Dow Jones Factiva, we investigated the newspaper coverage of each study. Their replication validity was assessed using a comparison with their corresponding meta-analyses.

Results: Among the 5029 articles of our database, 156 primary studies (of which 63 were lifestyle studies) and 5 meta-analysis articles were reported in 1561 newspaper articles. The percentage of covered studies and the number of newspaper articles per study strongly increased with the impact factor of the journal that published each scientific study. Newspapers almost equally covered initial (5/39 12.8%) and subsequent (58/600 9.7%) lifestyle studies. In contrast, initial non-lifestyle studies were covered more often (48/366 13.1%) than subsequent ones (45/3718 1.2%). Newspapers never covered initial studies reporting null findings and rarely reported subsequent null observations. Only 48.7% of the 156 studies reported by newspapers were confirmed by the corresponding meta-analyses. Initial non-lifestyle studies were less often confirmed (16/48) than subsequent ones (29/45) and than lifestyle studies (31/63). Psychiatric studies covered by newspapers were less often confirmed (10/38) than the neurological (26/41) or somatic (40/77) ones. This is correlated to an even larger coverage of initial studies in psychiatry. Whereas 234 newspaper articles covered the 35 initial studies that were later disconfirmed, only four press articles covered a subsequent null finding and mentioned the refutation of an initial claim.

Conclusion: Journalists preferentially cover initial findings although they are often contradicted by meta-analyses and rarely inform the public when they are disconfirmed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172650PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319681PMC
August 2017

Decision making under uncertainty in a spiking neural network model of the basal ganglia.

J Integr Neurosci 2016 Dec 21;15(4):515-538. Epub 2016 Dec 21.

* University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.

The mechanisms of decision-making and action selection are generally thought to be under the control of parallel cortico-subcortical loops connecting back to distinct areas of cortex through the basal ganglia and processing motor, cognitive and limbic modalities of decision-making. We have used these properties to develop and extend a connectionist model at a spiking neuron level based on a previous rate model approach. This model is demonstrated on decision-making tasks that have been studied in primates and the electrophysiology interpreted to show that the decision is made in two steps. To model this, we have used two parallel loops, each of which performs decision-making based on interactions between positive and negative feedback pathways. This model is able to perform two-level decision-making as in primates. We show here that, before learning, synaptic noise is sufficient to drive the decision-making process and that, after learning, the decision is based on the choice that has proven most likely to be rewarded. The model is then submitted to lesion tests, reversal learning and extinction protocols. We show that, under these conditions, it behaves in a consistent manner and provides predictions in accordance with observed experimental data.
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http://dx.doi.org/10.1142/S021963521650028XDOI Listing
December 2016

Memories of Opiate Withdrawal Emotional States Correlate with Specific Gamma Oscillations in the Nucleus Accumbens.

Neuropsychopharmacology 2017 Apr 6;42(5):1157-1168. Epub 2016 Dec 6.

Université de Bordeaux, INCIA, UMR 5287, Bordeaux, France.

Affective memories associated with the negative emotional state experienced during opiate withdrawal are central in maintaining drug taking, seeking, and relapse. Nucleus accumbens (NAC) is a key structure for both acute withdrawal and withdrawal memories reactivation, but the NAC neuron coding properties underpinning the expression of these memories remain largely unknown. Here we aimed at deciphering the role of NAC neurons in the encoding and retrieval of opiate withdrawal memory. Chronic single neuron and local field potentials recordings were performed in morphine-dependent rats and placebo controls. Animals were subjected to an unbiased conditioned placed aversion protocol with one compartment (CS+) paired with naloxone-precipitated withdrawal, a second compartment with saline injection (CS-), and a third being neutral (no pairing). After conditioning, animals displayed a typical place aversion for CS+ and developed a preference for CS- characteristic of safety learning. We found that distinct NAC neurons code for CS+ or CS-. Both populations also displayed highly specific oscillatory dynamics, CS+ and CS- neurons, respectively, following 80 Hz (G80) and 60 Hz (G60) local field potential gamma rhythms. Finally, we found that the balance between G60 and G80 rhythms strongly correlated both with the ongoing behavior of the animal and the strength of the conditioning. We demonstrate here that the aversive and preferred environments are underpinned by distinct groups of NAC neurons as well as specific oscillatory dynamics. This suggest that G60/G80 interplay-established through the conditioning process-serves as a robust and versatile mechanism for a fine coding of the environment emotional weight.
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http://dx.doi.org/10.1038/npp.2016.272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506790PMC
April 2017

Replication Validity of Initial Association Studies: A Comparison between Psychiatry, Neurology and Four Somatic Diseases.

PLoS One 2016 23;11(6):e0158064. Epub 2016 Jun 23.

CNRS, UMR 5293, Institute of Neurodegenerative diseases, Bordeaux, France.

Context: There are growing concerns about effect size inflation and replication validity of association studies, but few observational investigations have explored the extent of these problems.

Objective: Using meta-analyses to measure the reliability of initial studies and explore whether this varies across biomedical domains and study types (cognitive/behavioral, brain imaging, genetic and "others").

Methods: We analyzed 663 meta-analyses describing associations between markers or risk factors and 12 pathologies within three biomedical domains (psychiatry, neurology and four somatic diseases). We collected the effect size, sample size, publication year and Impact Factor of initial studies, largest studies (i.e., with the largest sample size) and the corresponding meta-analyses. Initial studies were considered as replicated if they were in nominal agreement with meta-analyses and if their effect size inflation was below 100%.

Results: Nominal agreement between initial studies and meta-analyses regarding the presence of a significant effect was not better than chance in psychiatry, whereas it was somewhat better in neurology and somatic diseases. Whereas effect sizes reported by largest studies and meta-analyses were similar, most of those reported by initial studies were inflated. Among the 256 initial studies reporting a significant effect (p<0.05) and paired with significant meta-analyses, 97 effect sizes were inflated by more than 100%. Nominal agreement and effect size inflation varied with the biomedical domain and study type. Indeed, the replication rate of initial studies reporting a significant effect ranged from 6.3% for genetic studies in psychiatry to 86.4% for cognitive/behavioral studies. Comparison between eight subgroups shows that replication rate decreases with sample size and "true" effect size. We observed no evidence of association between replication rate and publication year or Impact Factor.

Conclusion: The differences in reliability between biological psychiatry, neurology and somatic diseases suggest that there is room for improvement, at least in some subdomains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919034PMC
July 2017

The globus pallidus pars interna in goal-oriented and routine behaviors: Resolving a long-standing paradox.

Mov Disord 2016 08 22;31(8):1146-54. Epub 2016 Feb 22.

University of Bordeaux, UMR 5293, IMN, Bordeaux, France.

Background: There is an apparent contradiction between experimental data showing that the basal ganglia are involved in goal-oriented and routine behaviors and clinical observations. Lesion or disruption by deep brain stimulation of the globus pallidus interna has been used for various therapeutic purposes ranging from the improvement of dystonia to the treatment of Tourette's syndrome. None of these approaches has reported any severe impairment in goal-oriented or automatic movement.

Method: To solve this conundrum, we trained 2 monkeys to perform a variant of a 2-armed bandit-task (with different reward contingencies). In the latter we alternated blocks of trials with choices between familiar rewarded targets that elicit routine behavior and blocks with novel pairs of targets that require an intentional learning process.

Results: Bilateral inactivation of the globus pallidus interna, by injection of muscimol, prevents animals from learning new contingencies while performance remains intact, although slower for the familiar stimuli. We replicate in silico these data by adding lateral competition and Hebbian learning in the cortical layer of the theoretical model of the cortex-basal ganglia loop that provided the framework of our experimental approach.

Conclusion: The basal ganglia play a critical role in the deliberative process that underlies learning but are not necessary for the expression of routine movements. Our approach predicts that after pallidotomy or during stimulation, patients should have difficulty with complex decision-making processes or learning new goal-oriented behaviors. © 2016 Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26542DOI Listing
August 2016

Arkypallidal Cells Send a Stop Signal to Striatum.

Neuron 2016 Jan;89(2):308-16

Universite de Bordeaux, Institut des Maladies Neurodegeneratives, 33076 Bordeaux, France

The suppression of inappropriate actions is critical for flexible behavior. Cortical-basal ganglia networks provide key gating mechanisms for action suppression, yet the specific roles of neuronal subpopulations are poorly understood. Here, we examine Arkypallidal (‘‘Arky’’) and Prototypical (‘‘Proto’’) globus pallidus neurons during a Stop task, which requires abrupt cancellation of an imminent action. We first establish that Arky neurons can be identified by their firing properties across the natural sleep/wake cycle. We then show that Stop responses are earlier and stronger in the Arky compared to the Proto subpopulation. In contrast to other basal ganglia neurons, pallidal Stop responses are selective to Stop, rather than Go, cues. Furthermore, the timing of these Stop responses matches the suppression of developing striatal Go-related activity. Our results support a two-step model of action suppression: actions-inpreparation are first paused via a subthalamic-nigral pathway, then cancelled via Arky GABAergic projections to striatum.
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http://dx.doi.org/10.1016/j.neuron.2015.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871723PMC
January 2016

Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression.

Acta Neuropathol Commun 2015 Jul 25;3:46. Epub 2015 Jul 25.

University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species.

Results: Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration.

Conclusions: In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.
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http://dx.doi.org/10.1186/s40478-015-0222-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513748PMC
July 2015

A long journey into reproducible computational neuroscience.

Front Comput Neurosci 2015 5;9:30. Epub 2015 Mar 5.

INRIA Bordeaux Sud-Ouest Bordeaux, France ; Institut des Maladies Neurodégénératives, Université de Bordeaux, UMR 5293 Bordeaux, France ; Institut des Maladies Neurodégénératives, Centre National de la Recherche Scientifique, UMR 5293 Bordeaux, France ; LaBRI, Université de Bordeaux, Institut Polytechnique de Bordeaux, Centre National de la Recherche Scientifique, UMR 5800 Talence, France.

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http://dx.doi.org/10.3389/fncom.2015.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350388PMC
March 2015

Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia.

Biol Psychiatry 2016 Mar 9;79(5):345-353. Epub 2014 Sep 9.

Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France. Electronic address:

Background: A systematic search of brain nuclei putatively involved in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease shed light, notably, upon the lateral habenula (LHb), which displayed an overexpression of the ∆FosB, ARC, and Zif268 immediate-early genes only in rats experiencing abnormal involuntary movements (AIMs). We thus hypothesized that LHb might play a role in LID.

Methods: ∆FosB immunoreactivity, 2-deoxyglucose uptake, and firing activity of LHb were studied in experimental models of Parkinson's disease and LID. ΔFosB-expressing LHb neurons were then targeted using the Daun02-inactivation method. A total of 18 monkeys and 55 rats were used.

Results: LHb was found to be metabolically modified in dyskinetic monkeys and its neuronal firing frequency significantly increased in ON L-DOPA dyskinetic 6-hydroxydopamine-lesioned rats, suggesting that increased LHb neuronal activity in response to L-DOPA is related to AIM manifestation. Therefore, to mechanistically test if LHb neuronal activity might affect AIM severity, following induction of AIMs, 6-hydroxydopamine rats were injected with Daun02 in the LHb previously transfected with ß-galactosidase under control of the FosB promoter. Three days after Daun02 administration, animals were tested daily with L-DOPA to assess LID and L-DOPA-induced rotations. Inactivation of ∆FosB-expressing neurons significantly reduced AIM severity and also increased rotations. Interestingly, the dopaminergic D1 receptor was overexpressed only on the lesioned side of dyskinetic rats in LHb and co-localized with ΔFosB, suggesting a D1 receptor-mediated mechanism supporting the LHb involvement in AIMs.

Conclusions: This study highlights the role of LHb in LID, offering a new target to innovative treatments of LID.
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http://dx.doi.org/10.1016/j.biopsych.2014.08.022DOI Listing
March 2016

Easy rider: monkeys learn to drive a wheelchair to navigate through a complex maze.

PLoS One 2014 15;9(5):e96275. Epub 2014 May 15.

University of Bordeaux, Institut des Maladies Neurodegeneratives UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodegeneratives UMR 5293, Bordeaux, France.

The neurological bases of spatial navigation are mainly investigated in rodents and seldom in primates. The few studies led on spatial navigation in both human and non-human primates are performed in virtual, not in real environments. This is mostly because of methodological difficulties inherent in conducting research on freely-moving monkeys in real world environments. There is some incertitude, however, regarding the extrapolation of rodent spatial navigation strategies to primates. Here we present an entirely new platform for investigating real spatial navigation in rhesus monkeys. We showed that monkeys can learn a pathway by using different strategies. In these experiments three monkeys learned to drive the wheelchair and to follow a specified route through a real maze. After learning the route, probe tests revealed that animals successively use three distinct navigation strategies based on i) the place of the reward, ii) the direction taken to obtain reward or iii) a cue indicating reward location. The strategy used depended of the options proposed and the duration of learning. This study reveals that monkeys, like rodents and humans, switch between different spatial navigation strategies with extended practice, implying well-conserved brain learning systems across different species. This new task with freely driving monkeys provides a good support for the electrophysiological and pharmacological investigation of spatial navigation in the real world by making possible electrophysiological and pharmacological investigations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022652PMC
January 2015

The Michelin red guide of the brain: role of dopamine in goal-oriented navigation.

Front Syst Neurosci 2014 18;8:32. Epub 2014 Mar 18.

Institut des Maladies Neurodegeneratives UMR 5293, University of Bordeaux Bordeaux, France ; Institut des Maladies Neurodegeneratives UMR 5293, CNRS Bordeaux, France.

Spatial learning has been recognized over the years to be under the control of the hippocampus and related temporal lobe structures. Hippocampal damage often causes severe impairments in the ability to learn and remember a location in space defined by distal visual cues. Such cognitive disabilities are found in Parkinsonian patients. We recently investigated the role of dopamine in navigation in the 6-Hydroxy-dopamine (6-OHDA) rat, a model of Parkinson's disease (PD) commonly used to investigate the pathophysiology of dopamine depletion (Retailleau et al., 2013). We demonstrated that dopamine (DA) is essential to spatial learning as its depletion results in spatial impairments. Our results showed that the behavioral effect of DA depletion is correlated with modification of the neural encoding of spatial features and decision making processes in hippocampus. However, the origin of these alterations in the neural processing of the spatial information needs to be clarified. It could result from a local effect: dopamine depletion disturbs directly the processing of relevant spatial information at hippocampal level. Alternatively, it could result from a more distributed network effect: dopamine depletion elsewhere in the brain (entorhinal cortex, striatum, etc.) modifies the way hippocampus processes spatial information. Recent experimental evidence in rodents, demonstrated indeed, that other brain areas are involved in the acquisition of spatial information. Amongst these, the cortex-basal ganglia (BG) loop is known to be involved in reinforcement learning and has been identified as an important contributor to spatial learning. In particular, it has been shown that altered activity of the BG striatal complex can impair the ability to perform spatial learning tasks. The present review provides a glimpse of the findings obtained over the past decade that support a dialog between these two structures during spatial learning under DA control.
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http://dx.doi.org/10.3389/fnsys.2014.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957057PMC
June 2014

Complex population response of dorsal putamen neurons predicts the ability to learn.

PLoS One 2013 14;8(11):e80683. Epub 2013 Nov 14.

UMR 5293, University of Bordeaux, Bordeaux, France ; UMR 5293, CNRS, Bordeaux, France.

Day-to-day variability in performance is a common experience. We investigated its neural correlate by studying learning behavior of monkeys in a two-alternative forced choice task, the two-armed bandit task. We found substantial session-to-session variability in the monkeys' learning behavior. Recording the activity of single dorsal putamen neurons we uncovered a dual function of this structure. It has been previously shown that a population of neurons in the DLP exhibits firing activity sensitive to the reward value of chosen actions. Here, we identify putative medium spiny neurons in the dorsal putamen that are cue-selective and whose activity builds up with learning. Remarkably we show that session-to-session changes in the size of this population and in the intensity with which this population encodes cue-selectivity is correlated with session-to-session changes in the ability to learn the task. Moreover, at the population level, dorsal putamen activity in the very beginning of the session is correlated with the performance at the end of the session, thus predicting whether the monkey will have a "good" or "bad" learning day. These results provide important insights on the neural basis of inter-temporal performance variability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828263PMC
February 2015

Why am I lost without dopamine? Effects of 6-OHDA lesion on the encoding of reward and decision process in CA3.

Neurobiol Dis 2013 Nov 1;59:151-64. Epub 2013 Aug 1.

University of Bordeaux, Institut des Maladies Neurodegeneratives UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodegeneratives UMR 5293, Bordeaux, France.

There is growing evidence that Parkinson's disease, generally characterized by motor symptoms, also causes cognitive impairment such as spatial disorientation. The hippocampus is a critical structure for spatial navigation and receives sparse but comprehensive dopamine (DA) innervation. DA loss is known to be the cause of Parkinson's disease and therefore it has been hypothesized that the associated spatial disorientation could result from hippocampal dysfunction. Because DA is involved in the prediction of reward expectation, it is possible to infer that spatial disorientation in DA depleted subjects results from the loss of the ability to detect the rewarding features within the environment. Amongst hippocampal formation subdivisions, CA3 properties such as the high liability of its place fields make it a serious candidate for interfacing DA reward system and spatial information encoding. We addressed this issue using multiple electrode recordings of CA3 in normal and dopamine depleted rats performing a spatial learning in a Y-maze. Our data confirm that DA is essential to spatial learning as its depletion results in spatial impairments. The present work also shows that CA3 involvement in the detection of spatial feature contextual significance is under DA control. Finally, it also shows that CA3 contributes to the decision making processes of navigation tasks. The data also reveal a lateralization effect of DA depletion underlined by neural correlates.
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http://dx.doi.org/10.1016/j.nbd.2013.07.014DOI Listing
November 2013

Coordinated reset has sustained aftereffects in Parkinsonian monkeys.

Ann Neurol 2012 Nov;72(5):816-20

Institute for Medicine and Neurosciences, Research Center Jülich, Jülich, Germany.

Coordinated reset neuromodulation consists of the application of consecutive brief high-frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long-lasting aftereffects on motor function in parkinsonian nonhuman primates. Long-lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients.
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http://dx.doi.org/10.1002/ana.23663DOI Listing
November 2012

Why most biomedical findings echoed by newspapers turn out to be false: the case of attention deficit hyperactivity disorder.

PLoS One 2012 12;7(9):e44275. Epub 2012 Sep 12.

Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France.

Context: Because positive biomedical observations are more often published than those reporting no effect, initial observations are often refuted or attenuated by subsequent studies.

Objective: To determine whether newspapers preferentially report on initial findings and whether they also report on subsequent studies.

Methods: We focused on attention deficit hyperactivity disorder (ADHD). Using Factiva and PubMed databases, we identified 47 scientific publications on ADHD published in the 1990s and soon echoed by 347 newspapers articles. We selected the ten most echoed publications and collected all their relevant subsequent studies until 2011. We checked whether findings reported in each "top 10" publication were consistent with previous and subsequent observations. We also compared the newspaper coverage of the "top 10" publications to that of their related scientific studies.

Results: Seven of the "top 10" publications were initial studies and the conclusions in six of them were either refuted or strongly attenuated subsequently. The seventh was not confirmed or refuted, but its main conclusion appears unlikely. Among the three "top 10" that were not initial studies, two were confirmed subsequently and the third was attenuated. The newspaper coverage of the "top 10" publications (223 articles) was much larger than that of the 67 related studies (57 articles). Moreover, only one of the latter newspaper articles reported that the corresponding "top 10" finding had been attenuated. The average impact factor of the scientific journals publishing studies echoed by newspapers (17.1 n = 56) was higher (p<0.0001) than that corresponding to related publications that were not echoed (6.4 n = 56).

Conclusion: Because newspapers preferentially echo initial ADHD findings appearing in prominent journals, they report on uncertain findings that are often refuted or attenuated by subsequent studies. If this media reporting bias generalizes to health sciences, it represents a major cause of distortion in health science communication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440402PMC
March 2013