NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia.

The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1's activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia (SZ) risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on (i) the risk for SZ, (ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and (iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder's clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 x CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 x BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their mediation role in the path from genetics to complex clinical manifestation.

Long-term use of intrathecal baclofen reduces neuropathic pain and its interference with general activity in spinal cord injury individuals.

INTRODUCTION: Long-term analgesic effect of intrathecal baclofen was reported in individuals with spinal cord injury. We conducted a prospective study to evaluate the effect of intrathecal baclofen on subtypes of neuropathic pain and its interference with general activity. MATERIALS AND METHODS: Nine spinal cord injury individuals who presented with severe spasticity and moderate to severe neuropathic pain received intrathecal baclofen via an implanted pump. We applied the ASIA Impairment Scale to assess spinal cord injury severity. Neuropathic pain was evaluated by numerical rating scale, Neuropathic Pain Symptom Inventory, and Brief Pain Inventory. Evaluations were performed at baseline and after at least 6 months of continuous intrathecal baclofen treatment. RESULTS: Intrathecal baclofen led to significant pain reduction as measured by numerical rating scale, Neuropathic Pain Symptom Inventory, and Brief Pain Inventory (p < 0.05). Improvements were significant for paroxysmal pain and dysesthesia and for pain interference with general activity, as assessed by the Brief Pain Inventory (p < 0.05). There was a significant relationship between the time since spinal cord injury and changes in paroxysmal pain as well as in the total Neuropathic Pain Symptom Inventory score (p < 0.05). The baclofen dose correlated also to the percentage changes in neuropathic pain improvement and sleep (p < 0.003). CONCLUSIONS: The present results provide evidence that intrathecal baclofen effectively reduces neuropathic pain, particularly paroxysmal pain and dysesthesia, and improves pain interference and overall well-being in individuals with spinal cord injury. Clinicians should be aware of this less well-known beneficial effect of intrathecal baclofen and should consider such a treatment option for better control of neuropathic pain in individuals with spinal cord injury.

Improvement in Motor and Walking Capacity during Multisegmental Transcutaneous Spinal Stimulation in Individuals with Incomplete Spinal Cord Injury.

Transcutaneous multisegmental spinal cord stimulation (tSCS) has shown superior efficacy in modulating spinal locomotor circuits compared to single-site stimulation in individuals with spinal cord injury (SCI). Building on these findings, we hypothesized that administering a single session of tSCS at multiple spinal segments may yield greater enhancements in muscle strength and gait function during stimulation compared to tSCS at only one or two segments. In our study, tSCS was applied at single segments (C5, L1, and Coc1), two segments (C5-L1, C5-Coc1, and L1-Coc1), or multisegments (C5-L1-Coc1) in a randomized order. We evaluated the 6-m walking test (6MWT) and maximum voluntary contraction (MVC) and assessed the Hmax/Mmax ratio during stimulation in ten individuals with incomplete motor SCI. Our findings indicate that multisegmental tSCS improved walking time and reduced spinal cord excitability, as measured by the Hmax/Mmax ratio, similar to some single or two-site tSCS interventions. However, only multisegmental tSCS resulted in increased tibialis anterior (TA) muscle strength. These results suggest that multisegmental tSCS holds promise for enhancing walking capacity, increasing muscle strength, and altering spinal cord excitability in individuals with incomplete SCI.

Duration of Untreated Psychosis and Outcomes in First-Episode Psychosis: Systematic Review and Meta-analysis of Early Detection and Intervention Strategies.

BACKGROUND: The role of duration of untreated psychosis (DUP) as an early detection and intervention target to improve outcomes for individuals with first-episode psychosis is unknown. STUDY DESIGN: PRISMA/MOOSE-compliant systematic review to identify studies until February 1, 2023, with an intervention and a control group, reporting DUP in both groups. Random effects meta-analysis to evaluate (1) differences in DUP in early detection/intervention services vs the control group, (2) the efficacy of early detection strategies regarding eight real-world outcomes at baseline (service entry), and (3) the efficacy of early intervention strategies on ten real-world outcomes at follow-up. We conducted quality assessment, heterogeneity, publication bias, and meta-regression analyses (PROSPERO: CRD42020163640). STUDY RESULTS: From 6229 citations, 33 intervention studies were retrieved. The intervention group achieved a small DUP reduction (Hedges' g = 0.168, 95% CI = 0.055-0.283) vs the control group. The early detection group had better functioning levels (g = 0.281, 95% CI = 0.073-0.488) at baseline. Both groups did not differ regarding total psychopathology, admission rates, quality of life, positive/negative/depressive symptoms, and employment rates (P > .05). Early interventions improved quality of life (g = 0.600, 95% CI = 0.408-0.791), employment rates (g = 0.427, 95% CI = 0.135-0.718), negative symptoms (g = 0.417, 95% CI = 0.153-0.682), relapse rates (g = 0.364, 95% CI = 0.117-0.612), admissions rates (g = 0.335, 95% CI = 0.198-0.468), total psychopathology (g = 0.298, 95% CI = 0.014-0.582), depressive symptoms (g = 0.268, 95% CI = 0.008-0.528), and functioning (g = 0.180, 95% CI = 0.065-0.295) at follow-up but not positive symptoms or remission (P > .05). CONCLUSIONS: Comparing interventions targeting DUP and control groups, the impact of early detection strategies on DUP and other correlates is limited. However, the impact of early intervention was significant regarding relevant outcomes, underscoring the importance of supporting early intervention services worldwide.

Socio-ecological Barriers to Leisure Time Physical Activity in Spanish Wheelchair Users With Spinal Cord Injury: Associations With Sociodemographic Characteristics and Functional Independence.

OBJECTIVE: (1) To assess prevalence and severity of socio-ecological barriers to leisure time physical activity (LTPA) in a sample of adults with spinal cord injury (SCI); (2) to examine the association of these barriers with sociodemographic characteristics and functional independence (FI); and (3) to explore which socio-ecological levels of barriers might be associated with LTPA. DESIGN: Cross-sectional study. SETTING: Neurorehabilitation Hospital specialized in SCI. PARTICIPANTS: 207 wheelchair users with SCI living in the community who attended a comprehensive check-up (22.7% women, 47.5±10.7 mean age; N=207). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The short version of the Barriers to Physical Activity Questionnaire for People with Mobility Impairments was used to measure socio-ecological barriers to LTPA. The Spinal Cord Independence Measure III was used to measure FI. The Physical Activity Recall Assessment for People with SCI was used to quantify LTPA. Several multiple linear regression models were computed to examine the associations between socio-ecological barriers and sociodemographic factors, LTPA and FI. RESULTS: A high prevalence of barriers to LTPA was found. Seven of these barriers (2 intrapersonal, 3 organizational, and 2 community) were present for >60% of the participants. Intrapersonal and organizational barriers had a higher effect on participants with lower FI and women. Interpersonal barriers were higher for older participants and with lower FI, while community barriers were higher for unemployed participants. Finally, intrapersonal and interpersonal barriers were negatively associated with LTPA, and FI revealed as a moderator of the intrapersonal barriers-LTPA relation. CONCLUSIONS: Given their high prevalence and their association with LTPA, the development of interventions targeting socio-ecological barriers to LTPA in people with SCI becomes crucial. The associations of these barriers with FI and sociodemographic characteristics should also be considered for these interventions to be as specific and effective as possible.

Cortical volume abnormalities in schizophrenia: Correlations with symptoms and cognitive impairment.

BACKGROUND: Schizophrenic symptoms are known to segregate into reality distortion, negative and disorganization syndromes, but the correlates of these syndromes with regional brain structural change are not well established. Cognitive impairment is a further clinical feature of schizophrenia, whose brain structural correlates are the subject of conflicting findings. METHODS: 165 patients with schizophrenia were rated for symptoms using the PANSS, and cognitive impairment was indexed by estimated premorbid-current IQ discrepancy. Cortical volume was measured using surface-based morphometry in the patients and in 50 healthy controls. Correlations between clinical and cognitive measures and cortical volume were examined using whole-brain FreeSurfer tools. RESULTS: No clusters of volume reduction were seen associated with reality distortion or disorganization. Negative symptom scores showed a significant inverse correlation with volume in a small cluster in the left medial orbitofrontal gyrus. Larger estimated premorbid-current IQ discrepancies were associated with clusters of reduced cortical volume in the left precentral gyrus and the left temporal lobe. The cluster of association with negative symptoms disappeared when estimated premorbid-current IQ discrepancy was controlled for. CONCLUSIONS: This study does not provide support for an association between brain structural abnormality and reality distortion or disorganization syndromes in schizophrenia. The cluster of volume reduction found in the left medial orbitofrontal cortex correlated with negative symptoms may have reflected the association between this class of symptoms and cognitive impairment. The study adds to existing findings of an association between cognitive impairment and brain structural changes in the disorder.

What is the duration of untreated psychosis worldwide? - A meta-analysis of pooled mean and median time and regional trends and other correlates across 369 studies.

Duration of untreated psychosis (DUP) has been associated with poor mental health outcomes. We aimed to meta-analytically estimate the mean and median DUP worldwide, evaluating also the influence of several moderating factors. This PRISMA/MOOSE-compliant meta-analysis searched for non-overlapping individual studies from inception until 9/12/2022, reporting mean ± s.d. or median DUP in patients with first episode psychosis (FEP), without language restrictions. We conducted random-effect meta-analyses, stratified analyses, heterogeneity analyses, meta-regression analyses, and quality assessment (PROSPERO:CRD42020163640). From 12 461 citations, 369 studies were included. The mean DUP was 42.6 weeks (95% confidence interval (CI) 40.6-44.6, k = 283, n = 41 320), varying significantly across continents (p < 0.001). DUP was (in descending order) 70.0 weeks (95% CI 51.6-88.4, k = 11, n = 1508) in Africa; 48.8 weeks (95% CI 43.8-53.9, k = 73, n = 12 223) in Asia; 48.7 weeks (95% CI 43.0-54.4, k = 36, n = 5838) in North America; 38.6 weeks (95% CI 36.0-41.3, k = 145, n = 19 389) in Europe; 34.9 weeks (95% CI 23.0-46.9, k = 11, n = 1159) in South America and 28.0 weeks (95% CI 20.9-35.0, k = 6, n = 1203) in Australasia. There were differences depending on the income of countries: DUP was 48.4 weeks (95% CI 43.0-48.4, k = 58, n = 5635) in middle-low income countries and 41.2 weeks (95% CI 39.0-43.4, k = 222, n = 35 685) in high income countries. Longer DUP was significantly associated with older age (ß = 0.836, p < 0.001), older publication year (ß = 0.404, p = 0.038) and higher proportion of non-White FEP patients (ß = 0.232, p < 0.001). Median DUP was 14 weeks (Interquartile range = 8.8-28.0, k = 206, n = 37 215). In conclusion, DUP is high throughout the world, with marked variation. Efforts to identify and intervene sooner in patients with FEP, and to promote global mental health and access to early intervention services (EIS) are critical, especially in developing countries.

Attitudes of psychiatrists towards people with mental illness: a cross-sectional, multicentre study of stigma in 32 European countries.

Background: Mental health-related stigma occurs among the public and professionals alike. The lived experience of mental illness has been linked to less stigmatising attitudes. However, data on psychiatrists and the relationship between stigmatising attitudes and psychotherapeutic activity or case discussion groups remains scarce. Methods: A cross-sectional multicentre study was performed in 32 European countries to investigate the lived experiences and attitudes of psychiatrists toward patients with mental illness as well as the relationship between stigma, psychosocial and professional factors. The self-reported, anonymous, internet-based Opening Minds Stigma Scale for Health Care Providers was used to measure the stigmatising attitudes. The survey was translated into the local language of each participating country. All participants were practising specialists and trainees in general adult or child and adolescent psychiatry. The study took place between 2nd October, 2019 and 9th July, 2021 and was preregistered at ClinicalTrial.gov (NCT04644978). Findings: A total of 4245 psychiatrists completed the survey. The majority, 2797 (66%), had completed training in psychiatry, and 3320 (78%) worked in adult psychiatry. The final regression model showed that across European countries more favourable attitudes toward people with mental illness were statistically significantly associated with the lived experience of participants (including seeking help for their own mental health conditions (d = -0.92, 95% confidence interval (CI) = -1.68 to -0.15, p = 0.019), receiving medical treatment for a mental illness (d = -0.88, 95% CI = -1.71 to -0.04, p = 0.040), as well as having a friend or a family member similarly affected (d = -0.68, 95% CI = -1.14 to -0.22, p = 0.004)), being surrounded by colleagues who are less stigmatising (d = -0.98, 95% CI = -1.26 to -0.70, p < 0.001), providing psychotherapy to patients (d = -1.14, 95% CI = -1.63 to -0.65 p < 0.001), and being open to (d = -1.69, 95% CI = -2.53 to -0.85, p < 0.001) and actively participating in (d = -0.94, 95% CI = -1.45 to -0.42, p < 0.001) case discussion, supervision, or Balint groups. Interpretation: Our study highlights the importance of psychotherapy training, supervision, case discussions and Balint groups in reducing the stigmatising attitudes of psychiatrists toward patients. As the findings represent cross-national predictors, Europe-wide policy interventions, national psychiatric education systems and the management of psychiatric institutions should take these findings into consideration. Funding: National Youth Talent Award (Ministry of Human Resources, Hungary, (NTP-NFTÖ-20-B-0134). All authors received no funding for their contribution.

Transcutaneous Spinal Cord Stimulation Improves Respiratory Muscle Strength and Function in Subjects with Cervical Spinal Cord Injury: Original Research.

(1) Background: Respiratory muscle weakness is common following cervical spinal cord injury (cSCI). Transcutaneous spinal cord stimulation (tSCS) promotes the motor recovery of the upper and lower limbs. tSCS improved breathing and coughing abilities in one subject with tetraplegia. Objective: We therefore hypothesized that tSCS applied at the cervical and thoracic levels could improve respiratory function in cSCI subjects; (2) Methods: This study was a randomized controlled trial. Eleven cSCI subjects received inspiratory muscle training (IMT) alone. Eleven cSCI subjects received tSCS combined with IMT (six of these subjects underwent IMT alone first and then they were given the opportunity to receive tSCS + IMT). The subjects evaluated their sensation of breathlessness/dyspnea and hypophonia compared to pre-SCI using a numerical rating scale. The thoracic muscle strength was assessed by maximum inspiratory (MIP), expiratory pressure (MEP), and spirometric measures. All assessments were conducted at baseline and after the last session. tSCS was applied at C3-4 and Th9-10 at a frequency of 30 Hz for 30 min on 5 consecutive days; (3) Results: Following tSCS + IMT, the subjects reported a significant improvement in breathlessness/dyspnea and hypophonia (p < 0.05). There was also a significant improvement in MIP, MEP, and forced vital capacity (p < 0.05). Following IMT alone, there were no significant changes in any measurement; (4) Conclusions: Current evidence supports the potential of tSCS as an adjunctive therapy to accelerate and enhance the rehabilitation process for respiratory impairments following SCI. However, further research is needed to validate these results and establish the long-term benefits of tSCS in this population.

Psychometric properties of the Opening Minds Stigma Scale for Health Care Providers in 32 European countries - A bifactor ESEM representation.

Aims: To measure the stigma of healthcare providers toward people suffering from mental illness, the Opening Minds Stigma Scale for Health Care Providers (OMS-HC) is a commonly applied instrument. However, this scale has not been thoroughly validated in many European countries, its psychometric properties are still unknown and data on practicing psychiatrists is lacking. Therefore, this multicenter study aimed to assess the psychometric characteristics of the 15-item OMS-HC in trainees and specialists in adult and child psychiatry in 32 countries across Europe. Materials and methods: The OMS-HC was conducted as an anonymous online survey and sent via Email to European adult and child psychiatrists. Parallel analysis was used to estimate the number of OMS-HC dimensions. Separate for each country, the bifactor ESEM, a bifactor exploratory structural equation modeling approach, was applied to investigate the factor structure of the scale. Cross-cultural validation was done based on multigroup confirmatory factor analyses and reliability measures. Results: A total of 4,245 practitioners were included, 2,826 (67%) female, 1,389 (33%) male. The majority (66%) of participants were specialists, with 78% working in adult psychiatry. When country data were analyzed separately, the bifactor model (higher-order factor solution with a general factor and three specific factors) showed the best model fit (for the total sample χ2/df = 9.760, RMSEA = 0.045 (0.042-0.049), CFI = 0.981; TLI = 0.960, WRMR = 1.200). The average proportion of variance explained by the general factor was high (ECV = 0.682). This suggests that the aspects of 'attitude,' 'disclosure and help-seeking,' and 'social distance' could be treated as a single dimension of stigma. Among the specific factors, the 'disclosure and help-seeking' factor explained a considerable unique proportion of variance in the observed scores. Conclusion: This international study has led to cross-cultural analysis of the OMS-HC on a large sample of practicing psychiatrists. The bifactor structure displayed the best overall model fit in each country. Rather than using the subscales, we recommend the total score to quantify the overall stigmatizing attitudes. Further studies are required to strengthen our findings in countries where the proposed model was found to be weak.

Multicentric investigation on the safety, feasibility and usability of the ABLE lower-limb robotic exoskeleton for individuals with spinal cord injury: a framework towards the standardisation of clinical evaluations.

BACKGROUND: Robotic lower-limb exoskeletons have the potential to provide additional clinical benefits for persons with spinal cord injury (SCI). However, high variability between protocols does not allow the comparison of study results on safety and feasibility between different exoskeletons. We therefore incorporated key aspects from previous studies into our study protocol and accordingly conducted a multicentre study investigating the safety, feasibility and usability of the ABLE Exoskeleton in clinical settings. METHODS: In this prospective pretest-posttest quasi-experimental study across two SCI centres in Germany and Spain, in- and outpatients with SCI were recruited into a 12-session training and assessment protocol, utilising the ABLE Exoskeleton. A follow-up visit after 4 weeks was included to assess after-training outcomes. Safety outcomes (device-related adverse events (AEs), number of drop-outs), feasibility and usability measures (level of assistance, donning/doffing-time) were recorded at every session together with changes in gait parameters and function. Patient-reported outcome measures including the rate of perceived exertion (RPE) and the psychosocial impact of the device were performed. Satisfaction with the device was evaluated in both participants and therapists. RESULTS: All 24 participants (45 ± 12 years), with mainly subacute SCI (< 1 year after injury) from C5 to L3, (ASIA Impairment Scale A to D) completed the follow-up. In 242 training sessions, 8 device-related AEs (pain and skin lesions) were reported. Total time for don and doff was 6:50 ± 2:50 min. Improvements in level of assistance and gait parameters (time, steps, distance and speed, p < 0.05) were observed in all participants. Walking function and RPE improved in participants able to complete walking tests with (n = 9) and without (n = 6) the device at study start (p < 0.05). A positive psychosocial impact of the exoskeleton was reported and the satisfaction with the device was good, with best ratings in safety (participants), weight (therapists), durability and dimensions (both). CONCLUSIONS: Our study results prove the feasibility of safe gait training with the ABLE Exoskeleton in hospital settings for persons with SCI, with improved clinical outcomes after training. Our study protocol allowed for consistent comparison of the results with other exoskeleton trials and can serve as a future framework towards the standardisation of early clinical evaluations. Trial Registration https://trialsearch.who.int/ , DRKS00023503, retrospectively registered on November 18, 2020.

Do the negative symptoms of schizophrenia reflect reduced responsiveness to reward? Examination using a reward prediction error (RPE) task.

BACKGROUND: A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations. METHODS: Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE. RESULTS: In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI. CONCLUSIONS: The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.

Transcutaneous Cervical Spinal Cord Stimulation Combined with Robotic Exoskeleton Rehabilitation for the Upper Limbs in Subjects with Cervical SCI: Clinical Trial.

(1) Background: Restoring arm and hand function is a priority for individuals with cervical spinal cord injury (cSCI) for independence and quality of life. Transcutaneous spinal cord stimulation (tSCS) promotes the upper extremity (UE) motor function when applied at the cervical region. The aim of the study was to determine the effects of cervical tSCS, combined with an exoskeleton, on motor strength and functionality of UE in subjects with cSCI. (2) Methods: twenty-two subjects participated in the randomized mix of parallel-group and crossover clinical trial, consisting of an intervention group (n = 15; tSCS exoskeleton) and a control group (n = 14; exoskeleton). The assessment was carried out at baseline, after the last session, and two weeks after the last session. We assessed graded redefined assessment of strength, sensibility, and prehension (GRASSP), box and block test (BBT), spinal cord independence measure III (SCIM-III), maximal voluntary contraction (MVC), ASIA impairment scale (AIS), and WhoQol-Bref; (3) Results: GRASSP, BBT, SCIM III, cylindrical grip force and AIS motor score showed significant improvement in both groups (p ≤ 0.05), however, it was significantly higher in the intervention group than the control group for GRASSP strength, and GRASSP prehension ability (p ≤ 0.05); (4) Conclusion: our findings show potential advantages of the combination of cervical tSCS with an exoskeleton to optimize the outcome for UE.

Neural correlates of referential/persecutory delusions in schizophrenia: examination using fMRI and a virtual reality underground travel paradigm.

BACKGROUND: The brain functional correlates of delusions have been relatively little studied. However, a virtual reality paradigm simulating travel on the London Underground has been found to evoke referential ideation in both healthy subjects and patients with schizophrenia, making brain activations in response to such experiences potentially identifiable. METHOD: Ninety patients with schizophrenia/schizoaffective disorder and 28 healthy controls underwent functional magnetic resonance imaging while they viewed virtual reality versions of full and empty Barcelona Metro carriages. RESULTS: Compared to the empty condition, viewing the full carriage was associated with activations in the visual cortex, the cuneus and precuneus/posterior cingulate cortex, the inferior parietal cortex, the angular gyrus and parts of the middle and superior temporal cortex including the temporoparietal junction bilaterally. There were no significant differences in activation between groups. Nor were there activations associated with referentiality or presence of delusions generally in the patient group. However, patients with persecutory delusions showed a cluster of reduced activation compared to those without delusions in a region in the right temporal/occipital cortex. CONCLUSIONS: Performance of the metro task is associated with a widespread pattern of activations, which does not distinguish schizophrenic patients and controls, or show an association with referentiality or delusions in general. However, the finding of a cluster of reduced activation close to the right temporoparietal junction in patients with persecutory delusions specifically is of potential interest, as this region is believed to play a role in social cognition.

Brain correlates of speech perception in schizophrenia patients with and without auditory hallucinations.

The experience of auditory verbal hallucinations (AVH, "hearing voices") in schizophrenia has been found to be associated with reduced auditory cortex activation during perception of real auditory stimuli like tones and speech. We re-examined this finding using 46 patients with schizophrenia (23 with frequent AVH and 23 hallucination-free), who underwent fMRI scanning while they heard words, sentences and reversed speech. Twenty-five matched healthy controls were also examined. Perception of words, sentences and reversed speech all elicited activation of the bilateral superior temporal cortex, the inferior and lateral prefrontal cortex, the inferior parietal cortex and the supplementary motor area in the patients and the healthy controls. During the sentence and reversed speech conditions, the schizophrenia patients as a group showed reduced activation in the left primary auditory cortex (Heschl's gyrus) relative to the healthy controls. No differences were found between the patients with and without hallucinations in any condition. This study therefore fails to support previous findings that experience of AVH attenuates speech-perception-related brain activations in the auditory cortex. At the same time, it suggests that schizophrenia patients, regardless of presence of AVH, show reduced activation in the primary auditory cortex during speech perception, a finding which could reflect an early information processing deficit in the disorder.

Clinical Prediction Rule Validation for Ambulation Outcome After Traumatic Spinal Cord Injury in a Spanish Population.

BACKGROUND: Predicting the ability to walk after traumatic spinal cord injury is of utmost importance in the clinical setting. Nevertheless, only a small fraction of predictive models are evaluated on their performance by other authors using external data. The Dutch Clinical Prediction Rule for long-term walking ability was developed and validated using neurological assessments performed within 15 days postinjury. However, in reality, this assessment is most often performed between 11 and 55 days. When considering a longer time from injury to neurological assessments, the Dutch Clinical Prediction Rule has only been externally validated for patients after non-traumatic spinal cord injury. OBJECTIVE: We aimed to validate the Dutch Clinical Prediction Rule with neurological assessment performed within 3-90 days after traumatic spinal cord injury, using (a) the Dutch Clinical Prediction Rule logistic regression coefficients (Equation 1); (b) the Dutch Clinical Prediction Rule weighted coefficients (Equation 2); and (c) the reestimated (using a Spanish population) weighted coefficients (Equation 3). METHODS: We conducted a retrospective (STROBE-compliant) study involving 298 adults with traumatic spinal cord injury admitted to a hospital between 2010 and 2019 in Spain. The Spinal Cord Independence Measure item-12 was used for walking assessment. RESULTS: Using Equation 1, the model yielded 86.2% overall classification accuracy, 94.5% sensitivity, and 83.4% specificity (area under the curve [AUC] = 0.939, 95% confidence interval [CI]: 0.915-0.965; p < .001).Using Equation 2 yielded 86.2% overall classification accuracy, 93.2% sensitivity, and 83.9% specificity (AUC = 0.9392, 95% CI: 0.914-0.964; p < .001).Using Equation 3 yielded 86.9% overall classification accuracy, 68.9% sensitivity, and 92.8% specificity (AUC = 0.939, 95% CI: 0.914-0.964; p < .001). CONCLUSIONS: This study validates the Dutch Clinical Prediction Rule in a Spanish traumatic spinal cord injury population with assessments performed up to 90 days postinjury with similar performance, using the original coefficients and including a reestimation of the coefficients.

Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect.

BACKGROUND: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. METHOD: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. CONCLUSIONS: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this.

Regularized Functional Connectivity in Schizophrenia.

Regularization may be used as an alternative to dimensionality reduction when the number of variables in a model is much larger than the number of available observations. In a recent study from our group regularized regression was employed to quantify brain functional connectivity in a sample of healthy controls using a brain parcellation and resting state fMRI images. Here regularization is applied to evaluate resting state connectivity abnormalities at the voxel level in a sample of patients with schizophrenia. Specifically, ridge regression is implemented with different degrees of regularization. Results are compared to those delivered by the weighted global brain connectivity method (GBC), which is based on averaged bivariate correlations and from the non-redundant connectivity method (NRC), a dimensionality reduction approach that applies supervised principal component regressions. Ridge regression is able to detect a larger set of abnormally connected regions than both GBC and NRC methods, including schizophrenia related connectivity reductions in fronto-medial, somatosensory and occipital structures. Due to its multivariate nature, the proposed method is much more sensitive to group abnormalities than the GBC, but it also outperforms the NRC, which is multivariate too. Voxel based regularized regression is a simple and sensitive alternative for quantifying brain functional connectivity.

Combining fMRI and DISC1 gene haplotypes to understand working memory-related brain activity in schizophrenia.

The DISC1 gene is one of the most relevant susceptibility genes for psychosis. However, the complex genetic landscape of this locus, which includes protective and risk variants in interaction, may have hindered consistent conclusions on how DISC1 contributes to schizophrenia (SZ) liability. Analysis from haplotype approaches and brain-based phenotypes can contribute to understanding DISC1 role in the neurobiology of this disorder. We assessed the brain correlates of DISC1 haplotypes associated with SZ through a functional neuroimaging genetics approach. First, we tested the association of two DISC1 haplotypes, the HEP1 (rs6675281-1000731-rs999710) and the HEP3 (rs151229-rs3738401), with the risk for SZ in a sample of 138 healthy subjects (HS) and 238 patients. This approach allowed the identification of three haplotypes associated with SZ (HEP1-CTG, HEP3-GA and HEP3-AA). Second, we explored whether these haplotypes exerted differential effects on n-back associated brain activity in a subsample of 70 HS compared to 70 patients (diagnosis × haplotype interaction effect). These analyses evidenced that HEP3-GA and HEP3-AA modulated working memory functional response conditional to the health/disease status in the cuneus, precuneus, middle cingulate cortex and the ventrolateral and dorsolateral prefrontal cortices. Our results are the first to show a diagnosis-based effect of DISC1 haplotypes on working memory-related brain activity, emphasising its role in SZ.