Prevalence of disordered eating in adults with gastrointestinal disorders: A systematic review.

BACKGROUND: Patients with gastrointestinal disorders are prone to heightened awareness of dietary intake. When diet-related thoughts or behaviors are excessive, they may lead to psychological distress, nutritional compromise, and impair medical treatment. Identification of disordered eating behavior and eating disorders is crucial for effective management, but data on their prevalence within this population remain scarce. We conducted a systematic review of the prevalence of disordered eating behavior and eating disorders in adults with gastrointestinal disorders. METHODS: MEDLINE, PubMed, and PsycInfo databases were searched up to June 2021. Studies examining disordered eating in adult patients with a primary gastrointestinal diagnosis were included. KEY RESULTS: A total of 17 studies met the inclusion criteria for the review. The range of gastrointestinal disorders examined included disorders of gut-brain interaction (DGBI), coeliac disease, and inflammatory bowel disease (IBD). The methods for examining disordered eating were highly variable. The prevalence of disordered eating ranged from 13-55%. The prevalence was higher in patients with disorders of gut-brain interaction (DGBI) than in those with organic gastrointestinal disorders. Factors associated with disordered eating included female sex, younger age, gastrointestinal symptom severity, anxiety and depression, and lower quality of life. CONCLUSIONS & INFERENCES: Disordered eating is highly prevalent in adult patients with gastrointestinal illness, particularly those with DGBI. Understanding whether a patient's primary underlying diagnosis is that of an eating disorder or gastroenterological disorder remains a challenge for clinicians. There is an unmet need to identify at-risk patients so that psychological intervention can be included in the therapeutic strategy.

Long-Term Outcome of Multidisciplinary Versus Standard Gastroenterologist Care for Functional Gastrointestinal Disorders: A Randomized Trial.

BACKGROUND & AIMS: Functional gastrointestinal disorders are common and costly to the healthcare system. In the Multidisciplinary Treatment of Functional Gastrointestinal Disorders study, we demonstrated that multidisciplinary care resulted in superior clinical and cost outcomes, when compared with standard gastroenterologist-only care at end of treatment. In this study we evaluate the longer-term outcomes. METHODS: In a single-center, pragmatic trial patients with Rome IV criteria-defined functional gastrointestinal disorders were randomized 1:2 to a gastroenterologist-only standard care vs a multidisciplinary clinic comprising gastroenterologists, dietitians, gut hypnotherapists, psychiatrists, and biofeedback physiotherapists. Outcomes in this study were assessed 12 months after the end of treatment. Global symptom improvement was assessed by using a 5-point Likert scale. Symptoms, specific disorder status, psychological state, quality of life, and cost were additional outcomes. A modified intention-to-treat analysis was performed. RESULTS: Of 188 randomized patients, 143 (46 standard care, 97 multidisciplinary) formed the longer-term modified intention-to-treat analysis. Sixty-two percent of multidisciplinary clinic patients saw allied clinicians. Sixty-five percent (30/46) standard care versus 76% (74/97) multidisciplinary clinic patients achieved global symptom improvement 12 months after end of treatment (P = .17), whereas 20% (9/46) versus 37% (36/97) rated their symptoms as "5/5 much better" (P = .04). A ≥50-point reduction in Irritable Bowel Syndrome Severity Scoring System occurred in 38% versus 66% (P = .02), respectively, for irritable bowel syndrome patients. Anxiety and depression were greater in the standard care than multidisciplinary clinic (12 vs 10, P = .19), and quality of life was lower in standard care than the multidisciplinary clinic (0.75 vs 0.77, P =·.03). An incremental cost-effectivness ratio found that for every additional 3555AUD spent in the multidisciplinary clinic, a further quality-adjusted life year was gained. CONCLUSIONS: Twelve months after the completion of treatment, integrated multidisciplinary clinical care achieved a greater proportion of patients with improvement of symptoms, psychological state, quality of life, and cost, compared with gastroenterologist-only care. CLINICAL TRIALS: gov: number NCT03078634.

Standard gastroenterologist versus multidisciplinary treatment for functional gastrointestinal disorders (MANTRA): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Functional gastrointestinal disorders are common and costly to the health-care system. Most specialist care is provided by a gastroenterologist, but only a minority of patients have improvement in symptoms. Although they have proven to be effective, psychological, behavioural, and dietary therapies are not provided routinely. We aimed to compare the outcome of gastroenterologist-only standard care with multidisciplinary care. METHODS: In an open-label, single-centre, pragmatic trial, consecutive new referrals of eligible patients aged 18-80 years with Rome IV criteria-defined functional gastrointestinal disorders were randomly assigned (1:2) to receive gastroenterologist-only standard care or multidisciplinary clinic care. The multidisciplinary clinic included gastroenterologists, dietitians, gut-focused hypnotherapists, psychiatrists, and behavioural (biofeedback) physiotherapists. Randomisation was stratified by Rome IV disorder and whether referred from gastroenterology or colorectal clinic. Outcomes were assessed at clinic discharge or 9 months after the initial visit. The primary outcome was a score of 4 (slightly better) or 5 (much better) on a 5-point Likert scale assessing global symptom improvement. Modified intention-to-treat analysis included all patients who attended at least one clinic visit and who had answered the primary outcome question. This study is registered with ClinicalTrials.gov, NCT03078634. FINDINGS: Between March 16, 2017, and May 10, 2018, 1632 patients referred to the hospital gastrointestinal clinics were screened, of whom 442 were eligible for a screening telephone call and 188 were randomly assigned to receive either standard care (n=65) or multidisciplinary care (n=123). 144 patients formed the modified intention-to-treat analysis (n=46 in the standard-care group and n=98 in the multidisciplinary-care group), 90 (63%) of whom were women. 61 (62%) of 98 patients in the multidisciplinary-care group patients saw allied clinicians. 26 (57%) patients in the standard-care group and 82 (84%) patients in the multidisciplinary-care group had global symptom improvement (risk ratio 1·50 [95% CI 1·13-1·93]; p=0·00045). 29 (63%) patients in the standard-care group and 81 (83%) patients in the multidisciplinary-care group had adequate relief of symptoms in the past 7 days (p=0·010). Patients in the multidisciplinary-care group were more likely to experience a 50% or higher reduction in all Gastrointestinal Symptom Severity Index symptom clusters than were patients in the standard-care group. Of the patients with irritable bowel syndrome, a 50-point or higher reduction in IBS-SSS occurred in 10 (38%) of 26 patients in the standard care group compared with 39 (66%) of 59 patients in the multidisciplinary-care group (p=0·017). Of the patients with functional dyspepsia, a 50% reduction in the Nepean Dyspepsia Index was noted in three (11%) of 11 patients in the standard-care group and in 13 (46%) of 28 in the multidisciplinary-care group (p=0·47). After treatment, the median HADS scores were higher in the standard-care group than in the multidisciplinary-care group (13 [8-20] vs 10 [6-16]; p=0·096) and the median EQ-5D-5L quality of life visual analogue scale was lower in the standard-care group compared with the multidisciplinary-care group (70 [IQR 50-80] vs 75 [65-85]; p=0·0087). The eight SF-36 scales did not differ between the groups at discharge. After treatment, median Somatic Symptom Scale-8 score was higher in the standard-care group than in the multidisciplinary-care group (10 [IQR 7-7] vs 9 [5-13]; p=0·082). Cost per successful outcome was higher in the standard-care group than the multidisciplinary-care group. INTERPRETATION: Integrated multidisciplinary clinical care appears to be superior to gastroenterologist-only care in relation to symptoms, specific functional disorders, psychological state, quality of life, and cost of care for the treatment of functional gastrointestinal disorders. Consideration should be given to providing multidisciplinary care for patients with a functional gastrointestinal disorder. FUNDING: None.

Delivery of care for functional gastrointestinal disorders: A systematic review.

BACKGROUND: A diverse range of treatments are available for the treatment of functional gastrointestinal disorders (FGIDs). Individual treatments, including drug therapies, behavioral therapy ("biofeedback"), psychological therapies, and dietary therapies, have been well validated in controlled, randomized trials and real-life case series. However, few studies have evaluated models of delivery of care for the whole population of referred patients with an FGID. This review evaluates models of specialist outpatient care for the management of FGIDs. METHODS: A systematic review was performed of full-text articles published until October 2018 in Pubmed/Medline and Embase. Studies were included if they evaluated a model of outpatient care in a specialist setting for the treatment of adult patients with an FGID and included patient-reported outcomes comprising symptoms, quality of life, or psychological well-being. RESULTS: Few studies have evaluated the delivery of care for the whole population of referred patients with an FGID, and there was one randomized comparison of different models of care. Two studies that evaluated the outcome of gastroenterologist-only clinics suggested poor long-term results. Two non-comparative case series reported the outcome of multidisciplinary care, including gastroenterologists and psychological therapists, suggesting improved patient quality of life and psychological well-being. CONCLUSIONS: Despite the high prevalence and cost of treating FGIDs, and the availability of effective treatments, there are few data and limited randomized comparisons reporting the outcome of different types of specialist care. The few data available suggest that multidisciplinary care is superior to gastroenterologist-only care, but this needs to be validated in prospective comparative studies.

Environmental enrichment imparts disease-modifying and transgenerational effects on genetically-determined epilepsy and anxiety.

INTRODUCTION: The absence epilepsies are presumed to be caused by genetic factors, but the influence of environmental exposures on epilepsy development and severity, and whether this influence is transmitted to subsequent generations, is not well known. We assessed the effects of environmental enrichment on epilepsy and anxiety outcomes in multiple generations of GAERS - a genetic rat model of absence epilepsy that manifests comorbid elevated anxiety-like behaviour. METHODS: GAERS were exposed to environmental enrichment or standard housing beginning either prior to, or after epilepsy onset, and underwent EEG recordings and anxiety testing. Then, we exposed male GAERS to early enrichment or standard housing and generated F1 progeny, which also underwent EEG recordings. Hippocampal CRH mRNA expression and DNA methylation were assessed using RT-PCR and pyrosequencing, respectively. RESULTS: Early environmental enrichment delayed the onset of epilepsy in GAERS, and resulted in fewer seizures in adulthood, compared with standard housed GAERS. Enrichment also reduced the frequency of seizures when initiated in adulthood. Anxiety levels were reduced by enrichment, and these anti-epileptogenic and anxiolytic effects were heritable into the next generation. We also found reduced expression of CRH mRNA in GAERS exposed to enrichment, but this was not due to changes in DNA methylation. CONCLUSIONS: Environmental enrichment produces disease-modifying effects on genetically determined absence epilepsy and anxiety, and these beneficial effects are transferable to the subsequent generation. Reduced CRH expression was associated with these phenotypic improvements. Environmental stimulation holds promise as a naturalistic therapy for genetically determined epilepsy which may benefit subsequent generations.

Using the common sense model of illness to examine interrelationships between symptom severity and health outcomes in end-stage osteoarthritis patients.

OBJECTIVE: The aim was to evaluate the utility of the common sense model (CSM) in characterizing contributors to psychological well-being and quality of life (QoL) in patients with end-stage OA. METHODS: One hundred and twenty patients [34 males, 86 females; mean (s.d.) age 65.52 (9.14) years] with end-stage OA (57.5% hip, 42.5% knee) were recruited. OA symptom severity was evaluated according to the WOMAC; coping styles were assessed with the Carver Brief COPE scale; illness perceptions were explored with the Brief Illness Perceptions Questionnaire; self-efficacy was assessed with the Arthritis Self-efficacy scale; anxiety, depression and overall distress were measured using the Hospital Anxiety and Depression Scale; and QoL was assessed using the WHO Quality of Life-short version. The CSM was used to explore the interrelationships between OA symptom severity, illness perceptions and coping strategies in patients. RESULTS: Two structural equation models were developed, with both found to have good fit. Consistent with the CSM, the standard model indicated that self-reported OA symptom severity directly influenced illness perceptions, which in turn had direct impacts upon maladaptive coping, distress and QoL. The addition of self-efficacy to the CSM resulted in a complex interaction, with OA severity directly influencing self-efficacy and self-efficacy influencing maladaptive coping, distress and QoL. CONCLUSION: We found interrelationships amongst OA activity, illness perceptions, coping strategies, self-efficacy, psychological distress and QoL broadly consistent with the CSM. The CSM may help inform the approach to the psychological support that patients with end-stage OA often require.

Environmental enrichment delays limbic epileptogenesis and restricts pathologic synaptic plasticity.

OBJECTIVE: Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy (MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment (EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms. METHODS: At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys; n = 43) or standard housing (SH; standard laboratory cages; n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects. RESULTS: EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes. SIGNIFICANCE: We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE.

What factors contribute to the risk of depression in epilepsy?--Tasmanian Epilepsy Register Mood Study (TERMS).

OBJECTIVE: To model the factors associated with depression in a community sample of people with epilepsy. The factors investigated were derived from proposed risk factors for depression from patients with epilepsy, other chronic illness, and the general population. METHODS: Multivariate analysis using general linear regression models of factors associated with depression in the Tasmanian Epilepsy Register Mood Study (TERMS), a cross-sectional community sample of 440 patients with epilepsy. RESULTS: A model with acceptable fit was created that explained 66% of the variance of depression. Associated factors included in this model were neuroticism, physical functioning, social support, past history of depression, and stressful life events. SIGNIFICANCE: In this cross-sectional study designed specifically to investigate depression in epilepsy, we showed that general risk factors for depression in other illness and in the general population are also important in patients with epilepsy, with little support for disease-related risk factors.

Risk factors for depression in community-treated epilepsy: systematic review.

OBJECTIVE: Depression is one of the most common psychiatric comorbidities in epilepsy; however, the factors contributing to this association remain unclear. There is a growing consensus that methodological limitations, particularly selection bias, affect many of the original studies. A systematic review focussed on community-based studies offers an alternative approach for the identification of the risk factors for depression. METHODS: Searches were performed in MEDLINE (Ovid), 2000 to 31 December 2013, EMBASE, and Google Scholar to identify studies examining risk factors for depression in epilepsy. Community-based studies of adults with epilepsy that reported at least one risk factor for depression were included. RESULTS: The search identified 17 studies that met selection criteria, representing a combined total of 12,212 people with epilepsy with a mean sample size of 718. The most consistent risk factors for depression were sociodemographic factors, despite the fact that most studies focus on epilepsy-related factors. SIGNIFICANCE: Most studies lacked a systematic conceptual approach to investigating depression, and few risk factors were consistently well studied. Future community-based studies require a detailed systematic approach to improve the ability to detect risk factors for depression in epilepsy. Psychological factors were rarely studied in community-based samples with epilepsy, although the consistent association with depression in the few studies that did suggests this warrants further examination.

Serotonin transporter gene × environment and risk of depression in community-treated epilepsy.

OBJECTIVES: This study aimed to test whether a specific serotonin transporter (5HTT) gene polymorphism interacting with life stress increased the risk of depression in patients with epilepsy. METHODS: The Tasmanian Epilepsy Register Mood Study (TERMS) used a cross-sectional study design of a community sample of patients with epilepsy previously recruited into the Tasmanian Epilepsy Register. It employed a mailed self-complete questionnaire and saliva DNA collection. Depression was assessed using the Center for Epidemiologic Studies Depression Scale. Environmental measures were selected to cover recent stressful events, epilepsy-related stress, current social support, and early life stress. RESULTS: Of 820 eligible participants, 553 (67%) participants completed the study. Experience of at least one stressful life event was very common, with a significant association between depression and the stressful life events (F=26.2, df=3, p<0.001). There was no association between serotonin transporter genotype and level of depressive symptoms reported (F=0.421, df=2, p=0.7). There was no evidence of any adverse life experiences interacting with serotonin transporter genotype to moderate the risk of depression. SIGNIFICANCE: The failure to demonstrate a main effect of genotype on depression or a gene × environment interaction differs from several studies of patients with other chronic diseases. However, it is consistent with larger general population studies.

The effect of mindfulness training prior to total joint arthroplasty on post-operative pain and physical function: study protocol for a randomised controlled trial.

BACKGROUND: Osteoarthritis is a leading cause of disability in developed nations. In Australia it afflicts 16.5% of the adult population. Total joint arthroplasty is considered the treatment of choice for end stage osteoarthritis. The number of total joint arthroplasties undertaken in Australia has doubled over the last decade (more than 80,000 procedures in 2011). The incidence of pre-operative psychological distress in this group of patients is reported between 30% and 60% and pre-operative psychological distress is associated with poorer pain and functional outcomes after surgery. This study will use a mindfulness-based psychological intervention to enhance outcomes in people undergoing total joint arthroplasty and, in addition, will test hypotheses about coping with chronic illness in an aged population. This study is the first of its kind and will provide a greater understanding of the role of a mental health enhancement program on the physical recovery of total joint arthroplasty patients. METHODS/DESIGN: One hundred and fifty people with end-stage arthritis on the waiting list for total hip or knee arthroplasty will be recruited and randomly allocated to one of two groups using computer-generated block randomisation. A randomised controlled trial adhering to CONSORT guidelines will evaluate the efficacy of a mindfulness training program (weekly group-based classes in mindfulness practice, 2 ½ hours, for 8 weeks plus a 7-hour Saturday session in Week 6) prior to total joint arthroplasty, compared to a "standard care" group who will undergo routine total joint arthroplasty. Primary outcomes will be evaluated by a blinded examiner at baseline, 3 and 12 months post-surgery, using a validated self-reported pain and physical function scale. Secondary outcomes will include i) a range of validated measures of psychological wellbeing and ii) health economic analysis. All analyses will be conducted on an intention to treat basis using linear regression models. Health economic modelling will be applied to estimate the potential cost-effectiveness of mindfulness training and total joint arthroplasty. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTRN12611001184965). Date of registration; 15th November 2011.

Risk factors for psychological distress in community-treated epilepsy.

The study aimed to determine risk factors for psychological distress in a community-treated sample of patients with epilepsy. This study investigated the Tasmanian Epilepsy Register participants. Participants included were as follows: aged 13 years and over, able to complete the individual computer-assisted participant interview, and diagnosed with epilepsy following an epilepsy specialist review of the diagnostic epilepsy interview, which was interpreted using standardized diagnostic guidelines. Psychological distress was assessed with the Kessler-10 questionnaire. Risk factors were grouped into four domains: sociodemographic factors, disease-related factors, psychological factors, and treatment-related factors. High or very high levels of psychological distress were reported by 22% of the participants, with 7.8% having very high distress. The regression model showed that psychological distress was significantly associated with female gender (F=18.1, p<0.001), diabetes mellitus (F=8.7, p=0.003), intellectual disability (F=7.1, p=0.06), and not receiving phenytoin (F=5.1, p=0.02). While the model was significant (F=5.78, p<0.001), only 11% of the variance of the K-10 score was explained by these factors (adjusted R-squared=0.11). This study identifies female gender and comorbid medical conditions as risk factors for psychological distress and the use of phenytoin as a protective factor. The few factors identified and the limited variance explained suggest that a focus on epilepsy-related variables is unlikely to explain key influences underlying psychiatric comorbidity in patients with epilepsy.

Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming.

Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown. Here, we tested whether hypothalamic-pituitary-adrenal (HPA) axis hyper-reactivity induced by MS - specifically the excessive secretion of corticosterone following a seizure - was involved in this vulnerability. In adult female rats subjected to MS from postnatal days 2-14, seizure-induced corticosterone responses were significantly augmented and prolonged for at least two hours post-seizure, compared to control early-handled (EH) rats. This was accompanied by reduced seizure threshold (p<0.05) and increased vulnerability to the kindling-induced progression of seizure duration (p<0.05) in MS rats. Pre-seizure treatment with the corticosterone synthesis inhibitor, metyrapone (MET) (50mg/kgsc) effectively blocked seizure-induced corticosterone responses. When delivered throughout kindling, MET treatment also reversed the MS-induced reduction in seizure threshold and the lengthened seizure duration back to levels of EH rats. These observations suggest that adverse early life environments induce a vulnerability to kindling epileptogenesis mediated by HPA axis hyper-reactivity, which could have relevance for the pathogenesis of MTLE.

Chronic antidepressant treatment accelerates kindling epileptogenesis in rats.

OBJECTIVES: Due to the high comorbidity of epilepsy and depression, antidepressant treatment is commonly indicated for patients with epilepsy. Studies in humans and animal models suggest that selective serotonin reuptake inhibitors (SSRIs) may reduce seizure frequency and severity, and these drugs are generally considered safe for use in epilepsy. No studies have investigated the effects of SSRIs on epileptogenesis, the neurobiological process underlying the development of the epileptic state. METHODS: The effect of continuous infusion of the SSRI, fluoxetine (10mg/kg/day sc), versus vehicle control on amygdala kindling was examined in adult male Wistar rats. Seizure threshold and kindling rates were compared between SSRI-treated rats and controls. The study was then repeated examining the effect of a different SSRI, citalopram (10mg/kg/day sc), versus vehicle control. Hippocampal mRNA expression of the serotonin transporter (SERT) and the 5-HT1A receptor was examined in the brains of the rats post-mortem. RESULTS: Treatment with either fluoxetine or citalopram significantly accelerated kindling epileptogenesis, as evidenced by fewer stimulations to reach Class V seizures compared to their respective vehicle-treated group (p<0.01 for both drugs). Seizure duration was also increased in fluoxetine-treated rats. No differences in seizure threshold were observed between treatments (p>0.05). mRNA analysis did not reveal any molecular changes which were common to both treatments. CONCLUSIONS: The rate of epileptogenesis in rats is enhanced by chronic treatment with SSRIs. This could potentially have implications regarding the effect of SSRIs on the development or progression of human epilepsy.

Systematic review of the efficacy of pre-surgical mind-body based therapies on post-operative outcome measures.

OBJECTIVES: A large body of research has demonstrated that patient factors are strong predictors of recovery from surgery. Mind-body therapies are increasingly targeted at pre-operative psychological factors. The objective of this paper was to evaluate the efficacy of pre-operative mind-body based interventions on post-operative outcome measures amongst elective surgical patients. METHODS: A systematic review of the published literature was conducted using the electronic databases MEDLINE, CINAHL and PsychINFO. Randomised controlled trials (RCTs) with a prospective before-after surgery design were included. RESULTS: Twenty studies involving 1297 patients were included. Mind-body therapies were categorised into relaxation, guided imagery and hypnotic interventions. The majority of studies did not adequately account for the risk of bias thus undermining the quality of the evidence. Relaxation was assessed in eight studies, with partial support for improvements in psychological well-being measures, and a lack of evidence for beneficial effects for analgesic intake and length of hospital stay. Guided imagery was examined in eight studies, with strong evidence for improvements in psychological well-being measures and moderate support for the efficacy of reducing analgesic intake. Hypnosis was investigated in four studies, with partial support for improvements in psychological well-being measures. Evidence for the effect of mind-body therapies on physiological indices was limited, with minimal effects on vital signs, and inconsistent changes in endocrine measures reported. CONCLUSIONS: This review demonstrated that the quality of evidence for the efficacy of mind-body therapies for improving post-surgical outcomes is limited. Recommendations have been made for future RCTs.

Enduring Effects of Early Life Stress on Firing Patterns of Hippocampal and Thalamocortical Neurons in Rats: Implications for Limbic Epilepsy.

Early life stress results in an enduring vulnerability to kindling-induced epileptogenesis in rats, but the underlying mechanisms are not well understood. Recent studies indicate the involvement of thalamocortical neuronal circuits in the progression of kindling epileptogenesis. Therefore, we sought to determine in vivo the effects of early life stress and amygdala kindling on the firing pattern of hippocampus as well as thalamic and cortical neurons. Eight week old male Wistar rats, previously exposed to maternal separation (MS) early life stress or early handling (EH), underwent amygdala kindling (or sham kindling). Once fully kindled, in vivo juxtacellular recordings in hippocampal, thalamic and cortical regions were performed under neuroleptic analgesia. In the thalamic reticular nucleus cells both kindling and MS independently lowered firing frequency and enhanced burst firing. Further, burst firing in the thalamic reticular nucleus was significantly increased in kindled MS rats compared to kindled EH rats (p<0.05). In addition, MS enhanced burst firing of hippocampal pyramidal neurons. Following a stimulation-induced seizure, somatosensory cortical neurons exhibited a more pronounced increase in burst firing in MS rats than in EH rats. These data demonstrate changes in firing patterns in thalamocortical and hippocampal regions resulting from both MS and amygdala kindling, which may reflect cellular changes underlying the enhanced vulnerability to kindling in rats that have been exposed to early life stress.

Repeatedly stressed rats have enhanced vulnerability to amygdala kindling epileptogenesis.

Psychiatric disorders associated with elevated stress levels, such as depression, are present in many epilepsy patients, including those with mesial Temporal Lobe Epilepsy (mTLE). Evidence suggests that these psychiatric disorders can predate the onset of epilepsy, suggesting a causal/contributory role. Prolonged exposure to elevated corticosterone, used as a model of chronic stress/depression, accelerates limbic epileptogenesis in the amygdala kindling model. The current study examined whether exposure to repeated stress could similarly accelerate experimental epileptogenesis. Female adult non-epileptic Wistar rats were implanted with a bipolar electrode into the left amygdala, and were randomly assigned into stressed (n=18) or non-stressed (n=19) groups. Rats underwent conventional amygdala kindling (two electrical stimulations per day) until 5 Class V seizures had been experienced ('the fully kindled state'). Stressed rats were exposed to 30min restraint immediately prior to each kindling stimulation, whereas non-stressed rats received control handling. Restraint stress increased circulating corticosterone levels (pre-stress: 122±17ng/ml; post-stress: 632±33ng/ml), with no habituation observed over the experiment. Stressed rats reached the 'fully kindled state' in significantly fewer stimulations than non-stressed rats (21±1 vs 33±3 stimulations; p=0.022; ANOVA), indicative of a vulnerability to epileptogenesis. Further, seizure durations were significantly longer in stressed rats (p<0.001; ANOVA). These data demonstrate that exposure to repeated experimental stress accelerates the development of limbic epileptogenesis, an effect which may be related to elevated corticosterone levels. This may have implications for understanding the effects of chronic stress and depression in disease onset and progression of mTLE in humans.

Acute administration of typical and atypical antipsychotics reduces EEG γ power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in γ power.

A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.

Early life stress enhancement of limbic epileptogenesis in adult rats: mechanistic insights.

BACKGROUND: Exposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsy (MTLE) and its associated psychopathology, research findings regarding underlying mechanisms are sparse. Of several possibilities, one important candidate mechanism is early life 'programming' of the hypothalamic-pituitary-adrenal (HPA) axis by postnatal stress. Elevated corticosterone (CORT) in turn has consequences for neurogenesis and cell death relevant to epileptogenesis. Here we tested the hypotheses that MS would augment seizure-related corticosterone (CORT) release and enhance neuroplastic changes in the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Eight-week old Wistar rats, previously exposed on postnatal days 2-14 to either maternal separation stress (MS) or control brief early handling (EH), underwent rapid amygdala kindling. We measured seizure-induced serum CORT levels and post-kindling neurogenesis (using BrdU). Three weeks post-kindling, rats were euthanized for histology of the hippocampal CA3c region (pyramidal cell counts) and dentate gyrus (DG) (to count BrdU-labelled cells and measure mossy fibre sprouting). As in our previous studies, rats exposed to MS had accelerated kindling rates in adulthood. Female MS rats had heightened CORT responses during and after kindling (p<0.05), with a similar trend in males. In both sexes total CA3c pyramidal cell numbers were reduced in MS vs. EH rats post-kindling (p = 0.002). Dentate granule cell neurogenesis in female rats was significantly increased post-kindling in MS vs. EH rats. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that early life stress results in enduring enhancement of HPA axis responses to limbic seizures, with increased hippocampal CA3c cell loss and augmented neurogenesis, in a sex-dependent pattern. This implicates important candidate mechanisms through which early life stress may promote vulnerability to limbic epileptogenesis in rats as well as to human MTLE and its associated psychiatric disorders.