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The existence of sex differences in schizophrenia is a well documented phenomenon which led to the hypothesis that female sex hormones are neuroprotective and hence responsible for the more favorable disease characteristics seen in women. The current study sought to investigate the effects of estrogen-like agents administered during early adolescence on behavioral outcomes in adulthood using the neurodevelopmental maternal immune activation (MIA) rodent model of schizophrenia. Female MIA offspring were administered during the asymptomatic period of adolescence with either 17β-estradiol, raloxifene or saline and were tested in late adolescence and adulthood for schizophrenia-related behavioral performance. We report here that whereas adult female MIA offspring exhibited cognitive deficits in the form of retarded spatial learning, the administration of raloxifene during adolescence was sufficient in preventing these deficits and resulted in intact performance in the MIA group.

Purpose of the Review Development of addiction involves a transition from reward-driven to habitual behavior, mediated by neuroplastic changes. Based on preclinical findings, this article article reviews the current knowledge on the use of neuromodulation therapies to target alcohol addiction and essentially reduce relapse. Recent Findings To date, only a limited number of preclinical studies have investigated the use of neuromodulation in alcohol addiction, with the focus being on targeting the brain reward system. However, as addiction develops, additional circuits are recruited. Therefore, a differential setup may be required when seeking to alter the chronic alcohol-dependent brain, as opposed to treating earlier phases of alcohol addiction. Summary To promote enduring relapse prevention, the choice of brain target should match the stage of the disorder. Further studies are needed to investigate which brain areas should be targeted by neuromodulating strategies, in order to sufficiently alter the behavior and pathophysiology as alcohol addiction progresses.

Background Many people suffering from migraine combine pharmacological and non-pharmacological treatments. The purpose of this systematic review is to provide an updated guideline for some widely used non-pharmacological treatment options for migraine. Methods We conducted a systematic literature review of randomized studies of adults with migraine treated with manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education. The main outcomes measured were days with headache and quality of life. Recommendations were formulated based on the Grade of Recommendation, Assessment, Development and Evaluation (GRADE) approach including patient preferences based on expert opinion and questionnaire data. Results The overall level of certainty of the evidence was low to very low. Manual therapy techniques and psychological treatment did not change the studied outcomes. Supervised physical activity might have a positive impact on quality of life, acupuncture on headache frequency, intensity, quality of life and the use of attack-medicine. Patient education might improve self-rated health and quality of life and increase the number of well-informed patients. Conclusion Based on observed effects, the lack of serious adverse events, and patients’ preferences, we make weak recommendations for considering the investigated interventions as a supplement to standard treatment. Protocol registration: Prospero CRD42020220132.

BackgroundA recently updated Cochrane review supports the efficacy of psychotherapy for borderline personality disorder (BPD).AimsTo evaluate the effects of standalone and add-on psychotherapeutic treatments more concisely.MethodWe applied the same methods as the 2020 Cochrane review, but focused on adult samples and comparisons of active treatments and unspecific control conditions. Standalone treatments (i.e. necessarily including individual psychotherapy as either the sole or one of several treatment components) and add-on interventions (i.e. complementing any ongoing individual BPD treatment) were analysed separately. Primary outcomes were BPD severity, self-harm, suicide-related outcomes and psychosocial functioning. Secondary outcomes were remaining BPD diagnostic criteria, depression and attrition.ResultsThirty-one randomised controlled trials totalling 1870 participants were identified. Among standalone treatments, statistically significant effects of low overall certainty were observed for dialectical behaviour therapy (self-harm: standardised mean difference (SMD) −0.54, P = 0.006; psychosocial functioning: SMD −0.51, P = 0.01) and mentalisation-based treatment (self-harm: risk ratio 0.51, P < 0.0007; suicide-related outcomes: risk ratio 0.10, P < 0.0001). For adjunctive interventions, moderate-quality evidence of beneficial effects was observed for DBT skills training (BPD severity: SMD −0.66, P = 0.002; psychosocial functioning: SMD −0.45, P = 0.002), and statistically significant low-certainty evidence was observed for the emotion regulation group (BPD severity: mean difference −8.49, P < 0.00001), manual-assisted cognitive therapy (self-harm: mean difference −3.03, P = 0.03; suicide-related outcomes: SMD −0.96, P = 0.005) and the systems training for emotional predictability and problem-solving (BPD severity: SMD −0.48, P = 0.002).ConclusionsThere is reasonable evidence to conclude that psychotherapeutic interventions are helpful for individuals with BPD. Replication studies are needed to enhance the certainty of findings.

A range of dopamine-dominating neuropsychiatric disorders present with cognitive deficits. In accordance, the dopamine transporter overexpressing rat model (DAT-tg rat) displays cognitive deficits by means of behavioral inflexibility and learning disabilities. It remains to be investigated when cognitive deficits emerge, due to the inherent DA irregularities, during the life course of the DAT-tg rat and what may relieve symptoms. The Morris water maze (MWM) was used to assess cognitive abilities in three cohorts of DAT-tg rats. In the first cohort, the development of cognitive deficits was assessed by repeatedly testing animals in the MWM at postnatal day (PND) 35, 60, and 90. In the second and third cohort, pharmacological interventions and transcranial direct current stimulation (tDCS) were tested in adult animals to understand what drives, and thus relieves, the deficits. Minor differences were observed between DAT-tg rats and control rats at PND 35 and 60, whereas cognitive deficits fully emerged at PND 90. A high dosage of methylphenidate diminished both behavioral inflexibility and improved learning abilities in adult rats. Interestingly, rats subjected early in life to the MWM also displayed improved behavioral flexibility as compared to rats naïve to the paradigm. Cognitive deficits gradually develop over time and fully emerge in adulthood. Pharmacological modulation of the ubiquitous DAT overexpression overall improves deficits in adult rats, whereas early training decreases later development of behavioral inflexibility. Thus, former training may constitute a preventive avenue that alters some aspects of cognitive deficits resulting from inherent DA abnormalities.

Background: The standard treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) constitutes of systemic oral corticosteroid. Although oral corticosteroid might revert the acute deafness, some patients with ISSNHL display a more treatment refractory course. For these patients, corticosteroid installed directly into the middle ear has become a more frequent treatment, due to the potential benefits of a high, local concentration compared to a systemic administration. As such, for patients being refractory to standard treatment, intratympanic injection of a high dosage of corticosteroid as salvage therapy may be beneficial.Objectives: To evaluate the efficacy of intratympanic corticosteroid (ITC) as a salvage treatment of ISSNHL.Methods: A systematic literature search was performed in relevant databases. Both randomized trials and observational studies were considered for inclusion. The risk of bias was evaluated using the Cochrane risk of bias tool (randomized trials) or ROBINS-I tool (observational studies). Meta-analysis was performed to investigate the improvement of PTA (dB) and number of patients displaying recovery following salvage ITC injections. Occurrence of serious side effects was investigated. Finally, the certainty of the evidence was evaluated using the GRADE approach.Results: Eleven relevant studies were identified (4 randomized trials and 7 observational studies). Both observational and randomized trials showed that salvage ITC significantly increased the number of patients displaying recovery. No serious adverse events were identified in any of the included studies. The certainty of evidence ranged from moderate to very low, due to risk of bias, imprecision, and heterogeneity.Conclusion: Collectively, our findings indicate that salvage ITC treatment may be a beneficial and safe treatment for patients with sudden hearing loss, who otherwise are refractory to standard treatment approaches. However, the evidence level indicates need for a cautious interpretation of especially the magnitude of effect and thus the extrapolation on how much the individual may improve from this treatment. Furthermore, it remains to be investigated whether treatment outcomes may vary across different patient groups presenting with ISSNHL. This potential variation in treatment response should be kept in mind, when counselling the patient.Trial registration number: The protocol is registered in PROSPERO. Registration number: CRD42019130586.

Key Points Question What is the evidence for nonpharmacological interventions to treat persistent postconcussion symptoms? Findings Following a systematic review and meta-analysis of 19 randomized clinical trials comprising 2007 participants, using the Grading of Recommendations, Assessment, Development, and Evaluations method, weak recommendations for the following were assigned: systematic provision of early information and advice, use of graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, psychological treatment, and interdisciplinary rehabilitation. No studies were identified regarding oculomotor vision treatment, resulting in a consensus-based statement. Meaning Based on very low to low certainty of evidence or on consensus, individually tailored nonpharmacological treatment of persistent symptoms was recommended, both through specific disciplines and interdisciplinary rehabilitation., This systematic review and meta-analysis assesses the outcomes related to 7 nonpharmacological interventions for persistent postconcussion symptoms in adults and provides recommendations for clinical practice., Importance Persistent (>4 weeks) postconcussion symptoms (PPCS) are challenging for both patients and clinicians. There is uncertainty about the effect of commonly applied nonpharmacological treatments for the management of PPCS. Objective To systematically assess and summarize evidence for outcomes related to 7 nonpharmacological interventions for PPCS in adults (aged >18 years) and provide recommendations for clinical practice. Data Sources Systematic literature searches were performed via Embase, MEDLINE, PsycINFO, CINAHL, PEDro, OTseeker, and Cochrane Reviews (via MEDLINE and Embase) from earliest possible publication year to March 3, 2020. The literature was searched for prior systematic reviews and primary studies. To be included, studies had to be intervention studies with a control group and focus on PPCS. Study Selection A multidisciplinary guideline panel selected interventions based on frequency of use and need for decision support among clinicians, including early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, oculomotor vision treatment, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. To be included, studies had to be intervention studies within the areas of the predefined clinical questions, include a control group, and focus on symptoms after concussion or mild traumatic brain injury. Data Extraction and Synthesis Extraction was performed independently by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data abstraction and data quality assessment. Included studies were assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Cochrane Risk of Bias (randomized clinical trials) tool. Meta-analysis was performed for all interventions where possible. Random-effects models were used to calculate pooled estimates of effects. The level and certainty of evidence was rated and recommendations formulated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Main Outcomes and Measures All outcomes were planned before data collection began according to a specified protocol. The primary outcomes were the collective burden of PPCS and another outcome reflecting the focus of a particular intervention (eg, physical functioning after graded exercise intervention). Results Eleven systematic reviews were identified but did not contribute any primary studies; 19 randomized clinical trials comprising 2007 participants (1064 women [53.0%]) were separately identified and included. Evidence for the 7 interventions ranged from no evidence meeting the inclusion criteria to very low and low levels of evidence. Recommendations were weak for early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of the neck and back, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. No relevant evidence was identified for oculomotor vision treatment, so the panel provided a good clinical practice recommendation based on consensus. Conclusions and Relevance Based on very low to low certainty of evidence or based on consensus, the guideline panel found weak scientific support for commonly applied nonpharmacological interventions to treat PPCS. Results align with recommendations in international guidelines. Intensified research into all types of intervention for PPCS is needed.

Background Tension-type headache (TTH) has been ranked the second most prevalent health condition worldwide. Non-pharmacological treatments for TTH are widely used as a supplement or an alternative to medical treatment. However, the evidence for their effects are limited. Therefore, the aim of this study was to review the evidence for manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education as treatments for TTH on the effect of headache frequency and quality of life. Methods A systematic literature search was conducted from February to July 2020 for clinical guidelines, systematic reviews, and individual randomised controlled trials (RCT). The primary outcomes measured were days with headache and quality of life at the end of treatment along with a number of secondary outcomes. Meta-analyses were performed on eligible RCTs and pooled estimates of effects were calculated using the random-effect model. The overall certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE). In addition, patient preferences were included in the evaluation. Results In all, 13 RCTs were included. Acupuncture might have positive effects on both primary outcomes. Supervised physical activity might have a positive effect on pain intensity at the end of treatment and headache frequency at follow-up. Manual joint mobilisation techniques might have a positive effect on headache frequency and quality of life at follow-up. Psychological treatment might have a positive effect on stress symptoms at the end of treatment. No relevant RCTs were identified for patient education. The overall certainty of evidence was downgraded to low and very low. No serious adverse events were reported. A consensus recommendation was made for patient education and weak recommendations for the other interventions. Conclusion Based on identified benefits, certainty of evidence, and patient preferences, manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture, and patient education can be considered as non-pharmacological treatment approaches for TTH. Some positive effects were shown on headache frequency, quality of life, pain intensity and stress symptoms. Few studies and low sample sizes posed a challenge in drawing solid conclusions. Therefore, high-quality RCTs are warranted.

Schizophrenia is a severe neurodevelopmental psychiatric affliction manifested behaviorally at late adolescence/early adulthood. Current treatments comprise antipsychotics which act solely symptomatic, are limited in their effectiveness and often associated with side-effects. We here report that application of non-invasive transcranial direct current stimulation (tDCS) during adolescence, prior to schizophrenia-relevant behavioral manifestation, prevents the development of positive symptoms and related neurobiological alterations in the maternal immune stimulation (MIS) model of schizophrenia.

Based on epidemiological and animal studies, the rationale for using polyunsaturated fatty acids (PUFAs) as a treatment for Attention Deficit Hyperactivity Disorder (ADHD) seems promising. Here, the objective was to systematically identify and critically assess the evidence from clinical trials. The primary outcome was ADHD core symptoms. The secondary outcomes were behavioral difficulties, quality of life, and side effects. We performed a systematic search in Medline, Embase, Cinahl, PsycInfo, and the Cochrane Library up to June 2020. The overall certainty of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified 31 relevant randomized controlled trials including 1755 patients. The results showed no effect on ADHD core symptoms rated by parents (k = 23; SMD: −0.17; 95% CI: −0.32, −0.02) or teachers (k = 10; SMD: −0.06; 95% CI: −0.31, 0.19). There was no effect on behavioral difficulties, rated by parents (k = 7; SMD: −0.02; 95% CI: −0.17, 0.14) or teachers (k = 5; SMD: −0.04; 95% CI: −0.35, 0.26). There was no effect on quality of life (SMD: 0.01; 95% CI: −0.29, 0.31). PUFA did not increase the occurrence of side effects. For now, there seems to be no benefit of PUFA in ADHD treatment; however, the certainty of evidence is questionable, and thus no conclusive guidance can be made. The protocol is registered in PROSPERO ID: CRD42020158453.

Background and Objectives The Australian National COVID-19 Clinical Evidence Taskforce is a consortium of 31 Australian health professional organisations developing living, evidence-based guidelines for care of people with COVID-19, which are updated weekly. This article describes the methods used to develop and maintain the guidelines. Methods The guidelines use the GRADE methods and are designed to meet Australian NHMRC standards. Each week, new evidence is reviewed, current recommendations are revised, and new recommendations made. These are published in MAGIC and disseminated through traditional and social media. Relevant new questions to be addressed are continually sought from stakeholders and practitioners. For prioritized questions, the evidence is actively monitored and updated. Evidence surveillance combines horizon scans and targeted searches. An evidence team appraises and synthesizes evidence and prepares evidence-to-decision frameworks to inform development of recommendations. A guidelines leadership group oversees the development of recommendations by multidisciplinary guidelines panels and is advised by a consumer panel. Results : The Taskforce formed in March 2020, and the first recommendations were published 2 weeks later. The guidelines have been revised and republished on a weekly basis for 24 weeks, and as of October 2020, contain over 90 treatment recommendations, suggesting that living methods are feasible in this context. Conclusions The Australian guidelines for care of people with COVID-19 provide an example of the feasibility of living guidelines and an opportunity to test and improve living evidence methods.

Background Evidence suggests that schizophrenia constitutes a neurodevelopmental disorder, characterized by a gradual emergence of behavioral and neurobiological abnormalities over time. Therefore, applying early interventions to prevent later manifestation of symptoms is appealing. Objective This review focuses on the use of cortical neuromodulation in schizophrenia and its potential as a preventive treatment approach. We present clinical and preclinical findings investigating the use of neuromodulation in schizophrenia, including the current research focusing on cortical non-invasive stimulation and its possibility as a future preventive treatment. Methods We performed a search in Medline (PubMed) in September 2020 using a combination of relevant medical subject headings (MeSH) and text words. The search included human and preclinical trials as well as existing systematic reviews and meta-analysis. There were no restrictions on language or the date of publication. Results Neurodevelopmental animal models may be used to investigate how the disease progresses and thus which brain areas ideally should be targeted at a given time point. Here, abnormalities of the prefrontal cortex have been often identified as an early and persistent impairment in schizophrenia. Currently there is insufficient evidence to either support or refute the use of neuromodulation to the cortex in adult patients with already manifested symptoms. However, preclinical results show that early non-invasive neuromodulation to the prefrontal cortex of adolescent animals, sufficiently prevents later psychosis-relevant abnormalities in adulthood. This points to the promising potential of cortical non-invasive neuromodulation as a preventive treatment when applied early in the course of the disease. Conclusion Preclinical translational-oriented findings indicate, that neuromodulation to cortical areas offers the possibility of targeting early neuropathology and through this diminish the progression of a later schizophrenic profile. Further studies are needed to investigate whether such early cortical stimulation may serve as a future preventive treatment in schizophrenia.

Background: Endolymphatic sac surgery is an invasive procedure recommended to patients with Menière’s disease. Aims/Objectives: To provide an overview and quality assessment of the existing evidence and to provide an updated assessment of the utility of endolymphatic sac surgery in Menière’s disease. Material and Methods: We performed a systematic literature search for systematic reviews and randomized controlled trials (RCTs). The AMSTAR tool was used to assess the quality of systematic reviews and the Cochrane risk of bias tool for RCTs. The overall certainty of effects for the individual outcomes was evaluated using the GRADE approach. Results: One systematic review of high quality matched the inclusion criteria, and included three RCTs. An updated literature search from the last search date of the included review provided no further relevant RCTs. The identified RCTs individually reported a positive effect of both the placebo and active treatment groups following surgery, strongly indicative of a placebo effect. The overall certainty of the effect was very low. Conclusions and significance: There is still a lack of high-quality research suggesting that endolymphatic sac surgery provides a significant amount of symptomatic relief for Menière’s patients.

In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease.

Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.

OBJECTIVES: To investigate the beneficial effects and safety of intratympanic steroid installation compared with placebo in patients with Menière's disease.METHODS: We performed a systematic literature search in MEDLINE and EMBASE for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated the usage intratympanic steroids in patients aged 18 and above, with definite or probable Menière's disease. The quality of the identified existing reviews was assessed using the AMSTAR tool. The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool and overall quality of the individual outcomes was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method.RESULTS: The literature search provided four systematic reviews, from which one yielded a sufficient AMSTAR evaluation and subsequently provided three RCTs relevant for inclusion. Due to the lack of sufficient reporting of the data, quantitative synthesis was not applicable. In the qualitative synthesis for the primary outcome, the results from the RCTs showed that there was a slight indication of steroid treatment reducing the frequency of vertiginous attacks. No serious adverse events were reported. Based on the GRADE approach the quality for both findings is very low. No studies reported on the secondary outcomes.CONCLUSION: The effect of intratympanic steroid treatment in Menière's disease is questionable. There is a great need for further research to sufficiently assess whether steroid treatment may be considered as a safe and effective treatment for patients with Menière's disease.

OBJECTIVE: The objective was to critically assess the current evidence investigating the efficacy of using a positive pressure device in patients with definite or probable Menière's disease.METHODS: We performed a systematic literature search in MEDLINE, EMBASE and PsycINFO up to February 2018. We included both systematic reviews and primary literature [randomized controlled trials (RCTs)] investigating positive pressure treatment, in patients (≥ 18 years of age), with Menière's disease. We assessed the internal validity of systematic reviews using the AMSTAR tool and risk of bias of primary studies using the Cochrane Risk of bias tool. We performed a meta-analysis for each outcome based on the identified studies. The overall certainty of evidence for the outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE).RESULTS: The search for systematic reviews identified four relevant reviews. These all included the same four RCTs. An updated search identified one additional RCT. In total, five RCTs were included in the data synthesis. Our data synthesis showed no effect of positive pressure treatment on primary nor secondary outcomes. No serious adverse events were reported. The overall certainty of evidence ranged from very low to low, due to the serious risk of bias and imprecision.CONCLUSION: The current available evidence does not support positive pressure device treatment in patients with Menière's disease. However, the limitations of the current literature hinder the possibility of any solid conclusion. There remains a need for randomized controlled trials of high quality to fully access the utility of this treatment.

BACKGROUND: Pulmonary rehabilitation (PR), delivered as a supervised multidisciplinary program including exercise training, is one of the cornerstones in the chronic obstructive pulmonary disease (COPD) management. We performed a systematic review and meta-analysis to assess the effect on mortality of a supervised early PR program, initiated during or within 4 weeks after hospitalization with an acute exacerbation of COPD compared with usual post-exacerbation care or no PR program. Secondary outcomes were days in hospital, COPD related readmissions, health-related quality of life (HRQoL), exercise capacity (walking distance), activities of daily living (ADL), fall risk and drop-out rate.METHODS: We identified randomized trials through a systematic search using MEDLINE, EMBASE and Cocharne Library and other sources through October 2017. Risk of bias was assessed regarding randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases using the Cochrane Risk of Bias tool.RESULTS: We included 13 randomized trials (801 participants). Our meta-analyses showed a clinically relevant reduction in mortality after early PR (4 trials, 319 patients; RR = 0.58 (95% CI: [0.35 to 0.98])) and at the longest follow-up (3 trials, 127 patients; RR = 0.55 (95% CI: [0.12 to 2.57])). Early PR reduced number of days in hospital by 4.27 days (1 trial, 180 patients; 95% CI: [- 6.85 to - 1.69]) and hospital readmissions (6 trials, 319 patients; RR = 0.47 (95% CI: [0.29 to 0.75])). Moreover, early PR improved HRQoL and walking distance, and did not affect drop-out rate. Several of the trials had unclear risk of bias in regard to the randomization and blinding, for some outcome there was also a lack of power.CONCLUSION: Moderate quality of evidence showed reductions in mortality, number of days in hospital and number of readmissions after early PR in patients hospitalized with a COPD exacerbation. Long-term effects on mortality were not statistically significant, but improvements in HRQoL and exercise capacity appeared to be maintained for at least 12 months. Therefore, we recommend early supervised PR to patients with COPD-related exacerbations. PR should be initiated during hospital admission or within 4 weeks after hospital discharge.

Involuntary movements as seen in repetitive disorders such as Tourette Syndrome (TS) results from cortical hyperexcitability that arise due to striato-thalamo-cortical circuit (STC) imbalance. Transcranial direct current stimulation (tDCS) is a stimulation procedure that changes cortical excitability, yet its relevance in repetitive disorders such as TS remains largely unexplored. Here, we employed the dopamine transporter-overexpressing (DAT-tg) rat model to investigate behavioral and neurobiological effects of frontal tDCS. The outcome of tDCS was pathology dependent, as anodal tDCS decreased repetitive behavior in the DAT-tg rats yet increased it in wild-type (wt) rats. Extensive deep brain stimulation (DBS) application and computational modeling assigned the response in DAT-tg rats to the sensorimotor pathway. Neurobiological assessment revealed cortical activity changes and increase in striatal inhibitory properties in the DAT-tg rats. Our findings show that tDCS reduces repetitive behavior in the DAT-tg rat through modulation of the sensorimotor STC circuit. This sets the stage for further investigating the usage of tDCS in repetitive disorders such as TS.

Background: In recent years, deep brain stimulation (DBS) has emerged as a promising treatment option for patients suffering from treatment-resistant depression (TRD). Several stimulation targets have successfully been tested in clinical settings, including the subgenual cingulum (Cg25) and the medial forebrain bundle (MFB). MFB-DBS has led to remarkable results, surpassing the effect of previous targets in terms of response latency and number of responders. However, the question remains as to which mechanisms underlie this difference. Objective/hypothesis: The aim of the present study was to thoroughly study the anti-depressant effect of MFB-DBS in the Flinders sensitive line (FSL) rat model of depression as well as to investigate whether MFB-DBS and Cg25-DBS operate through the same neurobiological circuits. Methods: FSL and control rats received bilateral high-frequency stimulation to the MFB at the level of the lateral hypothalamus, while being subjected to a variety of depression-and anxiety-related behavioral paradigms. To further compare the effects of MFB-DBS and Cg25-DBS on reward-related behavior, animals were stimulated in either the MFB or ventromedial prefrontal cortex (vmPFC, rodent analog to Cg25), while being tested in the intra-cranial self-stimulation paradigm. Results: A marked symptom-specific anti-depressant effect of MFB-DBS was demonstrated. The ICSS-paradigm revealed that MFB-DBS, as opposed to vmPFC-DBS interacts with the reward system. Conclusion: Our data suggest that MFB-DBS and Cg25-DBS do not operate via the same neurobiological circuits. This differentiation might be of interest when selecting patients for either Cg25- or MFB-DBS. (C) 2015 Elsevier Inc. All rights reserved.

The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders.

Previous studies assessing the involvement of the face-sensitive N170 component of the event-related potential (ERP) in the processing of face identity have shown controversial results when assessing N170 amplitude in repetition suppression (RS) designs. On the other hand, N170 adaptation is robustly associated with the inter-stimulus interval (ISI) between immediate face repetitions. Interestingly, interactions of face identity and ISI could provide valuable information on early encoding of face identity, but have not been investigated so far. We employed a repetition suppression paradigm using identical and non-identical repetitions as well as parametrically varied ISIs between 500 msec and 2,000 msec in 27 healthy subjects to investigate N170 adaptation effects. Both face identity and varying ISIs significantly influenced N170 adaptation effects, albeit with small effects sizes. Most importantly, however, face identity and ISIs strongly interacted with rapid N170 amplitude recovery in non-identical trials, but sustained N170 adaptation in identical trials. We excluded low-level sensory contributions to the N170 adaptation effect by analyzing the P1 component and by running an additional experiment employing different stimulus sizes. This specific result strongly argues in favor of neuronal sensitivity to face identity, which is primarily mirrored in the N170 temporal decay function that essentially differentiates identical and non-identical face trials. In general, taking advantage of the temporal dimension of adaptation processes, i.e., their decay over time, provides additional dissections of neuronal function into feature-specific selectivity versus non-selectivity.

Introduction Treating Tourette syndrome (TS) remains challenging as therapies fail to take temporal presentation of symptoms into account. Therefore, to optimize therapies the investigation of biomarkers predicting repetitive behavior is required. Objectives We are currently studying repetitive behavior and associated electrophysiological changes in a new animal model of Tourette syndrome – the dopamine transporter (DAT) over-expressing rat model. The DAT rat resembles TS pathology in various aspects, including marked up-regulation of D2/D1 receptors, brain site-specific dopamine alterations and decrease in parvalbumin expressing interneurons in the caudate putamen. In line with clinical findings, the DAT rats display time-locked increase in tic-like behavior following amphetamine application. Math/meth To study stereotypic behavior, extracellular bipolar in vivo recordings were conducted under urethane anesthesia in different areas of the basal-ganglia thalamo-cortical loop for 4 h (2 h before (baseline) and 2 h after amphetamine). Signals were amplified, filtered (0.05–250 Hz) and sampled at 1 kHz. Power Spectral Densities were calculated using Spike 2 software (FFT size 1024/0.0256 s, Hanning Window) for baseline and post amphetamine time-windows, where behavioral analysis revealed stereotypy or not. Power-spectra were normalized to the mean s. d. of power between 103–147 Hz and 153–197 Hz power. Results Results show that DAT rats at the time-point of tic induction, exhibit time-locked abnormalities in alpha and beta bands, especially in the dorsomedial thalamus. This indicates characteristic electrophysiological modulation temporally related to distinct repetitive behavior. Conclusion The time-locked manifestation allows us to further investigate biomarkers of repetitive behavior and to employ this in constructing a close-loop stimulation device treating repetitive behavior in a controlled fashion.