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      Long-term functional recovery and compensation after cerebral ischemia in rats

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          • Skilled reaching task allowed to differentiate between compensation and recovery.

          • Infarct size correlated with long-term motor function, not with social behavior.

          • Acute IL-1Ra led to recovery while compensation is seen in vehicle-treated animals.


          Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-term motor and cognitive impairments with limited therapeutic possibilities. Treatment options have proven efficient in preclinical models of cerebral ischemia but have failed in the clinical setting. This limited translation may be due to the suitability of models used and outcomes measured as most studies have focused on the early period after injury with gross motor scales, which have limited correlation to the clinical situation. The aim of this study was to determine long-term functional outcomes after cerebral ischemia in rats, focusing on fine motor function, social and depressive behavior as clinically relevant measures. A secondary objective was to evaluate the effects of an anti-inflammatory treatment (interleukin-1 receptor antagonist (IL-1Ra)) on functional recovery and compensation. Infarct volume was correlated with long-term (25 days) impairments in fine motor skills, but not with emotional components of behavior. Motor impairments could not be detected using conventional neurological tests and only detailed analysis allowed differentiation between recovery and compensation. Acute systemic administration of IL-1Ra (at reperfusion) led to a faster and more complete recovery, but delayed (24 h) IL-1Ra treatment had no effect. In summary functional assessment after brain injury requires detailed motor tests in order to address long-term impairments and compensation processes that are mediated by intact tissues. Functional deficits in skilled movement after brain injury represent ideal predictors of long-term outcomes and should become standard measures in the assessment of preclinical animal models.

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          Most cited references 33

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          Frequency of depression after stroke: a systematic review of observational studies.

          Although depression is an important sequelae of stroke, there is uncertainty regarding its frequency and outcome. We undertook a systematic review of all published nonexperimental studies (to June 2004) with prospective consecutive patient recruitment and quantification of depressive symptoms/illness after stroke. Data were available from 51 studies (reported in 96 publications) conducted between 1977 and 2002. Although frequencies varied considerably across studies, the pooled estimate was 33% (95% confidence interval, 29% to 36%) of all stroke survivors experiencing depression. Differences in case mix and method of mood assessment could explain some of the variation in estimates across studies. The data also suggest that depression resolves spontaneously within several months of onset in the majority of stroke survivors, with few receiving any specific antidepressant therapy or active management. Depression is common among stroke patients, with the risks of occurrence being similar for the early, medium, and late stages of stroke recovery. There is a pressing need for further research to improve clinical practice in this area of stroke care.
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            Inflammation-associated depression: from serotonin to kynurenine.

            In the field of depression, inflammation-associated depression stands up as an exception since its causal factors are obvious and it is easy to mimic in an animal model. In addition, quasi-experimental studies can be carried out in patients who are treated chronically with recombinant cytokines for a medical condition since these patients can be studied longitudinally before, during and after stimulation of the immune system. These clinical studies have revealed that depression is a late phenomenon that develops over a background of early appearing sickness. Incorporation of this feature in animal models of inflammation-associated depression has allowed the demonstration that alterations of brain serotoninergic neurotransmission do not play a major role in the pathogenesis. This is in contrast to the activation of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase that generates potentially neurotoxic kynurenine metabolites such as 3-hydroxy kynurenine and quinolinic acid. Although the relative importance of peripherally versus centrally produced kynurenine and the cellular source of production of this compound remain to be determined, these findings provide new targets for the treatment of inflammation-associated depression that could be extended to other psychiatric conditions mediated by activation of neuroimmune mechanisms. Copyright © 2010 Elsevier Ltd. All rights reserved.
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              Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes.

              The benefits of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke are time dependent, and guidelines recommend an arrival to treatment initiation (door-to-needle) time of ≤60 minutes. Data from acute ischemic stroke patients treated with tPA within 3 hours of symptom onset in 1082 hospitals participating in the Get With the Guidelines-Stroke Program from April 1, 2003, to September 30, 2009 were studied to determine frequency, patient and hospital characteristics, and temporal trends in patients treated with door-to-needle times ≤60 minutes. Among 25 504 ischemic stroke patients treated with tPA, door-to-needle time was ≤60 minutes in only 6790 (26.6%). Patient factors most strongly associated with door-to-needle time ≤60 minutes were younger age, male gender, white race, or no prior stroke. Hospital factors associated with ≤60 minute door-to-needle time included greater annual volumes of tPA-treated stroke patients. The proportion of patients with door-to-needle times ≤60 minutes varied widely by hospital (0% to 79.2%) and increased from 19.5% in 2003 to 29.1% in 2009 (P 60 minutes. Fewer than one-third of patients treated with intravenous tPA had door-to-needle times ≤60 minutes, with only modest improvement over the past 6.5 years. These findings support the need for a targeted initiative to improve the timeliness of reperfusion in acute ischemic stroke.

                Author and article information

                Behav Brain Res
                Behav. Brain Res
                Behavioural Brain Research
                Elsevier/North-Holland Biomedical Press
                15 August 2014
                15 August 2014
                : 270
                : 100
                : 18-28
                [a ]Faculty of Life Science, University of Manchester, Manchester, UK
                [b ]Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada
                Author notes
                [* ]Corresponding author. Current address: Department of Obstetrics and Gynecology, University of Montreal, Sainte-Justine Hospital Research Centre, Quebec, Canada. Tel.: +1 514 345 4931; fax: +1 514 345 4698. sylvie.girard@
                © 2014 The Authors

                This is an open access article under the CC BY license (

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