Carolin Hoyer

A glass full of optimism: Enrichment effects on cognitive bias in a rat model of depression

Investigations of cognitive biases in animals are conceptually and translationally valuable because they contribute to animal welfare research and help to extend and refine our understanding of human emotional disorders, where biased information processing is a critical causal and maintenance factor. We employed the “learned helplessness” genetic rat model of depression in studying cognitive bias and its modification by environmental manipulations. Using a spatial judgment task, responses to ambiguous spatial cues were assessed before and after environmental enrichment to test whether this manipulation would cause an optimistic shift in emotional state. Twenty-four congenitally helpless and nonhelpless male rats were trained to discriminate two different locations, “rewarded” versus “aversive.” After successful acquisition of this spatial discrimination, cognitive bias was probed by measuring responses to three ambiguous locations. Latencies to “reach” and to actively “choose” a goal pot were recorded alongside exploratory behaviors. An overall strain difference was observed, with helpless rats displaying longer “reach” latencies than nonhelpless rats. This implies a “pessimistic” response bias in helpless rats, underscoring their depressive-like phenotype. No strain differences were observed regarding other behavioral measures. Half of the animals were then transferred to enriched cages and retested. Environmental enrichment resulted in reduced “choose” latencies in both rat strains, associating enrichment with more optimistic interpretations of ambiguous cues. Our results emphasize the suitability of cognitive bias measurement for animal emotion assessment. They extend the methodological repertoire for characterizing complex phenotypes and bear implications for animal welfare research and for the use of animal models in preclinical research.

The endocannabinoid system as a target for modelling psychosis

IntroductionModel psychosis is characterised by experimentally induced symptoms of withdrawal from reality, frequently accompanied by perceptual disturbances, thought disorders, delusional ideas and sometimes by hallucinations. These “altered states of consciousness” provide a long-standing and valid approach to enhance our understanding of certain aspects of schizophrenia.DiscussionTargeting the endocannabinoid system to investigate its involvement in the pathophysiology of schizophrenia became increasingly relevant with the discovery of this system and amounting epidemiological evidence for a deleterious influence of cannabis use on both manifestation and course of the disease. The majority of studies in the field are targeted to investigate drug effect of cannabis and cannabinoids not immediately related to psychosis.ConclusionIn this review, we summarise studies relevant for or designed as model psychosis experiments. Based on the data available, we examine the contribution of these studies to an improved neurobiological assessment of endocannabinoid functioning in psychosis and schizophrenia. An outline for future studies in the field and cross-links to other approaches to model psychosis is provided.

Increase of hippocampal glutamate after electroconvulsive treatment: A quantitative proton MR spectroscopy study at 9.4 T in an animal model of depression

Abstract Objectives. Recent evidence suggests that alterations in hippocampal glutamate and γ-aminobutyric acid (GABA) are associated with the pathomechanism of depression and treatment effects of electroconvulsive therapy (ECT). Thus, proton magnetic resonance spectroscopy (1H MRS) at a 9.4 T animal system seems a promising tool to study underlying mechanisms since it allows for an accurate quantification of metabolites with distinction of glutamate, GABA and glutamine, as well as separation of taurine from choline. Methods. A well-validated animal model of treatment resistant depression (congenital learned helpless rats = cLH) was investigated by hippocampal in vivo 1H MRS with and without a 1-week course of electroconvulsive shocks (ECS), an animal model of ECT, and compared to wild type (WT) animals, while saline and clomipramine injections served as additional controls. Results. Untreated cLH rats showed significantly lower glucose and higher taurine concentrations compared to WT animals. Besides alterations on these metabolites, ECS increased glutamate in WT and cLH and choline in cLH rats. Moreover, correlations between glutamate and GABA concentrations with learned helpless behaviour were revealed. Conclusions. These findings support the idea of disordered hippocampal metabolism in an animal model of treatment resistant depression and suggest an early impact of ECS on MR-detectable hippocampal metabolites.

Repetitive exposure to a 7 Tesla static magnetic field of mice in utero does not cause alterations in basal emotional and cognitive behavior in adulthood

In the past three decades, magnetic resonance imaging (MRI) has been increasingly used in obstetrics to aid diagnostics of maternal and fetal conditions and has generally been considered a safe imaging method. However, the development of higher-performance systems employing, for example, stronger fields to improve the techniques diagnostic potential, necessitates on-going safety evaluation. Rodent studies provide an excellent opportunity to investigate not only acute but also long-term effects of magnetic field exposure in a systematic manner, and a behavioral analysis might help to uncover subtler effects which might result from magnetic field exposure of the vulnerable developing brain. We conducted a comprehensive investigation of emotional and cognitive behavior in adult mice which had been repeatedly exposed to a 7 Tesla static magnetic field in utero. Using well-validated tests, we did not observe any adverse behavioral alterations regarding emotional behavior as well as spatial and emotional learning.

Cerebrospinal fluid diagnostics in first-episode schizophrenia

We evaluated the clinical use and the safety of cerebrospinal fluid diagnostics in 155 patients with the suspected diagnosis of first-episode schizophrenia. Five patients (3.2%) revealed pathological findings that lead to diagnostic re-evaluation and changes in clinical management. No serious adverse events occurred, but we documented 16 (10.3%) cases of mild to moderate headache or local pain at the puncture site. Our results underline the value of lumbar puncture in the clinical workup of first-episode patients with suspected schizophrenia.

Preliminary evaluation of clinical outcome and safety of ketamine as an anesthetic for electroconvulsive therapy in schizophrenia

Abstract Objectives. Electroconvulsive therapy (ECT) is an effective and safe option in the treatment of affective disorders and schizophrenia. One parameter known to influence ECT treatment efficacy is the choice of narcotic, and ketamine has emerged as an interesting alternative to conventional anaesthetics like barbiturates since it does not negatively influence seizure threshold. However, due to the potential to provoke dissociative symptoms, ketamine anaesthesia is rather hesitantly used in schizophrenia patients for fear of causing disease exacerbation. Methods. We retrospectively investigated clinical outcome and safety in patients treated with ECT for schizophrenia and receiving ketamine anaesthesia, either exclusively or as switch from another narcotic and compared seizure parameters to a group of ECT-treated schizophrenia patients with thiopental anaesthesia. Results. In none of the six patients undergoing ECT with ketamine did we observe disease exacerbation, and except for one patient, all patients responded or remitted under ECT. A preliminary analysis of seizure parameters shows an association with longer seizures in patients exclusively receiving ketamine. Conclusions. While the small sample size and retrospective character are limitations of our study, our preliminary results nonetheless challenge wide-spread preconceptions about the use of ketamine in schizophrenia patients and encourage further research into the option of using ketamine anaesthesia for ECT.

Medial Forebrain Bundle Stimulation—Speed Access to an Old or Entry into a New Depression Neurocircuit?

To the Editor: Arecent study by Schlapfer et al. (1) demonstrated an impressive and rapid antidepressant effect of deep brain stimulation (DBS) of the medial forebrain bundle (MFB) in patients with treatment-resistant depression (TRD), thus adding a new candidate to the current list of DBS targets for TRD, such as the subgenual cingulate, the nucleus accumbens, the lateral habenula (LHb), and the anterior limb of internal capsule. These data raise the question to what degree the various stimulation sites can be conceptualized as being part of, and entry points into, a single dysregulated neurocircuit (2). In favor of such a proposal, posterior MFB stimulation exerts suppressive influence onto lateral parts of the LHb (3). In turn, LHb stimulation induces a functional down-regulation of the monoaminergic pathways (serotonergic via dorsal raphe nucleus, dopaminergic via ventral tegmental area, and noradrenergic via locus coeruleus) (4,5). Since finally, the MFB acts as an integrative extension of these pathways to frontal structures, direct MFB stimulation may thus provide a shorter route to the prefrontal cortex as speed access toward this previously elaborated circuit (Figure 1). However, this notion contrasts with the striking observation in this new study that at least some of the patients reported immediate relief, reminiscent of effects induced by selfstimulation of the MFB (6). This rapid onset, if confirmed in further work, contrasts with the strongly asymmetric time course (DBS-off: fast relapse, DBS-on: slow remission) seen in responders to subgenual cingulate stimulation, nucleus accumbens stimulation, and LHb DBS (7,8). While, therefore, the sustained response to MFB stimulation might be compatible with entry into the same neurocircuit that previous stimulation sites have accessed, the immediate effect should prompt an investigation into nonoverlapping (possibly fast prefrontal) effects of MFB stimulation, especially in conjunction with rapid response pharmacologic approaches such as

One ring to rule them all? - Temporospatial specificity of deep brain stimulation for treatment-resistant depression

Deep brain stimulation (DBS) for intractable cases of depression has emerged as a valuable therapeutic option during the last decade. While several locations have been intensely investigated in recent years, the literature is lacking an all-encompassing perspective thereupon asking if and how these stimulation sites relate to each other and what this may imply for the underlying mechanisms of action of this treatment modality. We aim at proposing a model of DBS mechanism of action with particular focus on several puzzling aspects regarding an apparent temporo-spatial specificity of antidepressant action, i.e. the discrepancy between protracted response after initiation of stimulation and rapid relapse upon discontinuation, as well as differential effects on psychopathology. We suggest that the pre-treatment depressive state is determined by the interaction of individual traits with dysfunctional adaptive processes as responses to stress, resulting in a disease-associated, overtly dysfunctional, equilibrium. The antidepressant action of DBS is thought to modify and re-set this equilibrium in a temporospatially distinct manner by influencing the activity states of two different brain circuitries. The idea of sequential and temporospatially distinct mechanisms of action bears implications for the assessment of psychopathology and behavior in clinical and preclinical studies as well as investigations into brain circuit activity states.

Impact of pre-admission treatment with non-vitamin K oral anticoagulants on stroke severity in patients with acute ischemic stroke

BackgroundNon-vitamin K antagonist oral anticoagulants (NOACs) have gained increasing importance for stroke prevention in patients with non-valvular atrial fibrillation (AF). With changing prescription practice, among other factors, clinicians can expect to see rising numbers of patients with ischemic stroke and pre-existing NOAC therapy. Few data exist regarding a potential impact of NOAC on stroke severity and outcome.AimsTo evaluate the impact of pre-admission NOAC therapy on ischemic stroke severity.MethodsRetrospective analysis of medical data of 376 patients with newly detected AF or known AF with either no pre-admission oral anticoagulation (n = 277) or existing NOAC therapy (n = 99; Apixaban, n = 33, Dabigatran, n = 16; Edoxaban, n = 1; Rivaroxaban, n = 49) consecutively admitted for acute ischemic stroke between January 2015 and December 2016.ResultsPatients with pre-admission NOAC had significantly more often experienced a prior stroke than patients not on NOAC therapy (45.5 vs. 18.4%, p < 0.001) and were significantly more frequently non-smokers (1.0 vs. 7.2%, p = 0.021). Significantly more patients without pre-admission NOAC received thrombolysis (33.8 vs. 8.1%, p < 0.001). Pre-admission NOAC therapy was associated with significantly lower NIHSS and mRS scores upon admission (median NIHSS score 6 vs. 10, p = 0.018, median mRS score 4 vs. 5, p = 0.035) and trend-level lower NIHSS scores at discharge (median NIHSS score 3 vs. 5, p = 0.057). There were no differences regarding the frequency of symptomatic intracerebral hemorrhage between NOAC and non-NOAC patients (p > 0.05).ConclusionsWe report a positive impact of pre-admission NOAC on ischemic stroke severity, which is particularly remarkable in light of the increased prevalence of prior stroke and lower rates of thrombolysis in this patient population.