Maternal immune activation leads to activated inflammatory macrophages in offspring

Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg polyinosinic–polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFN-γ/LPS. Following stimulation with LPS alone, or the combination of IFN-γ/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-γ/LPS (p < 0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood.     

Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.     

Behaviour and hippocampus-specific changes in spiny mouse neonates after treatment of the mother with the viral-mimetic Poly I:C at mid-pregnancy

Epidemiological studies have suggested a link between prenatal exposure to bacterial or viral infections and subsequent development of mental disorders such as schizophrenia and autism. Animal models to study the prenatal origin of such outcomes of pregnancy have largely used conventional rodents which are immature at birth compared to the human neonate, and doses of the infective agent (i.e., lipopolysaccharide, Poly I:C) have been large enough to cause sickness behaviour in the mother. In this study we have used the spiny mouse (Acomys cahirinus) whose offspring have completed organogenesis at birth, and a single subcutaneous injection of a low (0.5 mg/kg) dose of polyriboinosinic–polyribocytidilic acid (Poly I:C) at mid gestation (20 days, term is 39 days). The treatment had no effect on maternal, fetal or neonatal survival, or postnatal growth of the offspring. However, offspring showed significant impairments in non-spatial memory and learning tasks, and motor activity. Brain histology examined at 1 and 100 days of age revealed significant decreases in reelin, increased GFAP expression, and increased numbers of activated microglia, specifically in the hippocampus. This study provides evidence that a prenatal subclinical infection can have profound effects on brain development that are long-lasting.     

Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours,kynurenine pathway activation and reduced BDNF expression

In this study we characterised the ability of the viral mimetic poly I:C to induce a neuroinflammatory response and induce symptoms of depression and anxiety in rats. Furthermore, the ability of poly I:C to deplete central tryptophan and serotonin via induction of indolamine 2,3 dioxygenase (IDO), and also the ability of poly I:C to impact upon expression of the neurotrophin BDNF and its receptor TrkB were examined as potential mechanisms to link inflammation to depression. Poly I:C induced a neuroinflammatory response characterised by increased expression of IL-1β, IL-6, TNF-α and CD11b in frontal cortex and hippocampus. In the first 24 h following poly I:C administration rats displayed sickness behaviour characterised by reduced locomotor activity and weight gain. Anhedonia measured using the saccharin preference test was used as an indicator of depressive behaviour, and poly I:C induced depressive behaviour that persisted for up to 72 h following administration. Anxiety was measured using the open field test and anxious behaviour was observed 24 h following poly I:C, a time-point when sickness behaviour had resolved. These behavioural changes were accompanied by decreased expression of BDNF and TrkB in hippocampus and frontal cortex. In addition, poly I:C increased central IDO expression and increased concentrations of tryptophan, and its metabolite kynurenine. However this activation of the kynurenine pathway did not result in reduced central serotonin concentrations. These findings suggest that depressive and anxiety-like behaviours elicited by poly I:C are associated with a reduction in BDNF signalling, and activation of the kynurenine pathway, but not a reduction in serotonin.     

Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring

Gestational infection constitutes a risk factor for the occurrence of psychiatric disorders in the offspring. Activation of the maternal immune system (MIA) with subsequent impact on the development of the fetal brain is considered to form the neurobiological basis for aberrant neural wiring and the psychiatric manifestations later in offspring life. The examination of validated animal models constitutes a premier resource for the investigation of the neural underpinnings.Here we used a mouse model of MIA based upon systemic treatment of pregnant mice with Poly(I:C) (polyriboinosinic-polyribocytidilic acid), for the unbiased and comprehensive analysis of the impact of MIA on adult offspring brain activity, morphometry, connectivity and function by a magnetic resonance imaging (MRI) approach.Overall lower neural activity, smaller brain regions and less effective fiber structure were observed for Poly(I:C) offspring compared to the control group. The corpus callosum was significantly smaller and presented with a disruption in myelin/ fiber structure in the MIA progeny. Subsequent resting-state functional MRI experiments demonstrated a paralleling dysfunctional interhemispheric connectivity. Additionally, while the overall flow of information was intact, cortico-limbic connectivity was hampered and limbic circuits revealed hyperconnectivity in Poly(I:C) offspring.Our study sheds new light on the impact of maternal infection during pregnancy on the offspring brain and identifies aberrant resting-state functional connectivity patterns as possible correlates of the behavioral phenotype with relevance for psychiatric disorders.     

Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: no evidence for the "double-hit hypothesis"

Environmental disruptions can influence neurodevelopment during pre- and postnatal periods. Given such a large time window of opportunity for insult, the “double-hit hypothesis” proposes that exposure to an environmental challenge may impact development such that an individual becomes vulnerable to developing a psychopathology, which then manifests upon exposure to a second challenge later in life. The present study in male rats utilized the framework of the “double-hit hypothesis” to investigate potential compounding effects of maternal immune activation (MIA) during pregnancy and exposure of offspring to stress during juvenility on physiological and behavioural indications of anxiety in adulthood. We used an established rat model of MIA via maternal treatment with polyinosinic:polycytidylic acid (poly I:C) on gestation day 15 in combination with a model of juvenile stress (applied ages 27-29 d) in offspring to explore potential interacting/additive effects. First, we confirmed our employment of the MIA model by replicating previous findings that prenatal treatment with poly I:C caused deficits in sensorimotor gating in adult offspring, as measured by prepulse inhibition. Juvenile stress, on the other hand, had no effect on prepulse inhibition. In terms of anxiety-related behaviour and physiology, we found that prenatal poly I:C alone or in combination with juvenile stress had no effects on body weight, adrenal weight, and plasma concentration of corticosterone and cytokines in adult rats. MIA and juvenile stress increased anxiety-related behaviour on the elevated plus maze, but did so independently of each other. In all, our findings do not support an interaction between MIA and juvenile stress in terms of producing marked changes related to anxiety-like behaviour in adulthood.     

Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring

ObjectiveThe aim of this study was to examine the association between maternal serum vitamin D status in first trimester and risk of ASD at age 3–7 years in the offspring.MethodsUsing a case-control design, 68 children diagnosed with ASD and 68 sex and age matched typically-developing children were included. Archived maternal blood samples from the first trimester of pregnancy (11–13 weeks gestational age) were identified for those participants. Maternal serum levels of 25 hydroxyvitamin D3 [25(OH) D], unmetabolized folic acid (FA), vitamin B12, homocysteine (HCY) and High Sensitivity C Reactive protein (CRP) were measured from those samples. We examined the associations between those factors in pregnancy and diagnosis of ASD with logistic regression using SPSS.ResultsMothers in autistic group had significantly lower maternal serum levels of 25(OH) D than in typically-developing group [19.2(IQR: 15.8–22.9)ng/ml vs. 24.3(19.3–27.3)ng/ml, P < 0.001], with 55.9% and 29.4% being vitamin D deficient, respectively (P < 0.001). Levels of 25(OH) D increased with decreasing severity of ASD as defined by the CARS score (r = − 0.302, P < 0.001). Maternal first trimester serum levels of 25(OH) D in the lower 3 quartiles (quartile 1, 2, 3) (compared to the highest quartile) was associated with increased odds of ASD diagnosis in offspring [OR (95% CI) Q1: 1.36(0.84–2.58, P = 0.25); Q2: 2.68(1.44–4.29, P = 0.006); Q3:3.99(2.58–7.12, P < 0.001)].ConclusionsLower first trimester maternal serum levels of 25(OH) D were associated with increased risk of developing autism in offspring. If these findings are confirmed, this may present an opportunity for prenatal intervention to reduce the risk for ASD.     

Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring

Multiple sclerosis (MS) is characterized by an autoimmune response against myelin antigens driven by autoreactive T cells. Several lines of evidence indicate that environmental factors, such as previous infection, can influence and trigger autoimmune responses. However, the importance of the gestational period, particularly under inflammatory conditions, on the modulation of MS and related neuroinflammation by the offspring is unknown. This study aimed to evaluate the impact of prenatal exposure to lipopolysaccharide (LPS) during late gestation on the neuroinflammatory response in primary mixed glial cultures and on the progression of experimental autoimmune encephalomyelitis (EAE, an animal model of MS) in the offspring. LPS (Escherichia coli 0127:B8, 120 μg/kg) was administered intraperitoneally to pregnant C57BL/6J mice on gestational day 17, and the offspring were assigned to two experiments: (1) mixed glial cultures generated using the brain of neonates, stimulated in vitro with LPS, and (2) adult offspring immunized with MOG_35–55. The EAE clinical symptoms were followed for 30 days. Different sets of animals were sacrificed either during the onset (7 days post-immunization [p.i.]), when spleen and lymph nodes were collected, or the peak of disease (20 days p.i.), when CNS were collected for flow cytometry, cytokine production, and protein/mRNA-expression analysis. The primary CNS cultures from the LPS-treated group produced exaggerated amounts of IL-6, IL-1β and nitrites after in vitro stimulus, while IL-10 production was lowered compared to the data of the control group. Prenatal exposure to LPS worsened EAE disease severity in adult offspring, and this worsening was linked to increased CNS-infiltrating macrophages, Th1 cells and Th17 cells at the peak of EAE severity; additionally, exacerbated gliosis was evidenced in microglia (MHC II) and astrocytes (GFAP protein level and immunoreactivity). The IL-2, IL-6 and IL-17 levels in the spleen and lymph nodes were increased in the offspring of the LPS-exposed dams. Our results indicate that maternal immune activation during late gestation predispose the offspring to increased neuroinflammation and potentiate the autoimmune response and clinical manifestation of EAE.     

Maternal immune activation alters nonspatial information processing in the hippocampus of the adult offspring

The observation that maternal infection increases the risk for schizophrenia in the offspring suggests that the maternal immune system plays a key role in the etiology of schizophrenia. In a mouse model, maternal immune activation (MIA) by injection of poly(I:C) yields adult offspring that display abnormalities in a variety of behaviors relevant to schizophrenia. As abnormalities in the hippocampus are a consistent observation in schizophrenia patients, we examined synaptic properties in hippocampal slices prepared from the offspring of poly(I:C)- and saline-treated mothers. Compared to controls, CA1 pyramidal neurons from adult offspring of MIA mothers display reduced frequency and increased amplitude of miniature excitatory postsynaptic currents. In addition, the specific component of the temporoammonic pathway that mediates object-related information displays increased sensitivity to dopamine. To assess hippocampal network function in vivo, we used expression of the immediate-early gene, c-Fos, as a surrogate measure of neuronal activity. Compared to controls, the offspring of poly(I:C)-treated mothers display a distinct c-Fos expression pattern in area CA1 following novel object, but not novel location, exposure. Thus, the offspring of MIA mothers may have an abnormality in modality-specific information processing. Indeed, the MIA offspring display enhanced discrimination in a novel object recognition, but not in an object location, task. Thus, analysis of object and spatial information processing at both synaptic and behavioral levels reveals a largely selective abnormality in object information processing in this mouse model. Our results suggest that altered processing of object-related information may be part of the pathogenesis of schizophrenia-like cognitive behaviors.     

Startle reactivity in children at risk for migraine

ObjectiveNumerous studies have shown a higher responsiveness and/or a lack of habituation to sensory stimuli of various modalities in migraine. This study investigated psychophysiological responses to aversive acoustic stimuli in children at risk for migraine.MethodsWe measured eyeblink responses to acoustic stimuli (40 ms bursts of white noise at 102 dB) during anticipation of unpleasant stimuli in 74 adolescents (40 females, age 17.6 ± 2.9). A mixed effects linear model was applied to test group differences in startle reactivity during baseline, safe and threat conditions among adolescents by maternal and personal history of migraine.ResultsThe strongest association with migraine vulnerability emerged for baseline startle reactivity, which was significantly elevated in high risk youth with a history of maternal migraine. This group of offspring also had enhanced startle response during the threat condition and the threat–safe difference.ConclusionOur findings indicate that migraine is associated with a higher acoustic startle responsiveness that is present already in children at risk for developing the disorder. Significance: The significant effect of both maternal history of anxiety disorder and migraine on baseline startle indicates that these two diagnostic entities might in part share common pathophysiological mechanisms, and that the anxiety–migraine comorbidity should be considered when investigating each of these disorders.     

Anhedonia in schizophrenia: The role of subjective experiences

BackgroundHigh levels of anhedonia have been found in patients with schizophrenia; specifically they report higher levels of social anhedonia rather than physical anhedonia, and further, in the anticipatory rather than consummatory facets of pleasure. Nonetheless, contrasting results emerged regarding the underlying mechanisms of this deficit. Basic Symptoms (BS) disturb subjective experiences present for most of the illness’ course; this impacts patients’ daily lives leading to a loss of the ability to organize the experience of the self and the world in a fluid and automatic way. Considering the role played by negative emotions in the subjective evaluation of anhedonia, the aim of the study is to clarify the role of BS in the assessment of anhedonia in a sample of patients with schizophrenia (n = 53) compared with healthy controls (n = 46).MethodsParticipants completed a self-administered trait questionnaire evaluating social anhedonia (Revised-Social Anhedonia Scale), physical anhedonia (Physical Anhedonia Scale), and the consummatory and anticipatory pleasure experiences (Temporal Experience of Pleasure Scale). BS were evaluated with the Frankfurter Beschwerde-Frageboden (FBF) whereas psychopathology was assessed with the Positive and Negative Syndromes Scale.ResultsPatients scored higher than healthy controls in social, physical and anticipatory anhedonia, but not in consummatory anhedonia and these relationships were mediated by the FBF. Basic Symptoms of Memory, Overstimulation and Lack of Automatism were related to some facets of anhedonia, independently from depressive symptoms.ConclusionsWe hypothesize that a subjective cognitive deficit and a reduced ability in information processing, could prevent patients from retaining a positive experience from past pleasant activities. Therefore the lack of pleasure would be, at least in part, related to an avoidance of potentially stressful new scenarios.     

The interaction of subjective experience and attitudes towards specific antipsychotic-related adverse effects in schizophrenia patients

BackgroundDiscontinuation of antipsychotic drugs in schizophrenia patients is a major concern, since it results in relapse and re-hospitalizations. Non-adherence is strongly associated with negative-subjective response to antipsychotics, which is composed of the subjective experience of negative drug effects and attitude towards the treatment.ObjectiveTo investigate the elements of subjective experience and subjective attitude towards specific drug-related adverse effects, leading to a generally negative-subjective attitude towards antipsychotics.MethodsSchizophrenia inpatients (n = 84) were administered a questionnaire measuring attitude and experience on eight subscales: weight gain, sedation, sexual anhedonia, extra-pyramidal syndrome, affective flattening, excessive sleep, diminished sociability and metabolic syndrome. DAI-30 was used to measure attitude towards drugs, and PANSS to assess psychopathology.ResultsWeak correlation was found between subjective experience and attitude on most of the subscales. The only strong, albeit inverse, correlation between experience and attitude that was found was with regard to affective flattening, experienced by 37% of the sample, and it also predicted negative drug attitude as measured by the DAI-30, RR: 1.87 (95% CI: 1.06–3.3, df = 1, χ² = 4.525, P < 0.05).ConclusionNegative attitude towards most adverse drug effects did not correlate with personal experience. Drug-related affective flattening should be evaluated routinely, since experiencing it may predict negative attitude towards drugs, potentially leading to poor compliance and relapse.     

Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice

Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic–polyribocytidilic acid (PolyIC, 5 mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n = 105), was administered systemic bromodeoxyuridine (BrdU, 50 mg/kg) (n = 52) or intracerebral retroviral injection into the DG (n = 53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation.     

Individual differences in maternal response to immune challenge predict offspring behavior: contribution of environmental factors

Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown. The present study investigated the impact of individual differences in maternal response to the viral mimic polyinosinic:polycytidylic acid (poly I:C) on offspring behavior. We observed significant variability in body weight alterations of pregnant rats induced by administration of poly I:C on gestational day 14. Furthermore, the presence or absence of maternal weight loss predicted MK-801 and amphetamine stimulated locomotor abnormalities in offspring. MK-801 stimulated locomotion was altered in offspring of all poly I:C treated dams; however, the presence or absence of maternal weight loss resulted in decreased and modestly increased locomotion, respectively. Adult offspring of poly I:C treated dams that lost weight exhibited significantly decreased amphetamine stimulated locomotion, while offspring of poly I:C treated dams without weight loss performed similarly to vehicle controls. Social isolation and increased maternal age predicted weight loss in response to poly I:C but not vehicle injection. In combination, these data identify environmental factors associated with the maternal response to immune challenge and functional outcome of offspring exposed to maternal immune activation.     

Positive modulation of α5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABA_A receptors (α5GABA_ARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABA_ARs in offspring’s preadolescence (from postnatal day 22–28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 μg/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of α5GABA_ARs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of α5GABA_ARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.     

Spinal neuropeptide modulation,functional assessment and cartilage lesions in a monosodium iodoacetate rat model of osteoarthritis

Background and aimsCharacterising the temporal evolution of changes observed in pain functional assessment, spinal neuropeptides and cartilage lesions of the joint after chemical osteoarthritis (OA) induction in rats.Methods and resultsOn day (D) 0, OA was induced by an IA injection of monosodium iodoacetate (MIA). Rats receiving 2 mg MIA were temporally assessed at D3, D7, D14 and D21 for the total spinal cord concentration of substance P (SP), calcitonin gene related-peptide (CGRP), bradykinin (BK) and somatostatin (STT), and for severity of cartilage lesions. At D21, the same outcomes were compared with the IA 1 mg MIA, IA 2 mg MIA associated with punctual IA injection of lidocaine at D7, D14 and D21, sham (sterile saline) and naïve groups. Tactile allodynia was sequentially assessed using a von Frey anaesthesiometer. Non-parametric and mixed models were applied for statistical analysis. Tactile allodynia developed in the 2 mg MIA group as soon as D3 and was maintained up to D21. Punctual IA treatment with lidocaine counteracted it at D7 and D14. Compared to naïve, [STT], [BK] and [CGRP] reached a maximum as early as D7, which plateaued up to D21. For [SP], the increase was delayed up to D14 and maintained at D21. No difference in levels of neuropeptides was observed between MIA doses, except for higher [STT] in the 2 mg MIA group (P = 0.029). Neuropeptides SP and BK were responsive to lidocaine treatment. The increase in severity of cartilage lesions was significant only in the 2 mg MIA groups (P = 0.01).ConclusionIn the MIA OA pain model, neuropeptide modulation appears early, and confirms the central nervous system to be an attractive target for OA pain quantification. The relationship of neuropeptide release with severity of cartilage lesions and functional assessment are promising and need further validation.     

Anhedonia and cognitive impairment in Parkinson's disease: Italian validation of the Snaith–Hamilton Pleasure Scale and its application in the clinical routine practice during the PRIAMO study

ObjectiveTo assess the psychometric properties of the Italian version of the Snaith–Hamilton Pleasure Scale (SHAPS) and to study the relationship between anhedonia, depression and cognitive impairment in patients with Parkinson's disease (PD).MethodsThe SHAPS (14 items) was translated into Italian and pre-tested in a pilot study. Two items evaluating physical anhedonia related to sexual issues were added. The Italian version of SHAPS was validated in 274 consecutive PD patients, divided into patients with major depression according to DSM-IV criteria (dPD) and patients without depression (nPD), and in healthy subjects. To test the feasibility of the instrument and to determine whether clinical data affect anhedonia, we also administered SHAPS to 1307 patients with different types of parkinsonism.ResultsThe Italian SHAPS proved to be easy to understand as regards the question and answer modes. Intraclass coefficient for test–retest reliability was 0.65 for the total score. KR index was 0.61. ANOVA of the SHAPS total score revealed that scores were higher in dPD patients than in healthy controls and nPD (p < 0.05). In the 1307 patients with various types of parkinsonism, the SHAPS data showed that anhedonia was related to age, type of parkinsonism, apathy, depression and cognitive impairment. Anhedonia was correlated with frontal dysfunctions in supranuclear palsy and PD patients (r = -0.682 and ?0.264 respectively, p < 0.05).ConclusionThe Italian version of the SHAPS is a reliable tool with which to assess anhedonia in patients with PD and other forms of parkinsonism.     

Safety,Awareness, and Familiarity regarding Epilepsy in Teenage Years (SAFETY): Understanding the adolescents' perspective about their disease

ObjectiveThe objective of this study was to evaluate the understanding of adolescent patients regarding epilepsy.MethodsThe SAFETY (Safety, Awareness, and Familiarity regarding Epilepsy in Teenage Years) questionnaire (content validity index: 0.96, Flesch readability score: 66.6) was administered to 165 cognitively normal adolescents with epilepsy (85 females, mean age: 15.2 ± 1.6 years, range: 13–18 years). The first part of the questionnaire was devised to evaluate knowledge about epilepsy and antiepileptic medications (SAFETY-K: 7 questions). The second part queried lifestyle modifications and safety (SAFETY-S: 10 questions). Female participants answered 5 additional questions related to reproductive health (RH questionnaire).ResultsThe correct response rate for the composite SAFETY questionnaire was 51.5%. The average rates of correct responses for the SAFETY-K and SAFETY-S questions were 47.9% and 53.9%, respectively. On univariate logistic regression analysis, factors which were significant predictors of correct responses included age (odds ratio: 1.8, C.I. = 1.3–2.4), race (Caucasian vs. African-American; odds ratio: 3.9, C.I. = 1.4–10.4), and employment of at least one parent in a professional occupation (odds ratio: 3.3, C.I. = 1.1–10.3). The correct response rate did not correlate with the duration of epilepsy, extent of seizure control, number of antiepileptic medications, parental educational, or (un)employment status. The mean rate of correct responses for the RH questions amongst teenage girls was 17.4%.ConclusionsThere is lack of awareness about epilepsy and its associated lifestyle modifications in adolescents with epilepsy seen at our institution. This is especially true in young adolescents, African-American patients, and those whose parents are not employed in professional occupations. Teenage girls with epilepsy appear to have limited knowledge with respect to contraception and childbearing.     

Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability—the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors—that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring. Even more surprising is that the intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring. Importantly, we identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors. Together, our results highlight considerations for optimizing MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.