Schizophrenia is associated with various deficits in social cognition that remain relatively unaltered by antipsychotic treatment. While faulty glutamate signaling has been associated with general cognitive deficits as well as negative symptoms of schizophrenia, no direct link between manipulation of glutamate signaling and deficits in mentalizing has been demonstrated thus far. Here, we experimentally investigated whether ketamine, an uncompetitive N-methyl-D-aspartate receptor antagonist known to induce psychotomimetic effects, influences mentalizing and its neural correlates. In a randomized, placebo-controlled between-subjects experiment, we intravenously administered ketamine or placebo to healthy participants performing a video-based social cognition task during functional magnetic resonance imaging. Psychotomimetic effects of ketamine were assessed using the Positive and Negative Syndrome Scale. Compared to placebo, ketamine led to significantly more psychotic symptoms and reduced mentalizing performance . Ketamine also influenced blood oxygen level dependent (BOLD) response during mentalizing compared to placebo. Specifically, ketamine increased BOLD in right posterior superior temporal sulcus (pSTS) and increased connectivity between pSTS and anterior precuneus. These increases may reflect a dysfunctional shift of attention induced by ketamine that leads to mentalizing deficits. Our findings show that a psychotomimetic dose of ketamine impairs mentalizing and influences its neural correlates, a result compatible with the notion that deficient glutamate signaling may contribute to deficits in mentalizing in schizophrenia. The results also support efforts to seek novel psychopharmacological treatments for psychosis and schizophrenia targeting glutamatergic transmission. These impairments affect community functioning more than impairments in other cognitive domains4. Deficits in mentalizing—the ability to infer mental states in others or oneself—can be observed across all stages of the disorder7 and can consist of over- or undermentalizing, corresponding to excessive or insufficient attribution of mental states to other agents8. While overmentalizing is more frequently associated with positive symptoms—paranoid thoughts often consist of attributing more intentions to social situations than are actually present—undermentalizing has been associated with negative or disorganized symptoms that numb experiences of the surrounding world, leading to diminished attribution of intentions to others10. Neural correlates of mentalizing deficits in schizophrenia include abnormal activation of the superior temporal sulcus (STS), anterior cingulate cortex (AC), bilateral temporo-parietal junctions (TPJ), medial prefrontal cortex (mPFC) and precuneus14. Both hypo- and hyperactivation of STS and precuneus have been reported during mentalizing16.People with schizophrenia frequently show deficits in social cognition, a cognitive domain comprising multiple processes including social cue perception, mentalizing, regulation of emotion and experience sharing18, deficits in these domains remain largely unchanged during the course of the illness19. At present, evidence about the use of antipsychotics targeting faulty dopamine-signaling via D2-receptor-binding to treat social cognition deficits appears inconclusive20. However, various studies point to a significant role of the glutamatergic N-methyl-D-aspartate (NMDA) receptor in the development of negative and cognitive symptoms. The mechanism by which NMDA-receptors are believed to contribute to the provenance of cognitive symptoms involves hypofunctioning of these receptors on gamma-aminobutyric acid (GABA) interneurons. In this hypothesis, impairment of these interneurons then leads to disinhibition of pyramidal cells in corticolimbic circuits. To test theories about deficient glutamate signaling and its connection to schizophrenia in a behavioural design, multiple studies have used NMDA-receptor antagonists to evoke psychosis-like states in healthy subjects or animals21. One such uncompetitive NMDA-receptor antagonist is ketamine. Mainly used to induce a narcotic state, it blocks the NMDA-receptor ion channels and thus the influx of 22.While in some instances social cognition or mentalizing were shown to improve upon treatment with atypical antipsychotics23. In a study of Phensy and colleagues, male mice postnatally injected with ketamine showed disrupted social investigation patterns when introduced to unfamiliar conspecifics24. Disruption of these patterns has repeatedly been shown in similar experiments with ketamine in the animal model26. However, mentalizing, a key social cognitive skill deficient in schizophrenia, is arguably best tested in humans. And while studies with human subjects have explored ketamine effects with respect to memory28, modulation of emotion-cognition interaction29, response inhibition30, probabilistic inference31, metacognition32 and processing of emotional faces33, to our knowledge, no study has investigated the influence of ketamine on mentalizing.Since discovery of its psychotomimetic qualities, subanesthetic ketamine has been used as a model for psychosis in humans and rodents34, a task on which patients with schizophrenia were shown to exhibit different mentalizing patterns than controls35. We expected volunteers subjected to ketamine to display more undermentalizing or no-mentalizing than individuals receiving placebo. We also predicted abnormal activation of brain regions associated with mentalizing.The aim of this study was to find out whether manipulating NMDA-receptor activation via ketamine would influence mentalizing and its neural correlates in healthy volunteers. We used a modified version of the Movies for the Assessment of Social Cognition (MASC) task by Dziobek and colleagues to assess the level of mentalizing X2  = 0.15, p = 0.701] or age .387 participants were recruited via online message boards at the University of Bonn and screened for eligibility via an online questionnaire between June 2019 and September 2020. Among 85 eligible participants, 70 participants  took part in the MRI study. Randomization algorithms were created by U.E. and all personnel except anesthesiologists remained blinded until preprocessing of fMRI data had been conducted. There were no significant differences between ketamine and placebo groups in terms of gender , cuneus , middle occipital gyrus , precuneus  and right pSTS . This pattern of findings is compatible with involvement of brain regions associated with social cognition during the social trials48.We expected social trials to evoke BOLD signal increases in social brain regions when compared to physical trials (control). This manipulation check was performed on the data of the placebo participant group creating a second-level model, using the SOC > PHY contrast images for the question part of the trial. Results Fig. A revealet(244) = 4.42, p(Corr) = 0.02; Fig. We proceeded to evaluate effects of ketamine on social cognition during the MASC by comparing, for each of the four trial parts, the social with the physical trials (SOC > PHY) between groups. We found a significant increase in BOLD signal in the ketamine group during presentation of the questions in a cluster located in the right posterior superior temporal sulcus region  and posterior cingulate gyrus . Decreases in connectivity with right pSTS during the social compared to the physical trials were found  =  − 5.14, p(Corr) = 0.002] as well as in middle occipital gyrus . In the ketamine group, clusters of voxels showing higher connectivity with the right pSTS during the question phase of the social compared to the physical trials were found in anterior precuneus  = 4.98, p(Corr) < 0.001) and left middle temporal gyrus ; clusters showing lower connectivity with the right pSTS in the social compared to the physical trials were identified in posterior precuneus  and superior occipital gyrus . Of particular importance for our study, a t-test for independent samples across participant groups revealed one cluster showing a larger difference in connectivity with the right pSTS between social and physical trials under ketamine compared to placebo, in the anterior precuneus .Clusters of voxels that exhibited increased functional connectivity with the right pSTS in the placebo group during the question phase of the social compared to the physical trials were found 49. In the present study, participants under ketamine also mentalized less . These findings lead to the question of how NMDA-receptor blockade by an agent like ketamine might cause a reduction in mentalizing, and whether such mechanisms might be occurring in schizophrenia or ASD. As previously mentioned, changes in glutamate signaling lead to dysfunctions in social cognition in animal models, in particular to a disruption of social preference 24, a key factor for the development of healthy social cognition that is deficient in schizophrenia50.The MASC task used here allows to characterize mentalizing deficits specifically by differentiating over- from undermentalizing51. Another MRS study revealed that healthy people with higher scores in an ASD/schizotypy-questionnaire, which quantifies social dysfunction, exhibit a higher glutamate concentration in the superior temporal region (ST) bilaterally and increased glutamate to GABA ratio in the right ST52. Links between increased glutamate and dysfunctions of mentalizing have also been reported in schizophrenia and ASD53. For example, a negative correlation between total glutamatergic metabolites in the left thalamus and social functioning has been found in people with schizophrenia54. In ASD, GABA receptor down-regulation is thought to lead to cortical disinhibition, which also leads to an increased excitation/inhibition ratio52. One study reported that higher glutamate levels in the right superior temporal cortex were related to poorer social and interpersonal skills in people with ASD, and that this relationship was increasingly strong when GABA was reduced55. Overall, there seems to be a functional link between altered glutamate signaling and complex social cognition in ASD and schizophrenia, the underlying mechanisms of which are not yet fully understood56.While no study has investigated the causal effects of acute blockade of NMDA-receptors on mentalizing in healthy volunteers, several correlational studies have linked high glutamate concentration, or high glutamate to GABA ratios, with social cognitive dysfunction. For example, glutamate concentration in dorsolateral prefrontal cortex of healthy participants measured with magnetic resonance spectroscopy (MRS) was negatively correlated with perspective taking scores in a task designed to assess empathy in people with schizophrenia and ASD57. Additionally, we cannot rule out the possibility that stress might be a mediator driving changes in behavior. A study found that ketamine evoked stress-like alertness in healthy participants58 correlating with hyperconnectivity of hippocampus and precuneus at rest. As such, an alternative explanation to our findings might be that participants experience stress as result of changes to their perception, which in turn leads to a well-established, stress-induced decrease of memory function, resulting in worse performance in a variety of tasks. This possibility should also be addressed in future studies when looking at effects of ketamine on task performance.Our results support this hypothesis by demonstrating causal alteration of mentalizing in participants undergoing NMDA-receptor blockade by ketamine. We note that we cannot make conclusions specific to mentalizing, as performance in the non-social condition of our task was also reduced under ketamine. The lower performance observed in both the control and social cognition conditions within the ketamine group can possibly be partly attributed to the dissociative effects of ketamine14. However, activations in cuneus and middle occipital gyrus are not typically linked to the mentalizing network, and may reflect the complexity of the task structure, in which multi-part trials build sequentially on each other in the social condition. Ketamine increased differences in the right posterior STS BOLD signal evoked by answering a question related to emotions or intentions of others , compared to a non-social control question. Activation in the pSTS, particularly in the right hemisphere, is frequently observed during mentalizing59. For instance, a meta-analysis by Schurz and colleagues revealed that mentalizing evoked by different sets of social animation tasks was associated with a high probability of activation in the right pSTS60. Our results are also compatible with findings in participants with schizophrenia: for example, one study using comic strips reported increased activity during mentalizing compared to a non-social control task in a very closely located pSTS-cluster13, while a different study using static face stimuli reported higher activation in another right pSTS location during mentalizing compared to emotion recognition in patients compared to controls16. Repeatedly observed hyperactivity of pSTS in schizophrenia during social tasks led the authors to state increased BOLD activity in pSTS might constitute an endophenotype of schizophrenia61. Severity of positive symptoms was positively correlated to observed disinhibition of pSTS during social cognition in another recent study62. The authors used dynamic causal modeling to estimate connectivity between two brain regions active during motion perception  and found that connectivity increased between V5 and pSTS in patients, concluding that this increased connectivity might contribute to wrongful attribution of social states to agents.At the neural level, we found activation in left pSTS, cuneus, middle occipital gyrus, precuneus and right pSTS during the question phase of the MASC in the placebo group during our manipulation check. Some of these regions (pSTS and precuneus) are part of the mentalizing network and are thus typical of activations expected in a social cognition task64. The fact that, compared to other studies, we found decreased connectivity with cuneus and middle occipital gyrus could potentially be attributed to the complexity of the naturalistic mentalizing task performed by our participants or the use of PPI to investigate functional connectivity in our study. Decreased connectivity between these regions might reflect the participants’ attempt to focus more on social situations and less on objects65. When compared to ketamine, one cluster in the anterior precuneus showed a larger difference in connectivity between the social compared to the physical condition under ketamine. Generally, activation in anterior precuneus is frequently observed during mentalizing66 and self-related consciousness in healthy participants67. One study in healthy participants reported increased task-based connectivity in the network of the dmPFC, pSTS and precuneus during a task evoking spontaneous mentalizing68. The authors concluded that the integrative functions of the precuneus, along with its association with self-awareness might explain why social cognition tasks lead to an increase in connectivity between these regions. Findings from two studies in patients with schizophrenia support this idea: increased perfusion of the precuneus, measured with single photon emission computed tomography, was correlated to better insight into one’s own mental disorder67, while functional connectivity of precuneus negatively correlated with apathy in another study69.Several regions showed changes in functional connectivity with the seed cluster under placebo during the question phase : connectivity with STG and posterior cingulate increased, possibly reflecting reasoning about mental states of others and oneself70. However, also more abstract tasks that involve animacy and biological motion have been linked to connectivity between right pSTS and precuneus in healthy participants71. This is unsurprising, as both precuneus and pSTS play an important role in the mentalizing network. Increased functional connectivity between pSTS and precuneus in patients with schizophrenia compared to controls was found during processing of ambiguous word pairs that could be understood either literally  or as part of a metaphor 72. These connectivity findings may be related to abnormal glutamate and GABA signalling in schizophrenia, as these neurotransmitters are known to modulate functional connectivity in the healthy brain73. What might our functional connectivity findings represent? The authors of the above-mentioned study proposed that increased precuneus-pSTS connectivity reflects their patients’ attempt to compensate for their impaired metaphor comprehension72. Thus, both in schizophrenia and in our ketamine study, the increases in precuneus-pSTS functional connectivity may represent neural correlates of an attempt to compensate for abnormal neurotransmission. In this context, functional connectivity with precuneus might reflect a shift of attention, as observed e.g. during attentional deployment for emotion regulation when the attentional focus is moved away from negative emotional stimuli such as a car accident and towards something else. One study reported increased precuneus-to-amygdala functional connectivity when participants could freely view unpleasant images and focused their gaze on a non-arousing region74. Following this idea, we could propose that our connectivity finding represents a dysfunctional shift of attention away from a mentalizing perspective (needed to correctly identify intentions or emotions of others) and towards a more concretistic layer of attention . For patients with schizophrenia, this finding might imply that they miss social cues due to their heightened attention towards non-social attributes of their surrounding environment. This in turn might lead to difficulties with social interactions and thus, finally, to social avoidance, leading to diminished social functioning3. The scarcity of pSTS-related connectivity findings in schizophrenia, however, constrains our interpretation attempts and calls for additional research.Coactivation of pSTS and precuneus in healthy participants has been observed during naturalistic social tasks involving reasoning about emotional and mental states of othersLimitations in our study concern the behavioral task, the ketamine-model for psychosis and whether changes evoked by ketamine reflect changes in glutamate-signalling. In our task, participants relied both on visual and acoustic features of the video clips to perform the social task, while solely visual information mattered in the physical condition, which yields asymmetry between the conditions.75) compared to the PANSS levels observed during clinically relevant psychotic symptoms in schizophrenia .Therefore, comparisons between the effect of our manipulation and the effect of psychosis in schizophrenia on mentalizing should be made with caution. In addition, blinding is difficult in ketamine studies77, partly due to nausea and disorientation at the start of the ketamine infusion57. To minimize these effects, we only recruited ketamine-naïve participants who were unlikely to be able to tell whether their experience was related to ketamine or to undergoing MRI. As using a control substance such as midazolam might result in unwanted influences of neural activation78, we decided against this strategy. Conclusively, blinding in our study may have been single- rather than double-blind, in particular for the ketamine-receiving group.A limitation of the ketamine-model for psychosis comes from the smaller impact on PANSS levels of ketamine (mean of 40 in our and similar studies80. An early study reported that the direction of these changes in the prefrontal cortex varied as a function of the amount of ketamine administered81. Unfortunately, as of today, no studies have explored direct manipulation of the glutamatergic system within our regions of interest, i.e., pSTS or precuneus. Future studies could therefore explore the direction of change in glutamatergic transmission following administration of subanesthetic doses of ketamine in mentalizing regions.Finally, since we did not measure glutamate levels after administering ketamine, conclusions about whether the fMRI results were caused by changes in glutamate transmission cannot be drawn. Even though most MRS studies showed that ketamine causes changes in glutamatergic transmission in anterior cingulate, not all studies were able to replicate these effectsTaken together, our findings show that people who received ketamine were exhibiting neurocognitive and social cognitive deficits in a naturalistic mentalizing-task. They mentalized less and demonstrated changes in BOLD-activity and task-related connectivity in right pSTS and precuneus, hinting to how glutamatergic neurotransmission might be tied to emergence of these deficits in disorders like schizophrenia.Supplementary Information.


Different ecosystems evolved and are maintained by fire, with their vegetation hosting species with a wide diversity of persistence strategies allowing them to insulate their body and resprout new branches after fire disturbance. Changes in fire regime are predicted due to climate change, either by promoting more frequent and/or severe fires or by reducing the number of fire events due to the limitation of fuel load. Predicting the future of fire-driven ecosystems is a complex task as species’ survival depends on many factors that vary in space and time. Since plants are constantly experiencing new environments as they grow through meristem development, woody plant modularity, modules morpho-physiological aspects and their integration should be considered when investigating species strategies in fire-prone ecosystems: according to their position and their tissue composition, plants’ modules experience fire differently and will contribute differently to other modules and the whole plant survival, with consequences cascading over the overall vegetation structure. Growth modules may hold the key to understanding how fast plants can get protected from fire, ultimately helping us to predict which species will persist across changing fire regimes. We present an empirical example showing how different fire-return intervals translate into distinct pressures on the timing, protection and location of modules, and discuss how these can translate into modifications in the vegetation structure due to climate change. The response of woody plants to fire is influenced by the timing and spatial distribution of their growth modules relative to the flames. Predictions suggest changes in fire regimes for different vegetation types, emphasizing the need to understand which plant species will thrive and the underlying mechanisms enabling their survival. Considering the modularity of plants over time and space is essential. As plants develop through growth modules' production, their modules can gain increased protection against flames. Additionally, new modules produced farther from the direct impact of the flames may survive by being exposed only to the flame plume. Importantly, the survival capacity of modules during a fire is strongly dependent on trait expression (such as bark production and bud protection) and heat transference from one module to another. The recognition that plants are composed of different parts has been present in the field of botany since its earliest days . How theFire-related plant strategies are closely related to each fire-adapted species’ life history and changes across ecosystems with different fire regimes—that is, fire’s size, frequency, intensity, season and extent . Fire reAmong the many fire-prone ecosystems on earth, tropical grassy biomes have been gaining attention from both the scientific community and decision-makers since they encompass a wide range of vegetation types, from open grasslands to woody savannas  and provIn the frequently burned savannas, the woody vegetation is usually primarily composed of sub-shrubs and forbs capable of storing most of their biomass belowground . Trees aWoody species can persist in fire-prone vegetation types through a variety of strategies, but how they will respond to changing fire regimes remains unclear. Climate change affects some of the core climatic variables affecting fire regimes and should—in most parts of the world—create conditions for novel fire regimes. Future scenarios predict for different regions increases in the number of fire events as a response to extreme weather or longer fire intervals due to fuel limitation , we urgeWoody plants develop through repeating developmental units whose properties are shaped by both endogenous and exogenous processes and constraints . During 4 grasses. This fire regime leads to higher fire-induced damages to structures closer to the ground and to the grassy layer, as the temperatures during fire events are much higher closer to the ground and decrease sharply with increasing height  above the flames and around the plant body  to closed savannas  have a continuous layer of C4 grasses covering ~80% of the vegetation and scattered short trees (up to 4 m); woody savannas (cerrado sensu stricto) present less grassy cover (up to ~50%), and a denser woody layer composed of taller trees : this species grows both as a tree and a shrub  and Handroanthus ochraceus (Bignoniaceae)  , and 4. M. albicans (M. albicans developing as a shrub in open savannas and as a short tree in woody savannas (The height at which plant resprouts is highly informative of their ability to tolerate fires of different severity (albicans  and B. Isavannas .M. albicans and are likely to be favoured under changing fire regimes. Hence, assessing their commonality and distribution across different fire-prone ecosystems can offer important information about how changes in fire regimes will impact different species and vegetation types worldwide.Finally, there is a need to investigate how plastic protection against fire can be. The strategies of species in fire-prone ecosystems to persist and survive have been identified along the spectrum of either growing in diameter or prioritizing the elongation of shoots—Corky and Lanky strategies . This stWoody species present a wide diversity of traits and strategies allowing them to survive fire, reflecting the high diversity of fire regimes. Therefore, there is a need to investigate in more detail the diversity of fire persistence traits to predict which species will prevail when fire regimes become altered by climate and land uses and why. Thus, we urgently need to study plant responses at the module level, because these responses are sensitive to the modules position relative to the flame height, and they are determined by ontogenetic patterns that translate into plants being protected fast or slow, depending on the ability of plants to cope their development with the environment. Studying fire persistence traits of woody plants and their inclusion in intermediate strategies should be considered priority tasks, since the structure of open ecosystems is strongly affected by changes in woody plant density worldwide, as a result of altered fire regimes.Further studies should focus on how modules at different stages of development are impacted by various heat fluxes considering their vertical distribution in relation to the flames, and how the surviving modules avoid post-fire death caused by second-order effects such as hydraulic failure and vital inner tissues’ necrosis. This approach offers a promising opportunity for us to understand how long it takes for woody plants to become protected from fire either by positioning their foliage and aerial buds in strata where fire induces non-lethal damages or by becoming insulated against the flames. By doing so, it will be possible to assess which strategies will be more likely to allow species to prevail under changing fire regimes, allowing us to direct conservation efforts to the most vulnerable species to these changes.


Aripiprazole is a third generation atypical antipsychotic and a dopamine serotonin system stabilizer, effective against positive and negative symptoms of schizophrenia. Within the group of atypical antipsychotics, aripiprazole shows a relatively benign safety profile , although the reported rate of extrapyramidal side effects is measurable.Oculogyric crisis (OGC) is a rare movement disorder characterized by a prolongued involuntary upward deviation of the eyes, lasting minutes to hours. In most cases, OCG is a drug-induced adverse event with acute or tardive onset often attributable to a functional impairment of dopaminergic neurotransmission.OGC is seldom reported in children and young adults during treatment with aripiprazole, althouh it is commonly used in youths.We report a case of an aripiprazole-induced oculogyric crisis in a 19 year old girl who diagnosed with schizophrenia (paranoid).There was a complete remission of the OGC’s following aripiprazole dose reduction, suggesting the clinical manifestation was a dose-dependent phenomenon.The present report should raise awarness among clinicians for this relevant possible adverse event, that can happen also with the use of aripiprazol, not only with typical or more antidopaminergic antipsychotics. Future research in the field should emphasize neurobiological dysfunctions as the basis of EPS/OGC in patients.None Declared


Physical activity (PA) in the form of aerobic exercise (AE) preserves and improves neurocognitive function across the lifespan. However, a mechanistic understanding of the pathways by which aerobic exercise impacts brain health is still lacking, particularly with respect to stress-related pathways. One mechanistic hypothesis is that AE improves neurocognitive health in part by modifying circulating levels of stress-related hormones and signaling factors associated with the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), as commonly measured by the biomarkers cortisol (CORT) and salivary α-amylase (sAA). Thus, this hypothesis predicts that changes in stress biomarkers, such as CORT and sAA, are possible explanatory pathways mediating the positive effects of AE on neurocognitive health. In the present review article, we provide a summary of available studies examining the possibility that exercise-induced changes to stress biomarkers could partly account for exercise-related improvements in neurocognitive health. Our review indicates that despite the intuitive appeal of this hypothesis, there is insufficient evidence available to conclude that chronic and habitual AE affects neurocognitive health by altering stress biomarker pathways. The cross-sectional nature of the majority of reviewed studies highlights the need for well-controlled studies to adequately test this hypothesis. Physical activity (PA), in the form of aerobic exercise (AE), is an accessible and cost-effective non-pharmaceutical approach to preserve and improve neurocognitive health across the lifespan . UnfortuThe purpose of this scoping review is to 1) summarize and synthesize the results of AE interventions measuring stress biomarkers such as CORT and sAA and 2) determine their relationship to neurocognitive changes associated with AE training. Before we discuss the evidence for stress biomarker changes due to AE in relation to neurocognitive improvements, we will first define the relationship between stress biomarkers, stress exposure, and neurocognitive function, as they will be used throughout the following sections.a set of constructs representing stages in a process by which environmental demands that tax or exceed the adaptive capacity of an organism occasion psychological, behavioral, and biological responses that may place persons at risk for disease”  by internal or external adverse forces , termed stressors ” hypothesis proposes that exercise can facilitate diverse adaptive physiological responses  affecting the HPA axis and the ANS  there is substantial evidence that acute bouts of AE transiently increase CORT levels, but ii) promising–but methodologically weaker-evidence that chronic exposure to AE attenuates the CORT response to psychosocial stressors .There is a wealth of data demonstrating that acute bouts of AE transiently elevate CORT levels . This acInterestingly, a different CORT dynamic has been observed during longer bouts of exercise (>2 h). In this case, there is an initial increase in CORT after 20–30 min of exercise followed by a decrease in CORT , and finally, a second increase in CORT after ∼2-h of exercise, with this second rise more pronounced in trained individuals . This biThere is also evidence that acute bouts of AE influences stress reactivity after ending the exercise exposure. For example, In contrast to the studies on acute exercise, the effect of more chronic exercise behaviors and interventions on CORT levels is more equivocal. Complicating this issue is lack of clarity regarding the amount of exercise exposure needed to be considered ‘chronic’ or ‘habitual’. Unfortunately, intervention studies that increase exposure to AE over long periods of time  and examine basal levels of CORT or changes in CORT in response to a stressor remain relatively sparse and have methodological limitations that prevent definitive conclusions . For exaMost studies examining the effect of regular exercise behaviors on the HPA axis emerge from cross-sectional work examining whether self-reported engagement in exercise or measurements of fitness or PA levels are associated with individual variation in patterns of CORT responses. Several studies have reported that higher cardiorespiratory fitness levels are associated with reduced physiological responses (including CORT reactivity) to acute AE bouts compared to lower-fit individuals when exercising at the same intensity . Yet, a CSA hypothesis postulates that favorable adaptations to AE that occur due to repeated exposure to exercise could be generalized to responses to other challenges in daily life  is also likely contributing to the heterogeneity of findings across studies.In contrast to the detrimental effects of chronic stress, engaging in exercise exerts beneficial effects on cognitive and brain outcomes  . Many syThere are multiple possible pathways explaining how exercise influences neurocognitive health. Animal models have shown that voluntary exercise affects neurogenesis and neuronal survival in the dentate gyrus subfield of the hippocampus . Also, hBecause of the associations between AE and HPA-axis biomarkers, HPA-axis biomarkers and cognitive function, and between AE and cognitive function, it has been speculated that exercise-induced modifications in HPA-activity and stress-reactivity could be one mechanism by which the cognitive effects of exercise are realized.In this section, we describe the evidence that examines whether AE-induced or PA-induced changes in stress physiology could be a plausible biological pathway by which exercise influences cognition. For instance, Gothe et al. (2016) found that an 8-week yoga intervention in sedentary older adults (N = 118) improved working memory performance and this improvement was mediated by an attenuated CORT response . This stThe few studies that have examined the effects of AE interventions on cognitive function and peripheral measures of HPA and SNS activity show mixed results . Baker aCould the effects of acute exercise on cognitive outcomes be mediated by changes in stress biomarkers? We found only two studies that have included sAA and cognition measurements in the context of PA . One stuThere are three main sources of heterogeneity in the methods and results across studies that have examined links between exercise, cognition, and stress biomarkers. First, different collection methods, and intervals of collection for stress biomarkers are used across studies. This variation makes it difficult to understand the outcomes and interpretations of the CORT, sAA, or other results. Second, there is significant heterogeneity in the length and types of exercise interventions employed without clearly defined parameters. Since there is evidence that this impacts CORT and sAA (as well as brain and cognition), this heterogeneity is likely contributing to the various patterns of results. Third, studies were conducted in highly diverse samples, ranging from children to older adults and from healthy to patient groups. This makes it difficult to understand whether stress pathways are a possible mechanism for exercise-related changes in cognition as the sample characteristics could conflate the outcomes. For instance, the secretion of CORT and sAA varies across the lifespan .The present review summarized the results from studies examining associations and effects of AE and PA with markers of peripheral pathways that respond to stress, particularly CORT and sAA, and how these patterns might relate to neurocognitive changes associated with AE. We, and others, have speculated that the neurocognitive benefits of exercise might be mediated by exercise-induced changes in the activation of stress pathways . Our conWhereas psychological stress impairs cognitive functions, exercise has been shown to exert physiological, psychological, and cognitive benefits. Stress biomarkers such as CORT or sAA have been discussed as possible neuroendocrinological explanatory factors of exercise induced cognitive changes . However, there is an absence of studies that have examined biomarkers of HPA axis or ANS activities as proxies for the mechanisms underlying the neurocognitive benefits of AE training. In fact, only a few AE interventions to date have measured both stress biomarkers (CORT and/or sAA) and cognitive outcomes in the same study. However, these studies have been focused on acute effects of AE interventions. Because of the wealth of controlled laboratory data of acute exercise effects on stress biomarkers, it can be hypothesized that the acute exercise-induced benefits to cognition are mediated through this pathway. But the lack of long-term well-controlled laboratory exercise experiments or randomized exercise interventions on changes in stress biomarkers limits support for the hypothesis. Most of the literature in this area emerges from cross-sectional studies or are of short duration. In contrast, there is a wealth of literature about chronic stressors and stress biomarkers on neurocognitive function and the benefits of long-term exercise behaviors. But, as described above, studies that have linked exercise-induced changes in stress pathways to neurocognitive changes are scarce. More longitudinal and RCT studies are needed to examine the impact of long-term exercise or dose of exercise on CORT and sAA, and whether changes in CORT and/or sAA mediate exercise-induced neurocognitive benefits.On the other hand, it has been suggested that dysregulation of stress reactivity may represent a mechanism by which psychological stress contributes to the development of future health and disease outcomes . Similarly, early life exposure to stressful events can have protracted effects on the brain and cognition, which might be mitigated by engagement in exercise behaviors . Following these lines, a protective effect over allostatic load has been attributed to exercise, where AE seems to improve stress reactivity leading to a better stability through stressful events that harm body homeostasis. Although acute exercise seems to influence stress reactivity , the evidence is limited by mostly cross-sectional studies instead of laboratory-controlled exercise interventions. Therefore, whether chronic exercise in the context of controlled manipulations show modifications in sAA or CORT levels or reactivity remains an open question.versus those with clamped “normal” cortisol.In conclusion, we know that while acute and chronic exercise promotes cognitive and brain health, acute stress is detrimental and chronic stress exposure is closely linked to many diseases and psychological conditions like anxiety or depression. The benefits of acute and chronic exercise on cognitive function and stress reactivity have been extensively covered in the literature; however, no studies have examined the long-term effects of exercise on stress pathways as a mediator for cognitive improvements. Based on this, our conclusion from this review is that a greater number of well-controlled studies are needed to adequately test the hypothesis that exercise-induced changes in the activation of stress pathways might mediate neurocognitive benefits of exercise. Furthermore, developing novel models that focus on different populations, such as those with primary adrenal insufficiency (Addison’s disease), may aid in understanding the effects of exercise on neurocognitive metrics in individuals with normal cortisol responses


Background and Objectives: Trigger points (TrPs) are prevalent in patients with migraine headaches. Needling interventions targeting TrPs in migraine patients may reduce the intensity and frequency of headaches, yet systematic reviews reveal a lack of robust evidence. Intramuscular electrical stimulation (IMES) is a modality that delivers electrical current into muscles and TrPs, with recent studies suggesting it may amplify the therapeutic effects of dry needling peripherally and centrally. This could be advantageous for patients with migraine and symptomatic TrPs. Materials and Methods: This study will implement a multiple baseline single-case experimental design (SCED). In a clinical setting, a SCED study lends itself to conducting research with only a few patients that each serve as their own controls. In this SCED study, four participants with chronic migraine will be enrolled in a non-concurrent manner and randomized to one of four baseline measurement periods , leading to four potentially different start dates for each participant in the intervention phase. During the intervention phase, patients will receive five sessions of dry needling with IMES, one session per week for five weeks. The primary outcome measure will be headache frequency, i.e., the reduction in the number of headache days over a one-month period using electronic headache diary data from the Migraine Buddy smartphone application. Secondary outcome measures will be changes in mean migraine pain intensity using a numeric pain rating scale (NPRS), migraine disability using the Migraine Disability Assessment Test (MIDAS), the Headache Impact Test (HIT-6), and changes in selected cervical musculoskeletal impairments including pressure pain thresholds (PPTs) over TrPs, the craniocervical flexion test (CCFT), and cervical active range of motion (AROM). Primary and secondary outcome measures will be analyzed separately using both visual and statistical analyses. Results: Actively recruiting participants. This project was approved by the Mass General Brigham Institutional Review Board (protocol #2023P000931) and is registered with ClinicalTrials.gov (NCT05893914). Conclusions: This study will seek to determine the effects of a five-week intervention period of IMES to TrPs in the posterior cervical muscles of subjects with chronic migraine. Migraine is a recurrent headache disorder characterized by attacks lasting 4–72 h with a range of associated symptoms and degrees of severity . It is aSeveral studies have demonstrated a high prevalence of trigger points (TrPs) in patients with migraine compared to healthy controls  and in mNeedling interventions targeting TrPs in patients with migraine show favorable reductions in the intensity and frequency of headaches ,22,23. YTo our knowledge, no studies have investigated the effects of IMES on TrPs in the posterior cervical muscles in patients with chronic migraine. This exploratory study will implement a single-case experimental design (SCED). The use of a SCED study lends itself to conducting research in a clinical setting with few patients that serve as their own controls. Single-case experimental design studies have long been used in the education and psychology professions, but more recently have been implemented in medical and rehabilitation research, including physical therapy ,30. In SThe primary aim of this proposed pilot study using a single-case experimental design is to investigate the effects of five weeks of IMES for the treatment of TrPs on the frequency of headaches in a small sample of patients with chronic migraine. Additionally, the secondary aims of this study will be to evaluate the effects of IMES on mean headache intensity, overall headache impact, disability, and the influence of IMES on various cervical musculoskeletal impairments.This study protocol and subsequent experiment will follow the Single-Case Reporting Guideline in Behavioral Interventions (SCRIBE) 2016 . This prThis SCED study will recruit four participants with chronic migraine, in a non-concurrent manner. A recent systematic review recommended an average of four participants across SCED studies using a multiple-baseline design . PatientTo be eligible, patients must be adults between the ages of 18 and 65 years. Participants will be included if they have at least a 6-month history of headaches consistent with a diagnosis of chronic migraine headache according to International Headache Society (IHS) criteria [Participants will be excluded if they have other primary or secondary headache diagnoses, including medication overuse headache; cervical radiculopathy; cervical spondylosis or stenosis; previous surgery in the cervical spine region; history of whiplash; pregnancy; a current diagnosis of fibromyalgia; received TrP injection, anesthetic blocks, radiofrequency lesioning, botulinum toxin injections, acupuncture, dry needling, or physical therapy treatment within the past 12 months for the treatment of neck pain or migraine headache.Before the clinical examination procedures begin, eligible patients based on pre-screening criteria, must sign the informed consent form indicating their willingness to participate in the study. Once signed, all participants will first undergo a comprehensive subjective history followed by various clinical examination tests to determine full eligibility, which will all be completed by the principal investigator who is a licensed Physical Therapist with board certification as an Orthopedic Clinical Specialist with over 15 years of clinical experience. All participants will undergo a manual examination for TrPs in the posterior cervical muscles using diagnostic criteria supported by expert consensus . ThroughTo ensure a comprehensive examination of the cervical spine in participants with migraine, cervical range of motion, manual joint testing, and the flexion-rotation test (FRT) will be assessed . In addiDuring the intervention phase, patients will receive five sessions of dry needling with IMES, one session per week for five weeks total during the intervention phase. Dry needling will be delivered by a Physical Therapist  who has over 10 years of clinical dry needling experience and is certified by a course program that provides 80 h of dry needling instruction. Sterilized disposable stainless-steel needles will be used and will include one standard size, 0.30 mm × 50 mm APS needles . Dry needling will be applied to TrPs in at least two of the following posterior cervical muscles: splenius capitis, splenius cervicis, semispinalis capitis/cervicis, cervical multifidi (from C2–4), and obliquus capitis inferior. These muscles were chosen because they receive innervation from the upper cervical dorsal rami and therefore may influence the TCC. Trigger points will be treated on the side of the headache or bilaterally if they are present. For the posterior cervical muscles, they will be treated as one muscle group with all needling to be performed posterior to the transverse processes and lateral to the spinous processes of C2 to C6. A medial–caudal–ventral approach will be used, progressively treating deeper toward the lamina of the caudal vertebrae while monitoring for reproduction of symptoms  and for a local twitch response (LTR). A LTR is characterized by a contraction of part of the taut band when needling a sensitive area within a TrP and is often used clinically to confirm the needle has reached a trigger point ,59. SincFollowing elicitation of an LTR, needles will be left in place and connected to a charge generating device, the ITO ES-160 unit , For this study, the reduction in headache frequency, which is the reduction in the number of headache days over a one-month period, will be the primary outcome measure . The priSecondary outcome measures will include the Headache Impact Test-6 (HIT-6) and the Migraine Disability Assessment Test (MIDAS). The HIT-6 is a six-item questionnaire assessing headache severity and change in a participant’s clinical status over a short period of time (4 weeks) . The MIDIn this SCED study, the primary and secondary outcome measures will be analyzed separately using both visual and statistical analyses. First, we will conduct an exploratory data analysis to observe within- and between-phase patterns in the data with emphasis on level (mean score for the data), trend (slope), variability (spread of data points), and overlap  ,31,78. TA longitudinal mixed-effects statistical model  will be used to analyze the overlap between baseline to post-intervention for all outcome measures , provideNeither the participants nor the principal investigator will be blinded to baseline period allocation. Due to the nature of the intervention, the clinician  will not be blinded to the intervention. Statistical analyses will be conducted by an independent statistician.Monitoring for adverse events (AEs) will be performed at each treatment visit by the principal investigator and will be recorded on the participants’ behalf using the headache diary. Participants will be given an informative handout describing what steps to take in the event of an adverse reaction to dry needling, and participants will be advised to immediately seek medical attention and notify the principal investigator and their physician. Possible minor side effects of dry needling may include temporary pain during needling, numbness or tingling, minor bleeding, bruising, drowsiness, tiredness, dizziness, and possible fainting . More siIn this exploratory study, our primary aim is to determine if a five-week intervention with IMES to TrPs in the posterior cervical muscles of participants with chronic migraine leads to a reduction in the headache frequency. Our secondary aims are to assess the effects of IMES on headache pain intensity, migraine disability, overall headache impact, and on selected cervical musculoskeletal impairments, including PPTs, CCFT, and cervical AROM. Trigger points may serve as a perpetuating factor of migraine symptoms by activating nociceptive pathways that project to convergent dorsal horn neurons in the TCC. On the other hand, in some cases, TrP-related pain could merely be comorbid with chronic migraine and represent a nociplastic phenomenon that is more reflective of central sensitization . Based oThis study design has several limitations. First, participants will be enrolled in a non-concurrent manner due to the impracticality of having all patients begin the baseline measures simultaneously. Second, as we have stated previously, neither the participants nor the principal investor will be blinded in any phase of this study. Absent or ineffective blinding in dry needling studies has the potential to exaggerate the specific effectiveness of dry needling interventions ,89. AsseCurrent management for chronic migraine relies heavily on prophylactic drug treatments, yet the adherence to preventative medications in patients with chronic migraine is low and worsens with the duration of medication use . Since tThis study will seek to determine the effects of IMES to TrPs in the posterior cervical muscles of participants with chronic migraine. Intramuscular electrical stimulation over a five-week intervention period could demonstrate an improvement in headache outcomes in patients with chronic migraine.


In the context of historic reckoning with the role of the criminal-legal system as a structural driver of health harms, there is mounting evidence that punitive drug policies have failed to prevent problematic drug use while fueling societal harms. In this explainer article, we discuss how simulation modeling provides a methodological framework to explore the potential outcomes  of various drug policy alternatives, from incremental to radical. We discuss potential simulation modeling opportunities while calling for a more active role of simulation modeling in visioning and operationalizing transformative change.This article discusses opportunities for simulation modeling in projecting health and economic impacts  of drug-related criminal justice reforms.We call on modelers to explore radical interventions to reduce drug-related harm and model grand alternative futures in addition to more probable scenarios, with a goal of opening up policy discourse to these options. In the face of this crisis, many evidence-informed policy and clinical responses  have demonstrated efficacy yet remain underutilized.The overdose crisis has unfolded over the past 2 decades and surged during the COVID-19 pandemic in the United States. While incarceration is associated with poor health outcomes generally, punitive drug policies and incarceration of people who use drugs are also associated with an elevated risk of drug overdose, HIV, hepatitis C virus, and tuberculosis.35At the same time, criminal-legal responses to illicit drug use remain heavily resourced and disproportionately affect people of color—despite mounting evidence that the war on drugs has failed to prevent problematic drug use while fueling societal harms including disruption of community and familial bonds and exclusion from the formal labor market. Such reenvisaged drug policies include diversion and deflection interventions , discretionary policing , depenalization , decriminalization , outright legalization of particular substances , prison abolition , and more. In practice, each of these policy changes could be written and enacted in different ways and therefore vary in both structure and impact.Frustrated by the failure of incrementalist reforms, social movements focused on racism, police violence, the carceral state, and drug policy are calling for a reenvisioning of how societies tackle these core challenges. Currently, more than 50 US counties and tribes are implementing diversion or deflection programs. Calls for decriminalization of drug use have led to policy change in some jurisdictions. The Netherlands, Czech Republic, Portugal, and Mexico, among other countries, have implemented various types of decriminalization reforms. In Canada, the province of British Columbia has begun a 3-y trial of decriminalization of personal possession of opioids, crack and powder cocaine, methamphetamine, and MDMA. In 2021, Oregon became the first US state to decriminalize drug use and expand access to addiction treatment and harm reduction services, More narrowly, nonmedical use of cannabis is legal in 23 US states and decriminalized in 8 states as of 2023.A recent Lancet Commission on “Responding to the Opioid Crisis in North America and Beyond” recommended that “policies of incarcerating individuals for illicit possession of opioids or drug-related equipment intended for personal use should be abandoned because they present significant public health risks without offsetting public health or public safety gains.”8 A complex debate about public safety policy is ongoing with special focus on benefits versus harms of continued investment in policing, prisons, and other elements of the carceral system.Public safety challenges and their perception drive investments in policing and other carceral systems. Residents of low-income communities and communities of color report increasing concerns regarding crime and public safety. In many cases, such concerns are framed in terms that assume a link between policing and other security elements on the one hand and safety on the other. Proponents of strict sentences for drug-related crimes argue that the benefits offset the harms and that these policies deter drug use and associated crime. Although an effective police presence can deter crimes against persons, claims that public safety is enhanced though harsh criminal-legal sanctions focusing on drug use and sales are seldom confirmed.Simulation modeling provides a methodological framework to explore the potential outcomes  of various drug policy alternatives, from incremental to radical. However, the role of simulation modeling in operationalizing the health and health economic outcomes of this vision remains underexamined. The following commentary arose from a panel discussion presented November 10, 2021, at the Opioid Overdose Modeling for Policy Change Webinar that sought to explore these questions.Epidemic and economic simulation modeling can aid policy makers in forecasting the population impact (both benefits and harms) and cost-effectiveness of different policy options. This is particularly useful when randomized trials are infeasible or difficult  or when trials are feasible but limited in their ability to track long-term outcomes  and multiple outcomes . Simulation models can provide a synthetic “test lab” to integrate data from multiple studies and estimate the complex and often interacting long-term health and economic impacts of policy changes. These simulation models can range in complexity from the relatively simple (decision tree or Markov models) to more sophisticated , depending on the question and data availability.10 there remains utility in using scenario modeling to explore potential policies and outcomes even prior to more widespread policy changes. As effectiveness data accumulate in settings exploring various types of drug decriminalization and diversion, modeling can be a critical tool in evaluating the current and future impact of these programs.Modeling can be useful both before an intervention or policy change occurs  or after an intervention (to assess observed impact and project future long-term population impacts). Although there is currently only sparse and inconsistent data in select settings on effectiveness of more radical criminal justice reform policies  on justice involvement and health outcomes among substance using populations, A follow-on study found that if MOUD was prescribed to all persons for whom it was clinically indicated in 2016, 1,840 deaths would have been prevented in the United States, with an additional 440 prevented if MOUD had been provided while they were incarcerated and postrelease. A modeling analysis in Australia showed that opiate agonist therapy  provision reduced overdose and other-cause mortality among people who received it by 53% from 2001 to 2020 and that postincarceration OAT linkage accounted for 12% of the deaths prevented. Cost-effectiveness models of post-incarceration MOUD have generally focused on economic implications of reducing recidivism, but one evaluation of OAT upon prison release in Australia found it cost-effective in reducing mortality. In addition, a recent economic evaluation in Massachusetts found that providing all 3 MOUDs to incarcerated individuals and on release would prevent overdose and is more cost-effective compared with a naltrexone-only strategy. Importantly, community interventions can also have criminal justice impacts; one US study found that MOUD in the community reduces both health and criminal justice costs (through the impact of MOUD on reducing recidivism).To date, most models assessing the health impact of interventions in carceral settings for people who use drugs have studied incremental reforms and focused narrowly on impacts in one health domain, such as opioid overdose. For example, a modeling study in Rhode Island showed that medications for opioid use disorder  at release from prison or jail would avert 5.8% of overdose deaths from 2017 to 2024.1620 and can reduce HCV incidence in the community. Similarly, models have shown HIV testing and treatment in prison, jails, or on release is cost-effective in preventing HIV transmission the United States.2124Other models have focused on corrections-based treatment programs for infectious diseases associated with substance use disorder, such as HIV and HCV. These models examined the impact of HCV testing and treatment programs in prison in the United Kingdom, Canada, Australia, Ireland, and the United States, showing initiatives are cost-effectivesupervised consumption sites). OPCs are places where individuals can consume preobtained drugs monitored by staff who can intervene if an overdose occurs. Modeling studies based on Canadian data indicate OPCs are effective in preventing HIV, HCV, and overdose and are cost-effective in Canada.2529 Theoretical modeling studies indicate OPCs could be effective and cost-effective in reducing HIV, HCV, overdose, skin and soft-tissue infections, and bacterial infections among people who use drugs in US settings.3033Numerous modeling studies have explored the potential impact of a highly localized form of drug decriminalization, enacted through overdose prevention centers  over 10 y. A study of Mexico’s 2012 public health–oriented drug law reforms, which depenalized drug possession and expanded diversion to drug treatment, used a modeling analysis based on longitudinal cohort data among PWID in Tijuana and found that a lack of implementation meant the reforms had little impact on HIV among PWID as of 2018. If fully implemented, however, these measures could prevent 21% of new HIV infections among PWID between 2018 and 2030.A handful of simulation modeling studiees have examined the impact of drug diversion programs and depenalization/decriminalization policy changes on health among substance using populations.Few studies examine the economic implications of potential decriminalization coupled with reinvestment in public health approaches. A recent theoretical study showed that decriminalization in Belarus, Kazakhstan, Kyrgyzstan, and St Petersburg could be cost-saving (saving 38–773 million euros). Reinvestment of these savings into public health  could prevent 59% to 84% of HIV infections among PWID over 20 y.Importantly, these analyses have explored a relatively narrow set of conceptualizations of “decriminalization” and associated benefits and harms. Further, as decriminalization includes multiple sectors , so a systems-level approach to modeling is required to fully capture the implications across different sectors. To our knowledge, there has been no concerted effort to explore an abolitionist framework with simulation modeling. While a few modeling studies have examined the contribution of incarceration to health harms, where the hypothetical alternative is no incarceration, these studies do not explicitly explore abolition futures or frame these as policy options per se.38A movement for prison abolition has gained momentum, seeking to decarcerate , excarcerate , and develop alternatives to incarceration that focus on rehabilitation and restorative justice rather than punishment. One advantage of simulation modeling, however, is that we need not limit analyses to what is likely or even—in the moment—practical or feasible. Instead, models can facilitate speculation on alternative futures, producing results that serve to provoke discussion of a broad range of policy alternatives, even those that may seem unlikely or utopian. In doing so, models need not just enumerate outcomes of different scenarios; they can create and shape discourse around which scenarios are even possible, bringing alternative futures that may be seen as unrealistic into the realm of the achievable. Recognizing incarceration as just one policy option among many opens up opportunities to model futures that do not include carceral settings or radically reimagine their focus and remit and, in the process, create the potential for those futures to become reality.The above models demonstrate the potential benefits of incremental reform or narrowly visioned depenalization and decriminalization. These models are appealing because, like much drug policy research, they take a recognizable and current reality and build in change that may be viewed as politically and administratively realistic or actionable. resource shifting from law enforcement to mental health and substance use treatment systems, drug legalization, overdose prevention centers , and safer opioid supply prescribing may all be warranted. Different effects may be observed for decriminalization policies  compared with excarceration (thus affecting those who are currently incarcerated), and models can be used to examine these different populations. Outcomes could include health , drug use, crime, housing, criminal justice costs, economic productivity, considerations of health disparities and social equity, among others. Such models could compare outcomes to the status quo, providing both realistic enumerations of benefits and harms of alternatives and an explicit assessment of outcomes associated with current law enforcement–based responses to drug use.What might such exploratory, speculative models look like? In the context of the overdose crisis, models exploring radical decarceration, excarceration, expungement, pardoning, reparations payments, Simulation models allow us to simultaneously examine health and crime implications of policy alternatives—and to examine contextual and program factors that may magnify or undermine a program’s intended social impact. Doing so is important, as policy makers likely will not take seriously an analysis that is unaware of such concerns. Data on drug offenses for the periods before and after decarceration efforts in response to the COVID-19 pandemic may be useful to this end.Another advantage of simulation models is that they can facilitate the discussion of tradeoffs and potential unintended consequences. For example, abolition provokes understandable anxiety around the potential for crime to increase in response to specific interventions.4345 Simulation models provide a platform for generating the “what if” data that activists can use when speaking to policy makers and advocating for change. Furthermore, they can make explicit the hidden toll of status quo policies that goes unacknowledged in policy discussions because there is no counterfactual world to which to compare outcomes.The potential impact of this type of visionary modeling could be profound. We note historical and contemporary examples of academic researchers and other individuals afforded “authority” in policy making  in supporting grass roots harm reduction movements, including acts of civil disobedience such as the establishment of unsanctioned overdose prevention centers in the face of escalating overdose deaths and inaction from official channels.40Together, incremental and more radical vision-changing models can complement each other in supporting policy making much in the same way that harm reduction policies have benefited from movements on each end of the spectrum. We therefore call on modelers to explore radical interventions to reduce drug-related harm and model grand alternative futures in addition to more probable scenarios, with a goal of opening up policy discourse to these options.


The phyllosphere microbiome is composed of microbial communities residing in the above-ground compartments of terrestrial plants, as well as the whole spectrum of biomolecules that they produce . Recent Yu et al. investigated the influence of sodium hypochlorite (NaClO), a commonly applied disinfectant for sample pre-treatment, on the diversity of endophytic bacteria and fungi in leaves and stems of tea plants. They found that diversity assessments of bacterial endophytes were significantly affected by certain NaClO concentrations as well as the treatment time. In contrast, the diversity of fungal endophytes was not significantly impacted according to the results obtained with HTS. Their results demonstrated that pre-treatments with NaClO should be carefully implemented in phyllosphere microbiome studies, especially in the case of precise assessments of bacterial diversity in different above-ground tissues.Surface sterilization of various plant samples is a commonly adopted processing step for high-throughput sequencing (HTS) approaches as well as for the isolation of endophytic microorganisms. However, the potential impact of different surface sterilization techniques on the composition and diversity of endophytes has remained largely overlooked. Candidatus Liberibacter asiaticus (CLas), was studied by Munir et al. They found that CLas density in citrus trees respond inversely proportional to the density of the beneficial phyllosphere bacterium. Its application on diseased citrus leaves reduced pathogen density in leaf midribs by 1,000-fold in vitro. This disease-suppressive phyllosphere bacterium can efficiently colonize the phloem of citrus leaves, which may offer more opportunities for future management of vascular pathogens. Further explorations will be required to decipher disease-suppressive mechanisms of highly active phyllosphere bacteria.The phyllosphere microbiome contributes to essential functions of host plants, such as defense against various phytopathogens. In one of the articles, the defensive function of an indigenous phyllosphere bacterium from healthy citrus plants against Huanglongbing (HLB), a devastating disease of citrus crops caused by 2O emissions. However, phyllosphere microbiome-related implications were not investigated so far. Nie et al. found that the N2O emission potential in palsa bogs is increase by certain phyllosphere bacteria of two dominant Sphagnum mosses; especially by such that are found on Sphagnum capillifolium. Pseudomonas and members of the bacterial family Enterobacteriaceae were identified as pH-responsive hyperactive N2O emitters. Their study revealed previously unknown hyperactive N2O emitters associated with Sphagnum capillifolium that naturally occurs in melting palsa mounds, and provided novel insights into the importance of the phyllosphere microbiome in the Anthropocene.Permafrost mounds in subarctic palsa mires are thawing due to climate change and becoming a substantial source of NKöberl et al. investigated microbial colonization of the East African highland banana cultivar “Mpologoma” under different mulch and manure treatments on three representative smallholder farms in Uganda. They found that the gammaproteobacterial community appeared stable with no significant response to organic matter inputs after 24 months of treatment. However, significant differences in the plant’s carpo-, phyllo-, and rhizosphere microbial community composition and diversity were found among individual farms, independent of the added soil inputs. Their results highlight short-term microbial stability in banana cropping systems in terms of a high resilience of gammaproteobacterial communities. However, future investigations that include whole bacterial as well as multi-kingdom communities are required to provide detailed insights into potential impacts of soil amendments on the banana microbiome.Organic matter inputs are used as a common agricultural practice to improve soil fertility and quality, but it is sparsely understood how this practice affects the plant microbiome. Sun et al., the effects of ozonated water, mancozeb, and thiophanate-methyl on the structure, composition, and diversity of strawberry phyllosphere microbial communities were investigated by high-throughput sequencing. Ozonated water was found to efficiently reduce the relative abundance of potentially pathogenic fungi and is therefore a potential biocide that could reduce environmental pollution in the future in contrast to conventional chemical agents. They also found that microbial communities in the strawberry phyllosphere showed a specific response to the employed fungicides. The observed, chemical-specific response may serve as a basis for the implementation of the phyllosphere microbiome as a highly-sensitive indicator for the use of agrochemicals and thus provide an alternative approach to available analytical approaches for residue detection.Application of conventional chemical fungicides is a common measure to counteract phytopathogens in agricultural production systems, but can also adversely affect food safety and cause environmental pollution. In the study by The other six studies published in this Research Topic have provided new insights into mechanisms of phyllosphere microbiome assembly and responses in different host plants, including barley, citrus, halophytes, rice, and wheat. They not only increased our understanding of phyllosphere microbiome functions, but also provided new clues for the development of phyllosphere microbiome-based applications that could increase sustainability in agriculture. It can be expected that the required knowledge base that is needed to develop such applications will substantially grow during the next years. Continuous improvements in sequencing technologies as well as data processing will enable a more comprehensive characterization of the phyllosphere microbiome at a finer taxonomic and functional resolution. Integration of multi-omics approaches will provide a deeper understanding of microbial interactions and metabolic networks within the phyllosphere. These advancements will allow us to uncover the hidden diversity and functional potential of the phyllosphere microbiome. They will also enhance our understanding of the intricate interplay between the phyllosphere microbiota and host plants; this also includes the apparent crosstalk with the rhizosphere microbiome. Collectively, it will be important to decipher functional complementarity and synergistic effects between plants and microbes that contribute to plant health and growth, enabling the development of targeted strategies to secure global food production.MW prepared the first draft of this editorial and TC conducted a critical revision. All authors contributed to the article and approved the submitted version.


Optimizing prescribing practices is important due to the substantial clinical and financial costs of polypharmacy and an increasingly aging population. Prior research shows the importance of social relationships in driving prescribing behaviour. Using social network analysis, we examine the relationship between a physician practices’ connectedness to peers and their prescribing performance in two German regions.We first mapped physician practice networks using links established between two practices that share 8 or more patients; we calculated network-level  and node-level measures . We defined prescribing performance as the total number of inappropriate medications prescribed or appropriate medications not prescribed (PIMs) to senior patients (over the age of 65) during the calendar year 2016. We used FORTA (Fit fOR The Aged) algorithm to classify medication appropriateness. Negative binomial regression models estimate the association between node-level measures and prescribing performance of physician practices controlling for patient comorbidity, provider specialization, percentage of seniors in practice, and region. We conducted two sensitivity analyses to test the robustness of our findings – i) limiting the network mapping to patients younger than 65; ii) limiting the network ties to practices that share more than 25 patients.We mapped two patient-sharing networks including 436 and 270 physician practices involving 28,508 and 20,935 patients and consisting of 217,126 and 154,274 claims in the two regions respectively. Regression analyses showed a practice’s network connectedness as represented by degree, betweenness, and eigenvector centrality, is significantly negatively associated with prescribing performance .Our study provides evidence that physician practice prescribing performance is associated with their peer connections and position within their network. We conclude that practices occupying strategic positions at the edge of networks with advantageous access to novel information are associated with better prescribing outcomes, whereas highly connected practices embedded in insulated information environments are associated with poor prescribing performance.The online version contains supplementary material available at 10.1186/s12874-023-02048-7. Optimizing prescribing practices is a priority in healthcare due to the substantial clinical and financial costs of drug-related complications. This is particularly a problem among seniors: in Germany, seniors over the age of 65 comprise 20% of the total population, and a regional study estimated that 22% of seniors are prescribed at least one potentially inappropriate medication , 2. In 2Polypharmacy, generally defined as the concomitant and long-term use of five or more medications, is a direct consequence of inappropriate prescribing and is associated with increased hospitalization, mortality, and adverse drug events –6. SenioThe Fit fOR The Aged (FORTA) classification was first developed in 2010 through consensus by German-based experts to support physicians in improving appropriate prescribing for seniors (aged over 65) in the German context . This waRecent decades have seen the rise of both evidence-based prescribing—prescribing based on the best available, critically appraised evidence—and rational prescribing, wherein judicious prescribing maximizes effectiveness while minimizing harm and avoiding waste . HoweverSuch peer relationships can be studied using network analysis, which considers the interaction and dynamics between individuals within a system. Network analysis can reveal implicit relationships between different actors within a system, who act as communication channels for information exchange and social influence . These rTime constraints among healthcare providers and low survey response rates are significant barriers to network analysis in healthcare . To overPhysician practices may share patients because of unresolved clinical problems that require complementary expertise, when different specialists are providing team-based care to a patient with complex and chronic disease, or when patients seek second opinions for further clinical information . Apart fHere we identify a patient-sharing provider network using German regional healthcare claims data and characterize the association between a physician practice’s level of connectedness to peers and its performance in prescribing quality. We hypothesized that more connected practices are better positioned to exercise their social capital and draw on the knowledge of peers, which may guide them to adopt quality prescribing practice and exhibit better performance. By applying a method previously validated in large medical centers and community hospitals in the United States , we demoSocial networks can be used to reveal underlying relationships between different actors in a system. Studying how different actors are connected can lead to insights on the relative social capital individuals have to draw on and how others in the proximity of their network might influence them. Networks consist of nodes and ties that represent how nodes are connected to one another. In our study, each node represents a physician practice, and a tie represents the relationship between two physician practices, inferred using the number of shared patients between the two corresponding practices.This is a retrospective, observational study using administrative claims data to examine the relationship between a physician practice’s positioning within a social network and their prescribing performance for senior patients in 2016. We follow the research framework for network analysis using administrative claims data proposed by Uddin following a systematic review of this field of work . We usedThis study is set in two areas in Germany: Billstedt-Horn, and Werra-Meißner-Kreis. Billstedt-Horn is a multicultural and urban district with a population of roughly 110,000 in Northern Germany . Werra-MThe population in this study included physician practices who were involved in the treatment and care of patients insured by the insurance companies in the year 2016 in Billstedt-Horn and Werra-Meissner-Kreis respectively. To identify eligible claims for network mapping, we started from the full claims record, and excluded practices whose specialty is not typically responsible for direct patient care and hence coordination ; claims that were categorized as emergency visits; and practices that had fewer than 30 patients in the 2016 calendar year. By filtering out practices with fewer than 30 unique patients that filed claims within the year, we effectively exclude practices that may not have a strong presence in the regional professional social network. As the claims data is based on the patient postal code, practices excluded may be physicians that patients seek out outside of the region of interest in this study; thus, while a large percentage of practices are excluded based on this criterion  and potentially inappropriate prescriptions (summed FORTA score). Spearman’s rank correlation was used as it does not make assumptions regarding the underlying distribution of the data, which did not follow a normal distribution. Variables were assessed for potential multicollinearity by measuring the variance inflation factors (VIF) and balanced with omitted variable bias when constructing the regression model.We defined quartiles within each region for all network centrality measures  and treated the quartiles as categorical variables. Data from both regions were pooled in the regression analyses to increase the power to determine the effect. Each region was identified using a dummy variable to account for underlying differences. We used a negative binomial regression to estimate the adjusted incidence rate ratio of prescribing a potentially inappropriate prescription due to the overdispersed count outcome variable. It is important to note that the unit of analysis is at the practice level, and thus patient-associated scores were aggregated.Our model specification is as follows:mentclass2pt{minimWe conducted two separate sensitivity analyses to check for robustness of effects in different subsamples. First, we address the challenge of endogeneity between the network measures and the outcome measure by remapping the social network with only physician practices that shared younger patients (defined as under the age of 65) and deriving practice-level centrality measures. We then retained our original analytical sample  and updated the associated centrality measures derived from physician practices sharing only younger patients. By doing so, we isolate the effects of practice centrality on prescribing quality from the contribution of senior patients who are more likely to have multiple comorbidities and thus simultaneously increasing the number of physician visits  and increasing the FORTA scores. Second, we tested the stability of effects by remapping the network using an increased threshold of 25 shared patients. By increasing the threshold of shared patients in which ties between practices are drawn, we effectively increase the specificity of linkages  . In otheAll statistical analyses were performed using the R statistical software (version 4.0.3).The two patient-sharing networks we mapped—Billstedt-Horn and Werra Meissner Kreis—included 436 and 270 practices; 28,508 and 20,935 patients; and consisted of 217,126 and 154,274 claims in the 2016 calendar year, respectively. We further excluded patients under the age of 65 and practices that did not care for patients over the age of 65 to reach the analytical sample consisting in total of 659 practices   including only clinical encounters involving younger patients (less than 65 years old); ii) increasing the threshold of shared patients that defines a tie between two practices from 8 to 25 patients. In both sensitivity analyses conducted, the results were in line with main analysis with slight changes in effect size, same directionality of association and significance . Research mapping social networks using administrative data has increased steadily in recent decades; while most studies are set in the US and Australia , studiesIn this study, we find practices that are well-connected to others , well-positioned to broker information between network practices  and connected to well-connected others , were more likely to be associated with an overall increased over- and under- prescribing scores . We interpret this finding by expanding on the following: i) occupying positions on the network fringes may confer advantage in accessing novel information; ii) highly connected practices may be subject to an insulated information environment; iii) negative resource exchanges in professional networks.This work draws upon social network theory, which posits that the embeddedness of each individual’s positioning within a network, and their connectedness to others, confer both advantages and drawbacks . In turnAccess and exchange of knowledge and information is particularly salient in our study of prescribing quality. While clinical knowledge is typically imparted through textbooks, clinical guidelines and journal articles , researcThe social cohesion perspective proposes that individuals in highly connected networks are likely to demonstrate homogeneous behavior due to the spread of norms, ideas, and practices through social relationships , 77. ThiWhile a variety of benefits may be derived from social capital, negative exchange relations also exist and have been associated with individual performance  and descPoor prescribing performance associated with well-connected practices found in our study reflects a fragmented healthcare system where physicians who are positioned to provide coordinated care lack formal structures and incentives to support this practice. In Germany, the lack of electronic patient health records that service providers from different settings can access undermines their ability to provide coordination of care and medication reconciliation , 83. IntOur research generates several implications for practice and policy. As health systems restructure to improve care coordination for the patient, it is critical for system administrators and policy makers to recognize the importance of relationships and positioning within existing networks in shaping behaviour and performance.Adherence to local prescribing norms creates a closed network where novel information, such as revised prescribing guidelines, fail to reach prescribers. Our findings that well-connected practices are associated with worse prescribing practices may be a result of practices conforming to local prescribing norms that depart from best practice guidelines. Implementing quality circles , where pPhysicians tap into their peers’ knowledge within their social and professional networks and rely on their community of practice as important sources of information for prescribing practices, even more so than national guidelines , 87. UsiLastly, social capital has long been recognized as integral in individual and team performance. Previous research shows the association between social capital and the maturity of a hospital’s quality management system  and valiOur study is subject to limitations. First, we derived provider relationships based on the presence of patients shared within a year using claims data from one insurance company in each region, which may have overlooked certain links based on shared patients insured by other companies. We minimized the impact of this risk by using data from health insurance companies that have substantial market share in both regions within our study. Additionally, methods have advanced in recent years to restrict linkages among provider dyads to only those that share patients with one another over one episode of care . While wSecond, networks are subject to boundary specification problems. In this study, the boundaries are artificially drawn based on providers sought by residents within the two geographical areas. We assume that healthcare utilization in these two areas is relatively self-contained, which is conceivable as one area is a rural community with a natural boundary and the other is a relatively deprived neighborhood in a larger city. Further considering that patients tend to seek care in their communities that are culturally appropriate, we assume in our study that those living in Billstedt-Horn district typically seek care within the district. Third, while there is no standard gate-keeping system in Germany, general practitioners remain well-positioned to coordinate care for patients. Where more comprehensive data with wider geographic coverage is available, future research should consider a general practitioner-only network to better investigate the relationship between prescribing quality and peer relationships. Fourth, pharmaceutical influence on prescribing is widely substantiated with a study showing 84% of physicians indicating weekly pharmaceutical sales representatives visits in Germany . It is cOur study builds on the momentum of research in patient-sharing network analysis in the last decade and finds well-connected practices to be associated with increased over- and under-prescribing for senior patients in two regions in Germany. From this, we conclude that practices occupying strategic positions at the edge of networks with advantageous access to novel information are associated with better prescribing outcomes, whereas highly connected practices embedded in insulated information environments are associated with poor prescribing performance.Additional file 1.