A hitchhikers' guide to the terminology of accreditation processes for health professionals and institutions.

Accreditation processes for health care professions are designed to ensure that individuals and programs in these fields meet established standards of quality and effectiveness. The accelerating pace of globalization in the health care professions has increased the need for a shared understanding of the vocabulary of evaluation, assessment, and accreditation. The psychometric principles of valid and reliable assessment are commonly accepted, but the terminology is confusing. We believe that all stakeholders - evaluators, faculty, students but also the community - will benefit from a shared language and common set of definitions. We recognize that not all readers will agree with the definitions we propose, but we hope that this guide will help to ensure clarity, consistency, transparency, and fairness, and that it will promote through the stimulation of a debate greater collaboration across national and international boundaries.

Shaping social behavior in an enriched environment.

Access to vital needs shapes social orders. In rats, social systems tend to maintain a certain stability, but alterations in the physical environment can change inter-individual relations, which consequently can alter social orders. Principles governing social systems are, however, difficult to study and most analyses have been restricted to dyads of animals over short periods of time, hardly capturing the complexity and temporal dynamics of social interactions. Herein, we studied social interactions in a colony of six rats living in a customized enriched environment (PhenoWorld, PhW), under variable conditions of access/availability to limited resources. Reductions in food accessibility and availability resulted in a marked heterogeneity in sniffing, chasing and fighting/struggling behaviors, and, in the latter condition, an overall increase of these displays. The introduction of the possibility of interaction with a female rat also increased the amount of sniffing and fighting/struggling in a homogeneous manner. Results also showed that individual food retrieval success had no association with fighting/struggling when food pellets are delivered to the animals. However, there was a statistically significant correlation between fighting/struggling and impulsivity as measured by the amount of premature responses in the Variable-to-Signal-Test outside of the PhW providing external validation to our measures. To sum up, through continuous monitoring of a group of rats in the PhW, we demonstrated how variations in access to reinforcers modulate social behavior.

Chronic pain causes Tau-mediated hippocampal pathology and memory deficits.

Persistent pain has been recently suggested as a risk factor for dementia. Indeed, chronic pain is frequently accompanied by maladaptive brain plasticity and cognitive deficits whose molecular underpinnings are poorly understood. Despite the emerging role of Tau as a key regulator of neuronal plasticity and pathology in diverse brain disorders, the role of Tau has never been studied in the context of chronic pain. Using a peripheral (sciatic) neuropathy to model chronic pain in mice-spared nerve injury (SNI) for 4 months-in wildtype as well as P301L-Tau transgenic mice, we hereby demonstrate that SNI triggers AD-related neuropathology characterized by Tau hyperphosphorylation, accumulation, and aggregation in hippocampus followed by neuronal atrophy and memory deficits. Molecular analysis suggests that SNI inhibits autophagy and reduces levels of the Rab35, a regulator of Tau degradation while overexpression of Rab35 or treatment with the analgesic drug gabapentin reverted the above molecular changes leading to neurostructural and memory recovery. Interestingly, genetic ablation of Tau blocks the establishment of SNI-induced hippocampal morphofunctional deficits supporting the mediating role of Tau in SNI-evoked hippocampal pathology and memory impairment. These findings reveal that exposure to chronic pain triggers Tau-related neuropathology and may be relevant for understanding how chronic pain precipitates memory loss leading to dementia.

Cerebral Organoids to Study Central Mechanisms of Pain: The Effect of Stem Cell Secretome on Opioid Receptors and Neuroplasticity.

Over 90% of chronic pain (CP) patients receive opioids-based treatments, which led to a public health crisis with lasting impacts on social and economic wellbeing based on opioid addiction. Opioids act through activation of µ (MOR), δ (DOR), and κ (KOR) opioid receptors, which are broadly and differentially distributed throughout the brain. Chronic opioid consumption leads to brain changes such as alterations on neurotransmission, dendritic branching, and spine density, as well as an increase in apoptosis. To overcome opioid-related issues, extensive efforts have been made to search for an alternative treatment. Bioactive molecules secreted by stem cells, collectively known as secretome, have shown a positive impact in different pain models. However, there is a lack of studies on the role of secretome in modulating opioid receptors. By using cerebral organoids (CeO), a self-organized, functional, and multicellular 3D structure that resemble the brain, we were able to identify MOR, DOR, and KOR at different stages of maturation. Treatment with secretome increased MOR expression highlighting a possible role in pain signaling mechanisms. Opioid treatments did not impact the expression of neuronal maturation markers but together with secretome, they increased astrogliogenesis. Opioid-treated organoids presented higher dopamine secretion recapitulating an important physiological event after opioid exposure. This work demonstrates that CeO is an important model system for the study of opioid signaling with potential implications to the understanding of basic mechanisms related to pain physiology.

Diet, body weight and pain susceptibility - A systematic review of preclinical studies.

Obesity has been associated with increased chronic pain susceptibility but causes are unclear. In this review, we systematize and analyze pain outcomes in rodent models of obesity as these can be important tools for mechanistic studies. Studies were identified using MEDLINE/PubMed and Scopus databases using the following search query: (((pain) OR (nociception)) AND (obesity)) AND (rat OR (mouse) OR (rodent))). From each eligible record we extracted the following data: species, strain, sex, pain/obesity model and main behavioral readouts. Out of 695 records 33 were selected for inclusion. 27 studies assessed nociception/acute pain and 17 studies assessed subacute or chronic pain. Overall genetic and dietary models overlapped in pain-related outcomes. Most acute pain studies reported either decreased or unaltered responses to noxious painful stimuli. However, decreased thresholds to mechanical innocuous stimuli, i.e. allodynia, were frequently reported. In most studies using subacute and chronic pain models, namely of subcutaneous inflammation, arthritis and perineural inflammation, decreased thresholds and/or prolonged pain manifestations were reported in obesity models. Strain comparisons and longitudinal observations indicate that genetic factors and the time course of the pathology might account for some of the discrepancies observed across studies. Two studies reported increased pain in animals subjected to high fat diet in the absence of weight gain. Pain-related outcomes in experimental models and clinical obesity are aligned indicating that the rodent can be an useful tool to study the interplay between diet, obesity and pain. In both cases weight gain might represent only a minor contribution to abnormal pain manifestation.

Assessing Impulsivity in Humans and Rodents: Taking the Translational Road.

Impulsivity is a multidimensional construct encompassing domains of behavioral inhibition as well as of decision making. It is often adaptive and associated with fast responses, being in that sense physiological. However, abnormal manifestations of impulsive behavior can be observed in contexts of drug abuse and attention-deficit/hyperactivity disorder (ADHD), among others. A number of tools have therefore been devised to assess the different facets of impulsivity in both normal and pathological contexts. In this narrative review, we systematize behavioral and self-reported measures of impulsivity and critically discuss their constructs and limitations, establishing a parallel between assessments in humans and rodents. The first rely on paradigms that are typically designed to assess a specific dimension of impulsivity, within either impulsive action (inability to suppress a prepotent action) or impulsive choice, which implies a decision that weighs the costs and benefits of the options. On the other hand, self-reported measures are performed through questionnaires, allowing assessment of impulsivity dimensions that would be difficult to mimic in an experimental setting (e.g., positive/negative urgency and lack of premeditation) and which are therefore difficult (if not impossible) to measure in rodents.

Chronic pain susceptibility is associated with anhedonic behavior and alterations in the accumbal ubiquitin-proteasome system.

ABSTRACT: It remains unknown why on similar acute/subacute painful conditions, pain persists in some individuals while in others it resolves. Genetic factors, mood, and functional alterations, particularly involving the mesolimbic network, seem to be key. To explore potential susceptibility or resistance factors, we screened a large population of rats with a peripheral neuropathy and we isolated a small subset (<15%) that presented high thresholds (HTs) to mechanical allodynia (reduced pain manifestation). The phenotype was sustained over 12 weeks and was associated with higher hedonic behavior when compared with low-threshold (LT) subjects. The nucleus accumbens of HT and LT animals were isolated for proteomic analysis by Sequential Window Acquisition of All Theoretical Mass Spectra. Two hundred seventy-nine proteins displayed different expression between LT and HT animals or subjects. Among several protein families, the proteasome pathway repeatedly emerged in gene ontology enrichment and KEGG analyses. Several alpha and beta 20S proteasome subunits were increased in LT animals when compared with HT animals (eg, PSMα1, PSMα2, and PSMß5). On the contrary, UBA6, an upstream ubiquitin-activating enzyme, was decreased in LT animals. Altogether these observations are consistent with an overactivation of the accumbal proteasome pathway in animals that manifest pain and depressive-like behaviors after a neuropathic injury. All the proteomic data are available through ProteomeXchange with identifier PXD022478.

New Horizons for Phenotyping Behavior in Rodents: The Example of Depressive-Like Behavior.

The evolution of the field of behavioral neuroscience is significantly dependent on innovative disruption triggered by our ability to model and phenotype animal models of neuropsychiatric disorders. The ability to adequately elicit and measure behavioral parameters are the fundaments on which the behavioral neuroscience community establishes the pathophysiological mechanisms of neuropsychiatric disorders as well as contributes to the development of treatment strategies for those conditions. Herein, we review how mood disorders, in particular depression, are currently modeled in rodents, focusing on the limitations of these models and particularly on the analyses of the data obtained with different behavioral tests. Finally, we propose the use of new paradigms to study behavior using multidimensional strategies that better encompasses the complexity of psychiatric conditions, namely depression; these paradigms provide holistic phenotyping that is applicable to other conditions, thus promoting the emergence of novel findings that will leverage this field.

Chronic pain impact on rodents' behavioral repertoire.

Rodent models have been fundamental to understand chronic pain (CP) pathophysiology and to test for potential treatments. Pain assessment in CP models is most frequently based on the evaluation of allodynia or hyperalgesia. However, these correspond only to a part of CP-related problems which include ongoing pain, depression, anxiety, disrupted sleep and attentional deficits. A growing number of preclinical studies have been assessing these manifestations in CP rodent models. We reviewed and systematized this information by behavioral domain. Observational studies in ethologically relevant conditions, paradigms of anxiety- and depressive-like behavior as well as of memory and executive function were selected. A considerable number of studies reported deficits similar to those observed in CP patients. These behavioral alterations are informative regarding ongoing maladaptive plasticity in multiple brain regions and its use as pain proxies has the potential to greatly improve the predictive value of CP models. However, the inclusion of female and/or older rodents is rare which is in clear dissonance with the clinical representation of CP.

Mesocorticolimbic monoamines in a rodent model of chronic neuropathic pain.

Chronic pain manifests in multiple disorders and is highly debilitating. While its pathophysiology is not fully understood, the involvement of the mesocorticolimbic monoaminergic systems have been shown to play a critical role in chronic pain emergence and/or maintenance. In this study, we analyzed the levels of monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in mesocorticolimbic areas - medial prefrontal cortex, orbitofrontal cortex, striatum, nucleus accumbens and amygdala - 1 month after a neuropathic lesion, Spared Nerve Injury (SNI). In SNI animals, were observed a marginal decrease of DA and 5-HT in the striatum and a rightward shift in the levels of NA in the nucleus accumbens. While mesocorticolimbic monoamines might be relevant for chronic pain pathophysiology its content appears to be relatively unaffected in our experimental conditions.

Unmasking the relevance of hemispheric asymmetries-Break on through (to the other side).

The pioneer works of Marc Dax and Paul Broca on the association between left hemisphere injuries and speech impairments, revealed one of the most intriguing properties of the brain - asymmetry. Since then, lateralized features have been observed in virtually all phylogenetic branches, suggesting evolutionary conservation, although its adaptive role is still not clear. In humans, the field remains greatly shaped by early observations on language, but the advent of brain imaging revealed that functional and structural laterality is not only widespread, extending to memory, decision-making and emotion, but also that it is plastic. In this review, we systematize information regarding structural and functional hemispheric asymmetries of the healthy brain and their associations with cognition and behavior. We briefly explore evolutionary theories and the pathways for asymmetry development, but mostly we focus on central nervous system asymmetries of the adult human, bridging towards the laboratory rodent for mechanistic explanations.

High trait impulsivity potentiates the effects of chronic pain on impulsive behavior.

Preclinical studies on impulsive decision-making in chronic pain conditions are sparse and often contradictory. Outbred rat populations are heterogeneous regarding trait impulsivity manifestations and therefore we hypothesized that chronic pain-related alterations depend on individual traits. To test this hypothesis, we used male Wistar-Han rats in two independent experiments. Firstly, we tested the impact of spared nerve injury (SNI) in impulsive behavior evaluated by the variable delay-to-signal test (VDS). In the second experiment, SNI impact on impulsivity was again tested, but in groups previously categorized as high (HI) and low (LI) trait impulsivity in the VDS. Results showed that in an heterogenous population SNI-related impact on motor impulsivity and delay intolerance cannot be detected. However, when baseline impulsivity was considered, HI showed a significantly higher delay intolerance than the respective controls more prevalent in left-lesioned animals and appearing to result from a response correction on prematurity from VDS I to VDS II, which was present in Sham and right-lesioned animals. In conclusion, baseline differences should be more often considered when analyzing chronic pain impact. While this study pertained to impulsive behavior, other reports indicate that this can be generalized to other behavioral dimensions and that trait differences can influence not only the manifestation of comorbid behaviors but also pain itself in a complex and not totally understood manner.

MORPhA Scale: Behavioral and electroencephalographic validation of a rodent anesthesia scale.

BACKGROUND: Laboratory practice commonly implies rodent anesthesia. Such is instrumental not only for animal welfare, but also for standardized assessment of new anesthetics. NEW METHOD: We developed and validated a grading system for a temporal follow-up of anesthesia. The Minho Objective Rodent Phenotypical Anesthesia (MORPhA) scale was tested in mice (C57BL/6 J) and rats (Wistar-Han) anesthetized with ketamine/dexmedetomidine (ket/dex). The scale comprises 12 behavioral readouts organized in 5 stages - (i) normal/(ii) hindered voluntary movement, elicited response to (iii) non-noxious/(iv) noxious stimuli and (v) absence of response - evaluated at regular time-points. Progression across stages was monitored by electroencephalography (EEG) in rats during anesthesia induction and reversal (atipamezole) and during induction with a second anesthetic drug (pentobarbital). RESULTS: Higher anesthetic doses decreased the time to reach higher levels of anesthesia during progression, while increasing the time to regain waking behavior during reversal in both mice and rats. A regular decrease in high frequencies (low and high gamma) power was observed as the MORPhA score increased during anesthesia induction, while the opposite pattern was observed during emergence from anesthesia through reversion of dex effect. COMPARISON WITH EXISTING METHODS: Degree of anesthesia in laboratory rodents is normally evaluated by testing loss of reflexes. While these are useful endpoint assessments, they are of limited application to study induction/reversal kinetics or factors affecting individual susceptibility. MORPhA allows graded standardized assessment of this progression in a biologically-relevant fashion. CONCLUSIONS: The devised anesthetic scale is of simple application and provides a semi-quantifiable readout of anesthesia induction/reversal.

Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model.

Chronic pain is frequently accompanied by the manifestation of emotional disturbances and cognitive deficits. While a causality relation between pain and emotional/cognitive disturbances is generally assumed, several observations suggest a temporal dissociation and independent mechanisms. We therefore studied Sprague-Dawley rats that presented a natural resistance to pain manifestation in a neuropathy model (spared nerve injury [SNI]) and compared their performance in a battery of behavioral paradigms-anxiety, depression and fear memory-with animals that presented a pain phenotype. Afterward, we performed an extensive volumetric analysis across prefrontal, orbitofrontal and insular cortical areas. The majority of SNI animals manifested mechanical allodynia (low threshold [LT]), but 13% were similar to Sham controls (high threshold [HT]). Readouts of spontaneous hypersensivity (paw flinches) were also significantly reduced in HT and correlated with allodynia. To increase the specificity of our findings, we segregated the SNI animals in those with left (SNI-L) and right (SNI-R) lesions and the lack of association between pain and behavior still remains. Left-lesioned animals, independent of the LT or HT phenotype, presented increased anxiety-like behaviors and decreased well-being. In contrast, we found that the insular cortex (agranular division) was significantly smaller in HT than in LT. To conclude, pain and emotional disturbances observed following nerve injury are to some extent segregated phenomena. Also, HT and LT SNI presented differences in insular volumes, an area vastly implicated in pain perception, suggesting a supraspinal involvement in the manifestation of these phenotypes.

Asymmetrical subcortical plasticity entails cognitive progression in older individuals.

Structural brain asymmetries have been associated with cognition. However, it is not known to what extent neuropsychological parameters and structural laterality covary with aging. Seventy-five subjects drawn from a larger normal aging cohort were evaluated in terms of MRI and neuropsychological parameters at two moments (M1 and M2), 18 months apart. In this time frame, asymmetry as measured by structural laterality index (ΔLI) was stable regarding both direction and magnitude in all areas. However, a significantly higher dispersion for this variation was observed in subcortical over cortical areas. Subjects with extreme increase in rightward lateralization of the caudate revealed increased M1 to M2 Stroop interference scores, but also a worsening of general cognition (MMSE). In contrast, subjects showing extreme increase in leftward lateralization of the thalamus presented higher increase in Stroop interference scores. In conclusion, while a decline in cognitive function was observed in the entire sample, regional brain asymmetries were relatively stable. Neuropsychological trajectories were associated with laterality changes in subcortical regions.

Trait determinants of impulsive behavior: a comprehensive analysis of 188 rats.

Impulsivity is a naturally occurring behavior that, when accentuated, can be found in a variety of neuropsychiatric disorders. The expression of trait impulsivity has been shown to change with a variety of factors, such as age and sex, but the existing literature does not reflect widespread consensus regarding the influence of modulating effects. We designed the present study to investigate, in a cohort of significant size (188 rats), the impact of four specific parameters, namely sex, age, strain and phase of estrous cycle, using the variable delay-to-signal (VDS) task. This cohort included (i) control animals from previous experiments; (ii) animals specifically raised for this study; and (iii) animals previously used for breeding purposes. Aging was associated with a general decrease in action impulsivity and an increase in delay tolerance. Females generally performed more impulsive actions than males but no differences were observed regarding delay intolerance. In terms of estrous cycle, no differences in impulsive behavior were observed and regarding strain, Wistar Han animals were, in general, more impulsive than Sprague-Dawley. In addition to further confirming, in a substantial study cohort, the decrease in impulsivity with age, we have demonstrated that both the strain and sex influences modulate different aspects of impulsive behavior manifestations.