Imaging correlates of behavioral impairments: An experimental PET study in the rat pilocarpine epilepsy model

Liberto, Valentina Di; Dijk, Roelof Maarten van; Brendel, Matthias; Waldron, Ann-Marie; Möller, Christina; Koska, Ines; Seiffert, Isabel; Gualtieri, Fabio; Gildehaus, Franz Josef; Ungern-Sternberg, Barbara von; Lindner, Magdalena; Ziegler, Sibylle; Palme, Rupert; Hellweg, Rainer; Gass, Peter; Bartenstein, Peter; Potschka, Heidrun

doi:10.1016/j.nbd.2018.06.010

Cited by 24 publications

(26 citation statements)

References 78 publications

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“…The current findings are supported by a previous study from our laboratory, in which we demonstrated reduced glucose metabolism in the hippocampus and thalamus of pilocarpine‐treated rats . Interestingly, thalamic [ 18 F]FDG correlated with seizure frequency and duration in both the pilocarpine‐induced and the electrically induced post‐SE model, whereas in both models hippocampal [ 18 F]FDG did not.…”

Section: Discussionsupporting

confidence: 90%

“…Due to a low number in the epilepsy group, we were not able to test whether a correlation exists between the [ 18 F]MPPF results and the number of seizures. However, we previously demonstrated a comparable correlation between a rise in [ 18 F]MPPF binding and neurobehavioral symptoms in the chronic phase of the pilocarpine post‐SE model in rats . That study found no relevant correlation with seizure frequency or duration.…”

Section: Discussionmentioning

confidence: 69%

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Imaging biomarkers of behavioral impairments: A pilot micro–positron emission tomographic study in a rat electrical post–status epilepticus model

et al. 2018

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Objective:In patients with epilepsy, psychiatric comorbidities can significantly affect the disease course and quality of life. Detecting and recognizing these comorbidities is central in determining an optimal treatment plan. One promising tool in detecting biomarkers for psychiatric comorbidities in epilepsy is positron emission tomography (PET). Methods: Behavioral and biochemical variables were cross-correlated with the results from two μPET scans using the tracers [ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) and 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18 F-fluoro-benzamidoethylpiperazine ([ 18 F]MPPF) to explore potential biomarkers for neurobehavioral comorbidities in an electrically induced post-status epilepticus rat model of epilepsy.Results: In rats with epilepsy, μPET analysis revealed a local reduction in hippocampal [ 18 F]FDG uptake, and a local increase in [ 18 F]MPPF binding. These changes exhibited a correlation with burrowing as a "luxury" behavior, social interaction, and anxiety-associated behavioral patterns. Interestingly, hippocampal [ 18 F]FDG uptake did not correlate with spontaneous recurrent seizure activity. Significance: In the electrically induced post-status epilepticus rat model, we demonstrated hippocampal hypometabolism and its correlation with a range of neurobehavioral alterations. These findings require further confirmation in other preclinical models and patients with epilepsy and psychiatric disorders to address the value of [ 18 F]FDG uptake as an imaging biomarker candidate for psychiatric comorbidities in patients as well as for severity assessment in rodent epilepsy models.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 69%

Imaging biomarkers of behavioral impairments: A pilot micro–positron emission tomographic study in a rat electrical post–status epilepticus model

et al. 2018

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“…In addition, behavioral test batteries in the electrical post-SE and other epilepsy models can be used to assess correlations between potential biomarker candidates and behavioral parameters under standardized conditions. 38,39 Finally, we were eager to obtain further information about whether replacement of tethered seizure monitoring by telemetric seizure monitoring reduces the burden for the animals as suggested by Lidster et al 2 Our findings from the pilocarpine model revealed that minor differences can be observed between animals with tethered and telemetric recordings with evidence for a higher level of distress in the group with tethered monitoring (Koska et al, manuscript in revision).…”

Section: Discussionmentioning

confidence: 83%

“…These data sets may also help to resolve some of the discrepancies in the field. In addition, behavioral test batteries in the electrical post‐SE and other epilepsy models can be used to assess correlations between potential biomarker candidates and behavioral parameters under standardized conditions …”

Section: Discussionmentioning

confidence: 99%

Toward evidence‐based severity assessment in rat models with repeated seizures: III. Electrical post‐status epilepticus model

et al. 2019

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Objective Ethical approval of experiments in chronic epilepsy models requires a careful balancing of the expected gain‐in‐knowledge with the level of distress. Thus recommendations for evidence‐based severity assessment and classification are urgently needed for preclinical epilepsy research. Methods Therefore, we have completed a comprehensive analysis of alterations in behavioral, biochemical, and physiological parameters in a rat electrical post‐status epilepticus model. Selected parameters were repeatedly analyzed during different experimental phases to obtain information about the level of distress throughout the course of the model. Results Behavioral patterns comprised an increase in activity along with a reduction in risk assessment behavior, active social interaction, saccharin preference as well as nonessential, but evolutionary‐determined behavior such as nest building and burrowing. Among the biochemical parameters, fecal corticosterone metabolites proved to be increased in different phases of the experiment. In the early post‐insult phase, this increase was reflected by elevated serum corticosterone concentrations. Telemetric recordings demonstrated increases in home cage activity and heart rate in selected experimental phases but argued against relevant changes in heart rate variability. Comparison between animals with tethered or telemetric recordings including a principal component analysis revealed differences between both groups. Significance The present findings further confirm that burrowing behavior and saccharin preference might serve as valid parameters for severity assessment in chronic epilepsy models. Considering the course of alterations providing evidence for a more pronounced level of distress in the early phase following status epilepticus (SE), we suggest a classification of the electrical post‐SE model as severe. This suggestion may serve as a guidance for laboratory‐specific evaluations. Comparison between data from animals with tethered and telemetric recordings indicated an impact of the mode of recordings. However, further research is necessary to analyze the validity of telemetry as a putative refinement measure.

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“…The behavioral tests were performed according to previous studies conducted in our facility . Behavioral assessments were made at different time points throughout the study.…”

Section: Methodsmentioning

confidence: 99%

Toward evidence‐based severity assessment in rat models with repeated seizures: II. Chemical post–status epilepticus model

et al. 2019

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Objective Considering the complexity of neuronal circuits and their epilepsy‐associated alterations, epilepsy models cannot be completely replaced by in vitro experimental approaches. Decisions about ethical approval of in vivo studies require a thorough weighing of the animal's burden and the benefit regarding the expected gain in knowledge. Methods Based on combined behavioral, biochemical, and physiological analyses, we assessed the impact on animal well‐being and condition in different phases of the pilocarpine post–status epilepticus (SE) model in rats. Results As a consequence of SE, increased levels of impairment were evident in the early postinsult phase and late chronic phase, whereas only mild impairment was observed in the interim phase. Parameters that stood out as sensitive indicators of animal distress include burrowing, which proved to be affected throughout all experimental phases, saccharin preference, fecal corticosterone metabolites, heart rate, and heart rate variability. Significance The cumulative burden with temporary but not long‐lasting phases of more pronounced impairment suggests a classification of severe as a basis for laboratory‐specific prospective and retrospective evaluation. Among the parameters analyzed, burrowing behavior and saccharin preference stand out as candidate parameters that seem to be well suited to obtain information about animal distress in epileptogenesis models.

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Imaging correlates of behavioral impairments: An experimental PET study in the rat pilocarpine epilepsy model

Cited by 24 publications

References 78 publications

Imaging biomarkers of behavioral impairments: A pilot micro–positron emission tomographic study in a rat electrical post–status epilepticus model

Imaging biomarkers of behavioral impairments: A pilot micro–positron emission tomographic study in a rat electrical post–status epilepticus model

Toward evidence‐based severity assessment in rat models with repeated seizures: III. Electrical post‐status epilepticus model

Toward evidence‐based severity assessment in rat models with repeated seizures: II. Chemical post–status epilepticus model

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