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Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca 2+  sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The development of drug addiction is characterized by molecular changes in brain reward regions that lead to the transition from recreational to compulsive drug use. These neurobiological processes in brain reward regions, such as the nucleus accumbens (NAc), are orchestrated in large part by transcriptional regulation. Our group recently identified the transcription factor E2F3a as a novel regulator of cocaine's rewarding effects and gene expression regulation in the NAc of male mice. Despite this progress, no information is available about the role of E2F3a in regulating cocaine reward at the sex- and cell-specific levels. Here, we used male and female mice expressing Cre-recombinase in either D1- or D2-type medium spiny neurons (MSNs) combined with viral-mediated gene transfer to bidirectionally control levels of E2F3a in a cell-type-specific manner in the NAc during conditioned place preference (CPP) to cocaine. Our findings show that selective overexpression of E2F3a in D1-MSNs increased cocaine CPP in both male and female mice, whereas opposite effects were observed under knockdown conditions. In contrast, equivalent E2F3a manipulations in D2-MSNs had no significant effects. To further explore the role of E2F3a in sophisticated operant and motivated behaviors, we performed viral manipulations of all NAc neurons in combination with cocaine self-administration and behavioral economics procedures in rats and demonstrated that E2F3a regulates sensitivity aspects of cocaine seeking and taking. These results confirm E2F3a as a central substrate of cocaine reward and demonstrate that this effect is mediated in D1-MSNs, thereby providing increased knowledge of cocaine action at the transcriptional level.

DNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underlying opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied in the context of addiction. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (m 5 C) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring. We identified dynamic changes in glycine tRNA (tRNA Gly GCC ) cytosine methylation, corresponding to altered expression levels of this tRNA at multiple timepoints following 15 days of daily morphine. Additionally, a robust increase in methylation, coupled with decreased expression, was present after 30 days of withdrawal, suggesting that repeated opioid administration produces changes to the tRNA regulome long after discontinuation. Furthermore, forebrain-wide knockout of neuronal Nsun2, a tRNA methyltransferase, was associated with disruption of opioid conditioned place preference, and this effect was recapitulated by regional mPFC Nsun2 knockout. Taken together, these studies provide a foundational link between the regulation of tRNA cytosine methylation and opioid reward and highlight the tRNA machinery as a potential therapeutic target in addiction., (© 2024. The Author(s).)

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b ( Pde1b ), a Ca 2+ /calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Introduction: Mal de Debarquement Syndrome (MdDS) is a rare central vestibular disorder characterised by a constant sensation of motion (rocking, swaying, bobbing), which typically arises after motion experiences (e.g. sea, air, and road travel), though can be triggered by non-motion events. The current standard of care is non-specific medications and interventions that only result in mild-to-moderate improvements. The vestibular ocular reflex (VOR) rehabilitation protocol, a specialised form of rehabilitation, has shown promising results in reducing symptoms amongst people with MdDS. Accumulating evidence suggests that it may be possible to augment the effects of VOR rehabilitation via non-invasive brain stimulation protocols, such as theta burst stimulation (TBS)., Methods: The aim of this randomised controlled trial was to evaluate the effectiveness of intermittent TBS (iTBS) over the dorsolateral prefrontal cortex in enhancing the effectiveness of a subsequently delivered VOR rehabilitation protocol in people with MdDS. Participants were allocated randomly to receive either Sham (n = 10) or Active (n = 10) iTBS, followed by the VOR rehabilitation protocol. Subjective outcome measures (symptom ratings and mental health scores) were collected 1 week pre-treatment and for 16 weeks post-treatment. Posturography (objective outcome) was recorded each day of the treatment week., Results: Significant improvements in subjective and objective outcomes were reported across both treatment groups over time, but no between-group differences were observed., Discussion: These findings support the effectiveness of the VOR rehabilitation protocol in reducing MdDS symptoms. Further research into iTBS is required to elucidate whether the treatment has a role in the management of MdDS. TRN: ACTRN12619001519145 (Date registered: 04 November 2019)., (© 2024. The Author(s).)

Drugs of abuse are thought to promote addiction in part by "hijacking" brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell type-specific manner. Combining FOS-Seq, CRISPR-perturbation, and single-nucleus RNA sequencing, we identified Rheb as a molecular substrate that regulates cell type-specific signal transduction in NAc while enabling drugs to suppress natural reward consumption. Mapping NAc-projecting regions activated by drugs of abuse revealed input-specific effects on natural reward consumption. These findings characterize the dynamic, molecular and circuit basis of a common reward pathway, wherein drugs of abuse interfere with the fulfillment of innate needs.

Background: The transcription factor ΔFOSB, acting in the nucleus accumbens, has been shown to control transcriptional and behavioral responses to opioids and other drugs of abuse. However, circuit-level consequences of ΔFOSB induction on the rest of the brain, which are required for its regulation of complex behavior, remain unknown., Methods: We used an epigenetic approach in mice to suppress or activate the endogenous Fosb gene and thereby decrease or increase, respectively, levels of ΔFOSB selectively in D1-type medium spiny neurons of the nucleus accumbens and tested whether these modifications affect the organization of functional connectivity (FC) in the brain. We acquired functional magnetic resonance imaging data at rest and in response to a morphine challenge and analyzed both stationary and dynamic FC patterns., Results: The 2 manipulations modified brainwide communication markedly and differently. ΔFOSB down- and upregulation had overlapping effects on prefrontal- and retrosplenial cortex-centered networks, but also generated specific FC signatures for epithalamus (habenula) and dopaminergic/serotonergic centers, respectively. Analysis of dynamic FC patterns showed that increasing ΔFOSB essentially altered responsivity to morphine and uncovered striking modifications of the roles of the epithalamus and amygdala in brain communication, particularly upon ΔFOSB downregulation., Conclusions: These novel findings illustrate how it is possible to link activity of a transcription factor within a single cell type of an identified brain region to consequent changes in circuit function brainwide by use of functional magnetic resonance imaging, and they pave the way for fundamental advances in bridging the gap between transcriptional and brain connectivity mechanisms underlying opioid addiction., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated., Methods: We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons-D1 or D2 medium spiny neurons-after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses., Results: The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors., Conclusions: These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.

The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here, we implicate in this process a nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction and paves the way for future studies of rexinoid signaling in psychiatric disease states., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice., Methods: To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice., Results: We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors., Conclusions: Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mal de Debarquement Syndrome (MdDS) is a puzzling central vestibular disorder characterized by a long-lasting perception of oscillatory postural instability that may occur after sea travels or flights. We have postulated that MdDS originates from the post-disembarking persistence of an adaptive internal oscillator consisting of a loop system, involving the right and left vestibular nuclei, and the Purkinje cells of the right and left flocculonodular cerebellar cortex, connected by GABAergic and glutamatergic fibers. We have formulated here a mathematical model of the vestibulo-cerebellar loop system and carried out a computational analysis based on a set of differential equations describing the interactions among the loop elements and containing Hill functions that model input-output firing rates relationships among neurons. The analysis indicates that the system acquires a spontaneous and permanent oscillatory behavior for a decrease of threshold and an increase of sensitivity in neuronal input-output responses. These results suggest a role for synaptic plasticity in MdDS pathophysiology, thus reinforcing our previous hypothesis that MdDS may be the result of excessive synaptic plasticity acting on the vestibulo-cerebellar network during its entraining to an oscillatory environment. Hence, our study points to neuroendocrine pathways that lead to increased synaptic response as possible new therapeutic targets for the clinical treatment of the disorder., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

Fibromyalgia (FM) is a chronic pain disorder with unclear pathophysiological mechanisms, which leads to challenges in patient management. In addition to pain, the disorder presents with a broad range of symptoms, such as sleep disruption, chronic fatigue, brain fog, depression, muscle stiffness, and migraine. FM has a considerable female prevalence, and it has been shown that symptoms are influenced by the menstrual cycle and periods of significant hormonal and immunological changes. There is increasing evidence that females with FM experience an aggravation of symptoms in pregnancy, particularly during the third trimester and after childbirth. In this perspective paper, we focus on the neuro-endocrine interactions that occur between progesterone, allopregnanolone, and cortisol during pregnancy, and propose that they align with our previously proposed model of FM pathogenesis based on GABAergic "weakening" in a thalamocortical neural loop system. Based on our hypothesis, we introduce the possibility of utilizing transcranial direct current stimulation (tDCS) as a non-invasive treatment potentially capable of exerting sex-specific effects on FM patients.

Population dynamics and evolutionary genetics underly the structure of ecosystems, changing on the same timescale for interacting species with rapid turnover, such as virus (e.g. HIV) and immune response. Thus, an important problem in mathematical modeling is to connect ecology, evolution and genetics, which often have been treated separately. Here, extending analysis of multiple virus and immune response populations in a resource-prey (consumer)-predator model from Browne and Smith (2018), we show that long term dynamics of viral mutants evolving resistance at distinct epitopes (viral proteins targeted by immune responses) are governed by epistasis in the virus fitness landscape. In particular, the stability of persistent equilibrium virus-immune (prey-predator) network structures, such as nested and one-to-one, and bifurcations are determined by a collection of circuits defined by combinations of viral fitnesses that are minimally additive within a hypercube of binary sequences representing all possible viral epitope sequences ordered according to immunodominance hierarchy. Numerical solutions of our ordinary differential equation system, along with an extended stochastic version including random mutation, demonstrate how pairwise or multiplicative epistatic interactions shape viral evolution against concurrent immune responses and convergence to the multi-variant steady state predicted by theoretical results. Furthermore, simulations illustrate how periodic infusions of subdominant immune responses can induce a bifurcation in the persistent viral strains, offering superior host outcome over an alternative strategy of immunotherapy with strongest immune response., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

Background: Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse., Methods: We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward., Results: We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI., Conclusions: These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The nucleus accumbens (NAc) is a canonical reward center that regulates feeding and drinking but it is not known whether these behaviors are mediated by same or different neurons. We employed two-photon calcium imaging in awake, behaving mice and found that during the appetitive phase, both hunger and thirst are sensed by a nearly identical population of individual D1 and D2 neurons in the NAc that respond monophasically to food cues in fasted animals and water cues in dehydrated animals. During the consummatory phase, we identified three distinct neuronal clusters that are temporally correlated with action initiation, consumption, and cessation shared by feeding and drinking. These dynamic clusters also show a nearly complete overlap of individual D1 neurons and extensive overlap among D2 neurons. Modulating D1 and D2 neural activities revealed analogous effects on feeding versus drinking behaviors. In aggregate, these data show that a highly overlapping set of D1 and D2 neurons in NAc detect food and water reward and elicit concordant responses to hunger and thirst. These studies establish a general role of this mesolimbic pathway in mediating instinctive behaviors by controlling motivation-associated variables rather than conferring behavioral specificity.

Aim: Mal de debarquement syndrome (MdDS) is a neurological condition characterized by a constant sensation of self-motion; onset may be motion-triggered (MT) or non-motion-triggered/spontaneous (NMT/SO). People with MdDS experience similar symptoms to those with vertical heterophoria, a subset of binocular visual dysfunction. Hence, we aimed to explore potential visual symptom overlaps., Methods: MdDS patients (n = 196) and controls (n = 197) completed a visual health questionnaire., Results: Compared with controls, the MdDS group demonstrated higher visual disorder scores and visual complaints. NMT/SO participants reported unique visual symptoms and a higher prevalence of mild traumatic brain injury., Conclusion: Our findings suggest visual disorders may coexist with MdDS, particularly the NMT/SO subtype. The difference in visual dysfunction frequency and medical histories between subtypes, warrants further investigation into differing pathophysiological mechanisms., (© 2022 The Authors.)

Fibromyalgia (FM) is a poorly understood, central pain processing disorder characterized by a broad range of symptoms, such as chronic pain, sleep disruption, chronic fatigue, and psychosomatic symptoms. In addition, recent studies have shown that FM patients also experience dizziness. We aimed to establish a prevalence rate of vestibular symptoms in a population of FM patients through a battery of questionnaires investigating socio-demographic, clinical and psychological characteristics, combined with the Dizziness Handicap Inventory (DHI) and the Situational Vertigo Questionnaire (SVQ). A total of 277 respondents, officially diagnosed with FM, completed the full study, while 80 controls were also included for DHI and SVQ questionnaires. We found that FM participants were significantly affected by vestibular symptoms, which correlated with FM-associated pain and non-pain symptoms. The dizziness reported by FM participants showed peculiar features suggesting an FM-intrinsic mechanism of vestibular dysfunction, possibly linked to migraine and dysautonomia conditions. Correlations between dizziness and depressive mood (or neuroticism), revealed an impact of dizziness on psychological status, leading to depressive reactions and interpersonal difficulties, and possibly involving a noxious, self-sustained stress condition. In conclusion, data showed a manifesting dizziness condition in FM patients that warrants careful clinical attention due to its possible inherent role in the syndrome.

Purpose of Review: Vestibular disorders are gender distributed with a higher prevalence in women. Although research has increased in this field, the mechanisms underlying this unbalance is unclear. This review summarises recent advances in this research sphere, and briefly discusses sex hormone effects on various vestibular conditions and highlights some recent theories., Recent Findings: Recent work has identified a direct link between aberrant gonadal hormone levels and vestibular dysfunction. Benign paroxysmal positional vertigo research suggests that the disorder may be linked to the rapid decrease in oestrogen, observed in menopausal women, which disrupts otoconial metabolism within the inner ear. A successful hormonal therapeutic intervention study has advanced our knowledge of hormonal influences in the inner ear in Ménière's disease. Also, several studies have focused on potential mechanisms involved in the interaction between Vestibular Migraine, Mal de Debarquement Syndrome, and gonadal hormones., Summary: In females, gonadal hormones and sex-specific synaptic plasticity may play a significant role in the underlying pathophysiology of peripheral and central vestibular disorders. Overall, this review concludes that clinical assessment of female vestibular patients requires a multifaceted approach which includes auditory and vestibular medicine physicians, gynaecologists and/or endocrinologists, in conjunction with hormonal profile evaluations., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The COVID-19 pandemic has led to widespread attention given to the notions of "flattening the curve" during lockdowns, and successful contact tracing programs suppressing outbreaks. However a more nuanced picture of these interventions' effects on epidemic trajectories is necessary. By mathematical modeling each as reactive quarantine measures, dependent on current infection rates, with different mechanisms of action, we analytically derive distinct nonlinear effects of these interventions on final and peak outbreak size. We simultaneously fit the model to provincial reported case and aggregated quarantined contact data from China. Lockdowns compressed the outbreak in China inversely proportional to population quarantine rates, revealing their critical dependence on timing. Contact tracing had significantly less impact on final outbreak size, but did lead to peak size reduction. Our analysis suggests that altering the cumulative cases in a rapidly spreading outbreak requires sustained interventions that decrease the reproduction number close to one, otherwise some type of swift lockdown measure may be needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility., Methods: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice., Results: When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature., Conclusions: Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Supplemental resources in science education are made available to students based on the belief that they will improve course-based student learning. This belief is ubiquitous, with supplemental resources being a traditional component of physiology education. In addition, the recent large-scale transition to remote learning caused by the Covid-19 pandemic suggests an increased relevance and necessity of digital versions of supplemental resources. However, the use of a supplemental resource is entirely dependent on whether students view it as beneficial. If students in a specific course do not perceive a supplemental resource as useful, there is little reason to believe the resources will be used and are worthy of investment. Consequently, measurement of student perception regarding the effectiveness of any digital learning tool is essential for educators and institutions in order to prioritize resources and make meaningful recommendations to students. In this study, a survey was used to determine student perceptions of a digital, supplemental resource. Quantitative methods, including exploratory factor analysis, were performed on data collected from the survey to examine the dimensionality and functionality of this survey. The findings from this study were used to devise an improved, standardized (i.e., reliable and valid) survey that can be used and adapted by physi3ology researchers and educators to determine student perception of a digital supplemental resource. The survey, with known construct validity and internal reliability, can provide useful information for administrators, instructors, and designers of digital supplemental resources.

Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.

Introduction: Mal de Debarquement Syndrome (MdDS) is a poorly understood neurological disorder affecting mostly perimenopausal women. MdDS has been hypothesized to be a maladaptation of the vestibulo-ocular reflex, a neuroplasticity disorder, and a consequence of neurochemical imbalances and hormonal changes. Our hypothesis considers elements from these theories, but presents a novel approach based on the analysis of functional loops, according to Systems and Control Theory. Hypothesis: MdDS is characterized by a persistent sensation of self-motion, usually occurring after sea travels. We assume the existence of a neuronal mechanism acting as an oscillator, i.e., an adaptive internal model, that may be able to cancel a sinusoidal disturbance of posture experienced aboard, due to wave motion. Thereafter, we identify this mechanism as a multi-loop neural network that spans between vestibular nuclei and the flocculonodular lobe of the cerebellum. We demonstrate that this loop system has a tendency to oscillate, which increases with increasing strength of neuronal connections. Therefore, we hypothesize that synaptic plasticity, specifically long-term potentiation, may play a role in making these oscillations poorly damped. Finally, we assume that the neuromodulator Calcitonin Gene-Related Peptide, which is modulated in perimenopausal women, exacerbates this process thus rendering the transition irreversible and consequently leading to MdDS. Conclusion and Validation: The concept of an oscillator that becomes noxiously permanent can be used as a model for MdDS, given a high correlation between patients with MdDS and sea travels involving undulating passive motion, and an alleviation of symptoms when patients are re-exposed to similar passive motion. The mechanism could be further investigated utilizing posturography tests to evaluate if subjective perception of motion matches with objective postural instability. Neurochemical imbalances that would render individuals more susceptible to developing MdDS could be investigated through hormonal profile screening. Alterations in the connections between vestibular nuclei and cerebellum, notably GABAergic fibers, could be explored by neuroimaging techniques as well as transcranial magnetic stimulation. If our hypothesis were tested and verified, optimal targets for MdDS treatment could be found within both the neural networks and biochemical factors that are deemed to play a fundamental role in loop functioning and synaptic plasticity., (Copyright © 2020 Mucci, Indovina, Browne, Blanchini, Giordano, Marinelli and Burlando.)

Anxiety disorders may be mediated in part by disruptions in serotonin (5-hydroxytryptamine, 5-HT) system function. Behavioral measures of approach-avoidance conflict suggest that serotonin neurons within the median raphe nucleus (MRN) promote an anxiogenic state, and some evidence indicates this may be mediated by serotonergic signaling within the dorsal hippocampus. Here, we test this hypothesis using an optogenetic approach to examine the contribution of MRN 5-HT neurons and 5-HT innervation of the dorsal hippocampus (dHC) to anxiety-like behaviours in female mice. Mice expressing the excitatory opsin ChR2 were generated by crossing the ePet-cre serotonergic cre-driver line with the conditional Ai32 ChR2 reporter line, resulting in selective expression of ChR2 in 5-HT neurons. Electrophysiological recordings confirmed that this approach enabled reliable optogenetic stimulation of MRN 5-HT neurons, and this stimulation produced downstream 5-HT release in the dHC as measured by in vivo microdialysis. Optogenetic stimulation of the MRN elicited behavioral responses indicative of an anxiogenic effect in three behavioural tests: novelty-suppressed feeding, marble burying and exploration on the elevated-plus maze. These effects were shown to be behaviourally-specific. Stimulation of 5-HT terminals in the dHC recapitulated the anxiety-like behaviour in the novelty-suppressed feeding and marble burying tests. These results show that activation of 5-HT efferents from the MRN rapidly induces expression of anxiety-like behaviour, in part via projections to the dHC. These findings reveal an important neural circuit implicated in the expression of anxiety in female mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Infection by distinct Dengue virus serotypes and host immunity are intricately linked. In particular, certain levels of cross-reactive antibodies in the host may actually enhance infection severity leading to Dengue hemorrhagic fever (DHF). The coupled immunological and epidemiological dynamics of Dengue calls for a multi-scale modeling approach. In this work, we formulate a within-host model which mechanistically recapitulates characteristics of antibody dependent enhancement in Dengue infection. The within-host scale is then linked to epidemiological spread by a vector-host partial differential equation model structured by host antibody level. The coupling allows for dynamic population-wide antibody levels to be tracked through primary and secondary infections by distinct Dengue strains, along with waning of cross-protective immunity after primary infection. Analysis of both the within-host and between-host systems are conducted. Stability results in the epidemic model are formulated via basic and invasion reproduction numbers as a function of immunological variables. Additionally, we develop numerical methods in order to simulate the multi-scale model and assess the influence of parameters on disease spread and DHF prevalence in the population.

There is a substantial interest in detailed models of viral infection and antiviral drug kinetics in order to optimize the treatment against viruses such as HIV. In this paper, we study within-viral dynamics under general intracellular distributed delays and periodic combination antiviral therapy. The basic reproduction number [Formula: see text] is established as a global threshold determining extinction versus persistence, and spectral methods are utilized for analytical and numerical computations of [Formula: see text]. We derive the critical maturation delay for virus and optimal phase difference between sinusoidally varying drug efficacies under various intracellular delays. Furthermore, numerical simulations are conducted utilizing realistic pharmacokinetics and gamma-distributed viral production delays for HIV. Our results demonstrate that the relative timing of the key viral replication cycle steps and periodic antiviral treatment schedule involving distinct drugs all can interact to critically affect the overall viral dynamics.

Opioid use kills tens of thousands of Americans each year, devastates families and entire communities, and cripples the health care system. Exposure to opioids causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug seeking and drug taking that can remain a lifelong struggle. The persistence of these neuroadaptations is mediated in part by epigenetic remodeling of gene expression programs in discrete brain regions. Although the majority of work examining how epigenetic modifications contribute to addiction has focused on psychostimulants such as cocaine, research into opioid-induced changes to the epigenetic landscape is emerging. This review summarizes our knowledge of opioid-induced epigenetic modifications and their consequential changes to gene expression. Current evidence points toward opioids promoting higher levels of permissive histone acetylation and lower levels of repressive histone methylation as well as alterations to DNA methylation patterns and noncoding RNA expression throughout the brain's reward circuitry. Additionally, studies manipulating epigenetic enzymes in specific brain regions are beginning to build causal links between these epigenetic modifications and changes in addiction-related behavior. Moving forward, studies must leverage advanced chromatin analysis and next-generation sequencing approaches combined with bioinformatics pipelines to identify novel gene networks regulated by particular epigenetic modifications. Improved translational relevance also requires increased focus on volitional drug-intake models and standardization of opioid exposure paradigms. Such work will significantly advance our understanding of how opioids cause persistent changes to brain function and will provide a platform on which to develop interventions for treating opioid addiction., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Several studies have reported dual pathways for HIV cell infection, namely the binding of free virions to target cell receptors (cell-free), and direct transmission from infected cells to uninfected cells through virological synapse (cell-to-cell). Furthermore, understanding spread of the infection may require a relatively in-depth comprehension of how the connection between organs, each with characteristic cell composition and infection kinetics, affects viral dynamics. We propose a virus model consisting of multiple compartments with cell populations subject to distinct infectivity kernels as a function of cell infection-age, in order to imitate the infection spread through various organs. When the within-host structure is strongly connected, we formulate the basic reproduction number to be the threshold value determining the viral persistence or extinction. On the other hand, in non-strongly connected cases, we also formulate a sequence of threshold values to find out the infection pattern in the whole system. Numerical results of derivative examples show that: (1) In a strongly connected system but lacking some directional connection between compartments therein, the migration of cells certainly affects the viral dynamics and it may not monotonously depend on the value of migration rate. (2) In a non-strongly connected structure, increasing migration rate may first change persistence of the virus to extinction in the whole system, and then for even larger migration rate, trigger the infection in a subset of compartments. (3) For data-informed cases of intracellular delay and gamma-distributed cell infectivity kernels, compartments with faster kinetics representative of cell-to-cell transmission mode, as opposed to cell-free, can promote persistence of the virus.

The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.

Aim: To evaluate if patients with Mal de Debarquement syndrome (MdDS) demonstrate different symptom levels or symptom type during pregnancy., Materials & Methods: 18 MdDS patients that were or had been pregnant during their condition were recruited to complete a retrospective online questionnaire. Respondents answered questions regarding their basic clinical data, diagnosis, triggers and differences in symptom level and symptom type during pregnancy and before pregnancy., Results: A total of 81.3% reported that their symptoms were reduced during pregnancy compared with before pregnancy. Respondents also reported a different perception of motion and experienced less dizziness while being pregnant., Conclusion: The physiological changes that occur during pregnancy improve the symptoms of patients with MdDS, and this is potentially attributable to the rise in estrogen and progesterone., Competing Interests: Financial & competing interests disclosure This publication was supported by the Future Science Early Research Career Award awarded to V Mucci. This work was supported by a Western Sydney University Research Initiatives Early Career Researchers Grant awarded to CJ Browne. V Mucci and A Van Ombergen were funded by the PRODEX programme of the Belgian Science Policy during the time the study was developed and performed. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilised in the production of this manuscript.

The host immune response can often efficiently suppress a virus infection, which may lead to selection for immune-resistant viral variants within the host. For example, during HIV infection, an array of CTL immune response populations recognize specific epitopes (viral proteins) presented on the surface of infected cells to effectively mediate their killing. However HIV can rapidly evolve resistance to CTL attack at different epitopes, inducing a dynamic network of interacting viral and immune response variants. We consider models for the network of virus and immune response populations, consisting of Lotka-Volterra-like systems of ordinary differential equations. Stability of feasible equilibria and corresponding uniform persistence of distinct variants are characterized via a Lyapunov function. We specialize the model to a "binary sequence" setting, where for n epitopes there can be [Formula: see text] distinct viral variants mapped on a hypercube graph. The dynamics in several cases are analyzed and sharp polychotomies are derived characterizing persistent variants. In particular, we prove that if the viral fitness costs for gaining resistance to each epitope are equal, then the system of [Formula: see text] virus strains converges to a "perfectly nested network" with less than or equal to [Formula: see text] persistent virus strains. Overall, our results suggest that immunodominance, i.e. relative strength of immune response to an epitope, is the most important factor determining the persistent network structure.

Introduction: Mal de Debarquement Syndrome (MdDS) is a neurological disorder which affects the vestibular system pathways, manifesting as a constant sensation of movement in the form of rocking, bobbing, or swaying. The mechanism of MdDS is poorly understood and there is a lack of awareness amongst medical professionals about the condition. This study aimed to examine treatments and symptom management strategies used by MdDS patients and evaluate their self-reported effectiveness. Method: Motion-Triggered and Spontaneous/Other onset MdDS patients responded to a set of comprehensive questions as a retrospective survey regarding epidemiological details, diagnostic procedures, onset, and symptom triggers, hormonal influences as well as treatments and symptom management strategies used to reduce symptoms. The Motion-Triggered questionnaire was made available through Survey Monkey and the Spontaneous/Other Onset questionnaire through Qualtrics. The link for each questionnaire was made available on online MdDS support groups and on various research websites. Descriptive statistics were used for epidemiological data and Pearson's Chi Square tests were used for comparisons between and within both subtype groups. Results: A total of 370 patients participated in the surveys, with 287 valid responses collected for the section regarding treatment and symptom management strategies. The success of the treatments and symptom management strategies did not vary between subtypes Benzodiazepines/Antidepressants were reported as being most beneficial in reducing symptoms in both groups. Conclusion: This was the first attempt to evaluate the reported success of treatments and symptom management strategies in MdDS patients by assessing the patients' perceived helpfulness. The treatments and symptom management strategies reported to be the most helpful in managing and/or reducing symptoms are proposed to be effective due to their stress-reducing capacities. We hope this study will broaden MdDS awareness and that this study will increase patient knowledge regarding treatments and symptom management strategies that other patients found helpful.

Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a sensation of motion in the absence of a stimulus, which presents with two subtypes depending on the onset: Motion-Triggered, and Spontaneous or Non-Motion Triggered. MdDS predominantly affects women around 40-50 years of age and a high number of patients report associated disorders, such as migraine and depression. The pathophysiology of MdDS is unclear, as is whether there are predisposing factors that make individuals more vulnerable to developing the condition. Hormonal changes in women similarly to what observed in migraineous patients, as well as depression disorder, have been examined as potential key factors for developing MdDS. Studies on migraine and depression have revealed correlations with hormonal fluctuations in females as well as aberrant levels of some key neurotransmitters such as Gamma-Aminobutyric Acid (GABA) and inflammatory neuropeptides like Calcitonin Gene-Related Peptide (CGRP). Consequently, this manuscript aims to propose a new hypothesis on the predisposing factors for MdDS and a new concept that could contribute to the understanding of its pathophysiology., New Hypothesis: Recent findings have demonstrated a role for hormonal influences in MdDS patients, similar to previous observations in patients with depression and migraine. We hypothesize the involvement of gonadal hormones and aberrant neurotransmitter levels, including the GABAergic and serotonergic systems, in MdDS pathophysiology. Our theory is that certain individuals are more vulnerable to develop MdDS during specific gonadal hormonal phases. Furthermore, we hypothesize that it may be possible to identify these individuals by measurement of an existing imbalance of these neurotransmitters or inflammatory neuropeptides like CGRP., Further Evaluation of the Hypothesis: According to one theory, MdDS is considered as a maladaptation of the Vestibular Ocular Reflex (VOR) and velocity storage. When considering this theory, it is essential to highlight that the brainstem nuclei involved in the VOR and the velocity storage include GABA b sensitive neurons, which appear to produce inhibitory control of velocity storage. Responses of these GABA b sensitive neurons are also modulated by CGRP. Thus an alteration of the GABAergic network by imbalances of inhibitory neurotransmitters or CGRP could influence signal integration in the velocity storage system and therefore be directly involved in MdDS pathophysiology., Consequence of the Hypothesis and Future Studies: A hormonal and neurotransmitter imbalance may act to predispose individuals in developing MdDS. Future studies should focus on the hormonal influences on neurotransmitters (e.g. GABA) and on the trial of CGRP antagonist drugs for the treatment of MdDS patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a perception of self-motion in the absence of a stimulus, with two onset types: Motion-Triggered and Spontaneous. Currently, the pathophysiology is unknown and consequently, the therapeutic options are limited. One proposed treatment protocol, developed by Dai and colleagues is based on optokinetic stimulation, which aims to re-adapt the vestibular ocular reflex. This study aimed to reproduce the treatment protocol developed by Dai and colleagues and to assess if a placebo effect is present in the treatment protocol and lastly, aimed to further investigate the treatment on MdDS patient outcomes. Method: Twenty-five MdDS patients (13 Motion-Triggered and 12 Spontaneous) were exposed to 5 consecutive days of optokinetic treatment (consisting of exposure to optokinetic stimuli with head movements). Eleven of these 25 patients were also exposed to 2 days of a sham treatment prior to the OKN treatment. Posturography measurements and reported symptoms [e.g., using the visual analog scale (VAS)] of patients were assessed throughout the treatment. Posturography data of the patients was compared with the data of 20 healthy controls. Results: No placebo effect was recorded with any changes in postural data and VAS scale. After the optokinetic treatment, a significant improvement in postural control was observed in 48% of patients, of whom 70% were of the Motion-Triggered subtype ( p -values: Area under the Curve-Anterior Posterior < 0.001; Area under the Curve-Medio Lateral p < 0.001, Confidence Ellipse Area (CEA) < 0.001, Velocity < 0.001). Conclusion: The protocol was effective in approximately half of the MdDS patients that took part in the study, with no placebo effect recorded. The Motion-Triggered group responded better to treatment than the Spontaneous group. In addition to this, this study indicates that the greatest postural changes occur within the first 3 days of treatment, suggesting that a shorter protocol is possible. Overall, these findings support what was previously observed in Dai's studies, that optokinetic stimulation can reduce and ease self-motion perception in those with MdDS. Thus, validating the reproducibility of this protocol, suggesting that a consistent and uncomplicated implementation across treatment centers is possible.

The nucleus accumbens (NAc) is a critical brain reward region that mediates the rewarding effects of drugs of abuse, including those of morphine and other opiates. Drugs of abuse induce widespread alterations in gene transcription and dendritic spine morphology in medium spiny neurons (MSNs) of the NAc that ultimately influence NAc excitability and hence reward-related behavioral responses. Growing evidence indicates that within the NAc small GTPases are common intracellular targets of drugs of abuse where these molecules regulate drug-mediated transcriptional and spine morphogenic effects. The RhoA small GTPase is among the most well-characterized members of the Ras superfamily of small GTPases, and recent work highlights an important role for hippocampal RhoA in morphine-facilitated reward behavior. Despite this, it remains unclear how RhoA pathway signaling in the NAc is affected by withdrawal from morphine. To investigate this question, using subcellular fractionation and subsequent protein profiling we examined the expression of key components of the RhoA pathway in NAc nuclear, cytoplasmic, and synaptosomal compartments during multiple withdrawal periods from repeated morphine administration. Furthermore, using in vivo viral-mediated gene transfer, we determined the consequences of revealed RhoA pathway alterations on NAc MSN dendritic spine morphology. Our findings reveal an important role for RhoA signaling cascades in mediating the effects of long-term morphine withdrawal on NAc MSN dendritic spine elimination., Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/., (© 2018 International Society for Neurochemistry.)

Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a persistent perception of self-motion, in most cases triggered from exposure to passive motion (e.g., boat travel, a car ride, flights). Patients whose onset was triggered in this way are categorized as Motion-Triggered (MT) subtype or onset group. However, the same syndrome can occur spontaneously or after non-motion events, such as childbirth, high stress, surgery, etc. Patients who were triggered in this way are categorized as being of the Spontaneous/Other (SO) subtype or onset group. The underlying pathophysiology of MdDS is unknown and there has been some speculation that the two onset groups are separate entities. However, despite the differences in onset between the subtypes, symptoms are parallel and a significant female predominance has been shown. To date, the role of gonadal hormones in MdDS pathophysiology has not been investigated. This study aimed to evaluate the hormonal profile of MdDS patients, the presence of hormonal conditions, the influence of hormones on symptomatology and to assess possible hormonal differences between onset groups. In addition, the prevalence of migraine and motion sickness and their relation to MdDS were assessed., Method: Retrospective online surveys were performed in 370 MdDS patients from both onset groups. Data were analyzed using Fisher's exact test or Fisher-Freeman-Hanlon exact test. When possible, data were compared with normative statistical data from the wider literature., Results: From the data collected, it was evident that naturally cycling female respondents from the MT group were significantly more likely to report an aggravation of MdDS symptoms during menses and mid-cycle ( p  < 0.001). A few preliminary differences between the onset groups were highlighted such as in regular menstrual cycling ( p  = 0.028), reporting menses during onset ( p  < 0.016), and migraine susceptibility after onset ( p  = 0.044)., Conclusion: These results demonstrate a potential relation between hormone fluctuations and symptom aggravation in the MT group. This study is an important first step to suggest a hormonal involvement in the pathophysiology of MdDS and provides a base for further hormonal investigation. Future prospective studies should expand upon these results and explore the implications for treatment.

Introduction: Mal de Debarquement Syndrome (MdDS) is a neurological condition typically characterized by a sensation of motion, that persists longer than a month following exposure to passive motion (e.g., cruise, flight, etc.). The most common form of MdDS is motion triggered (MT). However, recently it has been acknowledged that some patients develop typical MdDS symptoms without an apparent motion trigger. These cases are identified here as spontaneous or other onset (SO) MdDS. This study aimed to address similarities and differences between the MdDS subtypes. Diagnostic procedures were compared and extensive diagnostic guidelines were proposed. Second, potential triggers and associated psychological components of MdDS were revealed., Methods: This was a retrospective online survey study for MT and SO MdDS patients. Participants were required to respond to a set of comprehensive questions regarding epidemiological details, as well as the diagnostic procedures and onset triggers., Results: There were 370 patients who participated in the surveys. It is indicated that MdDS is often misdiagnosed; more so for the SO group. In addition to the apparent self-motion, both groups reported associated levels of stress, anxiety and depression., Discussion: It appears at present that both MdDS subtypes are still poorly recognised. This was the first attempt to evaluate the diagnostic differences between MdDS subtypes and to propose a set of comprehensive diagnostic guidelines for both MdDS subtypes. In addition, the current research addressed that associated symptoms such as stress, anxiety and depression should also be considered when treating patients. We hope this study will help the medical community to broaden their awareness and diagnostic knowledge of this condition.