The Hybrid Legal Geographies of a War Crimes Court

This paper explores the implications of understanding war crime trials as hybrid legal spaces. Drawing on twelve months of residential fieldwork in the Court of Bosnia and Herzegovina, Sarajevo, it examines the circulation of evidence, the choreography of the court room and the nature and possibilities for legal observation. Analyzing hybrid legal geographies foregrounds the material and embodied nature of trials, illuminating the forms of comportment, categorization and exclusion through which law establishes its legitimacy. Rather than emphasizing separation and distance, the lens of hybridity illuminates the multiple ways in which war crimes trials are grounded in the social and political context of present day Bosnia and Herzegovina. Consequently this analysis traces the disjuncture between the imagined geographies of legal jurisdiction and the material and embodied spaces of trial practices. In conclusion we argue that the establishment of the Court of Bosnia and Herzegovina illustrates the tensions that emerge when an institution of trial justice is used to strengthen the coherence of a post-conflict state.This paper is based on research funded by the Economic and Social Research Council (RES-061-25-0479).This is the accepted manuscript. The final version is available from http://www.tandfonline.com/doi/abs/10.1080/00045608.2014.892365

A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

[EN] Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework.This research was supported by grants from the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Ontario Ministry of Economic Development and Innovation (MEDI). We thank Dr. Hongying Wang for invaluable help with drug administration and animal careHassani, SA.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid-Ramírez, JS.; Van Der Meer, MA.; Tiesinga, P.... (2017). A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque. Scientific Reports. 7:1-19. https://doi.org/10.1038/srep40606S1197Arnsten, A. F., Wang, M. J. & Paspalas, C. D. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76, 223–239 (2012).Arnsten, A. F. & Dudley, A. G. Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct 1, 2 (2005).Clark, K. L. & Noudoost, B. The role of prefrontal catecholamines in attention and working memory. Front Neural Circuits 8, 33 (2014).Wang, M. et al. Neuronal basis of age-related working memory decline. Nature 476, 210–213 (2011).Wang, M. et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129, 397–410 (2007).Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28, 403–450 (2005).Yu, A. J. & Dayan, P. Uncertainty, neuromodulation, and attention. Neuron 46, 681–692 (2005).Mather, M., Clewett, D., Sakaki, M. & Harley, C. W. Norepinephrine ignites local hot spots of neuronal excitation: How arousal amplifies selectivity in perception and memory. Behav Brain Sci, 1–100, doi: 10.1017/S0140525X15000667 (2015).Amemiya, S. & Redish, A. D. Manipulating Decisiveness in Decision Making: Effects of Clonidine on Hippocampal Search Strategies. J Neurosci 36, 814–827 (2016).Doya, K. Metalearning and neuromodulation. Neural Netw 15, 495–506 (2002).Uhlen, S., Muceniece, R., Rangel, N., Tiger, G. & Wikberg, J. E. Comparison of the binding activities of some drugs on alpha 2A, alpha 2B and alpha 2C-adrenoceptors and non-adrenergic imidazoline sites in the guinea pig. Pharmacology & toxicology 76, 353–364 (1995).Mao, Z. M., Arnsten, A. F. & Li, B. M. Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biological psychiatry 46, 1259–1265 (1999).Arnsten, A. F. & Goldman-Rakic, P. S. Analysis of alpha-2 adrenergic agonist effects on the delayed nonmatch-to-sample performance of aged rhesus monkeys. Neurobiol Aging 11, 583–590 (1990).Franowicz, J. S. & Arnsten, A. F. The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136, 8–14 (1998).Caetano, M. S. et al. Noradrenergic control of error perseveration in medial prefrontal cortex. Frontiers in Integrative Neuroscience 6, 125 (2012).Kim, S., Bobeica, I., Gamo, N. J., Arnsten, A. F. & Lee, D. Effects of alpha-2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology 219, 363–375 (2012).Seu, E., Lang, A., Rivera, R. J. & Jentsch, J. D. Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys. Psychopharmacology 202, 505–519 (2009).Kawaura, K., Karasawa, J., Chaki, S. & Hikichi, H. Stimulation of postsynapse adrenergic alpha2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder. Behav Brain Res 270, 349–356 (2014).Aoki, C., Go, C. G., Venkatesan, C. & Kurose, H. Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity. Brain Res 650, 181–204 (1994).Barth, A. M., Vizi, E. S., Zelles, T. & Lendvai, B. Alpha2-adrenergic receptors modify dendritic spike generation via HCN channels in the prefrontal cortex. J Neurophysiol 99, 394–401 (2008).Ji, X. H., Ji, J. Z., Zhang, H. & Li, B. M. Stimulation of alpha2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat. Neuropsychopharmacology 33, 2263–2271 (2008).Yi, F., Liu, S. S., Luo, F., Zhang, X. H. & Li, B. M. Signaling mechanism underlying alpha2A -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats. Eur J Neurosci 38, 2364–2373 (2013).Engberg, G. & Eriksson, E. Effects of alpha 2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn-Schmiedeberg’s archives of pharmacology 343, 472–477 (1991).Jakala, P. et al. Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20, 460–470 (1999).Jakala, P. et al. Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology 20, 119–130 (1999).Muller, U. et al. Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology 182, 205–213 (2005).Scahill, L. et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. The American journal of psychiatry 158, 1067–1074 (2001).Huys, Q. J. M., Maia, T. V. & Frank, M. J. Computational psychiatry as a bridge from neuroscience to clinical applications. Nat Neurosci 19, 404–413 (2016).Stephan, K. E. et al. Computational neuroimaging strategies for single patient predictions. NeuroImage in press (2015).Arnsten, A. F., Cai, J. X. & Goldman-Rakic, P. S. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8, 4287–4298 (1988).Callado, L. F. & Stamford, J. A. Alpha2A- but not alpha2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data. Eur J Pharmacol 366, 35–39 (1999).Millan, M. J. et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nature reviews. Drug discovery 11, 141–168 (2012).Niv, Y. et al. Reinforcement learning in multidimensional environments relies on attention mechanisms. J Neurosci 35, 8145–8157 (2015).Balcarras, M., Ardid, S., Kaping, D., Everling, S. & Womelsdorf, T. Attentional Selection Can Be Predicted by Reinforcement Learning of Task-relevant Stimulus Features Weighted by Value-independent Stickiness. J Cogn Neurosci 28, 333–349 (2016).Redish, A. D., Jensen, S., Johnson, A. & Kurth-Nelson, Z. Reconciling reinforcement learning models with behavioral extinction and renewal: implications for addiction, relapse, and problem gambling. Psychol Rev 114, 784–805 (2007).Nassar, M. R. et al. Rational regulation of learning dynamics by pupil-linked arousal systems. Nat Neurosci 15, 1040–1046 (2012).O’Reilly, J. X. et al. Dissociable effects of surprise and model update in parietal and anterior cingulate cortex. Proc Natl Acad Sci USA 110, 3660–3669 (2013).Shenhav, A., Botvinick, M. M. & Cohen, J. D. The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron 79, 217–240 (2013).Womelsdorf, T. & Everling, S. Long-Range Attention Networks: Circuit Motifs Underlying Endogenously Controlled Stimulus Selection. Trends Neurosci 38, 682–700 (2015).Yang, Y. et al. Nicotinic alpha7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci USA 110, 12078–12083 (2013).Aston-Jones, G., Rajkowski, J. & Cohen, J. Role of locus coeruleus in attention and behavioral flexibility. Biological psychiatry 46, 1309–1320 (1999).Cole, B. J. & Robbins, T. W. Forebrain norepinephrine: role in controlled information processing in the rat. Neuropsychopharmacology 7, 129–142 (1992).Dalley, J. W., Cardinal, R. N. & Robbins, T. W. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neuroscience and biobehavioral reviews 28, 771–784 (2004).Devauges, V. & Sara, S. J. Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav Brain Res 39, 19–28 (1990).Connor, D. F., Arnsten, A. F., Pearson, G. S. & Greco, G. F. Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. Expert opinion on pharmacotherapy 15, 1601–1610 (2014).Sallee, F. R. et al. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 48, 155–165 (2009).Steere, J. C. & Arnsten, A. F. The alpha-2A noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys. Behav Neurosci 111, 883–891 (1997).Doya, K. Modulators of decision making. Nat Neurosci 11, 410–416 (2008).Wang, X. J. & Krystal, J. H. Computational psychiatry. Neuron 84, 638–654 (2014).Wiecki, T. V. et al. A Computational Cognitive Biomarker for Early-Stage Huntington’s Disease. PLoS One 11, e0148409, doi: 10.1371/journal.pone.0148409 (2016).Huys, Q. J., Pizzagalli, D. A., Bogdan, R. & Dayan, P. Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis. Biol Mood Anxiety Disord 3, 12 (2013).Gershman, S. J. & Niv, Y. Learning latent structure: carving nature at its joints. Curr Opin Neurobiol 20, 251–256 (2010).Voon, V. et al. Disorders of compulsivity: a common bias towards learning habits. Mol Psychiatry 20, 345–352 (2015).Maia, T. V. & Frank, M. J. From reinforcement learning models to psychiatric and neurological disorders. Nature Neuroscience 14, 154–162 (2011).Adams, R. A., Huys, Q. J. M. & Roiser, J. P. Computational Psychiatry: towards a mathematically informed understanding of mental illness. Journal of Neurology, Neurosurgery, and Psychiatry 87, 53–63 (2015).Schlagenhauf, F. et al. Striatal dysfunction during reversal learning in unmedicated schizophrenia patients. NeuroImage 89, 171–180 (2014).Harlé, K. M. et al. Bayesian neural adjustment of inhibitory control predicts emergence of problem stimulant use. Brain 138, 3413–3426 (2015).Zhang, J. et al. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease. Brain 139, 161–173 (2016).Frank, M. J. et al. fMRI and EEG Predictors of Dynamic Decision Parameters during Human Reinforcement Learning. Journal of Neuroscience 35, 485–494 (2015).Smith, A. C. & Brown, E. N. Estimating a state-space model from point process observations. Neural Comput 15, 965–991 (2003).Wilson, R. C. & Niv, Y. Inferring relevance in a changing world. Frontiers in human neuroscience 5, 189 (2011).Rämä, P. et al. Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys. Pharmacology Biochemistry and Behavior 55, 415–422 (1996).Arnsten, A. F. T. & Contant, T. A. Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task. Psychopharmacology 108, 159–169 (1992).O’Neill, J. et al. Effects of guanfacine on three forms of distraction in the aging macaque. Life Sciences 67, 877–885 (2000).Wang, M., Ji, J.-Z. & Li, B.-M. The α2A-Adrenergic Agonist Guanfacine Improves Visuomotor Associative Learning in Monkeys. Neuropsychopharmacology 29, 86–92 (2004).Witte, E. a. & Marrocco, R. T. Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting. Psychopharmacology 132, 315–323 (1997).Decamp, E., Clark, K. & Schneider, J. S. Effects of the alpha-2 adrenoceptor agonist guanfacine on attention and working memory in aged non-human primates. European Journal of Neuroscience 34, 1018–1022 (2011)

Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate

BACKGROUND: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required

The Virtual histology in CaroTids Observational RegistrY (VICTORY) study: A European prospective registry to assess the feasibility and safety of intravascular ultrasound and virtual histology during carotid interventions

Carotid occlusive disease is the most common determinant of thromboembolic stroke. However, limited insights in vivo into the pathophysiology and pathology of carotid plaques are available. We designed a prospective multicenter registry to appraise the safety and feasibility of intravascular ultrasound (IVUS) and IVUS-virtual histology (IVUS-VH) imaging before and immediately after carotid stenting

Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

Abnormal biology of \u3b1-synuclein (\u3b1-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other \u3b1-synucleinopathies. Herein, we demonstrate that C-terminally truncated \u3b1-Syn (\u3b1-Syn\u394C), enriched in the pathological \u3b1-Syn aggregates, is normally generated from full-length \u3b1-Syn independent of \u3b1-Syn aggregation in brains and in cultured cells. The accumulation of \u3b1-Syn\u394C is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant \u3b1-Syn is associated with the enhanced cellular accumulation of \u3b1-Syn\u394C Moreover, substoichiometric amounts of \u3b1-Syn\u394C enhance the in vitro aggregation of the more abundant full-length \u3b1-Syn. Finally, cases of a-synucleinopathy exhibit increases in the total soluble \u3b1-Syn and a higher proportion of soluble \u3b1-Syn\u394C, a condition favoring the aggregation of \u3b1-Syn. Collectively, our results indicate that the biology behind the generation and accumulation of \u3b1-Syn\u394C is likely to have relevance for the initiation and the progression of \u3b1-Syn aggregation in vivo