Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Impact of adult-onset multiple sclerosis on MRI-based intracranial volume: A study in clinically discordant monozygotic twins.

OBJECTIVE: Intracranial volume (ICV) represents the maximal brain volume for an individual, attained prior to late adolescence and remaining constant throughout life after. Thus, ICV serves as a surrogate marker for brain growth integrity. To assess the potential impact of adult-onset multiple sclerosis (MS) and its preceding prodromal subclinical changes on ICV in a large cohort of monozygotic twins clinically discordant for MS. METHODS: FSL software was used to derive ICV estimates from 3D-T1-weighted-3 T-MRI images by using an atlas scaling factor method. ICV were compared between clinically affected and healthy co-twins. All twins were compared to a large healthy reference cohort using standardized ICV z-scores. Mixed models assessed the impact of age at MS diagnosis on ICV. RESULTS: 54 twin-pairs (108 individuals/80female/42.45 ± 11.98 years), 731 individuals (375 non-twins, 109/69 monozygotic/dizygotic twin-pairs; 398female/29.18 ± 0.13 years) and 35 healthy local individuals (20male/31.34 ± 1.53 years). In 45/54 (83 %) twin-pairs, both clinically affected and healthy co-twins showed negative ICV z-scores, i.e., ICVs lower than the average of the healthy reference cohort (M = -1.53 ± 0.11, P<10-5). Younger age at MS diagnosis was strongly associated with lower ICVs (t = 3.76, P = 0.0003). Stratification of twin-pairs by age at MS diagnosis of the affected co-twin (≤30 versus > 30 years) yielded lower ICVs in those twin pairs with younger age at diagnosis (P = 0.01). Comparison within individual twin-pairs identified lower ICVs in the MS-affected co-twins with younger age at diagnosis compared to their corresponding healthy co-twins (P = 0.003). CONCLUSION: We offer for the first-time evidence for strong associations between adult-onset MS and lower ICV, which is more pronounced with younger age at diagnosis. This suggests pre-clinical alterations in early neurodevelopment associated with susceptibility to MS both in individuals with and without clinical manifestation of the disease.

Assessing the impact of sex on high-frequency repetitive transcranial magnetic stimulation´s clinical response in schizophrenia - results from a secondary analysis.

BACKGROUND: The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS: 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION: In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Association of Four Medication Classes and Non-suicidal Self-injury in Adolescents with Affective Disorders - A Retrospective Chart Review.

BACKGROUND: Non-suicidal self-injury (NSSI) behaviour is frequently observed in children and adolescents with psychiatric conditions. Affected individuals are regularly treated with psychotropic drugs, although the impact of these agents on NSSI behaviour remains elusive. METHODS: We performed a retrospective chart review from clinical routine data in a large cohort (N=1140) of adolescent inpatients with primary affective and non-affective psychiatric disorders according to ICD-10 (mean age=15.3±1.3 years; 72.6% female). Four separate mixed regression models compared the frequency of NSSI between treatment periods without any medication and four medication categories (benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), high- and low-potency antipsychotics). RESULTS: In those individuals with affective disorders as the primary diagnosis, periods without medication were associated with significantly lower NSSI/day compared to all four other medication conditions (benzodiazepines p<10-8, antidepressants/SSRIs p=0.0004, high-potency antipsychotics p=0.0009, low-potency antipsychotics p<10 -4). In individuals with a primary diagnosis other than an affective disorder, NSSI was significantly lower during the period without medication compared to the treatment periods with benzodiazepines (p=0.005) and antidepressants/SSRIs (p=0.01). However, NSSI rates in the no-medication condition were comparable to NSSI rates under high-potency (p=0.89) and low-potency antipsychotics (p=0.53). CONCLUSIONS: The occurrence of NSSI correlates with the treatment with a psychotropic drug in children and adolescents with psychiatric disorders. Due to the retrospective design, it remains elusive to what extent psychotropic drugs might alter the frequency of NSSI in adolescents or if NSSI might indicate a transdiagnostic feature of more pronounced disease severity.

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research.

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Intramodal cortical plastic changes after moderate visual impairment in human amblyopia.

Early blindness results in alterations in the neural responses to auditory stimuli. Here we show that even moderately reduced vision in one eye early in life is sufficient to induce neural plastic changes in voice processing. We asked individuals with reduced visual acuity in one eye due to amblyopia to attend to vocal cues during electroencephalogram recording. We found enhanced frontal auditory responses at 125 ms-225 ms, which were correlated with reduced vision in the amblyopic eye, but not the fellow eye. Our results indicate intramodal reorganization, typically observed after congenital profound visual deprivation.

Multiple sclerosis and subclinical neuropathology in healthy individuals with familial risk: A scoping review of MRI studies.

Multiple genetic and non-heritable factors have been linked to the risk of multiple sclerosis (MS). These factors seem to contribute to disease pathogenesis before the onset of clinical symptoms, as suggested by incidental MRI evidence of subclinical MS neuropathology in individuals without clinical symptoms. Individuals with high familial risk for MS, such as first-degree relatives of patients with MS, can be studied by MRI to characterize the neuropathology during a subclinical period of MS. 16 studies published in English, which performed brain MRI on healthy individuals with high familial risk of MS were included in this scoping review. Studies suggest either no conclusive (5), or inconclusive yet considerable (4), or conclusive evidence (7) for the incidence of subclinical neuropathology, including focal and diffuse tissue damage. Across all studies, white matter lesions fulfilling MS criteria were observed in 86 of 613 individuals (14%). Future research is needed to evaluate the longitudinal dynamics and clinical relevance of preclinical imaging abnormalities in MS.

Effects of bifrontal transcranial direct current stimulation on brain glutamate levels and resting state connectivity: multimodal MRI data for the cathodal stimulation site.

Transcranial direct current stimulation (tDCS) over prefrontal cortex (PFC) regions is currently proposed as therapeutic intervention for major depression and other psychiatric disorders. The in-depth mechanistic understanding of this bipolar and non-focal stimulation technique is still incomplete. In a pilot study, we investigated the effects of bifrontal stimulation on brain metabolite levels and resting state connectivity under the cathode using multiparametric MRI techniques and computational tDCS modeling. Within a double-blind cross-over design, 20 subjects (12 women, 23.7 ± 2 years) were randomized to active tDCS with standard bifrontal montage with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC. Magnetic resonance spectroscopy (MRS) was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma aminobutyric acid (GABA) concentration in these areas. Resting-state functional connectivity MRI (rsfcMRI) was acquired before and after the stimulation. The individual distribution of tDCS induced electric fields (efields) within the MRS voxel was computationally modelled using SimNIBS 2.0. There were no significant changes of Glu, Glx and GABA levels across conditions but marked differences in the course of Glu levels between female and male participants were observed. Further investigation yielded a significantly stronger Glu reduction after active compared to sham stimulation in female participants, but not in male participants. For rsfcMRI neither significant changes nor correlations with MRS data were observed. Exploratory analyses of the effect of efield intensity distribution on Glu changes showed distinct effects in different efield groups. Our findings are limited by the small sample size, but correspond to previously published results of cathodal tDCS. Future studies should address gender and efield intensity as moderators of tDCS induced effects.

Neural correlates of visual spatial selective attention are altered at early and late processing stages in human amblyopia.

Amblyopia is a neurodevelopmental visual disorder which results in reduced visual acuity in one eye and impaired binocular interactions. Previous studies suggest attentional deficits in amblyopic individuals. However, spatial cues which orient attention to a visual field improved performance. Here, we investigate the neural correlates of auditory-visual spatial selective attention in amblyopia during EEG recording. An auditory cue, that was followed by the presentation of two Gabor patches presented in the lower left and right visual fields, indicated the most likely location of an upcoming target Gabor. The target Gabor differed in orientation from the more frequently presented non-target Gabor patches. Adults with amblyopia and neurotypical observers were asked to detect the target Gabor monocularly at the cued location, while withholding their response to targets presented at the uncued location and to all non-target Gabor patches. Higher response rates were observed for cued compared to uncued targets in both groups. However, amblyopic individuals detected targets less efficiently with their amblyopic eye as compared to their fellow eye. Correspondingly, event-related potentials (ERPs) recorded to the onset of the non-target Gabor patches were delayed at early processing stages (150-300 ms: posterior N100) and reduced in amplitude at later time windows (150-350 ms: P200, 300-500 ms: sustained activity) in the amblyopic eye compared to the fellow eye. Such interocular differences were not observed in neurotypical observers. These findings suggest that neural resources allocated to the early formation of visual discrimination as well as later stimulus recognition processes are altered in the amblyopic eye.

Neural Correlates of Enhanced Visual Attentional Control in Action Video Game Players: An Event-Related Potential Study.

Action video game players (AVGPs) outperform non-action video game players (NAVGPs) on a range of perceptual and attentional tasks. Although several studies have reported neuroplastic changes within the frontoparietal networks of attention in AVGPs, little is known about possible changes in attentional modulation in low-level visual areas. To assess the contribution of these different levels of neural processing to the perceptual and attentional enhancements noted in AVGPs, visual event-related potentials (ERPs) were recorded from 14 AVGPs and 14 NAVGPs during a target discrimination task that required participants to attend to rapid sequences of Gabor patches under either focused or divided attention conditions. AVGPs responded faster to target Gabors in the focused attention condition compared with the NAVGPs. Correspondingly, ERPs to standard Gabors revealed a more pronounced negativity in the time range of the parietally generated anterior N1 component in AVGPs compared with NAVGPs during focused attention. In addition, the P2 component of the visual ERP was more pronounced in AVGPs than in NAVGPs over the hemisphere contralateral to the stimulus position in response to standard Gabors. Contrary to predictions, however, attention-modulated occipital components generated in the low-level extrastriate visual pathways, including the P1 and posterior N1, showed no significant group differences. Thus, the main neural signature of enhanced perceptual and attentional control functions in AVGPs appears linked to an attention-dependent parietal process, indexed by the anterior N1 component, and possibly to more efficient higher-order perceptual processing, indexed by the P2 component.

Neural signals of selective attention are modulated by subjective preferences and buying decisions in a virtual shopping task.

We investigated whether well-known neural markers of selective attention to motivationally-relevant stimuli were modulated by variations in subjective preference towards consumer goods in a virtual shopping task. Specifically, participants viewed and rated pictures of various goods on the extent to which they wanted each item, which they could potentially purchase afterwards. Using the event-related potentials (ERP) method, we found that variations in subjective preferences for consumer goods strongly modulated positive slow waves (PSW) from 800 to 3000 milliseconds after stimulus onset. We also found that subjective preferences modulated the N200 and the late positive potential (LPP). In addition, we found that both PSW and LPP were modulated by subsequent buying decisions. Overall, these findings show that well-known brain event-related potentials reflecting selective attention processes can reliably index preferences to consumer goods in a shopping environment. Based on a large body of previous research, we suggest that early ERPs (e.g. the N200) to consumer goods could be indicative of preferences driven by unconditional and automatic processes, whereas later ERPs such as the LPP and the PSW could reflect preferences built upon more elaborative and conscious cognitive processes.