Engagement of basal amygdala-nucleus accumbens glutamate neurons in the processing of rewarding or aversive social stimuli.

Basal amygdala (BA) neurons projecting to nucleus accumbens (NAc) core/shell are primarily glutamatergic and are integral to the circuitry of emotional processing. Several recent mouse studies have addressed whether neurons in this population(s) respond to reward, aversion or both emotional valences. The focus has been on processing of physical emotional stimuli, and here, we extend this to salient social stimuli. In male mice, an iterative study was conducted into engagement of BA-NAc neurons in response to estrous female (social reward, SR) and/or aggressive-dominant male (social aversion, SA). In BL/6J mice, SR and SA activated c-Fos expression in a high and similar number/density of BA-NAc neurons in the anteroposterior intermediate BA (int-BA), whereas activation was predominantly by SA in posterior (post-)BA. In Fos-TRAP2 mice, compared with SR-SR or SA-SA controls, exposure to successive presentation of SR-SA or SA-SR, followed by assessment of tdTomato reporter and/or c-Fos expression, demonstrated that many int-BA-NAc neurons were activated by only one of SR and SA; these SR/SA monovalent neurons were similar in number and present in both magnocellular and parvocellular int-BA subregions. In freely moving BL/6J mice exposed to SR, bulk GCaMP6 fibre photometry provided confirmatory in vivo evidence for engagement of int-BA-NAc neurons during social and sexual interactions. Therefore, populations of BA-NAc glutamate neurons are engaged by salient rewarding and aversive social stimuli in a topographic and valence-specific manner; this novel evidence is important to the overall understanding of the roles of this pathway in the circuitry of socio-emotional processing.

The risk of developing motor complications with Levodopa immediate versus dual release upon treatment initiation in Parkinson's disease.

Introduction: Motor complications (MCs) compromise therapy in many patients suffering from Parkinson's Disease. By achieving more physiologic stimulation of dopamine-receptors, the continuous dopamine stimulation hypothesis suggests that longer-acting levodopa formulations may improve outcome. The aim of this study was to compare the duration until onset of MCs and motor disease progression in patients during their treatment initiation with either an immediate (IR) or a combined rapid- and sustained-release (i.e. dual-release; DR) levodopa formulation. Methods: Using a sample of 69 patients, we applied time-varying survival regression analyses and linear mixed effect models to analyze the data. The latter involved preprocessing of the data to temporally align the response and predictors, including analyzing the extent of visit irregularity and potential predictors of visit intensity. Results: This retrospective study suggests that levodopa-benserazide DR is not superior to levodopa-benserazide IR in affecting duration until MCs and disease progression. Conversely, using DR levodopa-benserazide, similar disease progression was achieved with lower and more constant doses. Conclusions: The effects of DR levodopa-benserazide might not be strong enough to delay onset of MCs. The development of more powerful levodopa formulations remains a pressing clinical need.

[The Value of Deep Brain Stimulation in Difficult-To-Treat and Treatment-Refractory Depression]. / Der Stellenwert der tiefen Hirnstimulation bei der schwer behandelbaren sowie therapierefraktären Depression.

The Value of Deep Brain Stimulation in Difficult-To-Treat and Treatment-Refractory Depression Abstract: Deep Brain Stimulation ("DBS") is a minimally invasive, neurosurgical and hypothesis-driven therapeutic procedure for permanent local regulation of pathological circuits. While depression represents a heterogeneous syndrome with multifactorial etiopathogenesis, neuroscience research is advancing evidence to identify network-level mechanisms that play an important role in the pathophysiology of depression. In the following article, we will review the role of DBS in treatment-resistant or difficult-to-treat depression. The aim is to increase the awareness of DBS and to discuss the challenges of its therapy and implementation.

Worsening of Parkinson's Disease After Termination of COVID-19 Quarantine Cannot Be Reversed Despite Resumption of Physiotherapy.

In a retrospective analysis, we recently reported findings on the detrimental motor effects of interrupted physiotherapy following the COVID-19 pandemic in parkinsonian patients. Using an extended follow-up period, we investigated the beneficial effect of reinstated physiotherapy on patients' disease severity and reversal of interruption-induced motor deterioration. Compared to before the COVID-19 outbreak, we observed persistence of motor disease worsening despite full resumption of state-of-the-art physical therapy suggesting that motor deterioration after discontinuation of physical therapy could not be compensated for. Therefore, and considering possible future crises, establishing means to safeguard continuation of physical therapy and to foster remote provision of care should be major goals.

Stress deficits in reward behaviour are associated with and replicated by dysregulated amygdala-nucleus accumbens pathway function in mice.

Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) leads to reduced discriminative reward learning (DRL) associated with decreased BA-NAc activity, and to reduced reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc activity. Chronic tetanus toxin BA-NAc inhibition replicates the CSS-DRL effect and causes a mild REV reduction, whilst chronic DREADDs BA-NAc activation replicates the CSS effect on REV without affecting DRL. This study provides evidence that stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate opposite activity changes in reward (learning) neurons and aversion (effort) neurons in the BA-NAc pathway following chronic stress.

Evidence for Effects of Extracellular Vesicles on Physical, Inflammatory, Transcriptome and Reward Behaviour Status in Mice.

Immune-inflammatory activation impacts extracellular vesicles (EVs), including their miRNA cargo. There is evidence for changes in the EV miRNome in inflammation-associated neuropsychiatric disorders. This mouse study investigated: (1) effects of systemic lipopolysaccharide (LPS) and chronic social stress (CSS) on plasma EV miRNome; and (2) physiological, transcriptional, and behavioural effects of peripheral or central delivered LPS-activated EVs in recipient mice. LPS or CSS effects on the plasma EV miRNome were assessed by using microRNA sequencing. Recipient mice received plasma EVs isolated from LPS-treated or SAL-treated donor mice or vehicle only, either intravenously or into the nucleus accumbens (NAc), on three consecutive days. Bodyweight, spleen or NAc transcriptome and reward (sucrose) motivation were assessed. LPS and CSS increased the expression of 122 and decreased expression of 20 plasma EV miRNAs, respectively. Peripheral LPS-EVs reduced bodyweight, and both LPS-EVs and SAL-EVs increased spleen expression of immune-relevant genes. NAc-infused LPS-EVs increased the expression of 10 immune-inflammatory genes. Whereas motivation increased similarly across test days in all groups, the effect of test days was more pronounced in mice that received peripheral or central LPS-EVs compared with other groups. This study provides causal evidence that increased EV levels impact physiological and behavioural processes and are of potential relevance to neuropsychiatric disorders.

Basomedial amygdala activity in mice reflects specific and general aversion uncontrollability.

Learning adaptive behaviour to control aversion is a major brain function. Detecting the absence of control is also important, although chronic uncontrollable aversion can impact maladaptively on stimulus processing in general. The mouse basomedial amygdala (BMA) contributes to aversion processing with high BMA activity associated with active behavioural responding. The overall aim of the present study was to investigate the associations between aversion (un)controllability, BMA activity and behaviour. Fibre photometry of GCaMP6-expressing BMA neuron populations was applied in freely behaving adult male mice during exposure to mild electrical shocks, and effects of specific or general (un)controllability were investigated. In a discrete learned helplessness (LH) effect paradigm, mice underwent discrete sessions of pre-exposure to either escapable shock (ES) or inescapable shock (IES) followed by an escape test. IES mice acquired fewer escape attempts than ES mice, and this co-occurred with higher aversion-related BMA activity in the IES group. After 30 days, ES and IES mice were allocated equally to either chronic social stress (CSS)-exposure to continuous uncontrollable social aversion-or control handling (CON), and on days 5 and 15 underwent an IES session. CSS mice made fewer escape attempts than CON mice, and this was now associated with lower aversion-related BMA activity in the CSS group. These findings suggest that mouse BMA activity is higher when discrete aversion is uncontrollable but becomes lower following chronic uncontrollable aversion exposure. Therefore, BMA activity could be a neural marker of adaptive and maladaptive states consequent to specific and general uncontrollability, respectively.

Deconstructing Apathy in Parkinson's Disease: Challenges in Isolating Core Components of Apathy From Depression, Anxiety, and Fatigue.

Apathy, fatigue and depression are amongst the most debilitating non-motor syndromes of Parkinson's disease (PD). The aim of this study was to examine the prevalence of apathy, depression, anxiety and fatigue and whether these syndromes are separable in PD. A total of 337 patients were examined using the Unified Parkinson's Disease Rating Scale (UPDRS part III), the Apathy Evaluation Scale, the Hospital Anxiety and Depression Scale and the Fatigue Severity Scale. Using standard cutoff criteria, the prevalence rates of significant apathy, mild-to-severe depression, mild-to-severe anxiety and severe fatigue were 23.7, 13.4, 15.4, and 17.8%, respectively. Next, confirmatory factor analysis was employed of items from these three clinical scales. A priori hypothesis testing including four different factors (reduced motivation/interest, physical fatigue, reduced pleasure, anxiety) was performed. The factor analysis revealed strong fit statistics for the model with χ2 (57, N = 377) = 58.9, p = 0.41, CMIN/DF = 1,034, NFI = 0.977, CFI = 0.999, IFI = 0.999, RFI = 0.968, and TLI = 0.999. The RMSEA was 0.01, and the standardized RMR was 0.027. These results support the hypothesis that apathy, fatigue, depression and anxiety represent prevalent syndromes that can be separated in Parkinson's disease and that apathy is not just a subcomponent of depression or fatigue. The results of this study may contribute to a clearer diagnostic process for apathy, fatigue and depression and may aid in patient care.

Worsened Parkinson's Disease Progression: Impact of the COVID-19 Pandemic.

Whilst some studies investigated the impact of viral infection or reduced access to medication during the COVID-19 pandemic in patients with Parkinson's disease (PD), data on the effects of pandemic restrictions are still scarce. We retrospectively analyzed motor symptoms of longitudinally followed PD patients (n = 264) and compared motor disease progression before and during the COVID-19 pandemic. Additionally, we performed a trend analysis of the yearly evolution of motor symptoms in 755 patients from 2016 until 2021. We observed a worsening of motor symptoms and a significantly increased motor disease progression during pandemic-related restrictions as compared to before the COVID-19 outbreak.

Altered sleep intensity upon DBS to hypothalamic sleep-wake centers in rats.

Deep brain stimulation (DBS) has been scarcely investigated in the field of sleep research. We hypothesize that DBS onto hypothalamic sleep- and wake-promoting centers will produce significant neuromodulatory effects and potentially become a therapeutic strategy for patients suffering severe, drug-refractory sleep-wake disturbances. We aimed to investigate whether continuous electrical high-frequency DBS, such as that often implemented in clinical practice, in the ventrolateral preoptic nucleus (VLPO) or the perifornical area of the posterior lateral hypothalamus (PeFLH), significantly modulates sleep-wake characteristics and behavior. We implanted healthy rats with electroencephalographic/electromyographic electrodes and recorded vigilance states in parallel to bilateral bipolar stimulation of VLPO and PeFLH at 125 Hz and 90 µA over 24 h to test the modulating effects of DBS on sleep-wake proportions, stability and spectral power in relation to the baseline. We unexpectedly found that VLPO DBS at 125 Hz deepens slow-wave sleep (SWS) as measured by increased delta power, while sleep proportions and fragmentation remain unaffected. Thus, the intensity, but not the amount of sleep or its stability, is modulated. Similarly, the proportion and stability of vigilance states remained altogether unaltered upon PeFLH DBS but, in contrast to VLPO, 125 Hz stimulation unexpectedly weakened SWS, as evidenced by reduced delta power. This study provides novel insights into non-acute functional outputs of major sleep-wake centers in the rat brain in response to electrical high-frequency stimulation, a paradigm frequently used in human DBS. In the conditions assayed, while exerting no major effects on the sleep-wake architecture, hypothalamic high-frequency stimulation arises as a provocative sleep intensity-modulating approach.

Partners' view after subthalamic deep brain stimulation: Better relationships despite patients being less active.

INTRODUCTION: After deep brain stimulation (DBS) of the subthalamic nucleus (STN), Parkinson patients report difficulties in the relationship with their partners. The partners' experience after DBS appears to be variable and complex. Purpose of this pilot study was to investigate the partners' perspective on the relationship following STN-DBS. SUBJECTS AND METHODS: We conducted a postoperative questionnaire assessment in 56 partners of Parkinson patients with STN-DBS, using questionnaires addressing partnership satisfaction, dyadic coping, and role allocation in duties and activities of daily living. RESULTS: Regarding overall relationship satisfaction after surgery, 40% of partners were happier with their relationship than before DBS, and 14% were less satisfied. Partners reported that patients involved themselves distinctly less in duties and activities of daily living, leaving partners to take over. A need for more professional support for the relationship following surgery was noted by 27% of the partners. CONCLUSION: Although quality of relationship and dyadic coping improved or remained unchanged according to the majority of partners, patients became less prone to take over common duties and activities despite being in a better and more stable motor state. Potential conflicts and problems in role allocation in relationships following DBS need to be addressed in patients care.

Understanding the Effects and Adverse Reactions of Deep Brain Stimulation: Is It Time for a Paradigm Shift Toward a Focus on Heterogenous Biophysical Tissue Properties Instead of Electrode Design Only?

Deep brain stimulation (DBS) has been proven to be an effective treatment modality for various late-stage neurological and psychiatric disorders. However, knowledge on the electrical field distribution in the brain tissue is still scarce. Most recent attempts to understand electric field spread were primarily focused on the effect of different electrodes on rather simple tissue models. The influence of microanatomic, biophysical tissue properties in particular has not been investigated in depth. Ethical concerns restrict thorough research on field distribution in human in vivo brain tissue. By means of a simplified model, we investigated the electric field distribution in a broader area of the subthalamic nucleus (STN). Pivotal biophysical parameters including conductivity, permittivity and permeability of brain tissue were incorporated in the model. A brain tissue model was created with the finite element method (FEM). Stimulation was mimicked with parameters used for monopolar stimulation of patients suffering from Parkinson's disease. Our results were visualized with omnidirectional and segmented electrodes. The stimulated electric field was visualized with superimpositions on a stereotactic atlas (Morel). Owing to the effects of regional tissue properties near the stimulating electrode, marked field distortions occur. Such effects include, for example, isolating effects of heavily myelinated neighboring structures, e.g., the internal capsule. In particular, this may be illustrated through the analysis of a larger coronal area. While omnidirectional stimulation has been associated with vast current leakage, higher targeting precision was obtained with segmented electrodes. Finally, targeting was improved when the influence of microanatomic structures on the electric spread was considered. Our results confirm that lead design is not the sole influence on current spread. An omnidirectional lead configuration does not automatically result in an omnidirectional spread of current. In turn, segmented electrodes do not automatically imply an improved steering of current. Our findings may provide an explanation for side-effects secondary to current leakage. Furthermore, a possible explanation for divergent results in the comparison of the intraoperative awake patient and the postoperative setting is given. Due to the major influence of biophysical tissue properties on electric field shape, the local microanatomy should be considered for precise surgical targeting and optimal hardware implantation.

Image of Synthetic Biology and Nanotechnology: A Survey among University Students.

This study explores the image of synthetic biology and nanotechnology in comparison to agricultural biotechnology and communication technology by examining spontaneous associations with, and deliberate evaluations of, these technologies by university students. Data were collected through a self-completion online questionnaire by students from two universities in Switzerland. The survey aimed to capture implicit associations, explicit harm-benefit evaluations and views on regulation. The data suggest overall positive associations with emerging technologies. While positive associations were most pronounced for nanotechnology, agricultural biotechnology was attributed with the least favorable associations. In contrast to its positive result in the association task, respondents attributed a high harm potential for nanotechnology. Associations attributed to synthetic biology were demonstrated to be more positive than for agricultural biotechnology, however, not as favorable as for nanotechnology. Contrary to the evaluations of nanotechnology, the benefit-examples of synthetic biology were evaluated particularly positively. Accordingly, the investigated technologies enjoy different esteem, with synthetic biology and nanotechnology both showing a more "exciting" image. Even though, the image of nanotechnology was demonstrated to be more pronounced it was also more heterogeneous across tasks while agricultural biotechnology remains contested. For all technologies, the predominant spontaneous concerns pertain to risks rather than an immoral nature inherent to these technologies. Our data suggest that harm-benefit analyses reveal only one aspect of the attitude toward emerging technologies. Survey questions addressing spontaneous associations with these technologies are a valuable addition for our picture of the image of emerging technologies.

Measuring value sensitivity in medicine.

BACKGROUND: Value sensitivity - the ability to recognize value-related issues when they arise in practice - is an indispensable competence for medical practitioners to enter decision-making processes related to ethical questions. However, the psychological competence of value sensitivity is seldom an explicit subject in the training of medical professionals. In this contribution, we outline the traditional concept of moral sensitivity in medicine and its revised form conceptualized as value sensitivity and we propose an instrument that measures value sensitivity. METHODS: We developed an instrument for assessing the sensitivity for three value groups (moral-related values, values related to the principles of biomedical ethics, strategy-related values) in a four step procedure: 1) value identification (n = 317); 2) value representation (n = 317); 3) vignette construction and quality evaluation (n = 37); and 4) instrument validation by comparing nursing professionals with hospital managers (n = 48). RESULTS: We find that nursing professionals recognize and ascribe importance to principle-related issues more than professionals from hospital management. The latter are more likely to recognize and ascribe importance to strategy-related issues. CONCLUSIONS: These hypothesis-driven results demonstrate the discriminatory power of our newly developed instrument, which makes it useful not only for health care professionals in practice but for students and people working in the clinical context as well.

Deep Brain Stimulation: In Search of Reliable Instruments for Assessing Complex Personality-Related Changes.

During the last 25 years, more than 100,000 patients have been treated with Deep Brain Stimulation (DBS). While human clinical and animal preclinical research has shed light on the complex brain-signaling disturbances that underpin e.g., Parkinson's disease (PD), less information is available when it comes to complex psychosocial changes following DBS interventions. In this contribution, we propose to more thoroughly investigate complex personality-related changes following deep brain stimulation through refined and reliable instruments in order to help patients and their relatives in the post-surgery phase. By pursuing this goal, we first outline the clinical importance DBS has attained followed by discussing problematic and undesired non-motor problems that accompany some DBS interventions. After providing a brief definition of complex changes, we move on by outlining the measurement problem complex changes relating to non-motor symptoms currently are associated with. The latter circumstance substantiates the need for refined instruments that are able to validly assess personality-related changes. After providing a brief paragraph with regard to conceptions of personality, we argue that the latter is significantly influenced by certain competencies which themselves currently play only a tangential role in the clinical DBS-discourse. Increasing awareness of the latter circumstance is crucial in the context of DBS because it could illuminate a link between competencies and the emergence of personality-related changes, such as new-onset impulse control disorders that have relevance for patients and their relatives. Finally, we elaborate on the field of application of instruments that are able to measure personality-related changes.

Analyzing 7000 texts on deep brain stimulation: what do they tell us?

The enormous increase in numbers of scientific publications in the last decades requires quantitative methods for obtaining a better understanding of topics and developments in various fields. In this exploratory study, we investigate the emergence, trends, and connections of topics within the whole text corpus of the deep brain stimulation (DBS) literature based on more than 7000 papers (title and abstracts) published between 1991 to 2014 using a network approach. Taking the co-occurrence of basic terms that represent important topics within DBS as starting point, we outline the statistics of interconnections between DBS indications, anatomical targets, positive, and negative effects, as well as methodological, technological, and economic issues. This quantitative approach confirms known trends within the literature (e.g., regarding the emergence of psychiatric indications). The data also reflect an increased discussion about complex issues such as personality connected tightly to the ethical context, as well as an apparent focus on depression as important DBS indication, where the co-occurrence of terms related to negative effects is low both for the indication as well as the related anatomical targets. We also discuss consequences of the analysis from a bioethical perspective, i.e., how such a quantitative analysis could uncover hidden subject matters that have ethical relevance. For example, we find that hardware-related issues in DBS are far more robustly connected to an ethical context compared to impulsivity, concrete side-effects or death/suicide. Our contribution also outlines the methodology of quantitative text analysis that combines statistical approaches with expert knowledge. It thus serves as an example how innovative quantitative tools can be made useful for gaining a better understanding in the field of DBS.

A critical reflection on the technological development of deep brain stimulation (DBS).

Since the translational research findings of Benabid and colleagues which partly led to their seminal paper regarding the treatment of mainly tremor-dominant Parkinson patients through thalamic high-frequency-stimulation (HFS) in 1987, we still struggle with identifying a satisfactory mechanistic explanation of the underlying principles of deep brain stimulation (DBS). Furthermore, the technological advance of DBS devices (electrodes and implantable pulse generators, IPG's) has shown a distinct lack of dynamic progression. In light of this we argue that it is time to leave the paleolithic age and enter hellenistic times: the device-manufacturing industry and the medical community together should put more emphasis on advancing the technology rather than resting on their laurels.

How "moral" are the principles of biomedical ethics?--a cross-domain evaluation of the common morality hypothesis.

BACKGROUND: The principles of biomedical ethics - autonomy, non-maleficence, beneficence, and justice - are of paradigmatic importance for framing ethical problems in medicine and for teaching ethics to medical students and professionals. In order to underline this significance, Tom L. Beauchamp and James F. Childress base the principles in the common morality, i.e. they claim that the principles represent basic moral values shared by all persons committed to morality and are thus grounded in human moral psychology. We empirically investigated the relationship of the principles to other moral and non-moral values that provide orientations in medicine. By way of comparison, we performed a similar analysis for the business & finance domain. METHODS: We evaluated the perceived degree of "morality" of 14 values relevant to medicine (n1 = 317, students and professionals) and 14 values relevant to business & finance (n2 = 247, students and professionals). Ratings were made along four dimensions intended to characterize different aspects of morality. RESULTS: We found that compared to other values, the principles-related values received lower ratings across several dimensions that characterize morality. By interpreting our finding using a clustering and a network analysis approach, we suggest that the principles can be understood as "bridge values" that are connected both to moral and non-moral aspects of ethical dilemmas in medicine. We also found that the social domain (medicine vs. business & finance) influences the degree of perceived morality of values. CONCLUSIONS: Our results are in conflict with the common morality hypothesis of Beauchamp and Childress, which would imply domain-independent high morality ratings of the principles. Our findings support the suggestions by other scholars that the principles of biomedical ethics serve primarily as instruments in deliberated justifications, but lack grounding in a universal "common morality". We propose that the specific manner in which the principles are taught and discussed in medicine - namely by referring to conflicts requiring a balancing of principles - may partly explain why the degree of perceived "morality" of the principles is lower compared to other moral values.