36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease.

INTRODUCTION: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention. METHODS: In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5-item composite). Analyses were by modified intention-to-treat, excluding (ie, censoring) data collected after the start of open-label active product and/or AD medication. RESULTS: Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5-item composite (-60%; between-group difference 0.212 [95% confidence interval: 0.044 to 0.380]; P = 0.014), Clinical Dementia Rating-Sum of Boxes (-45%; P = 0.014), memory (-76%; P = 0.008), and brain atrophy measures; small to medium Cohen's d effect size (0.25-0.31) similar to established clinically relevant AD treatment. DISCUSSION: This multinutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long-term use.

Souvenaid for Alzheimer's disease.

BACKGROUND: Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been designed to support the formation and function of synapses in the brain, which are thought to be strongly correlated with cognitive function. If effective, it might improve symptoms of Alzheimer's disease and also prevent the progression from prodromal Alzheimer's disease to dementia. We sought in this review to examine the evidence for this proposition. OBJECTIVES: To assess the effects of Souvenaid on incidence of dementia, cognition, functional performance, and safety in people with Alzheimer's disease. SEARCH METHODS: We searched ALOIS, i.e. the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science (ISI Web of Science), Cinahl (EBSCOhost), Lilacs (BIREME), and clinical trials registries up to 24 June 2020. We also reviewed citations of reference lists of landmark papers, reviews, and included studies for additional studies and assessed their suitability for inclusion in the review. SELECTION CRITERIA: We included randomised, placebo-controlled trials which evaluated Souvenaid in people diagnosed with mild cognitive impairment (MCI) due to AD (also termed prodromal AD) or with dementia due to AD, and with a treatment duration of at least 16 weeks. DATA COLLECTION AND ANALYSIS: Our primary outcome measures were incidence of dementia, global and specific cognitive function, functional performance, combined cognitive-functional outcomes and adverse events. We selected studies, extracted data, assessed the quality of trials and intended to conduct meta-analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. We present all outcomes grouped by stage of AD. MAIN RESULTS: We included three randomised, placebo-controlled trials investigating Souvenaid in 1097 community-dwelling participants with Alzheimer's disease. One study each included participants with prodromal AD, mild AD dementia and mild-to-moderate AD dementia. We rated the risks of bias of all trials as low. One study (in prodromal AD) was funded by European grants. The other two studies were funded by the manufacturer of Souvenaid. One trial investigated the incidence of dementia in people with prodromal AD at baseline, and found little to no difference between the Souvenaid group and the placebo group after 24 months (RR 1.09, 95% CI 0.82 to 1.43; 1 trial, 311 participants; moderate quality of evidence). In prodromal AD, and in mild and mild-to-moderate Alzheimer's disease dementia, Souvenaid probably results in little or no difference in global or specific cognitive functions (moderate quality of evidence). Everyday function, or the ability to perform activities of daily living, were measured in mild and mild-to-moderate AD dementia. Neither study found evidence of a difference between the groups after 24 weeks of treatment (moderate quality of evidence). Two studies investigated combined cognitive-functional outcomes with the Clinical Dementia Rating Sum of Boxes and observed conflicting results. Souvenaid probably results in slight improvement, which is below estimates of meaningful change, in participants with prodromal Alzheimer's disease after 24 months (moderate quality of evidence), but probably has little to no effect in mild-to-moderate Alzheimer's disease dementia after 24 weeks (moderate quality of evidence). Adverse effects observed were low in all trials, and the available data were insufficient to determine any connection with Souvenaid. AUTHORS' CONCLUSIONS: Two years of treatment with Souvenaid probably does not reduce the risk of progression to dementia in people with prodromal AD. There is no convincing evidence that Souvenaid affects other outcomes important to people with AD in the prodromal stage or mild-to-moderate stages of dementia. Conflicting evidence on combined cognitive-functional outcomes in prodromal AD and mild AD dementia warrants further investigation. Adverse effects of Souvenaid seem to be uncommon, but the evidence synthesised in this review does not permit us to make a definitive statement on the long-term tolerability of Souvenaid. The effects of Souvenaid in more severe AD dementia or in people with AD at risk of nutritional deficiencies remain unclear.

11 C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis.

OBJECTIVE: Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11 C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11 C-PK11195 and PET imaging. METHODS: We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11 C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels. RESULTS: Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. INTERPRETATION: In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.

[Membrane lipids in schizophrenia and early phases of psychosis: Potential biomarkers and therapeutic targets?] / Lipides membranaires dans la schizophrénie et la psychose débutante : de potentiels biomarqueurs et pistes thérapeutiques ?

The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.

Longitudinal Neuroimaging over 30 Days: Temporal Characteristics of Migraine.

OBJECTIVE: Although migraine is defined by the headache and headache-associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well-described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. METHODS: Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well-established paradigm for functional MRI of trigeminal nociception. RESULTS: Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. INTERPRETATION: Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646-651.

Pine Bark Polyphenolic Extract Attenuates Amyloid-ß and Tau Misfolding in a Model System of Alzheimer's Disease Neuropathology.

Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer's disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-ß protein (Aß). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aß1-40 and Aß1-42, but also tau in vitro. Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O-ß-Glucuronide, Me-(±)-C-O-ß-glucuronide, EC-O-ß-glucuronide, and (±)-C-O-ß-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD.

A novel approach to improve stress regulation among traumatized youth in residential care: Feasibility study testing three game-based meditation interventions.

AIM: Many youth in residential care suffer from post-traumatic symptoms that have adverse effects on a range of psychological, behavioural and physiological outcomes. Although current evidence-based treatment options are effective, they have their limitations. Meditation interventions are an alternative to traditional trauma-focused treatment. This pilot study aimed to evaluate three game-based meditation interventions in a sample of traumatized youth in residential care. METHODS: Fifteen participants were randomly divided over three conditions (Muse, DayDream and Wild Divine) that all consisted of twelve 15-minute game-play sessions. Physiological measurements (heart rate variability) were conducted at baseline, post-treatment and during each intervention session. Post-traumatic symptoms, stress, depression, anxiety and aggression were assessed at baseline, post-treatment and 1-month follow-up. RESULTS: Physiological stress regulation was improved during the meditation sessions of all three interventions. User evaluations were in particular high for Muse with a rating of 8.42 out of 10 for game evaluation. Overall, outcomes on psychopathology demonstrated the most robust effect on stress. Muse performed best, with all participants showing reliable improvements (reliable change indexes [RCIs]) in post-traumatic symptoms, stress and anxiety. Participants who played Daydream or Wild Divine showed inconsistent progression: some participants improved, whereas others remained stable or even deteriorated based on their RCIs. CONCLUSIONS: Preliminary findings show promising outcomes on physiology, psychopathology and user evaluations. All indicate the potential of this innovative form of stress regulation intervention, and the potential of Muse in particular, although findings should be considered preliminary due to our small sample size. Further studies are warranted to assess intervention effectiveness effects of Muse or other game-based meditation interventions for traumatized youth.

Mindfulness-based cognitive therapy for children and adolescents with anxiety disorders at-risk for bipolar disorder: A psychoeducation waitlist controlled pilot trial.

AIM: Previous studies suggest that Mindfulness-Based Cognitive Therapy for Children (MBCT-C) is feasible and may improve anxiety and emotion regulation in youth with anxiety disorders at-risk for bipolar disorder. However, controlled studies are warranted to replicate and extend these findings. METHODS: In the current study, 24 youth with anxiety disorders who have at least one parent with bipolar disorder participated in a MBCT-C treatment period (n = 24; Mage = 13.6, 75% girls, 79% White) with a subset also participating in a prior psychoeducation waitlist control period (n = 19 Mage = 13.8, 68% girls, 84% White). Participants in both the waitlist and MBCT-C periods completed independently-rated symptom scales at each time point. Participants in the waitlist period received educational materials 12 weeks prior to the beginning of MBCT-C. RESULTS: There were significantly greater improvements in overall clinical severity in the MBCT-C period compared to the waitlist period, but not in clinician- and child-rated anxiety, emotion regulation or mindfulness. However, increases in mindfulness were associated with improvements in anxiety and emotion regulation in the MBCT-C period, but not the waitlist period. CONCLUSIONS: Findings suggest that MBCT-C may be effective for improving overall clinical severity in youth with anxiety disorders who are at-risk for bipolar disorder. However, waitlist controlled designs may inflate effect sizes so interpret with caution. Larger studies utilizing prospective randomized controlled designs are warranted.

Theatre improvisation training to promote social cognition: A novel recovery-oriented intervention for youths at clinical risk for psychosis.

AIM: Few interventions address social cognition or functioning in individuals at clinical risk (CR) for psychosis. Theatre Improvisation Training to Promote Social Cognition (TIPS) is a manualized intervention based on drama therapy. We aim to describe TIPS, evaluate feasibility and acceptability, and present a preliminary investigation of outcomes in a quasi-experimental design. METHODS: Thirty-six CR participants (15-25 years) were ascertained from the Philadelphia Neurodevelopmental Cohort. Twenty-six completed the TIPS protocol: 18 weekly 2-hour group sessions led by a theatre director and actor-assistant. Participants engaged in collaborative acting and improvisation exercises. Baseline and follow-up assessments included the Clinical Assessment Interview for Negative Symptoms (CAINS), Structured Interview for Prodromal Syndromes, Global Assessment of Functioning (GAF) and Penn Computerized Neurocognitive Battery (CNB), which includes social cognitive tests. Acceptability was assessed using focus groups. Preliminary outcomes were compared to CR controls who were not enrolled in the study but completed follow-up assessments using the same methods. RESULTS: There were no significant differences in baseline demographics, psychosis symptoms, or cognition between those who did and did not complete the protocol. Overall, TIPS was considered feasible and acceptable among CR. Preliminary outcomes suggest that TIPS may be effective in improving positive and negative psychosis-spectrum symptoms and GAF, but not performance on facial emotion processing. CONCLUSIONS: TIPS is a promising and acceptable intervention that may improve symptoms and functioning in CR while providing a framework for participants to develop more empowered and confident ways of relating to others. Larger randomized controlled trials investigating TIPS efficacy are warranted.

Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington's disease: A nine-month pilot study.

BACKGROUND: Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. OBJECTIVE: To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. METHODS: Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated. RESULTS: Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes. CONCLUSIONS: This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.

Cerebral glutamate and GABA levels in high-risk of psychosis states: A focused review and meta-analysis of 1H-MRS studies.

Disturbances in the brain glutamate and GABA (γ-aminobutyric acid) homeostasis may be markers of transition to psychosis in individuals at high-risk (HR). Knowledge of GABA and glutamate levels in HR stages could give an insight into changes in the neurochemistry underlying psychosis. Studies on glutamate in HR have provided conflicting data, and GABA studies have only recently been initialized. In this meta-analysis, we compared cerebral levels of glutamate and GABA in HR individuals with healthy controls (HC). We searched Medline and Embase for articles published on 1H-MRS studies on glutamate and GABA in HR states until April 9th, 2019. We identified a total of 28 eligible studies, of which eight reported GABA (243 HR, 356 HC) and 26 reported glutamate (299 HR, 279 HC) or Glx (glutamate + glutamine) (584 HR, 632 HC) levels. Sample sizes varied from 6 to 75 for HR and 10 to 184 for HC. Our meta-analysis of 1H-MRS studies on glutamate and GABA in HR states displayed significantly lower (P = 0.0003) levels of thalamic glutamate in HR individuals than in HC and significantly higher (P = 0.001) Glx in the frontal lobe of genetic HR individuals (1st-degree relatives) than in HC. No other significant differences in glutamate and GABA levels were found. Subject numbers in the studies on glutamate as well as GABA levels were generally small and the data conflicting. Our meta-analytical findings highlight the need for larger and more homogeneous studies of glutamate and GABA in high-risk states.

Interventions for prodromal stage of psychosis.

BACKGROUND: Psychosis is a serious mental condition characterised by a loss of contact with reality. There may be a prodromal period or stage of psychosis, where early signs of symptoms indicating onset of first episode psychosis (FEP) occur. A number of services, incorporating multimodal treatment approaches (pharmacotherapy, psychotherapy and psychosocial interventions), developed worldwide, now focus on this prodromal period with the aim of preventing psychosis in people at risk of developing FEP. OBJECTIVES: The primary objective is to assess the safety and efficacy of early interventions for people in the prodromal stage of psychosis. The secondary objective is, if possible, to compare the effectiveness of the various different interventions. SEARCH METHODS: We searched Cochrane Schizophrenia's study-based Register of studies (including trials registers) on 8 June 2016 and 4 August 2017. SELECTION CRITERIA: All randomised controlled trials (RCTs) evaluating interventions for participants older than 12 years, who had developed a prodromal stage of psychosis. DATA COLLECTION AND ANALYSIS: Review authors independently inspected citations, selected studies, extracted data, and assessed study quality. MAIN RESULTS: We included 20 studies with 2151 participants. The studies analysed 13 different comparisons. Group A comparisons explored the absolute effects of the experimental intervention. Group B were comparisons within which we could not be clear whether differential interactive effects were also ongoing. Group C comparisons explored differential effects between clearly distinct treatments. A key outcome for this review was 'transition to psychosis'. For details of other main outcomes please see 'Summary of findings' tables. In Group A (comparisons of absolute effects) we found no clear difference between amino acids and placebo (risk ratio (RR) 0.48 95% confidence interval (CI) 0.08 to 2.98; 2 RCTs, 52 participants; very low-quality evidence). When omega-3 fatty acids were compared to placebo, fewer participants given the omega-3 (10%) transitioned to psychosis compared to the placebo group (33%) during long-term follow-up of seven years (RR 0.24 95% CI 0.09 to 0.67; 1 RCT, 81 participants; low-quality evidence). In Group B (comparisons where complex interactions are probable) and in the subgroup focusing on antipsychotic drugs added to specific care packages, the amisulpiride + needs-focused intervention (NFI) compared to NFI comparison (no reporting of transition to psychosis; 1 RCT, 102 participants; very low-quality evidence) and the olanzapine + supportive intervention compared to supportive intervention alone comparison (RR 0.58 95% CI 0.28 to 1.18; 1 RCT, 60 participants; very low-quality evidence) showed no clear differences between groups. In the second Group B subgroup (cognitive behavioural therapies (CBT)), when CBT + supportive therapy was compared with supportive therapy alone around 8% of participants allocated to the combination of CBT and supportive therapy group transitioned to psychosis during follow-up by 18 months, compared with double that percentage in the supportive therapy alone group (RR 0.45 95% CI 0.23 to 0.89; 2 RCTs, 252 participants; very low-quality evidence). The CBT + risperidone versus CBT + placebo comparison identified no clear difference between treatments (RR 1.02 95% CI 0.39 to 2.67; 1 RCT, 87 participants; very low-quality evidence) and this also applies to the CBT + needs-based intervention (NBI) + risperidone versus NBI comparison (RR 0.75 95% CI 0.39 to 1.46; 1 RCT, 59 participants; very low-quality evidence). Group C (differential effects) also involved six comparisons. The first compared CBT with supportive therapy. No clear difference was found for the 'transition to psychosis' outcome (RR 0.74 95% CI 0.28 to 1.98; 1 RCT, 72 participants; very low-quality evidence). The second subgroup compared CBT + supportive intervention was compared with a NBI + supportive intervention, again, data were equivocal, few and of very low quality (RR 6.32 95% CI 0.34 to 117.09; 1 RCT, 57 participants). In the CBT + risperidone versus supportive therapy comparison, again there was no clear difference between groups (RR 0.76 95% CI 0.28 to 2.03; 1 RCT, 71 participants; very low-quality evidence). The three other comparisons in Group C demonstrated no clear differences between treatment groups. When cognitive training was compared to active control (tablet games) (no reporting of transition to psychosis; 1 RCT, 62 participants; very low quality data), family treatment compared with enhanced care comparison (RR 0.54 95% CI 0.18 to 1.59; 2 RCTs, 229 participants; very low-quality evidence) and integrated treatment compared to standard treatment comparison (RR 0.57 95% CI 0.28 to 1.15; 1 RCT, 79 participants; very low-quality evidence) no effects of any of these approaches was evident. AUTHORS' CONCLUSIONS: There has been considerable research effort in this area and several interventions have been trialled. The evidence available suggests that omega-3 fatty acids may prevent transition to psychosis but this evidence is low quality and more research is needed to confirm this finding. Other comparisons did not show any clear differences in effect for preventing transition to psychosis but again, the quality of this evidence is very low or low and not strong enough to make firm conclusions.

Current understanding of premonitory networks in migraine: A window to attack generation.

AIM: To describe neuronal networks underlying commonly reported migraine premonitory symptoms and to discuss how these might precipitate migraine pain. BACKGROUND: Migraine headache is frequently preceded by a distinct and well characterized premonitory phase including symptoms like yawning, sleep disturbances, alterations in appetite and food intake and hypersensitivity to certain external stimuli. Recent neuroimaging studies strongly suggest the hypothalamus as the key mediator of the premonitory phase and also suggested alterations in hypothalamic networks as a mechanism of migraine attack generation. When looking at the vast evidence from basic research within the last decades, hypothalamic and thalamic networks are most likely to integrate peripheral influences with central mechanisms, facilitating the precipitation of migraine headaches. These networks include sleep, feeding and stress modulating centers within the hypothalamus, thalamic pathways and brainstem centers closely involved in trigeminal pain processing such as the spinal trigeminal nucleus and the rostral ventromedial medulla, all of which are closely interconnected. CONCLUSION: Taken together, these networks represent the pathophysiological basis for migraine premonitory symptoms as well as a possible integration site of peripheral so-called "triggers" with central attack facilitating processes.

Hypothalamic regulation of headache and migraine.

BACKGROUND: The clinical picture, but also neuroimaging findings, suggested the brainstem and midbrain structures as possible driving or generating structures in migraine. FINDINGS: This has been intensely discussed in the last decades and the advent of modern imaging studies refined the involvement of rostral parts of the pons in acute migraine attacks, but more importantly suggested a predominant role of the hypothalamus and alterations in hypothalamic functional connectivity shortly before the beginning of migraine headaches. This was shown in the NO-triggered and also in the preictal stage of native human migraine attacks. Another headache type that is clinically even more suggestive of hypothalamic involvement is cluster headache, and indeed a structure in close proximity to the hypothalamus has been identified to play a crucial role in attack generation. CONCLUSION: It is very likely that spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in susceptibility thresholds that ultimately start but also terminate headache attacks. We will review clinical and neuroscience evidence that puts the hypothalamus in the center of scientific attention when attack generation is discussed.

Brain structural abnormalities as potential markers for detecting individuals with ultra-high risk for psychosis: A systematic review and meta-analysis.

OBJECTIVE: This study aims to determine whether structural alterations can be used as neuroimaging markers to detect individuals with ultra-high risk (UHR) for psychosis for the diagnosis of schizophrenia and improvement of treatment outcomes. METHODS: Embase and Pubmed databases were searched for related studies in July 2018. The search was performed without restriction on time and regions or languages. A total of 188 articles on voxel-based morphometry (VBM) and 96 articles on cortical thickness were obtained, and another 6 articles were included after the reference lists were checked. Our researchers assessed and extracted the data in accordance with the PRISMA guideline. The data were processed with a seed-based mapping method. RESULTS: Fourteen VBM and nine cortical thickness studies were finally included in our study. In individuals with UHR, the gray matter volumes in the bilateral median cingulate (Z = 1.034), the right fusiform gyrus (Z = 1.051), the left superior temporal gyrus (Z = 1.048), and the right thalamus (Z = 1.039) increased relative to those of healthy controls. By contrast, the gray matter volumes in the right gyrus rectus (Z = -2.109), the right superior frontal gyrus (Z = -2.321), and the left superior frontal gyrus (Z = -2.228) decreased. The robustness of these findings was verified through Jackknife sensitivity analysis, and heterogeneity across studies was low. Typically, cortical thickness alterations were not detected in individuals with UHR. CONCLUSIONS: Structural abnormalities of the thalamocortical circuit may underpin the neurophysiology of psychosis and mark the vulnerability of transition to psychosis in UHR subjects.

Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers.

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.

Current understanding of cortical structure and function in migraine.

OBJECTIVE: To review and discuss the literature on the role of cortical structure and function in migraine. DISCUSSION: Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks. CONCLUSION: Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications.

Functional asymmetry of thalamocortical networks in subjects at ultra-high risk for psychosis and first-episode schizophrenia.

Disrupted functional asymmetry has been implicated in schizophrenia. However, it remains unknown whether disrupted functional asymmetry originates from intra-hemispheric and/or inter-hemispheric functional connectivity (FC) in the patients, and whether it starts at very early stage of psychosis. Seventy-six patients with first-episode, drug-naive schizophrenia, 74 subjects at ultra-high risk for psychosis (UHR), and 71 healthy controls underwent resting-state functional magnetic resonance imaging. The 'Parameter of asymmetry' (PAS) metric was calculated and support vector machine (SVM) classification analysis was applied to analyze the data. Compared with healthy controls, patients exhibited decreased PAS in the left thalamus/pallidum, right hippocampus/parahippocampus, right inferior frontal gyrus/insula, right thalamus, and left inferior parietal lobule, and increased PAS in the left calcarine, right superior occipital gyrus/middle occipital gyrus, and right precentral gyrus/postcentral gyrus. By contrast, UHR subjects showed decreased PAS in the left thalamus relative to healthy controls. A negative correlation was observed between decreased PAS in the right hippocampus/parahippocampus and Brief Visuospatial Memory Test-Revised (BVMT-R) scores in the patients (r = -0.364, p = 0.002). Moreover, the PAS values in the left thalamus could discriminate the patients/UHR subjects from the controls with acceptable sensitivities (68.42%/81.08%). First-episode patients and UHR subjects shared decreased PAS in the left thalamus. This observed pattern of functional asymmetry highlights the involvement of the thalamus in the pathophysiology of psychosis and may also be applied as a very early marker for psychosis.

Auditory and Visual Oddball Stimulus Processing Deficits in Schizophrenia and the Psychosis Risk Syndrome: Forecasting Psychosis Risk With P300.

Identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may improve clinical prediction in the psychosis risk syndrome (PRS) and help elucidate the pathogenesis of schizophrenia. Amplitude reduction of the P300 event-related potential component reflects attention-mediated processing deficits and is among the most replicated biological findings in schizophrenia, making it a candidate biomarker of psychosis risk. The relative extent to which deficits in P300 amplitudes elicited by auditory and visual oddball stimuli precede psychosis onset during the PRS and predict transition to psychosis, however, remains unclear. Forty-three individuals meeting PRS criteria, 19 schizophrenia patients, and 43 healthy control (HC) participants completed baseline electroencephalography recording during separate auditory and visual oddball tasks. Two subcomponents of P300 were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. Auditory and visual target P3b and novel P3a amplitudes were reduced in PRS and schizophrenia participants relative to HC participants. In addition, baseline auditory and visual target P3b, but not novel P3a, amplitudes were reduced in 15 PRS participants who later converted to psychosis, relative to 18 PRS non-converters who were followed for at least 22 months. Furthermore, target P3b amplitudes predicted time to psychosis onset among PRS participants. These results suggest that P300 amplitude deficits across auditory and visual modalities emerge early in the schizophrenia illness course and precede onset of full psychosis. Moreover, target P3b may represent an important neurophysiological vulnerability marker of the imminence of risk for psychosis.