Investigation of health care use and a possible prodrome before the first attack in NMOSD and MOGAD.

BACKGROUND: Prodromal phases are well recognized in many inflammatory and neurodegenerative diseases, including multiple sclerosis. We evaluated the possibility of a prodrome in aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using health administrative data. METHODS: We investigated individuals with AQP4 + NMOSD and MOGAD, confirmed by medical chart review, in Ontario, Canada. Each NMOSD and MOGAD participant was matched 1:5 to general population controls by sex, birth year, immigrant status, and region. Total outpatient visits and hospitalizations were compared in the 5 years preceding the incident attack in multivariable negative binomial models. RESULTS: We identified 96 people with AQP4 + NMOSD, matched to 479 controls, and 61 people with MOGAD, matched to 303 controls. In the 5 years preceding the incident attack, health care use was elevated for outpatient visits and hospitalizations for the NMOSD cohort (adjusted rate ratio (aRR): 1.47; 95% confidence interval (CI): 1.25-1.73; aRR: 1.67; 95% CI: 1.19-2.36, respectively) but not for MOGAD. Rate ratios steadily increased in NMOSD for outpatient visits in the 2 years preceding the incident attack. CONCLUSION: Our findings support a prodromal phase preceding clinical onset of AQP4 + NMOSD. Earlier recognition and management of NMOSD patients may be possible.

Is there a prodrome to NMOSD? An investigation of neurologic symptoms preceding the first NMOSD attack.

BACKGROUND: It is unknown whether people with aquaporin-4 antibody positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) experience a prodrome, although a few cases report AQP4 + serology up to 16 years before the first attack. OBJECTIVES: To evaluate whether individuals with AQP4-IgG + NMOSD have prodromal neurologic symptoms preceding the first attack. METHODS: We reviewed medical records of participants meeting the 2015 diagnostic criteria for AQP4-IgG + NMOSD from four demyelinating disease centres in the Canadian NMOSD cohort study CANOPTICS. We searched for neurologic symptoms occurring at least 30 days before the first attack. RESULTS: Of 116 participants with NMOSD, 17 (14.7%) had prodromal neurologic symptoms. The median age was 48 years (range 25-83) at first attack; 16 (94.1%) were female. Participants presented with numbness/tingling (n = 9), neuropathic pain (n = 5), visual disturbance (n = 4), tonic spasms (n = 2), Lhermitte sign (n = 2), severe headache (n = 2), incoordination (n = 2), weakness (n = 1), psychosis (n = 1) or seizure (n = 1). Of eight who underwent magnetic resonance imaging (MRI) brain, orbits and/or spinal cord, five had T2 lesions. Within 1.5-245 months (median 14) from the onset of prodromal neurologic symptoms, participants experienced their first NMOSD attack. CONCLUSIONS: One in seven people with NMOSD experienced neurologic symptoms before their first attack. Further investigation of a possible NMOSD prodrome is warranted.

VISIBL-MS: A bilingual educational framework to increase awareness of early multiple sclerosis.

BACKGROUND: Despite advancements in treatments of multiple sclerosis (MS), there is a lack of awareness of early MS symptoms, especially in students and the public, contributing to delays in diagnosis and treatment. This review aims to identify gaps in tools to increase awareness and to provide a bilingual framework to facilitate recognition of early MS symptoms. METHODS: We performed a literature review to determine the use of English and Spanish mnemonics in MS education for medical students and patients. RESULTS: There is no educational tool to help remember the early signs of MS at present. Here we present a framework for early awareness encompassed in the bilingual mnemonics VISIBLY (English) and VISIBLE (Spanish). VISIBLY stands for (1) Vision changes: Painful vision loss, loss of color vision or double vision; (2) Belly or Back numbness and Balance issues; (3) Limb weakness or Numbness; (4), Young people. Spanish version is included in the manuscript. CONCLUSION: We posit that VISIBL-MS provides a framework for MS awareness that addresses the interconnection between language, culture, health literacy, and health outcomes and can be a useful educational tool to tackle the effects of health literacy on diverse communities.

Patterns and correlates of health service contact prior to serious offences by people with severe mental illness.

BACKGROUND: Contact with health services prior to offences committed by people with mental illness is an opportunity for intervention and prevention. This study examines the pattern and correlates of health service contact by people with severe mental illness before a serious offence. METHOD: Linkage of a cohort of 477 Forensic Patients found not guilty due to mental illness between 1990 and 2016, and statewide databases of contact with emergency departments, hospital admission and outpatient mental health services in the state of New South Wales, Australia. RESULTS: A total of 84% of the sample had contact with any health service and 76% had contact with an outpatient mental health service prior to the index offence. About two-thirds of the sample had contact with a mental health service in the year before the offence. Factors independently associated with the absence of contact at any point prior to the index offence were non-English-speaking background, being engaged in employment or study, and an absence of childhood abuse or neglect. Although nearly every Forensic Patient had a psychotic illness at the time of the index offence, psychosis was not diagnosed at the time of 61/106 (57.5%) emergency department presentations, in 54/174 (31.0%) hospital admissions and 149/222 (67.1%) attendances at outpatient mental health services prior to the offence. CONCLUSIONS: Most Forensic Patients had contact with health services prior to their offences but many were not identified as having a psychotic illness. Although the symptoms of psychosis may have emerged in the period between contact and the offence, the findings suggest that emerging or underlying psychosis were missed or attributed to other conditions.

The clinical course of individuals with 22q11.2 deletion syndrome converting to psychotic disorders: a long-term retrospective follow-up.

OBJECTIVES: This retrospective study aims to investigate the evolution and clinical course of psychotic disorders from three large international cohorts of individuals with 22q11.2 deletion syndrome (22q11.2DS) (Tel Aviv, Philadelphia, and Geneva). METHODS: We followed 118 individuals with 22q11.2DS from several years before the onset to several years after the onset of psychotic disorders. Data from structured baseline assessment of psychiatric disorders, symptoms of prodrome, indicators and types of psychotic disorders were collected. Additionally, cognitive evaluation was conducted using the age-appropriate Wechsler Intelligence Scale. Electronic medical records were reviewed for medication usage, occupational status, living situation, and psychiatric hospitalizations. RESULTS: At baseline evaluation, the most common psychiatric disorders were anxiety disorder (80%) and attention/deficit hyperactivity disorder (50%). The age of onset of prodromal symptoms and conversion to psychotic disorders were 18.6 ± 6.8 and 20.3 ± 7.2, respectively. The most common prodromal symptoms were exacerbation of anxiety symptoms and social isolation. Of the psychotic disorders, schizophrenia was the most common, occurring in 49% of cases. History of at least one psychiatric hospitalization was present in 43% of participants, and the number of psychiatric hospitalizations was 2.1 ± 1.4. Compared to the normalized chart, IQ scores in our cohort were lower after vs. before conversion to psychosis. Following conversion there was a decrease in the use of stimulants and antidepressants and an increase in antipsychotics use, and most individuals with 22q11.2DS were unemployed and lived with their parents. CONCLUSIONS: Our results indicate that 22q11.2DS psychosis is like non-22q11.2DS in its course, symptoms, and cognitive and functional impairments.

Prodromal symptoms and the duration of untreated psychosis in first episode of psychosis patients: what differences are there between early vs. adult onset and between schizophrenia vs. bipolar disorder?

To assess the role of age (early onset psychosis-EOP < 18 years vs. adult onset psychosis-AOP) and diagnosis (schizophrenia spectrum disorders-SSD vs. bipolar disorders-BD) on the duration of untreated psychosis (DUP) and prodromal symptoms in a sample of patients with a first episode of psychosis. 331 patients with a first episode of psychosis (7-35 years old) were recruited and 174 (52.6%) diagnosed with SSD or BD at one-year follow-up through a multicenter longitudinal study. The Symptom Onset in Schizophrenia (SOS) inventory, the Positive and Negative Syndrome Scale and the structured clinical interviews for DSM-IV diagnoses were administered. Generalized linear models compared the main effects and group interaction. 273 AOP (25.2 ± 5.1 years; 66.5% male) and 58 EOP patients (15.5 ± 1.8 years; 70.7% male) were included. EOP patients had significantly more prodromal symptoms with a higher frequency of trouble with thinking, avolition and hallucinations than AOP patients, and significantly different median DUP (91 [33-177] vs. 58 [21-140] days; Z = - 2.006, p = 0.045). This was also significantly longer in SSD vs. BD patients (90 [31-155] vs. 30 [7-66] days; Z = - 2.916, p = 0.004) who, moreover had different profiles of prodromal symptoms. When assessing the interaction between age at onset (EOP/AOP) and type of diagnosis (SSD/BD), avolition was significantly higher (Wald statistic = 3.945; p = 0.047), in AOP patients with SSD compared to AOP BD patients (p = 0.004). Awareness of differences in length of DUP and prodromal symptoms in EOP vs. AOP and SSD vs. BD patients could help improve the early detection of psychosis among minors.

Prodromes in demyelinating disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer's dementia.

A prodrome is an early set of symptoms, which indicates the onset of a disease; these symptoms are often non-specific. Prodromal phases are now recognized in multiple central nervous system diseases. The depth of understanding of the prodromal phase varies across diseases, being more nascent for multiple sclerosis for example, than for Parkinson disease or Alzheimer's disease. Key challenges when identifying the prodromal phase of a disease include the lack of specificity of prodromal symptoms, and consequent need for accessible and informative biomarkers. Further, heterogeneity of the prodromal phase may be influenced by age, sex, genetics and other poorly understood factors. Nonetheless, recognition that an individual is in the prodromal phase of disease offers the opportunity for earlier diagnosis and with it the opportunity for earlier intervention.

Reduced willingness to expend effort for rewards is associated with risk for conversion and negative symptom severity in youth at clinical high-risk for psychosis.

BACKGROUND: Schizophrenia (SZ) is typically preceded by a prodromal (i.e. pre-illness) period characterized by attenuated positive symptoms and declining functional outcome. Negative symptoms are prominent among individuals at clinical high-risk (CHR) for psychosis (i.e. those with prodromal syndromes) and predictive of conversion to illness. Mechanisms underlying negative symptoms are unclear in the CHR population. METHODS: The current study evaluated whether CHR participants demonstrated deficits in the willingness to expend effort for rewards and whether these impairments are associated with negative symptoms and greater risk for conversion. Participants included 44 CHR participants and 32 healthy controls (CN) who completed the Effort Expenditure for Reward Task (EEfRT). RESULTS: Compared to CN, CHR participants displayed reduced likelihood of exerting high effort for high probability and magnitude rewards. Among CHR participants, reduced effort expenditure was associated with greater negative symptom severity and greater probability of conversion to a psychotic disorder on a cross-sectional risk calculator. CONCLUSIONS: Findings suggest that effort-cost computation is a marker of illness liability and a transphasic mechanism underlying negative symptoms in the SZ spectrum.

Dynamic association of the first identifiable symptom with rapidity of progression to first-episode psychosis.

BACKGROUND: Rapid progression from the first identifiable symptom to the onset of first-episode psychosis (FEP) allows less time for early intervention. The aim of this study was to examine the association between the first identifiable symptom and the subsequent speed of illness progression. METHODS: Data were available for 390 patients attending a catchment-based early intervention service for FEP. Exposure to non-psychotic and subthreshold psychotic symptoms was retrospectively recorded using semi-structured interviews. Outcomes following the onset of the first identifiable symptom were (1) time to onset of FEP and (2) symptom incidence rate (i.e. number of symptoms emerging per person-year until FEP onset). These outcomes were respectively analyzed with Cox proportional hazards and negative binomial regressions. RESULTS: After Bonferroni correction, having a subthreshold psychotic (v. non-psychotic) symptom as the first symptom was not associated with time to FEP onset [hazard ratio (HR) = 1.39; 95% CI 0.94-2.04] but was associated with higher symptom incidence [incidence rate ratio (IRR) = 1.92; 95% CI 1.10-3.48]. A first symptom of suspiciousness was associated with shorter time to FEP onset (HR = 2.37; 95% CI 1.38-4.08) and higher symptom incidence rate (IRR = 3.20; 95% CI 1.55-7.28) compared to other first symptoms. In contrast, a first symptom of self-harm was associated with lower symptom incidence rate (IRR = 0.06; 95% CI 0.01-0.73) compared to other first symptoms. Several associations between symptoms and illness progression were moderated by the age at symptom onset. CONCLUSIONS: Appreciating the content and timing of early symptoms can identify windows and treatment targets for early interventions in psychosis.

Predictors of severity and outcome of multiple sclerosis relapses.

BACKGROUND: Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The most common type of MS is the relapsing-remitting MS (RRMS) where relapses are the main component of the disease course. However, the relationship between the characteristics of the relapses on one hand and their severity and outcome on the other hand has not been fully characterized. OBJECTIVES: To explore the characteristics of relapses among a cohort of Egyptian MS patients and their relation to the severity and outcome of the disease. SUBJECTS AND METHODS: We analyzed 300 attacks from 223 patients in a retrospective study to identify demographic, clinical and paraclinical (laboratory and radiological) factors affecting: 1- Severity of relapses (the difference between the EDSS at the day of maximum worsening and the EDSS before the onset of the attack). 2- Outcome of relapses (the difference between the EDSS at the day of maximum improvement and the EDSS before the onset of the relapse). RESULTS: Severe attacks were most likely to occur in patients who are males, single, presenting with poly-symptomatic presentation, slower tempo of evolution of attack symptoms, longer duration of the attack, absence of DMTs at the time of the attack. The risk of having a severe relapse is more than 3 times when the patient is single. Regarding attack outcome, poorly recovered attacks were more common in patients with older age at disease onset and at attack onset, male sex, higher number of relapses, longer duration of illness prior to the attack, severe relapses, polysymptomatic presentation, associated cognitive symptoms, slower tempo of symptom evolution, longer duration of the attack, patients on OCPs, smoking, and presence of black holes in brain MRI. The risk of having relapses with partial or no recovery is more than five times when the patient has black holes in brain MRI and more than 4 times when the patient is a smoker. CONCLUSION: Bearing in mind the demographic characteristics as well as the clinical and paraclinical characteristics of each attack and their relation to attack severity and outcome are a key to understanding the individual disease course of every patient and hence tailoring the best therapeutic plan suitable for his individual needs. In other words, prompt, rapid intervention in male patients, polysymptomatic attacks, slower tempo of evolution of attack symptoms and longer duration of the attack should be adopted since these factors are predictive of severe relapses as well as poor relapse outcome.

Regional cerebral perfusion during the premonitory phase of triggered migraine: A double-blind randomized placebo-controlled functional imaging study using pseudo-continuous arterial spin labeling.

OBJECTIVE: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)-triggered migraine attacks. BACKGROUND: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. METHODS: We undertook a functional imaging study using a double-blind placebo-controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine-like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty-three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo-continuous arterial spin labeling (3D pCASL). RESULTS: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family-wise error-corrected) during NTG-induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). CONCLUSIONS: We identified significant regional CBF changes associated with NTG-induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment-related heterogeneity is vital to evaluating functional imaging outcomes in migraine research.

Advances in the Diagnosis and Management of Psychotic Symptoms in Neurodegenerative Diseases: A Narrative Review.

Background: Approximately 15% of older adults may experience psychotic phenomena. Primary psychiatric disorders that manifest with psychosis (delusions, hallucinations, and disorganized thought or behavior) account for less than half. Up to 60% of late-life psychotic symptoms are due to systemic medical or neurological conditions, particularly neurodegenerative diseases. A thorough medical workup including laboratory tests, additional procedures if indicated, and neuroimaging studies is recommended. This narrative review summarizes current evidence regarding the epidemiology and phenomenology of psychotic symptoms encountered as part of the neurodegenerative disease continuum (including prodromal and manifest stages). Results: Prodromes are constellations of symptoms that precede the onset of overt neurodegenerative syndromes. Prodromal psychotic features, particularly delusions, have been associated with an increased likelihood of receiving a neurodegenerative disease diagnosis within several years. Prompt prodrome recognition is crucial for early intervention. The management of psychosis associated with neurodegenerative diseases includes behavioral and somatic strategies, although evidence is scarce and mostly limited to case reports, case series, or expert consensus guidelines, with few randomized controlled trials. Conclusion: The complexity of psychotic manifestations warrants management by interprofessional teams that provide coordinated, integrated care.

The effects of the COVID-19 pandemic on hallucinations and delusions in youth at clinical high-risk for psychosis and outpatients with schizophrenia.

Although the COVID-19 pandemic has had detrimental effects on mental health in the general population, the impact on those with schizophrenia-spectrum disorders has received relatively little attention. Assessing pandemic-related changes in positive symptoms is particularly critical to inform treatment protocols and determine whether fluctuations in hallucinations and delusions are related to telehealth utilization and treatment adherence. In the current longitudinal study, we evaluated changes in the frequency of hallucinations and delusions and distress resulting from them across three-time points. Participants included: (1) outpatients with chronic schizophrenia (SZ: n = 32) and healthy controls (CN: n = 31); (2) individuals at clinically high risk for psychosis (CHR: n = 25) and CN (n = 30). A series of questionnaires were administered to assess hallucination and delusion severity, medication adherence, telehealth utilization, and protective factors during the pandemic. While there were no significant increases in the frequency of hallucinations and delusions in SZ and CHR, distress increased from pre-pandemic to early pandemic in both groups and then decreased at the third time point. Additionally, changes in positive symptom severity in SZ were related to psychiatric medication adherence. Findings suggest that positive symptoms are a critical treatment target during the pandemic and that ongoing medication services will be beneficial.

Epileptic Prodromes: Insights from Surveying 196 Patients and 150 Caregivers.

OBJECTIVE: Uncontrolled epilepsy creates a constant source of worry for patients and puts them at a high risk of injury. Identifying recurrent "premonitory" symptoms of seizures and using them to recalibrate seizure prediction algorithms may improve prediction performances. This study aimed to investigate patients' ability to predict oncoming seizures based on preictal symptoms. METHODS: Through an online survey, demographics and clinical characteristics (e.g., seizure frequency, epilepsy duration, and postictal symptom duration) were collected from people with epilepsy and caregivers across Canada. Respondents were asked to answer questions regarding their ability to predict seizures through warning symptoms. A total of 196 patients and 150 caregivers were included and were separated into three groups: those who reported warning symptoms within the 5 minutes preceding a seizure, prodromes (symptoms earlier than 5 minutes before seizure), and no warning symptoms. RESULTS: Overall, 12.2% of patients and 12.0% of caregivers reported predictive prodromes ranging from 5 minutes to more than 24 hours before the seizures (median of 2 hours). The most common were dizziness/vertigo (28%), mood changes (26%), and cognitive changes (21%). Statistical testing showed that respondents who reported prodromes also reported significantly longer postictal recovery periods compared to those who did not report predictive prodromes (P < 0.05). CONCLUSION: Findings suggest that patients who present predictive seizure prodromes may be characterized by longer patient-reported postictal recovery periods. Studying the correlation between seizure severity and predictability and investigating the electrical activity underlying prodromes may improve our understanding of preictal mechanisms and ability to predict seizures.

Treatment with tecovirimat of the first two cases of monkeypox in Japan.

Outbreaks of monkeypox in Europe and North America have been reported since May 2022. At the end of July, we encountered the first two cases of monkeypox diagnosed in Japan. Case 1 was a white man who traveled to Spain where he had sexual intercourse with men. He presented to our hospital with fever, rash, and tiredness, and was diagnosed with monkeypox based on positive PCR test results from the skin lesions. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 15. Case 2 involved a Japanese man who visited us because of fatigue, muscle pain, headache, and oral ulcers. He was living in New York and traveled to Japan one day before presentation. He had experienced sexual intercourse with men four times during the previous month. The patient was diagnosed with monkeypox based on positive PCR results from the blood. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 14. These were the first two cases of monkeypox diagnosed in Japan. Based on their history and epidemiology, the viruses seem to have been imported from Europe and North America, respectively. After initiation of tecovirimat, both patients showed mild symptoms and immediate disappearance of viral DNA. The second case was notable for being diagnosed without skin rash. Our report suggests that tecovirimat could decrease the viral load rapidly, and that our prompt diagnosis contributed to the prevention of a monkeypox outbreak in Japan.

Environmental factors contributing to negative symptoms in youth at clinical high risk for psychosis and outpatients with schizophrenia.

BACKGROUND: A bioecosystem theory was recently proposed positing that negative symptoms of schizophrenia (SZ) are influenced by environmental factors. These environmental processes reflect sources of resource deprivation that manifest across multiple systems that impact individuals directly through microsystems and indirectly through the exosystem and macrosystem. As an initial test of this theory, the current study examined whether self-reported environmental resource deprivation was associated with anhedonia, avolition, and asociality. METHOD: Two samples were collected: (1) outpatients with schizophrenia or schizoaffective disorder (SZ: n = 38) and matched psychiatrically heathy controls (CN: n = 31); (2) youth at clinical high risk for psychosis (CHR: n = 34) and matched CN (n = 30). Measures of negative symptoms and environmental factors influencing the frequency of recreational, goal-directed, and social activities were collected. RESULTS: Negative symptoms were associated with environmental deprivation factors in the microsystem (number of social and activity settings) and exosystem (economy, mass media, politics/laws, neighborhood crime). These associations did not appear due to depression and were greater among those with SZ than CHR. CONCLUSIONS: These findings provide preliminary support for the bioecosystem theory and highlight an under-recognized role for environmental factors underlying negative symptoms across phases of psychotic illness. Environmental systems-focused treatment approaches may offer a novel means of treating negative symptoms, which could be promising when coupled with person-level pharmacological and psychosocial treatments.

Sensed Presence, Attenuated Psychosis, and Transliminality: At the Threshold of Consciousness.

INTRODUCTION: The experience of "sensed presence" or "felt presence" in the absence of "other" has been described as a complex multimodal experience to which meaning is given. Sensed presence (SenP) is a transdiagnostic experience that exists along a continuum that can appear during isolation, spirit quests, exposure to extreme elements, bereavement, anxiety, and psychosis. Given the prevalence and vast heterogeneity of SenP, in addition to a surprising lack of targeted research into this phenomenon, this research examined the interrelationship of SenP, attenuated psychosis symptoms (APS), and transliminality. Transliminality is composed of absorption, fantasy proneness, paranormal belief, mystical experiences, increased creativity, and hyperaesthesia. METHODS: A completely anonymous online survey of unusual experiences and mental health was distributed via social media (i.e., Twitter, Facebook, Reddit, and mass emailing lists) to recruit participants. Demographic data were analyzed using χ2 tests and one-way ANOVAs. A two-step cluster analysis was conducted to identify distinct sub-categories of transliminality followed by ANOVAs with bootstrapping at 1,000 iterations to compare SenP, increased APS, and transliminality. Pearson's bivariate correlations were conducted to determine the association between SenP, APS, and transliminality. RESULTS: Together with descriptive findings, we show distinct characteristics between clusters. T1 cluster consisted of individuals with few SenP experiences, low APS, and low transliminality. T2 consisted of individuals with a moderate prevalence of SenP, low APS, moderate transliminality, and increased overall feeling of closeness to G-d. There was no significant difference in APS between T1 and T2 or in the level of distress associated with APS. T3 individuals showed a significantly higher prevalence of SenP in all domains (frequency, distress, vividness, and total score), higher APS, and higher transliminality, compared to T1 and T2. The T3 cluster met criteria for high risk to develop psychosis. CONCLUSION: Thus, our findings demonstrate a strong association and entanglement of these experiences which suggests that the interrelatedness of transliminality/absorption and APS may serve as a potentially provocative underlying structure in the phenomenology of SenP.

Nicotine Exposure in a Phencyclidine-Induced Mice Model of Schizophrenia: Sex-Selective Medial Prefrontal Cortex Protein Markers of the Combined Insults in Adolescent Mice.

Tobacco misuse as a comorbidity of schizophrenia is frequently established during adolescence. However, comorbidity markers are still missing. Here, the method of label-free proteomics was used to identify deregulated proteins in the medial prefrontal cortex (prelimbic and infralimbic) of male and female mice modelled to schizophrenia with a history of nicotine exposure during adolescence. Phencyclidine (PCP), used to model schizophrenia (SCHZ), was combined with an established model of nicotine minipump infusions (NIC). The combined insults led to worse outcomes than each insult separately when considering the absolute number of deregulated proteins and that of exclusively deregulated ones. Partially shared Reactome pathways between sexes and between PCP, NIC and PCPNIC groups indicate functional overlaps. Distinctively, proteins differentially expressed exclusively in PCPNIC mice reveal unique effects associated with the comorbidity model. Interactome maps of these proteins identified sex-selective subnetworks, within which some proteins stood out: for females, peptidyl-prolyl cis-trans isomerase (Fkbp1a) and heat shock 70 kDa protein 1B (Hspa1b), both components of the oxidative stress subnetwork, and gamma-enolase (Eno2), a component of the energy metabolism subnetwork; and for males, amphiphysin (Amph), a component of the synaptic transmission subnetwork. These are proposed to be further investigated and validated as markers of the combined insult during adolescence.

Neuroimaging in the pre-ictal or premonitory phase of migraine: a narrative review.

BACKGROUND: The premonitory phase, or prodrome, of migraine, provides valuable opportunities to study attack initiation and for treating the attack before headache starts. Much that has been learned about this phase in recent times has come from the outcomes of functional imaging studies. This review will summarise these studies to date and use their results to provide some feasible insights into migraine neurobiology. MAIN BODY: The ability to scan repeatedly a patient without radiation and with non-invasive imaging modalities, as well as the recognition that human experimental migraine provocation compounds, such as nitroglycerin (NTG) and pituitary adenylate cyclase activating polypeptide (PACAP), can trigger typical premonitory symptoms (PS) and migraine-like headache in patients with migraine, have allowed feasible and reproducible imaging of the premonitory phase using NTG. Some studies have used serial scanning of patients with migraine to image the migraine cycle, including the 'pre-ictal' phase, defined by timing to headache onset rather than symptom phenotype. Direct observation and functional neuroimaging of triggered PS have also revealed compatible neural substrates for PS in the absence of headache. Various imaging methods including resting state functional MRI (rsfMRI), arterial spin labelling (ASL), positron emission tomography (PET) and diffusion tensor imaging (DTI) have been used. The results of imaging the spontaneous and triggered premonitory phase have been largely consistent and support a theory of central migraine attack initiation involving brain areas such as the hypothalamus, midbrain and limbic system. Early dysfunctional pain, sensory, limbic and homeostatic processing via monoaminergic and peptidergic neurotransmission likely manifests in the heterogeneous PS phenotype. CONCLUSION: Advances in human migraine research, including the use of functional imaging techniques lacking radiation or radio-isotope exposure, have led to an exciting opportunity to study the premonitory phase using repeated measures imaging designs. These studies have provided novel insights into attack initiation, migraine neurochemistry and therapeutic targets. Emerging migraine-specific therapies, such as those targeting calcitonin gene-related peptide (CGRP), are showing promise acutely when taken during premonitory phase to reduce symptoms and prevent subsequent headache. Therapeutic research in this area using PS for headache onset prediction and early treatment is likely to grow in the future.

Adolescent nicotine potentiates the inhibitory effect of raclopride, a D2R antagonist, on phencyclidine-sensitized psychotic-like behavior in mice.

The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D2 receptors in both schizophrenia and addiction, we further tested their role by exposing mice to raclopride. Adolescent mice that were either exposed to nicotine (24 mg/Kg/day) or not, received single daily raclopride (0.5 mg/kg, s.c.) or saline followed by phencyclidine injections (10 mg/Kg, s.c.) during open field testing for 6 consecutive days (Acquisition phase, ACQ). Phencyclidine and nicotine challenges (Sensitization Test, ST) were carried out after a 5-day withdrawal. Ambulation escalated in response to repeated phencyclidine exposure during ACQ and was increased after phencyclidine challenge, evidencing development and expression of locomotor sensitization. Raclopride prevented phencyclidine-evoked development of sensitization. However, raclopride pre-exposure during ACQ only shortened its expression in phencyclidine-challenged mice. Nicotine failed to interfere with phencyclidine stimulatory effects during ACQ but potentiated raclopride inhibition during the first ACQ days. During ST, nicotine history shortened the expression of phencyclidine-evoked sensitization. Nicotine challenge had no impact on locomotion, which is consistent with a lack of nicotine/phencyclidine cross-sensitization. In conclusion, our results show that nicotine does not worsen, and may even ameliorate phencyclidine-sensitized psychotic-like behavior in adolescent mice. The potentiation of raclopride-mediated inhibition further suggests that nicotine transiently improves the therapeutic efficacy of medication on psychotic symptoms through mechanisms that converge on D2 receptors.