Preserving the placebo effect after disclosure: A new perspective on non-deceptive placebos.

The present study explores whether a particular style of placebo disclosure could serve as a tool to foster a renewed trust in one's own inherent resources and elicit a meaningful placebo effect. In a motor performance task, two placebo groups received inert transcutaneous electrical nerve stimulation (TENS) in each of four sessions along with information on its force-enhancing properties. Before the final session, one of the placebo groups was informed about the placebo, which was portrayed as a means to unleash an inherent potential. Along with force, we systematically monitored task-specific self-efficacy to test whether this variable would be differentially modulated in the two placebo groups. Compared to two control groups, placebo groups showed higher force and self-efficacy in the last session. No differences in self-efficacy were observed in the placebo groups even after revealing the placebo procedure, suggesting that the disclosure was effective in 'safeguarding' individuals' self-efficacy. These findings may have important implications, paving the way for the use of placebos that not only are ethically permissible but also support individuals' self-efficacy.

Development and validation of a short version of the questionnaire of stressful life events (QSLE).

Stressful life events (SLE) tend to occur before the onset of psychosis, this highlights the importance of its detection and evaluation in these patients. The need to have instruments that assess SLE easily and quickly underpins the objective of this study, which is to validate a short version of the questionnaire of stressful life events (QSLE). 124 patients with first-episode psychosis and 218 healthy controls aged between 11 and 52 years were recruited. The QSLE scale underwent discrimination analysis, which revealed 18 items had good SLEs discriminability between the two samples. These 18 items were then used to create the shorter QSLE-SV. The QSLE-SV showed good internal consistency (Cronbach's alpha = 0.749). An AUC of 0.830 was observed, suggesting that the predictor was good. Using 2 as the cut-off score to predict an individual as a patient would yield a sensitivity of 91.1% and a specificity of 51.6%, and using a cut-off point of 3, the sensitivity was 77.4% and the specificity was 72.5%. QSLE-SV displayed satisfactory psychometric properties in a Spanish population. The QSLE-SV allows for investigating childhood, adolescent and adult life events by measuring current stress and age on a continuous scale in a quick and easy way.

Placebo effect on gait: a way to reduce the dual-task cost in older adults.

The ability to perform two tasks simultaneously is essential for daily activities. In older adults, this ability is markedly reduced, as evidenced by the dual-task cost on gait. Preliminary evidences indicate that the dual-task cost can be influenced by different types of manipulations. Here, we explored the effectiveness of a new approach to reduce the dual-task cost, based on the placebo effect, a psychobiological phenomenon whereby a positive outcome follows the administration of an inert device thought to be effective. Thirty-five healthy older adults were asked to walk on a sensorized carpet (single-task condition) and to walk while counting backward (dual-task condition) in two sessions (pre-test and post-test). A placebo group, randomly selected, underwent sham transcranial direct current stimulation over the supraorbital areas between sessions, along with information about its positive effects on concentration and attention. A control group did not receive any intervention between sessions. The dual-task cost was significantly reduced in the placebo group at the post-test session compared to the pre-test for several gait parameters (Cohen's d > 1.43). At the post-test session, the dual-task cost was also lower in the placebo group than in the control group (d > 0.73). Cognitive (number of subtractions and number of errors) and subjective (perceived mental fatigability) variables remained stable across sessions. The reduced dual-task cost in the placebo group could indicate the ability to re-establish the allocation of attentional resources between tasks. These findings could contribute to the development of cognitive strategies that leverage positive expectations to boost motor control in older adults.

The placebo effect shortens movement time in goal-directed movements.

The placebo effect is a powerful psychobiological phenomenon whereby a positive outcome follows the administration of an inert treatment thought to be effective. Growing evidence shows that the placebo effect extends beyond the healing context, affecting also motor performance. Here we explored the placebo effect on the control of goal-directed movement, a fundamental function in many daily activities. Twenty-four healthy volunteers performed upper-limb movements toward a target at different indexes of difficulty in two conditions: in the placebo condition, an electrical device (inert) was applied to the right forearm together with verbal information about its positive effects in improving movement precision; in the control condition, the same device was applied along with verbal information about its neutral effects on performance. Interestingly, we found shorter movement time in the placebo compared to the control condition. Moreover, subjective perception of fatigability was reduced in the placebo compared to the control condition. These findings indicate that the placebo effect can improve the execution of goal-directed movements, thus adding new evidence to the placebo effect in the motor domain. This study could inspire future applications to improve upper-limb movements or in clinical settings for patients with motor deficits.

CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders.

Purpose: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety. Patients and Methods: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype. Results: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05). Conclusion: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

Functional neurological disorder and placebo and nocebo effects: shared mechanisms.

Functional neurological disorder (FND) is characterized by neurological symptoms that cannot be explained by a structural neurological cause. Among the different aetiological models that have been proposed for FND, of note is the Bayesian predictive coding model, which posits that perception relies on top-down cortical predictions (priors) to infer the source of incoming sensory information. This model can also apply to non-pathological experiences, such as placebo and nocebo effects, wherein sensory information is shaped by prior expectations and learning. To date, most studies of the relationship between placebo and nocebo effects and FND have focused on the use of placebos for diagnosis and treatment of FND. Here, we propose that this relationship might go beyond diagnosis and therapy. We develop a framework in which shared cognitive, personality and neuroanatomical factors justify the consideration of a deeper link between FND and placebo and nocebo effects. This new perspective might offer guidance for clarification of the pathogenesis of FND and for the identification of potential biomarkers and therapeutic targets.

Event-Related Potentials as Markers of Efficacy for Combined Working Memory Training and Transcranial Direct Current Stimulation Regimens: A Proof-of-Concept Study.

Our brains are often under pressure to process a continuous flow of information in a short time, therefore facing a constantly increasing demand for cognitive resources. Recent studies have highlighted that a lasting improvement of cognitive functions may be achieved by exploiting plasticity, i.e., the brain's ability to adapt to the ever-changing cognitive demands imposed by the environment. Transcranial direct current stimulation (tDCS), when combined with cognitive training, can promote plasticity, amplify training gains and their maintenance over time. The availability of low-cost wearable devices has made these approaches more feasible, albeit the effectiveness of combined training regimens is still unclear. To quantify the effectiveness of such protocols, many researchers have focused on behavioral measures such as accuracy or reaction time. These variables only return a global, non-specific picture of the underlying cognitive process. Electrophysiology instead has the finer grained resolution required to shed new light on the time course of the events underpinning processes critical to cognitive control, and if and how these processes are modulated by concurrent tDCS. To the best of our knowledge, research in this direction is still very limited. We investigate the electrophysiological correlates of combined 3-day working memory training and non-invasive brain stimulation in young adults. We focus on event-related potentials (ERPs), instead of other features such as oscillations or connectivity, because components can be measured on as little as one electrode. ERP components are, therefore, well suited for use with home devices, usually equipped with a limited number of recording channels. We consider short-, mid-, and long-latency components typically elicited by working memory tasks and assess if and how the amplitude of these components are modulated by the combined training regimen. We found no significant effects of tDCS either behaviorally or in brain activity, as measured by ERPs. We concluded that either tDCS was ineffective (because of the specific protocol or the sample under consideration, i.e., young adults) or brain-related changes, if present, were too subtle. Therefore, we suggest that other measures of brain activity may be more appropriate/sensitive to training- and/or tDCS-induced modulations, such as network connectivity, especially in young adults.

The Role of Expectation and Beliefs on the Effects of Non-Invasive Brain Stimulation.

Non-invasive brain stimulation (NIBS) techniques are used in clinical and cognitive neuroscience to induce a mild magnetic or electric field in the brain to modulate behavior and cortical activation. Despite the great body of literature demonstrating promising results, unexpected or even paradoxical outcomes are sometimes observed. This might be due either to technical and methodological issues (e.g., stimulation parameters, stimulated brain area), or to participants' expectations and beliefs before and during the stimulation sessions. In this narrative review, we present some studies showing that placebo and nocebo effects, associated with positive and negative expectations, respectively, could be present in NIBS trials, both in experimental and in clinical settings. The lack of systematic evaluation of subjective expectations and beliefs before and after stimulation could represent a caveat that overshadows the potential contribution of placebo and nocebo effects in the outcome of NIBS trials.

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.

Early onset psychosis and cannabis use: Prevalence, clinical presentation and influence of daily use.

Most of the studies examining the impact of cannabis use in first episode psychosis (FEP) have been carried out in samples with adult-onset FEP. Data in persons with early onset psychosis (EOP) is scarce. The aims of the study were: To describe the prevalence of lifetime cannabis use, current use, and daily use in patients with EOP compared to healthy controls. To study the differences in clinical presentation between cannabis users and non-users. To examine the risk of presenting an EOP associated with cannabis use and the effect of doses and age of onset of use. An observational cross-sectional study was performed in 90 EOP cases and 62 healthy controls, aged between 7 and 17 years. Our results show a higher prevalence of lifetime use (p = 0002), current use (p < 0.001), and daily use (p < 0.001) in EOP cases in comparison with healthy controls. Regarding clinical presentation, we did not find significant differences in any subscale of the Positive and Negative Syndrome Scale (PANSS). Non-user patients presented more severe depressive symptoms (p = 0002) and worse social functioning than cannabis users (p = 0026). Compared with subjects who never used cannabis, the risk of an EOP was significantly higher for those with a lifetime use (OR = 2.88, p = 0.002)current use (O.R = 6.09, p < 0001), and especially in those with daily use (O.R = 42.77, p = <0001). We found a higher risk of EOP in patients that have used cannabis before 15 years of age. In conclusion, it is necessary to develop early- detection and specific treatment programs for adolescents with cannabis use.

The effect of motor and cognitive placebos on the serial reaction time task.

Motor learning is a key component of human motor functions. Repeated practice is essential to gain proficiency over time but may induce fatigue. The aim of this study was to determine whether motor performance and motor learning (as assessed with the serial reaction time task, SRTT) and perceived fatigability (as assessed with subjective scales) are improved after two types of placebo interventions (motor and cognitive). A total of 90 healthy volunteers performed the SRTT with the right hand in three sessions (baseline, training and final). Before the training and the final session, one group underwent a motor-related placebo intervention in which inert electrical stimulation (TENS) was applied over the hand and accompanied by verbal suggestion that it improves movement execution (placebo-TENS). The other group underwent a cognitive-related placebo intervention in which sham transcranial direct current stimulation (tDCS) was delivered to the supraorbital area and accompanied by verbal suggestion that it increases attention (placebo-tDCS). A control group performed the same task without receiving treatment. Overall better performance on the SRTT (not ascribed to sequence-specific learning) was noted for the placebo-TENS group, which also reported less perceived fatigability at the physical level. The same was observed in a subgroup tested 24 hr later. The placebo-tDCS group reported less perceived fatigability, both at the mental and physical level. These findings indicate that motor- and cognitive-related placebo effects differently shape motor performance and perceived fatigability on a repeated motor task.

Transgene-mediated skeletal phenotypic variation in zebrafish.

When considering relationships between genotype and phenotype we frequently ignore the fact that the genome of a typical animal, notably including that of a fish and a human, harbours a huge amount of foreign DNA. Such DNA, in the form of transposable elements, can affect genome function in a major way, and transgene biology needs to be included in our understanding of the genome. Here we examine an unexpected phenotypic effect of the chromosomally integrated transgene fli1a-F-hsp70l:Gal4VP16 that serves as a model for transgene function generally. We examine larval fras1 mutant zebrafish (Danio rerio). Gal4VP16 is a potent transcriptional activator that is already well known for toxicity and mediating unusual transcriptional effects. In the presence of the transgene, phenotypes in the neural crest-derived craniofacial skeleton, notably fusions and shape changes associated with loss of function fras1 mutations, are made more severe, as we quantify by scoring phenotypic penetrance, the fraction of mutants expressing the trait. A very interesting feature is that the enhancements are highly specific for fras1 mutant phenotypes, occurring in the apparent absence of more widespread changes. Except for the features due to the fras1 mutation, the transgene-bearing larvae appear generally healthy and to be developing normally. The transgene behaves as a genetic partial dominant: a single copy is sufficient for the enhancements, yet, for some traits, two copies may exert a stronger effect. We made new strains bearing independent insertions of the fli1a-F-hsp70l:Gal4VP16 transgene in new locations in the genome, and observed increased severities of the same phenotypes as observed for the original insertion. This finding suggests that sequences within the transgene, for example Gal4VP16, are responsible for the enhancements, rather than the effect on neighbouring host sequences (such as an insertional mutation). The specificity and biological action underlying the traits are subjects of considerable interest for further investigation, as we discuss. Our findings show that work with transgenes needs to be undertaken with caution and attention to detail.

Depressive symptoms and their relationship with negative and other psychotic symptoms in early onset psychosis.

The importance of depression in adult people with first-episode psychosis (FEP) has been demonstrated. However, it has hardly been studied in children and adolescents. There is a need to broaden knowledge of the relationship between psychotic symptoms and specific depression symptomatology. The aims of study were (a) to examine the frequency of presence and type of depressive symptoms in early onset FEP, and (b) to assess the relationship between depressive symptoms and psychotic symptomatology, and specifically negative symptoms. An observational cross-sectional study was performed in 62 FEP cases. Inclusion criteria were two or more psychotic symptoms, age 7-17 years old, first mental health service consultation, and fewer than 6 months from the first contact with the service. Participants were assessed with clinical and socio-demographic questionnaires: the Positive and Negative Syndrome Scale (PANSS) and the Children Depression Inventory (CDI). A Student t test was performed to compare psychotic symptoms in both groups: presence of depression and the absence of depression. A Pearson correlation was performed in order to relate subscales of the PANSS and each of the depression subscales and factors, as well the relation between negative and depressive symptoms. Our results show that a high percentage of people with an early onset of a FEP scored positively for depression. The most prevalent depressive symptoms were associated with schooling. The presence of depression was associated with negative, affective, and excited symptoms. Self-esteem, school problems, negative affect, and biological dysregulation were associated with psychotic symptoms. Finally, depressive items related to social functioning were more closely associated with negative symptoms of the PANSS. In conclusion, owing to the high incidence of depression in FEP in those suffering early onset of psychosis, there is a need for instruments to measure the depression more specifically in children and adolescent, and to uncover the clinical characteristics of depression in this population.

Correction: yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development.

[This corrects the article DOI: 10.1371/journal.pgen.1008841.].

Cathodal Cerebellar tDCS Combined with Visual Feedback Improves Balance Control.

Balance control is essential to maintain a stable body position and to prevent falls. The aim of this study was to determine whether balance control could be improved by using cerebellar transcranial direct current stimulation (tDCS) and visual feedback in a combined approach. A total of 90 healthy volunteers were randomly assigned to six groups defined by the delivery of tDCS (cathodal or anodal or sham) and the provision or not of visual feedback on balance during the acquisition phase. tDCS was delivered over the cerebellar hemisphere ipsilateral to the dominant leg for 20 min at 2 mA during a unipedal stance task. Body sway (i.e., ankle angle and hip position) was measured as an overall maximal unit in anteroposterior and mediolateral direction, together with participant rating of perception of stability, before (baseline), during (acquisition), and after (final) the intervention. We found a reduction in body sway during the acquisition session when visual feedback alone was provided. When the visual feedback was removed (final session), however, body sway increased above baseline. Differently, the reduction in overall maximal body sway was maintained during the final session when the delivery of cathodal tDCS and visual feedback was combined. These findings suggest that cathodal tDCS may support the short-term maintenance of the positive effects of visual feedback on balance and provide the basis for a new approach to optimize balance control, with potential translational implications for the elderly and patients with impaired posture control.

yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development.

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Positive verbal suggestion optimizes postural control.

Balance is a very important function that allows maintaining a stable stance needed for many daily life activities and for preventing falls. We investigated whether balance control could be improved by a placebo procedure consisting of verbal suggestion. Thirty healthy volunteers were randomized in two groups (placebo and control) and asked to perform a single-leg stance task in which they had to stand as steadily as possible on the dominant leg. The task was repeated in three sessions (T0, T1, T2). At T1 and T2 an inert treatment was applied on the leg, by informing the placebo group that it was effective in improving balance. The control group was overtly told that treatment was inert. An accelerometer applied on participants' leg allowed to measure body sways in different directions. Subjective parameters, like perception of stability, were also collected. Results showed that the placebo group had less body sways than the control group at T2, both in the three-dimensional space and in the anterior-posterior direction. Furthermore, the placebo group perceived to be more stable than the control group. This study represents the first evidence that placebo effect optimizes posture, with a potential translational impact in patients with postural and gait disturbances.

Predictive capacity of prodromal symptoms in first-episode psychosis of recent onset.

BACKGROUND: Both the nature and number of a wide range of prodromal symptoms have been related to the severity and type of psychopathology in the psychotic phase. However, at present there is an incomplete picture focused mainly on the positive pre-psychotic dimension. AIM: To characterize the prodromal phase retrospectively, examining the number and nature of prodromal symptoms as well as their relationship with psychopathology at the onset of first-episode psychosis. METHODS: Retrospective study of 79 patients experiencing a first-episode psychosis of less than 1 year from the onset of full-blown psychosis. All patients were evaluated with a comprehensive battery of instruments including socio-demographic and clinical questionnaire, IRAOS interview, PANSS, stressful life events scale (PERI) and WAIS/WISC (vocabulary subtest). Bivariate associations and multiple regression analysis were performed. RESULTS: Regression models revealed that several prodromal dimensions of IRAOS (delusions, affect, language, behaviour and non-hallucinatory disturbances of perception) predicted the onset of psychosis, with positive (22.4% of the variance) and disorganized (25.6% of the variance) dimensions being the most widely explained. CONCLUSION: In addition to attenuated positive symptoms, other symptoms such as affective, behavioural and language disturbances should also be considered in the definitions criteria of at-high-risk people.

Cog4 is required for protrusion and extension of the epithelium in the developing semicircular canals.

The semicircular canals in the inner ear sense angular acceleration. In zebrafish, the semicircular canals develop from epithelial projections that grow toward each other and fuse to form pillars. The growth of the epithelial projections is driven by the production and secretion of extracellular matrix components by the epithelium. The conserved oligomeric Golgi 4 protein, Cog4, functions in retrograde vesicle transport within the Golgi and mutations can lead to sensory neural hearing loss. In zebrafish cog4 mutants, the inner ear is smaller and the number of hair cells is reduced. Here, we show that formation of the pillars is delayed and that secretion of extracellular matrix components (ECM) is impaired in cog4-/- mutants. These results show that Cog4 is required for secretion of ECM molecules essential to drive the growth of the epithelial projections and thus regulates morphogenesis of the semicircular canals.