Lack of reproducibility of resting-state functional MRI findings in migraine with aura.

BACKGROUND: Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. METHODS: We recruited women aged 30-60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. RESULTS: Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. CONCLUSION: Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

Ictal and interictal SPECT with 99m Tc-HMPAO in presurgical epilepsy. II: Methodological considerations on hyper- and hypoperfusion.

OBJECTIVE: Single-photon emission computed tomography (SPECT) with the tracer 99m Tc-HMPAO is a method to visualize the cerebral hyperperfusion during an epileptic seizure and thus localize the epileptogenic zone and seizure propagation. Subtraction of interictal from Ictal SPECT Co-registered to MRI (SISCOM) visualizes areas with relative increases in cerebral blood flow. The purpose of this retrospective study is to explore the added value of visualizing areas of hypoperfusion as well as hyperperfusion, so-called reversed SISCOM. METHODS: Fifty-six patients operated for epilepsy who had been investigated with SISCOM were included in the analysis. The patients were divided into two groups based on seizure duration after tracer injection, above or below 30 s. The preoperative SISCOM description was compared to the area of resection and given a concordance score. The 56 SISCOM were recalculated visualizing also areas of hypoperfusion and again compared to the site of resection using the same scale of concordance. The reversed SISCOM were categorized into three subgroups: "Altered Conclusion," "Confirmed Conclusion," and "Adds Nothing." If an area of hyperperfusion had an area of hypoperfusion in close proximity, it was re-interpreted as noise, thus possibly altering the conclusion. If the areas of hypoperfusion were in the opposite hemisphere it was interpreted as confirming factor. Further the concordance scores from conventional SISCOM and reversed SISCOM was compared to surgical outcome to explore the difference in sensitivity, positive predictive value (PPV), and odds ratio. RESULTS: In approximately half of the cases reversed SISCOM added additional value, meaning either altered the conclusion or confirmed the conclusion. The sensitivity, PPV, and odds ratio was also better in the subgroup of long, >30 s seizure duration after injection, and got worse in the group with short, <30 s seizure duration after injection. SIGNIFICANCE: Adding reversed SISCOM performed better than conventional SISCOM at predicting good surgical outcome.

Ictal and interictal SPECT with 99m Tc-HMPAO in presurgical epilepsy. I: Predictive value and methodological considerations.

OBJECTIVE: This retrospective study investigates the predictive value of ictal subtraction single-photon emission computed tomography (SPECT) co-registered to magnetic resonance imaging (MRI) (SISCOM) for successful epilepsy surgery. METHODS: 57 patients examined with SISCOM as a part of epilepsy surgery evaluation were divided into two groups based on seizure duration after tracer injection (group 1: Seizure duration above or equal to 30 s, group 2: Seizure duration under 30 s). SISCOM was compared to the surgical site and categorized as good or poor concordance. Subsequently, Odds ratios (ORs) and positive predictive values (PPVs) were calculated for each group for good surgical outcome, freedom from disabling seizures. RESULTS: The PPVs and ORs for good surgical outcome was 74.1% and 5.71 for group 1 and 40% and 0.22 for group 2. SISCOM had a similar positive predictive value regardless of whether the focus was in the same or neighboring lobe, but same hemisphere as the resection. CONCLUSION: In conclusion, the implementation of a precise definition for a well-executed ictal SPECT scan with respect to seizure duration after injection enhances the positive predictive value (PPV) and odds ratio (OR) for successful surgical outcome, surpassing previous findings, whether the focus in resected lobe or the neighboring.

Dimethyl fumarate treatment of primary progressive multiple sclerosis: results of an open-label extension study.

INTRODUCTION: Dimethyl fumarate treatment is approved in Europe for patients with relapsing-remitting multiple sclerosis (MS) and in the US for relapsing forms of MS. We recently published the results of the first randomized placebo-controlled trial of 48 weeks of treatment with dimethyl fumarate or placebo in primary progressive MS (PPMS) (clinicaltrial.gov NCT02959658). The placebo-controlled phase of the trial did not meet its primary endpoint (reduction in cerebrospinal fluid concentrations of neurofilament light chain [NFL]). AIM: To investigate the effects of dimethyl fumarate treatment in the open-label extension phase of the trial (week 48-96), where all patients were treated with DMF. METHODS: Reported data are from screening, week 48, and week 96 visits. Patients were clinically evaluated with Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, and Brief Visuospatial Memory-Revised. Serum NFL concentrations were measured by single-molecule array analysis. MRI was performed on a 3 tesla MRI scanner and included: new/enlarging lesions, volume of lesions, cortical grey matter, putamen, thalamus, and normal-appearing white matter, and additional diffusion tensor imaging and magnetization transfer ratio measures. RESULTS: Forty-two patients entered the open-label treatment phase, and 33 patients (61%) had complete data sets at week 96. The remaining 39% did not complete the trial and were not evaluated at week 96. We found no evidence of differences in clinical and MRI measures between patients initially treated with dimethyl fumarate and patients initially treated with placebo from baseline to week 48 and from week 48-96, where all patients were treated with dimethyl fumarate. Serum NFL concentrations remained stable in both groups over 96 weeks. Assessed with either EDSS, T25FW, or 9HPT at week 96, progression was observed for 14 patients (45%). Interestingly, another 15 patients (46%) had improvement in one or more of these domains. Applying a cut-off of 8 points, 2 (6%) patients worsened on SDMT, 25 (78%) did not change, and 5 (16%) improved. CONCLUSIONS: Dimethyl fumarate treatment showed no effects on neither clinical nor MRI outcomes or changes in serum concentrations of NFL. An expected number of patients showed evidence of progression on standard clinical scales; however, this was matched by an equal number of patients improving. The reasons for the physical improvement in an unexpectedly high proportion of patients must be addressed in future studies.

Trisomy 20p/monosomy 18p associated with congenital bilateral perisylvian syndrome.

We report the association, not previously described, between trisomy 20/ monosomy 18 and congenital bilateral perisylvian syndrome (CBPS), a condition featuring intellectual disability, epilepsy, oro-motor dysfunction and bilateral perisylvian polymicrogyria (BPP) in a 29-year-old individual. Detailed clinical evaluation, long-term EEG and EEG analysis by means of electrical source imaging (ESI), 3T MRI and array-CGH were performed. Clinical examination showed moderate/severe intellectual disability, dysmorphic features, oro-motor dysfunction, short stature, abnormal hands and feet, bradykinesia and abnormal posture. The patient had suffered from drug-resistant epilepsy since infancy. Brain MRI showed that BPP was consistent with CBPS. Additional imaging features revealed corpus callosum and cerebellar hypoplasia and fusion of the C1-C2 vertebrae. Ictal EEG and ESI documented tonic seizures originating from the right polymicrogyric cortex. Facial gestalt included dysmorphic features reported in patients with 18- and 20+ chromosomal rearrangements. Array-CGH showed an unbalanced translocation, arr(18p)x1(20p)x3. In conclusion, we provide a detailed electro-clinical and MRI description of a novel condition characterized by the association between trisomy 20p/monosomy 18p and CBPS, also illustrating its clinical evolution into adulthood. This information may help paediatricians, neurologists and geneticists to better counsel families about the developmental prognosis of this rare unbalanced chromosomal rearrangement.

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

BACKGROUND: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle. METHODS: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls. RESULTS: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally. CONCLUSIONS: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure. IMPACT: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: EEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. METHODS: We have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. RESULTS: We analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66-85.37%). CONCLUSIONS: Automated ictal ESI has a high accuracy for localizing the seizure onset zone. SIGNIFICANCE: Automating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVE: To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). METHODS: In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. RESULTS: Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups. DISCUSSION: Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov identifier NCT02959658. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.

Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

Two Coarse Spatial Patterns of Altered Brain Microstructure Predict Post-traumatic Amnesia in the Subacute Stage of Severe Traumatic Brain Injury.

Introduction: Diffuse traumatic axonal injury (TAI) is one of the key mechanisms leading to impaired consciousness after severe traumatic brain injury (TBI). In addition, preferential regional expression of TAI in the brain may also influence clinical outcome. Aim: We addressed the question whether the regional expression of microstructural changes as revealed by whole-brain diffusion tensor imaging (DTI) in the subacute stage after severe TBI may predict the duration of post-traumatic amnesia (PTA). Method: Fourteen patients underwent whole-brain DTI in the subacute stage after severe TBI. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for five bilateral brain regions: fronto-temporal, parieto-occipital, and midsagittal hemispheric white matter, as well as brainstem and basal ganglia. Region-specific calculation of mean FA and MD only considered voxels that showed no tissue damage, using an exclusive mask with all voxels that belonged to local brain lesions or microbleeds. Mean FA or MD of the five brain regions were entered in separate partial least squares (PLS) regression analyses to identify patterns of regional microstructural changes that account for inter-individual variations in PTA. Results: For FA, PLS analysis revealed two spatial patterns that significantly correlated with individual PTA. The lower the mean FA values in all five brain regions, the longer that PTA lasted. A pattern characterized by lower FA values in the deeper brain regions relative to the FA values in the hemispheric regions also correlated with longer PTA. Similar trends were found for MD, but opposite in sign. The spatial FA changes as revealed by PLS components predicted the duration of PTA. Individual PTA duration, as predicted by a leave-one-out cross-validation analysis, correlated with true PTA values (Spearman r = 0.68, p permutation = 0.008). Conclusion: Two coarse spatial patterns of microstructural damage, indexed as reduction in FA, were relevant to recovery of consciousness after TBI. One pattern expressed was consistent with diffuse microstructural damage across the entire brain. A second pattern was indicative of a preferential damage of deep midline brain structures.

Migraine with aura in women is not associated with structural thalamic abnormalities.

Migraine with aura is a highly prevalent disorder involving transient neurological disturbances associated with migraine headache. While the pathophysiology is incompletely understood, findings from clinical and basic science studies indicate a potential key role of the thalamus in the mechanisms underlying migraine with and without aura. Two recent, clinic-based MRI studies investigated the volumes of individual thalamic nuclei in migraine patients with and without aura using two different data analysis methods. Both studies found differences of thalamic nuclei volumes between patients and healthy controls, but the results of the studies were not consistent. Here, we investigated whether migraine with aura is associated with changes in thalamic volume by analysing MRI data obtained from a large, cross-sectional population-based study which specifically included women with migraine with aura (N = 156), unrelated migraine-free matched controls (N = 126), and migraine aura-free co-twins (N = 29) identified from the Danish Twin Registry. We used two advanced, validated analysis methods to assess the volume of the thalamus and its nuclei; the MAGeT Brain Algorithm and a recently developed FreeSurfer-based method based on a probabilistic atlas of the thalamic nuclei combining ex vivo MRI and histology. These approaches were very similar to the methods used in each of the two previous studies. Between-group comparisons were corrected for potential effects of age, educational level, BMI, smoking, alcohol, and hypertension using a linear mixed model. Further, we used linear mixed models and visual inspection of data to assess relations between migraine aura frequency and thalamic nuclei volumes in patients. In addition, we performed paired t-tests to compare volumes of twin pairs (N = 29) discordant for migraine with aura. None of our analyses showed any between-group differences in volume of the thalamus or of individual thalamic nuclei. Our results indicate that the pathophysiology of migraine with aura does not involve alteration of thalamic volume.

Processing of Positive Visual Stimuli Before and After Symptoms Provocation in Posttraumatic Stress Disorder - A Functional Magnetic Resonance Imaging Study of Trauma-Affected Male Refugees.

BACKGROUND: Symptoms of anhedonia are often central to posttraumatic stress disorder (PTSD), but it is unclear how anhedonia is affected by processes induced by reliving past traumatic memories. METHODS: Sixty-nine male refugees (PTSD = 38) were interviewed and scanned with functional magnetic resonance imaging while viewing positive, neutral and Scrambled Pictures after being read personalized scripts evoking an emotionally neutral memory and a traumatic memory. We further measured postprovocation state symptoms, physiological measures and PTSD symptoms. We tested whether neural activity associated with positive picture viewing in participants with PTSD was differentially affected by symptom provocation compared to controls. RESULTS: For the pictures > scrambled contrast (Positive contrast), PTSD participants had significantly less activity than controls in fusiform gyrus, right inferior temporal gyrus and left middle occipital gyrus. The Positive contrast activity in fusiform gyrus scaled negatively with anhedonia symptoms in PTSD participants after controlling for total PTSD severity. Relative to the emotionally Neutral Script, the Trauma Script decreased positive picture viewing activity in posterior cingulate cortex, precuneus and left calcarine gyrus, but there was no difference between PTSD participants and controls. CONCLUSIONS: We found reduced responsiveness of higher visual processing of emotionally positive pictures in PTSD. The significant correlation found between positive picture viewing activity and anhedonia suggests the reduced responsiveness to be due to the severity of anhedonia.

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Associations of neural processing of reward with posttraumatic stress disorder and secondary psychotic symptoms in trauma-affected refugees.

Background: Psychological traumatic experiences can lead to posttraumatic stress disorder (PTSD). Secondary psychotic symptoms are not common but may occur. Objectives: Since psychotic symptoms of schizophrenia have been related to aberrant reward processing in the striatum, using the same paradigm we investigate whether the same finding extends to psychotic and anhedonic symptoms in PTSD. Methods: A total of 70 male refugees: 18 PTSD patients with no secondary psychotic symptoms (PTSD-NSP), 21 PTSD patients with secondary psychotic symptoms (PTSD-SP), and 31 healthy controls (RHC) were interviewed and scanned with functional magnetic resonance imaging (fMRI) during a monetary incentive delay task. Using region of interest analysis of the prefrontal cortex and ventral striatum, we investigated reward-related activity. Results: Compared to RHC, participants with PTSD had decreased neural activity during monetary reward. Also, participants with PTSD-SP exhibited decreased activity in the associative striatum relative to participants with PTSD-NSP during processing of motivational reward anticipation which correlated with severity of psychotic symptoms. However, the difference between the two PTSD groups disappeared when PTSD severity and trauma exposure were accounted for. Conclusions: Anhedonia and secondary psychotic symptoms in PTSD are characterized by dysfunctional reward consumption and anticipation processing, respectively. The latter may reflect a mechanism by which abnormal reward signals in the basal ganglia facilitates psychotic symptoms across psychiatric conditions.

Antecedentes: Las experiencias traumáticas psicológicas pueden conducir al trastorno de estrés postraumático (TEPT). Los síntomas psicóticos secundarios no son comunes, pero pueden ocurrir.Objetivos: Dado que los síntomas psicóticos de la esquizofrenia se han relacionado con el procesamiento aberrante de recompensas en el cuerpo estriado, utilizando el mismo paradigma, investigamos si el mismo hallazgo se extiende a los síntomas psicóticos y anhedónicos en el TEPT.Método: Un total de 70 refugiados varones: 18 pacientes con TEPT sin síntomas psicóticos secundarios (TEPT-NSP), 21 pacientes con TEPT con síntomas psicóticos secundarios (TEPT-SP) y 31 controles sanos (RHC) fueron entrevistados y escaneados con Imagen por resonancia magnética funcional (fMRI en su sigla en inglés) durante una tarea de retraso de incentivo monetario. Mediante el análisis de la región de interés de la corteza prefrontal y el estriado ventral, investigamos la actividad relacionada con la recompensa.Resultados: En comparación con los RHC, los participantes con TEPT habían disminuido la actividad neuronal durante la recompensa monetaria. Además, los participantes con TEPT-SP exhibieron disminución de la actividad en el estriado asociativo en relación con los participantes con TEPT-NSP durante el procesamiento de la anticipación de recompensa motivacional, lo cual estuvo correlacionado con la gravedad de los síntomas psicóticos. Sin embargo, la diferencia entre los dos grupos de TEPT desapareció cuando se controlaron la gravedad del TEPT y la exposición al trauma.Conclusiones: La anhedonia y los síntomas psicóticos secundarios en el TEPT se caracterizan por un consumo de recompensa disfuncional y un procesamiento de anticipación, respectivamente. Este último puede reflejar un mecanismo por el cual las señales de recompensa anormales en los ganglios basales facilitan los síntomas psicóticos a través de afecciones psiquiátricas.

Limited Colocalization of Microbleeds and Microstructural Changes after Severe Traumatic Brain Injury.

Severe traumatic brain injury (TBI) produces shearing forces on long-range axons and brain vessels, causing axonal and vascular injury. To examine whether microbleeds and axonal injury colocalize after TBI, we performed whole-brain susceptibility-weighted imaging (SWI) and diffusion tensor imaging (DTI) in 14 patients during the subacute phase after severe TBI. SWI was used to determine the number and volumes of microbleeds in five brain regions: the frontotemporal lobe; parieto-occipital lobe; midsagittal region (cingular cortex, parasagittal white matter, and corpus callosum); deep nuclei (basal ganglia and thalamus); and brainstem. Averaged fractional anisotropy (FA) and mean diffusivity (MD) were measured to assess microstructural changes in the normal appearing white matter attributed to axonal injury in the same five regions. Regional expressions of microbleeds and microstructure were used in a partial least-squares model to predict the impairment of consciousness in the subacute stage after TBI as measured with the Coma Recovery Scale-Revised (CRS-R). Only in the midsagittal region, the expression of microbleeds was correlated with regional changes in microstructure as revealed by DTI. Microbleeds and microstructural DTI-based metrics of deep, but not superficial, brain regions were able to predict individual CRS-R. Our results suggest that microbleeds are not strictly related to axonal pathology in other than the midsagittal region. While each measure alone was predictive, the combination of both metrics scaled best with individual CRS-R. Structural alterations in deep brain structures are relevant in terms of determining the severity of impaired consciousness in the acute stage after TBI.

Diagnostic pitfalls in vitamin B6-dependent epilepsy caused by mutations in the PLPBP gene.

Vitamin B6-responsive epilepsies are a group of genetic disorders including ALDH7A1 deficiency, PNPO deficiency, and others, usually causing neonatal onset seizures resistant to treatment with common antiepileptic drugs. Recently, biallelic mutations in PLPBP were shown to be a novel cause of vitamin B6-dependent epilepsy with a variable phenotype. The different vitamin B6-responsive epilepsies can be detected and distinguished by their respective biomarkers and genetic analysis. Unfortunately, metabolic biomarkers for early detection and prognosis of PLPBP deficiency are currently still lacking. Here, we present data from two further patients with vitamin B6-dependent seizures caused by variants in PLPBP, including a novel missense variant, and compare their genotype and phenotypic presentation to previously described cases. Hyperglycinemia and hyperlactatemia are the most consistently observed biochemical abnormalities in pyridoxal phosphate homeostasis protein (PLPHP) deficient patients and were present in both patients in this report within the first days of life. Lactic acidemia, the neuroradiological, and clinical presentation led to misdiagnosis of a mitochondrial encephalopathy in two previously published cases with an early fatal course. Similarly, on the background of glycine elevation in plasma, glycine encephalopathy was wrongly adopted as diagnosis for a patient in our report. In this regard, lactic acidemia as well as hyperglycinemia appear to be diagnostic pitfalls in patients with vitamin B6-responsive epilepsies, including PLPHP deficiency. SYNOPSIS: In vitamin B6-responsive epilepsies, including PLPHP deficiency, there are several diagnostic pitfalls, including lactic acidemia as well as hyperglycinemia, highlighting the importance of a pyridoxine trial, and genetic testing.

Diabetes & Women's Health (DWH) Study: an observational study of long-term health consequences of gestational diabetes, their determinants and underlying mechanisms in the USA and Denmark.

PURPOSE: Women who experience gestational diabetes mellitus (GDM) are at exceptionally high-risk of developing type 2 diabetes (T2DM) later in life. However, limited information is available about genetic and environmental factors that are implicated in the progression from GDM to T2DM. PARTICIPANTS: The Diabetes & Women's Health (DWH) Study applied a hybrid design, which combined new prospective data collection with existing data in two prospective cohorts, the Danish National Birth Cohort (DNBC) and the Nurses' Health Study II (NHS II). In total, the DWH Study identified 7759 women with a GDM diagnosis from both cohorts; 4457 women participated in the DWH Study data collection, which included two cycles of follow-up from 2012 to 2014 and 2014 to 2016. FINDINGS TO DATE: Progression from GDM to T2DM was high. In the NHS II group, by 2013, 23.1% (n=846/3667) developed T2DM. In the DNBC group, at cycle 1 (2012-2014), the progression rate was even higher: 27.2% (n=215/790) had developed T2DM. Furthermore, we have shown that women who had GDM experienced a significantly greater risk of hypertension and cardiovascular diseases, as well as early stages of glomerular hyperfiltration and renal damage. Moreover, the DWH Study findings have shown that healthful diet and lifestyle factors and weight control were related to a lower risk of T2DM, hypertension and cardiovascular diseases. FUTURE PLANS: Primary data collection for the DWH Study is complete and investigators are currently investigating interactions of the abovementioned modifiable factors with T2DM genetic susceptibility in determining the risk of progression from GDM to T2DM. Findings from ongoing work will provide further insights for identifying more precise prevention strategies for T2DM and comorbidities in this high-risk population. Future work will examine novel biomarkers of health and disease in this cohort.