Classification of musical hallucinations and the characters along with neural-molecular mechanisms of musical hallucinations associated with psychiatric disorders

BACKGROUND Musical hallucinations(MH)involve the false perception of music in the absence of external stimuli which links with different etiologies.The pathomechanisms of MH encompass various conditions.The etiological classification of MH is of particular importance and offers valuable insights to understand MH,and further to develop the effective treatment of MH.Over the recent decades,more MH cases have been reported,revealing newly identified medical and psychiatric causes of MH.Functional imaging studies reveal that MH activates a wide array of brain regions.An up-to-date analysis on MH,especially on MH comorbid psychiatric conditions is warranted.AIM To propose a new classification of MH;to study the age and gender differences of MH in mental disorders;and neuropathology of MH.METHODS Literatures searches were conducted using keywords such as“music hallucination,”“music hallucination and mental illness,”“music hallucination and gender difference,”and“music hallucination and psychiatric disease”in the databases of PubMed,Google Scholar,and Web of Science.MH cases were collected and categorized based on their etiologies.The t-test and ANOVA were employed(P<0.05)to compare the age differences of MH different etiological groups.Function neuroimaging studies of neural networks regulating MH and their possible molecular mechanisms were discussed.RESULTS Among the 357 yielded publications,294 MH cases were collected.The average age of MH cases was 67.9 years,with a predominance of females(66.8%females vs 33.2%males).MH was classified into eight groups based on their etiological mechanisms.Statistical analysis of MH cases indicates varying associations with psychiatric diagnoses.CONCLUSION We carried out a more comprehensive review of MH studies.For the first time according to our knowledge,we demonstrated the psychiatric conditions linked and/or associated with MH from statistical,biological and molecular point of view.

Selective serotonin reuptake inhibitors and Alzheimer’s disease

Given the failure to develop disease-modifying therapies for Alzheimer’s disease(AD),strategies aiming at preventing or delaying the onset of the disease are being prioritized.While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on,a key determining factor may be the timing of depression onset in older adults.There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline.Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden,tau deposits and neurogenesis.In humans,studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors.Paroxetine,which has strong anticholinergic properties,was associated with increased mortality and mixed effects on amyloid and tau deposits in mice,as well as increased odds of developing AD in humans.Although most of the data regarding selective serotonin reuptake inhibitors is promising,findings should be interpreted cautiously because of notable methodological heterogeneity between studies.There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation:Mechanisms and implications for psychopathology

Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid(DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In nonhuman primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with longstanding deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder(ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies.

Review of the genetic basis of emotion dysregulation in children and adolescents

Previous evidence suggests that emotion dysregulation may have different biological correlates between adults and children/adolescents. Although the role of genetic factors has been extensively studied in adult-onset emotion dysregulation, the genetic basis for pediatriconset emotion dysregulation remains elusive. The current review article presents a summary of previous studies that have suggested a few genetic variants associated with pediatric emotion dysregulation. Among these candidate loci, many prior studies have been focused on serotonin transporter promoter gene polymorphism 5-HTTLPR. Certain alleles of the 5-HTTLPR gene polymorphism have been found to be associated with traits associated with emotion dysregulation, such as aggression, affect reactivity, and insecure attachment. Additionally, genetic variants involving dopamine and neurophysiological biomarkers like the COMT Val158Met(rs460) and dopamine receptor D2/ ankyrin repeat and kinase domain containing one polymorphisms may play a role in emotion dysregulation. Inconsistent findings have been noted, possibly due to the heterogeneity in study designs and characteristics of different populations. Further research on the role of genetic predetermination of emotion dysregulation in children and adolescents is warranted.

Pharmacological characterizationof synthetic cannabinoid MAM-2201：radioligand binding and abuse-related effects

OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a "graymarket" drug of abuse bystructurally combining the known synthetic cannabinoids JWH-122 and AM-2201.There is currently no published information regarding the pharmacology of MAM-2201.METHODS The present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1 Rs]) and in vivo(in mice and rats).RESULTS In a radioligand binding assay using [3 H]CP55,940 in HEK cell membranes transfected with the CB1 R,MAM-2201(K i=5.4 nmol·L^(-1)),had higher binding affinity than WIN 55,212-2(K i=80 nmol·L^(-1)),and D9-THC(K i=8.3 nmol·L^(-1)).The E max values for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated c AMP were 85%(EC50=0.45 nmol·L^(-1)) and 95%,respectively,as compared with the D9-THC E max of 74%.In mice,MAM-2201(0.003-1.0 mg·kg^(-1),IP) produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of D9-THC.MAM-2201 and D9-THC dose-dependently produced hypothermia:ED50=0.287 and 25.4 mg·kg^(-1),analgesia:ED50=0.125 and 29.4 mg·kg^(-1),and catalepsy:ED50=0.301 and18.9 mg·kg^(-1) in adult male CD1 mice.Importantly,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg^(-1) in 8/8 murine subjects.In rats,MAM-2201 produced dose-dependent D9-THC-like interoceptive effects in subjects trained to discriminate 3.0 mg·kg^(-1)(IP) D9-THC from saline.CONCLUSION MAM-2201 binds CB1 Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.

Understanding academic clinicians' intent to treat pediatric obesity

AIM To examine the extent to which the theory of planned behavior(TPB) predicts academic clinicians' intent to treat pediatric obesity.METHODS A multi-disciplinary panel iteratively devised a Likert scale survey based on the constructs of the TPB applied to a set of pediatric obesity themes.A cross-sectional electronic survey was then administered to academic clinicians at tertiary care centers across Canada from January to April 2012.Descriptive statistics were used to summarize demographic and item agreement data.A hierarchical linear regression analysis controlling for demographic variables was conducted to examine the extent to which the TPB subscales predicted intent to treat pediatric obesity.RESULTS A total of 198 physicians,surgeons,and allied healthprofessionals across Canada(British Columbia,Alberta,Manitoba,Saskatchewan,Nova Scotia,Ontario and Quebec) completed the survey.On step 1,demographic factors accounted for 7.4% of the variance in intent scores.Together in step 2,demographic variables and TPB subscales predicted 56.9% of the variance in a measure of the intent to treat pediatric obesity.Perceived behavioral control,that is,confidence in one's ability to manage pediatric obesity,and subjective norms,congruent with one's context of practice,were the most significant predictors of the intent to treat pediatric obesity.Attitudes and barriers did not predict the intent to treat pediatric obesity in this context.CONCLUSION Enhancing self-confidence in the ability to treat pediatric obesity and the existence of supportive treatment environments are important to increase clinician's intent to treat pediatric obesity.

Young blood products:emerging treatment for Alzheimer's disease?

Alzheimer＇s disease is the most common neurodegenerative disorder and no disease-modifying treatment is currently available.Research has shown that while brain neurogenesis continues in adult life,it declines with age.Using parabiosis,plasma transfusions and direct administration of neural growth factors,animal studies have demonstrated the positive impact of exposure to young blood products on neurogenesis and synaptic plasticity in an aging brain.The hippocampus and the sub-ventricular zones were identified as the main regions affected.Promising findings have prompted researchers to experiment their effects in subjects with an established neurocognitive disorder,such as Alzheimer＇s disease.They argued that modification of brain vasculature,reactivation of adult neural stem cells,and remodeling of their synaptic activity/plasticity may lead to cognitive enhancement and increased neurogenesis.One pilot human study found that young donor plasma infusion protocols for adults with Alzheimer＇s disease were safe and feasible;however,no statistically significant improvements in cognition were detected.There is a need to conduct additional placebo-controlled human studies in larger samples.Future studies should focus on identifying an “optimal age” at which an intervention in humans may yield significant cognitive enhancement,as well as determining the types of transfusions with the best efficacy and tolerability profiles.

Vampiristic behaviors in a patient with traumatic brain injury induced disinhibition

Vampiristic behaviors are rarely seen clinically and less than 100 cases have been reported in the world literature to date. A distinction is usually made as to whether the patient drinks their own blood or the blood of others. We describe a 38-year-old patient who had vampiristic thoughts and fantasies that began in adolescence, but did not act on these thoughts until after she suffered a traumatic brain injury with a three-week loss of consciousness while serving in the military. Brain imaging showed focal damage to her bilateral frontal lobes. Psychological testing demonstrated impairment of executive function. We review the proposed diagnostic criteria for vampirism and discuss how behavioral disinhibition may have affected the emergence into behavior of her previously inhibited vampiristic thoughts.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease

Alzheimer's disease(AD)is the most common type of neurode generative disorder;it affects around 47 million individuals worldwide(Prince et al.,2013).AD rose from the 12 th most burdensome disease in the United States in 1990 to the sixth in 2016 in terms of disability-adjusted life years(Alzheimer's Disease.

出生前接触酒精对婴儿视力的影响

Objective: To examine the effects of prenatal alcohol exposure ascertained prospectively on infant visual acuity across a range of exposures and factors that mediate or moderate these effects. Study design: Infant visual acuity was examined in 131 Cape Coloured (mixed ancestry)maternal-infant pairs in Cape Town, South Africa. Drinking patterns were documented by maternal reporting during pregnancy. Grating acuity was assessed with Teller Acuity Cards (TAC) at 6.5 months after term. Data were analyzed by correlation, multiple regression, and analysis of variance. Results: Greater average daily prenatal alcohol exposure was related to poorer acuity, as indicated by lower TAC scores. The effect of alcohol on acuity was significant primarily for infants born to mothers ≥30 years of age at delivery, in comparison to infants born to younger mothers. This effect was not mediated by gestational age or birth size or attributable to alcohol-related neurocognitive deficits. Conclusions: This study linked prenatal alcohol exposure ascertained prospectively to poorer visual acuity in infancy. The results are consistent with clinical and animal evidence of alcohol-related disruption of the visual system.

人类海马和鼻腔区域的感觉门控

Objective: The objective of this work was to ascertain if sensory gating can be demonstrated within the human medial temporal lobe. Methods: Eight patients with intractable epilepsy with depth electrodes implanted in the medial temporal lobe for presurgery evaluation underwent evoked response recording to auditory paired-stimuli (S1-S2). Each of the eight subjects had a diagnosis of left medial temporal lobe epilepsy (MTLE).Results: Data from the non-focal right hippocampi revealed a large negative response on S1 (starting at about 190 ms and lasting for approximately 300 ms from stimulus onset). Rhinal region recordings revealed a positive response (starting at about 240 ms with a rapid incline, followed by a long-lasting decline). A significant attenuation of both responses to S2 stimuli was observed. Conclusions: Data are suggestive of an involvement of the human medial temporal lobe in the processing of simple auditory information which occurs in a time frame later than the neocortical auditory evoked components. The exact role of these anatomical structures in the sensory gating process remains to be defined. Significance: This study provides the first evidence of an activation of the rhinal cortex after simple auditory stimulation and provides new evidence that the activation of the medial temporal lobe structures occurs at a later stage than that of the neocortex.

ChatGPT:a promising AI technology for psychoradiology research and practice

Psychoradiology is a new interdisciplinary field that uses neu-roimaging to study the brain mechanisms of psychiatric disorders(Lui et al,2016).With the rapid advancement of artificial intelli-gence(AI)machine learning models,psychoradiology has moved beyond traditional case-control clinical designs that search forab-normnal patterns in neural images.

Storylines of family medicine Ⅳ:perspectives on practice—lenses of appreciation

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine,as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world.In‘Ⅳ:perspectives on practice—lenses of appreciation’,authors address the following themes:‘Relational connections in the doctor–patient partnership’,‘Feminism and family medicine’,‘Positive family medicine’,‘Mindful practice’,‘The new,old ethics of family medicine’,‘Public health,prevention and populations’,‘Information mastery in family medicine’and‘Clinical courage.’May readers nurture their curiosity through these essays.

Machine learning for detecting mesial temporal lobe epilepsy by structural and functional neuroimaging

Mesial temporal lobe epilepsy(mTLE),the most common type of focal epilepsy,is associated with functional and structural brain alterations.Machine learning(ML)techniques have been successfully used in discriminating mTLE from healthy controls.However,either functional or structural neuroimaging data are mostly used separately as input,and the opportunity to combine both has not been exploited yet.We conducted a multimodal ML study based on functional and structural neuroimaging measures.We enrolled 37 patients with left mTLE,37 patients with right mTLE,and 74 healthy controls and trained a support vector ML model to distinguish them by using each measure and the combinations of the measures.For each single measure,we obtained a mean accuracy of 74%and 69%for discriminating left mTLE and right mTLE from controls,respectively,and 64%when all patients were combined.We achieved an accuracy of 78%by integrating functional data and 79%by integrating structural data for left mTLE,and the highest accuracy of 84%was obtained when all functional and structural measures were combined.These findings suggest that combining multimodal measures within a single model is a promising direction for improving the classification of individual patients with mTLE.

Disruption of the white matter structural network and its correlation with baseline progression rate in patients with sporadic amyotrophic lateral sclerosis

Objective:There is increasing evidence that amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease impacting large-scale brain networks.However,it is still unclear which structural networks are associated with the disease and whether the network connectomics are associated with disease progression.This study was aimed to characterize the network abnormalities in ALS and to identify the network-based biomarkers that predict the ALS baseline progression rate.Methods:Magnetic resonance imaging was performed on 73 patients with sporadic ALS and 100 healthy participants to acquire difusion-weighted magnetic resonance images and construct white matter(WM)networks using tractography methods.The global and regional network properties were compared between ALS and healthy subjects.The single-subject WM network matrices of patients were used to predict the ALS baseline progression rate using machine learning algorithms.Results:Compared with the healthy participants,the patients with ALS showed signifcantly decreased clustering coefcient C_(p)(P=0.0034,t=2.98),normalized clustering coefcientγ(P=0.039,t=2.08),and small‐worldnessσ(P=0.038,t=2.10)at the global network level.The patients also showed decreased regional centralities in motor and non-motor systems including the frontal,temporal and subcortical regions.Using the single-subject structural connection matrix,our classifcation model could distinguish patients with fast versus slow progression rate with an average accuracy of 85%.Conclusion:Disruption of the WM structural networks in ALS is indicated by weaker small-worldness and disturbances in regions outside of the motor systems,extending the classical pathophysiological understanding of ALS as a motor disorder.The individual WM structural network matrices of ALS patients are potential neuroimaging biomarkers for the baseline disease progression in clinical practice.

Path from schizophrenia genomics to biology:gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing

Schizophrenia（SZ） is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies（GWASs） of SZ have identified 〉100 risk loci. However,the causal variants/genes and the causal mechanisms remain largely unknown,which hinders the translation of GWAS fi ndings into disease biology and drug targets. Most risk variants are noncoding,thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling,and open chromatin is a versatile predictor of regulatory sequences. Micro RNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specifi c induced pluripotent stem cells（i PSCs） provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specifi c to cell type and/or developmental stage. The emerging genome-editing technology enables the creation ofisogenic i PSCs and neurons to effi ciently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic,glutamatergic,and GABAergic neurotransmissions. SZ GWAS fi ndings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.

Neuropsychiatric symptoms associated with the COVID-19 and its potential nervous system infection mechanism:the role of imaging in the study

The epidemic of coronavirus disease 2019(COVID-19)has broken the normal spread mode of respiratory viruses,namely,mainly spread in winter,resulting in over 230 million confirmed cases of COVID-19.Many studies have shown that severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)can affect the nervous system by varying degrees.In this review,we look at the acute neuropsychiatric impacts of COVID-19 patients,including acute ischemic stroke,encephalitis,acute necrotizing encephalopathy,dysosmia,and epilepsy,as well as the long-term neuropsychiatric sequelae of COVID-19 survivors:mental disorder and neurodegenerative diseases.In particular,this review discusses long-term changes in brain structure and function associated with COVID-19 infection.We believe that the traditional imaging sequences are important in the acute phase,while the nontraditional imaging sequences are more meaningful for the detection of long-term neuropsychiatric sequelae.These long-term follow-up changes in structure and function may also help us understand the causes of neuropsychiatric symptoms in COVID-19 survivors.Finally,we review previous studies and discuss some potential mechanisms of SARS-CoV-2 infection in the nervous system.Continuous focus on neuropsychiatric sequelae and a comprehensive understanding of the long-term impacts of the virus to the nervous system is significant for formulating effective sequelae prevention andmanagement strategies,andmay provide important clues for nervous system damage in future public health crises.

Therapeutic approach targeting apolipoprotein E binding region and low-density lipoprotein receptor for Alzheimer's disease

Approximately 13% of the population over the age of 65 years is estimated to have AD. The total number of cases is expected to increase over the coming decades. The apolipoprotein E (ApoE) genotype is the greatest genetic deter-minant for Alzheimer's disease (AD) development. The ApoE4 allele increases the risk of AD by 4 to 14 fold while the ApoE2 allele has an opposing effect;decreasing risk. Indeed many studies have demonstrated that carriers of the ApoE2 allele are associated with greater likelihood of survival to advanced age, superior verbal learning ability in advanced age, and reduced accumulation of amyloid pathology in the aged brain. In addition, it is known that ApoE proteins have different affinities for the low-density lipoprotein receptor (LDLR), with ApoE2 having the weakest binding to the LDL receptor at < 2% relative to ApoE3 and E4. Because ApoE2 has shown protective effects in re-gard to AD, a novel approach for ApoE4 carriers may be to create a peptide antagonist that blocks the ApoE inter-actions with LDLR at its 135-150 N-terminal binding domain. This peptide may create a more ApoE2-like structure by decreasing the affinity of ApoE4 for LDLR thereby reducing AD onset, memory impairment, and amyloid plaque formation. In this review, we will discuss the different detrimental effects that ApoE4 can cause. Most importantly, we will review how ApoE4 binding to LDLR promotes AD pathogenesis and how blocking ApoE4 binding may be a promising novel therapeutic approach for AD.

The inferior frontal gyrus and familial risk for bipolar disorder

Bipolar disorder(BD)is a familial disorder with high heritability.Genetic factors have been linked to the pathogenesis of BD.Relatives of probands with BD who are at familial risk can exhibit brain abnormalities prior to illness onset.Given its involvement in prefrontal cognitive control and in frontolimbic circuitry that regulates emotional reactivity,the inferior frontal gyrus(IFG)has been a focus of research in studies of BD-related pathology and BD-risk mechanism.In this review,we discuss multimodal neuroimaging findings of the IFG based on studies comparing at-risk relatives and low-risk controls.Review of these studies in at-risk cases suggests the presence of both risk and resilience markers related to the IFG.At-risk individuals exhibited larger gray matter volume and increased functional activities in IFG compared with low-risk controls,which might result from an adaptive brain compensation to support emotion regulation as an aspect of psychological resilience.Functional connectivity between IFG and downstream limbic or striatal areas was typically decreased in at-risk individuals relative to controls,which could contribute to risk-related problems of cognitive and emotional control.Large-scale and longitudinal investigations on at-risk individuals will further elucidate the role of IFG and other brain regions in relation to familial risk for BD,and together guide identification of at-risk individuals for primary prevention.

Human stem cell modeling of neuropsychiatric disorders:from polygenicity to convergence

Neuropsychiatric disorders(NPD)are prevalent and devastating,posing an enormous socioeconomic burden to modern society.Recent genetic studies of NPD have identified a plethora of common genetic risk variants with small effect sizes and rare risk variants of high penetrance.While exciting,there is a pressing need to translate these genetic discoveries into better understanding of disease biology and more tailored clinical interventions.Human induced pluripotent stem cell(hiPSC)-derived 2D and 3D neural cultures are becoming a promising cellular model for bridging the gap between genetic findings and disease biology for NPD.Leveraging the accessibility of patient biospecimen to convert into stem cells and the power of genome editing technology to engineer disease risk variants,hiPSC model holds the promise to disentangle the disease polygenicity,model genetic interaction with environmental factors,and uncover convergent gene pathways that may be targeted for more tailored clinical intervention.