Coronary Artery Lesion Lipid Content and Plaque Burden in Diabetic and Nondiabetic Patients: PROSPECT II.

BACKGROUND: Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid content. METHODS: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion-related MACEs and high-risk plaque characteristics. RESULTS: Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% [odds ratio (OR), 1.94 (95% CI, 1.14-3.30)]), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% [OR, 3.78 (95% CI, 1.12-12.77)]) and nonculprit lesion-related spontaneous myocardial infarction (9.3% versus 3.8% [OR, 2.74 (95% CI, 1.25-6.04)]). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%, P=0.34; maximum lipid core burden index ≥324.7: 66% versus 70%, P=0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%, P=0.37; maximum lipid core burden index ≥324.7: 26% versus 24%, P=0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 [95% CI, 1.21-5.04]) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 [95% CI, 0.86-1.69]). CONCLUSIONS: Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02171065.

Encoding-related Brain Activity Predicts Subsequent Trial-level Control of Proactive Interference in Working Memory.

Proactive interference (PI) appears when familiar information interferes with newly acquired information and is a major cause of forgetting in working memory. It has been proposed that encoding of item-context associations might help mitigate familiarity-based PI. Here, we investigate whether encoding-related brain activation could predict subsequent level of PI at retrieval using trial-specific parametric modulation. Participants were scanned with event-related fMRI while performing a 2-back working memory task with embedded 3-back lures designed to induce PI. We found that the ability to control interference in working memory was modulated by level of activation in the left inferior frontal gyrus, left hippocampus, and bilateral caudate nucleus during encoding. These results provide insight to the processes underlying control of PI in working memory and suggest that encoding of temporal context details support subsequent interference control.

Macroscopic resting state model predicts theta burst stimulation response: A randomized trial.

Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative therapy for treatment-resistant depression, although its limited remission rate indicates room for improvement. As depression is a phenomenological construction, the biological heterogeneity within this syndrome needs to be considered to improve the existing therapies. Whole-brain modeling provides an integrative multi-modal framework for capturing disease heterogeneity in a holistic manner. Computational modelling combined with probabilistic nonparametric fitting was applied to the resting-state fMRI data from 42 patients (21 women), to parametrize baseline brain dynamics in depression. All patients were randomly assigned to two treatment groups, namely active (i.e., rTMS, n = 22) or sham (n = 20). The active treatment group received rTMS treatment with an accelerated intermittent theta burst protocol over the dorsomedial prefrontal cortex. The sham treatment group underwent the identical procedure but with the magnetically shielded side of the coil. We stratified the depression sample into distinct covert subtypes based on their baseline attractor dynamics captured by different model parameters. Notably, the two detected depression subtypes exhibited different phenotypic behaviors at baseline. Our stratification could predict the diverse response to the active treatment that could not be explained by the sham treatment. Critically, we further found that one group exhibited more distinct improvement in certain affective and negative symptoms. The subgroup of patients with higher responsiveness to treatment exhibited blunted frequency dynamics for intrinsic activity at baseline, as indexed by lower global metastability and synchrony. Our findings suggested that whole-brain modeling of intrinsic dynamics may constitute a determinant for stratifying patients into treatment groups and bringing us closer towards precision medicine.

GABAA Receptor Availability in Relation to Cortical Excitability in Depressed and Healthy: A Positron Emission Tomography and Transcranial Magnetic Stimulation Study.

INTRODUCTION: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABAA receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. METHODS: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [11C]flumazenil positron emission tomography to assess GABAA receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABAA receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABAA receptor activity, long-interval intracortical inhibition representing GABAB receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. RESULTS: No significant differences in baseline GABAA receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABAA receptor availability and TMS outcomes. Changes in GABAA receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. CONCLUSION: We found that a change in GABAA receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.

Hippocampal and motor regions contribute to memory benefits after enacted encoding: cross-sectional and longitudinal evidence.

The neurobiological underpinnings of action-related episodic memory and how enactment contributes to efficient memory encoding are not well understood. We examine whether individual differences in level (n = 338) and 5-year change (n = 248) in the ability to benefit from motor involvement during memory encoding are related to gray matter (GM) volume, white matter (WM) integrity, and dopamine-regulating genes in a population-based cohort (age range = 25-80 years). A latent profile analysis identified 2 groups with similar performance on verbal encoding but with marked differences in the ability to benefit from motor involvement during memory encoding. Impaired ability to benefit from enactment was paired with smaller HC, parahippocampal, and putamen volume along with lower WM microstructure in the fornix. Individuals with reduced ability to benefit from encoding enactment over 5 years were characterized by reduced HC and motor cortex GM volume along with reduced WM microstructure in several WM tracts. Moreover, the proportion of catechol-O-methyltransferase-Val-carriers differed significantly between classes identified from the latent-profile analysis. These results provide converging evidence that individuals with low or declining ability to benefit from motor involvement during memory encoding are characterized by low and reduced GM volume in regions critical for memory and motor functions along with altered WM microstructure.

PCI or CABG for left main coronary artery disease: the SWEDEHEART registry.

AIMS: An observational nationwide all-comers prospective register study to analyse outcomes after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in unprotected left main coronary artery (LMCA) disease. METHODS AND RESULTS: All patients undergoing coronary angiography in Sweden are registered in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Between 01/01/2005 and 12/31/2015, 11 137 patients with LMCA disease underwent CABG (n = 9364) or PCI (n = 1773). Patients with previous CABG, ST-elevation myocardial infarction (MI) or cardiac shock were excluded. Death, MI, stroke, and new revascularization during follow-up until 12/31/2015 were identified using national registries. Cox regression with inverse probability weighting (IPW) and an instrumental variable (IV), administrative region, were used. Patients undergoing PCI were older, had higher prevalence of comorbidity but lower prevalence of three-vessel disease. PCI patients had higher mortality than CABG patients after adjustments for known cofounders with IPW analysis (hazard ratio [HR] 2.0 [95% confidence interval (CI) 1.5-2.7]) and known/unknown confounders with IV analysis (HR 1.5 [95% CI 1.1-2.0]). PCI was associated with higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE; death, MI, stroke, or new revascularization) than CABG, with IV analysis (HR 2.8 [95% CI 1.8-4.5]). There was a quantitative interaction for diabetic status regarding mortality (P = 0.014) translating into 3.6 years (95% CI 3.3-4.0) longer median survival time favouring CABG in patients with diabetes. CONCLUSION: In this non-randomized study, CABG in patients with LMCA disease was associated with lower mortality and fewer MACCE compared to PCI after multivariable adjustment for known and unknown confounders.

Hub architecture of the human structural connectome: Links to aging and processing speed.

The human structural brain network, or connectome, has a rich-club organization with a small number of brain regions showing high network connectivity, called hubs. Hubs are centrally located in the network, energy costly, and critical for human cognition. Aging has been associated with changes in brain structure, function, and cognitive decline, such as processing speed. At a molecular level, the aging process is a progressive accumulation of oxidative damage, which leads to subsequent energy depletion in the neuron and causes cell death. However, it is still unclear how age affects hub connections in the human connectome. The current study aims to address this research gap by constructing structural connectome using fiber bundle capacity (FBC). FBC is derived from Constrained Spherical Deconvolution (CSD) modeling of white-matter fiber bundles, which represents the capacity of a fiber bundle to transfer information. Compared to the raw number of streamlines, FBC is less bias for quantifying connection strength within biological pathways. We found that hubs exhibit longer-distance connections and higher metabolic rates compared to peripheral brain regions, suggesting that hubs are biologically costly. Although the landscape of structural hubs was relatively age-invariant, there were wide-spread age effects on FBC in the connectome. Critically, these age effects were larger in connections within hub compared to peripheral brain connections. These findings were supported by both a cross-sectional sample with wide age-range (N = 137) and a longitudinal sample across 5 years (N = 83). Moreover, our results demonstrated that associations between FBC and processing speed were more concentrated in hub connections than chance level, and FBC in hub connections mediated the age-effects on processing speed. Overall, our findings indicate that structural connections of hubs, which demonstrate greater energy demands, are particular vulnerable to aging. The vulnerability may contribute to age-related impairments in processing speed among older adults.

Clinical impact of influenza vaccination after ST- and non-ST-segment elevation myocardial infarction - insights from the IAMI trial.

BACKGROUND: Influenza vaccination early after myocardial infarction (MI) improves prognosis but vaccine effectiveness may differ dependent on type of MI. METHODS: A total of 2,571 participants were prospectively enrolled in the Influenza vaccination after myocardial infarction (IAMI) trial and randomly assigned to receive in-hospital inactivated influenza vaccine or saline placebo. The trial was conducted at 30 centers in eight countries from October 1, 2016 to March 1, 2020. Here we report vaccine effectiveness in the 2,467 participants with ST-segment elevation MI (STEMI, n = 1,348) or non-ST-segment elevation MI (NSTEMI, n = 1,119). The primary endpoint was the composite of all-cause death, MI, or stent thrombosis at 12 months. Cumulative incidence of the primary and key secondary endpoints by randomized treatment and NSTEMI/STEMI was estimated using the Kaplan-Meier method. Treatment effects were evaluated with formal interaction testing to assess for effect modification. RESULTS: Baseline risk was higher in participants with NSTEMI. In the NSTEMI group the primary endpoint occurred in 6.5% of participants assigned to influenza vaccine and 10.5% assigned to placebo (hazard ratio [HR], 0.60; 95% CI, 0.39-0.91), compared to 4.1% assigned to influenza vaccine and 4.5% assigned to placebo in the STEMI group (HR, 0.90; 95% CI, 0.54-1.50, P = .237 for interaction). Similar findings were seen for the key secondary endpoints of all-cause death and cardiovascular death. The Kaplan-Meier risk difference in all-cause death at one year was more pronounced in participants with NSTEMI (NSTEMI: HR, 0.47; 95% CI 0.28-0.80, STEMI: HR, 0.86; 95% CI, 0.43-1.70, interaction P = .028). CONCLUSIONS: The beneficial effect of influenza vaccination on adverse cardiovascular events may be enhanced in patients with NSTEMI compared to those with STEMI.

Suppressing visual hallucinations in an adolescent by occipital transcranial magnetic stimulation: A single-case experimental research design.

Visual hallucinations after central or peripheral impairment, commonly called Charles Bonnet syndrome, are often highly distressing and with few available treatment options. Here we report a case where an adolescent developed severely distressing visual hallucinations after hypoxic damage to the occipital cortex following a suicide attempt. The patient received active and sham occipital continuous theta-burst stimulation (cTBS) in a single-case experimental research design and a subsequent open phase, to evaluate cTBS as a Charles Bonnet treatment. The visual hallucinations seemed to decrease more during active than sham cTBS in the blind phase, and in the following week of repeated five daily treatments they almost disappeared. A normalization of increased activity in the lateral visual network after cTBS was observed on a functional magnetic resonance imaging resting-state analysis compared with 42 healthy controls. Visual evoked potentials stayed largely unchanged both in the sham-controlled blind phase and the subsequent open phase. During the two weeks after the open phase with repeated cTBS sessions, the visual hallucinations gradually reappeared and almost returned to the baseline level. Our findings suggest that active cTBS over the primary visual cortex can reduce visual hallucinations through modulation of downstream visual regions, though the effect is temporally limited.

Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

BACKGROUND: Observational and small, randomized studies suggest that influenza vaccine may reduce future cardiovascular events in patients with cardiovascular disease. METHODS: We conducted an investigator-initiated, randomized, double-blind trial to compare inactivated influenza vaccine with saline placebo administered shortly after myocardial infarction (MI; 99.7% of patients) or high-risk stable coronary heart disease (0.3%). The primary end point was the composite of all-cause death, MI, or stent thrombosis at 12 months. A hierarchical testing strategy was used for the key secondary end points: all-cause death, cardiovascular death, MI, and stent thrombosis. RESULTS: Because of the COVID-19 pandemic, the data safety and monitoring board recommended to halt the trial before attaining the prespecified sample size. Between October 1, 2016, and March 1, 2020, 2571 participants were randomized at 30 centers across 8 countries. Participants assigned to influenza vaccine totaled 1290 and individuals assigned to placebo equaled 1281; of these, 2532 received the study treatment (1272 influenza vaccine and 1260 placebo) and were included in the modified intention to treat analysis. Over the 12-month follow-up, the primary outcome occurred in 67 participants (5.3%) assigned influenza vaccine and 91 participants (7.2%) assigned placebo (hazard ratio, 0.72 [95% CI, 0.52-0.99]; P=0.040). Rates of all-cause death were 2.9% and 4.9% (hazard ratio, 0.59 [95% CI, 0.39-0.89]; P=0.010), rates of cardiovascular death were 2.7% and 4.5%, (hazard ratio, 0.59 [95% CI, 0.39-0.90]; P=0.014), and rates of MI were 2.0% and 2.4% (hazard ratio, 0.86 [95% CI, 0.50-1.46]; P=0.57) in the influenza vaccine and placebo groups, respectively. CONCLUSIONS: Influenza vaccination early after an MI or in high-risk coronary heart disease resulted in a lower risk of a composite of all-cause death, MI, or stent thrombosis, and a lower risk of all-cause death and cardiovascular death, as well, at 12 months compared with placebo. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02831608.

Automatic and effortful control of interference in working memory can be distinguished by unique behavioral and functional brain representations.

Goal-irrelevant information in working memory (WM) may enter the focus of attention (FOA) during a task and cause proactive interference (PI). In the current study we used fMRI to test several hypotheses concerning the boundary conditions of PI in WM using a modified verbal 2-back task. Temporal distance between item and lure presentation was manipulated to evaluate potential differences among hypothesized states of FOA, short-term memory and long-term memory. PI was present for the most proximal 3-back lures but dissipated with lure distance along with increased activation in brain regions critical for memory recollection, such as right prefrontal cortex, parietal cortex, and hippocampus. Reduced PI and less IFG activation were also observed after repeated item presentation, supporting the notion that a rehearsed encoding of item-context information reduces the need for interference control. Moreover, a trial-by-trial approach revealed activity in ACC, insula, IFG, and parietal cortex with increasing lure trial interference regardless of distance. The current results are first evidence for an observable transition of cognitive control, to include MTL regions involved in recalling task-relevant information from outside the FOA when resolving PI in WM.

Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study.

BACKGROUND: Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs). METHODS: PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065. FINDINGS: Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55-70] years). Median follow-up was 3·7 (IQR 3·0-4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0-15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2-10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25-4·13) and non-culprit lesion-specific MACEs (7·83, 4·12-14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0-10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4-17·6). INTERPRETATION: Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes. FUNDING: Abbott Vascular, Infraredx, and The Medicines Company.

Neural correlates of sequence learning in children with developmental dyslexia.

Developmental Dyslexia (DD) is a condition in which reading accuracy and/or fluency falls substantially below what is expected based on the individuals age, general level of cognitive ability, and educational opportunities. The procedural circuit deficit hypothesis (PDH) proposes that DD may be largely explained in terms of alterations of the cortico-basal ganglia procedural memory system (in particular of the striatum) whereas the (hippocampus-dependent) declarative memory system is intact, and may serve a compensatory role in the condition. The present study was designed to test this hypothesis. Using Magnetic Resonance Imaging, we examined the functional and structural brain correlates of sequence-specific procedural learning (SL) on the serial reaction time task, in 17 children with DD and 18 typically developing (TD) children. The study was performed over 2 days with a 24-h interval between sessions. In line with the PDH, the DD group showed less activation of the striatum during the processing of sequential statistical regularities. These alterations predicted the amount of SL at day 2, which in turn explained variance in children's reading fluency. Additionally, reduced hippocampal activation predicted larger SL gains between day 1 and day 2 in the TD group, but not in the DD group. At the structural level, caudate nucleus volume predicted the amount of acquired SL at day 2 in the TD group, but not in the DD group. The findings encourage further research into factors that promote learning in children with DD, including through compensatory mechanisms.

Elevated neuroinflammation contributes to the deleterious impact of iron overload on brain function in aging.

Intracellular iron is essential for many neurobiological mechanisms. However, at high concentrations, iron may induce oxidative stress and inflammation. Brain iron overload has been shown in various neurodegenerative disorders and in normal aging. Elevated brain iron in old age may trigger brain dysfunction and concomitant cognitive decline. However, the exact mechanism underlying the deleterious impact of iron on brain function in aging is unknown. Here, we investigated the role of iron on brain function across the adult lifespan from 187 healthy participants (20-79 years old, 99 women) who underwent fMRI scanning while performing a working-memory n-back task. Iron content was quantified using R2* relaxometry, whereas neuroinflammation was estimated using myo-inositol measured by magnetic resonance spectroscopy. Striatal iron increased non-linearly with age, with linear increases at both ends of adulthood. Whereas higher frontostriatal activity was related to better memory performance independent of age, the link between brain activity and iron differed across age groups. Higher striatal iron was linked to greater frontostriatal activity in younger, but reduced activity in older adults. Further mediation analysis revealed that, after age 40, iron provided unique and shared contributions with neuroinflammation to brain activations, such that neuroinflammation partly mediated brain-iron associations. These findings promote a novel mechanistic understanding of how iron may exert deleterious effects on brain function and cognition with advancing age.

Arginase 1 is upregulated at admission in patients with ST-elevation myocardial infarction.

BACKGROUND: The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unresolved. Increased arginase 1 activity leads to reduced nitric oxide (NO) production and increased formation of reactive oxygen species due to uncoupling of the NO-producing enzyme endothelial NO synthase (eNOS). This contributes to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. OBJECTIVE: The purpose of this study was to test the hypothesis that arginase gene and protein expression are upregulated in patients with STEMI. METHODS: Two cohorts of patients with STEMI were included. In the first cohort (n = 51), expression of arginase and NO-synthases as well as arginase 1 protein levels were determined and compared to a healthy control group (n = 45). In a second cohort (n = 68), plasma arginase 1 levels and infarct size were determined using cardiac magnetic resonance imaging. RESULTS: Expression of the gene encoding arginase 1 was significantly elevated at admission and 24-48 h after STEMI but not 3 months post STEMI, in comparison with the control group. Expression of the genes encoding arginase 2 and endothelial NO synthase (NOS3) were unaltered. Arginase 1 protein levels were elevated at admission, 24 h post STEMI and remained elevated for up to 6 months. No significant correlation between plasma arginase 1 protein levels and infarct size was observed. CONCLUSION: The markedly increased gene and protein expression of arginase 1 already at admission indicates a role of arginase 1 in the development of STEMI.

Ambulatory Heart Rate Variability in Schizophrenia or Depression: Impact of Anticholinergic Burden and Other Factors.

BACKGROUND: Heart rate variability (HRV) has been found reduced in patients with schizophrenia and depression. However, there is a lack of knowledge on how demographic, lifestyle, and pharmacological factors contribute to the reduction in HRV in these patients. METHODS: We recruited 37 patients with schizophrenia, 43 patients with unipolar depression, and 64 healthy controls. A combined chest-worn HRV and accelerometer device was used in an ambulatory measurement. Age, sex, anticholinergic burden of medication, nicotine use, body mass index, and ongoing physical activity were assessed in multiple regression models regarding their influence on HRV, measured as the standard deviation of all the RR intervals (SDNN). RESULTS: In the fully adjusted model, schizophrenia (ß = -0.23, P = 0.019), depression (ß = -0.18, P = 0.028), age (ß = -0.34, P < 0.000), ongoing physical activity (ß = -0.23, P = 0.001), and anticholinergic burden (ß = -0.19, P = 0.025) influenced SDNN negatively. Sex, nicotine use, and BMI had negligible effects on SDNN. CONCLUSIONS: We show for the first time that a quantified score of anticholinergic burden of medication has a negative relationship to HRV in patients with schizophrenia or depression, but that the diagnoses themselves still exhibit an effect on HRV.

Long-term effect of remote ischemic conditioning on infarct size and clinical outcomes in patients with anterior ST-elevation myocardial infarction.

BACKGROUND: Conflicting evidence exists concerning the cardioprotective efficacy of remote ischemic conditioning as an adjunct to primary percutaneous intervention (PCI) in ST-elevation myocardial infarction (STEMI) and data on long-term outcomes are scarce. We evaluated final infarct size by cardiac magnetic resonance (CMR) performed 6 months after anterior STEMI treated with remote ischemic conditioning and clinical outcomes up to 3 years after the event. METHODS: One hundred and fifteen patients with anterior STEMI were randomized to remote ischemic per-postconditioning (RIperpostC) or sham procedure as adjunct to primary PCI. The primary outcome was myocardial salvage index (MSI) on CMR 6 months after the event. Secondary outcomes were absolute infarct size, left ventricular function, cardiac mortality, major adverse cardiac and cerebrovascular events (MACCE-composite of all-cause mortality, myocardial infarction, readmission for heart failure, ischemic stroke, and target lesion revascularization) and all the individual components of MACCE. RESULTS: There was no difference in MSI or left ventricular function between the RIperpostC and the control group after 6 months. Nor did clinical outcomes at 6 months or 3 years differ between the groups. CONCLUSIONS: RIperpostC as an adjunct to PCI in anterior STEMI did not result in better MSI or left ventricular function 6 months after the event. Furthermore, clinical outcomes at 6 months and 3 years were not altered.

Pain trajectories of dorsomedial prefrontal intermittent theta burst stimulation versus sham treatment in depression.

BACKGROUND: Prefrontal repetitive transcranial magnetic stimulation is an established add-on treatment for major depressive disorder and is increasingly feasible with protocols of short duration, such as intermittent theta burst stimulation (iTBS). The most common and limiting side effect is pain at the site of application. Our objective was to investigate how pain develops over time in patients with depression receiving iTBS compared to sham stimulation. METHODS: This is a subsample from a randomized clinical trial. Patients received daily sessions of 2400 pulses of dorsomedial prefrontal iTBS or sham stimulation with transcutaneous electric stimulation during 2 to 3 weeks. After unmasking of treatment allocation, patients receiving sham treatment were offered active iTBS in an open phase. Patients rated pain on a scale from 0 to 10 after the last train of stimulation on the first, fifth and final treatment day. A Mann-Whitney U-test was conducted to test for group differences and related-samples Friedman's tests to analyze changes in pain ratings over time. RESULTS: The scalp pain in the group receiving iTBS was rated higher than sham treatment on the first (U = 263.5, p = 0.035) and fifth day (U = 271.0, p = 0.020) but not on the final day (U = 210.5, p = 0.121). The pain decreased mainly during the first 5 days of treatment (χ2 = 0.875, p = 0.040). In the open phase the pain decreased from the first day to the final day (χ2 = 1.194, p = 0.001). CONCLUSIONS: The subjective pain perception of active dorsomedial iTBS was higher than sham treatment but decreased over time, indicating an analgesic effect, or habituation. The result from this study can be used to inform patients about what to expect regarding pain during an iTBS treatment course. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02905604 . Registered 19 September 2016.

Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study.

Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

Hemiplegic (unilateral) cerebral palsy in northern Stockholm: clinical assessment, brain imaging, EEG, epilepsy and aetiologic background factors.

BACKGROUND: The purpose of this study was to describe clinical presentation, epilepsy, EEG, extent and site of the underlying cerebral lesion with special reference towards aetiologic background factors in a population-based group of children with hemiplegic cerebral palsy. METHODS: Forty-seven children of school- age, fulfilling the SPCE (Surveillance of Cerebral palsy in Europe)-criteria of hemiplegic cerebral palsy, identified via the Swedish cerebral palsy register, were invited and asked to participate in the study. RESULTS: Fifteen boys and six girls participated. Of the sixteen children born at term, five had no risk factors for cerebral palsy. Two out of five preterm children presented additional risk factors. Debut of motor impairment was observed in the first year of life in sixteen children. Age at diagnosis varied from 2 months to 6 years. Epilepsy was common and associated with grey- and white matter injury. CONCLUSIONS: Recognizing the importance of risk factors for cerebral palsy, any child with these risk factors should be offered a check-up by a paediatrician or a paediatric neurologist. Thereby reducing diagnostic delay. Epilepsy is common in hemiplegic cerebral palsy and associated with grey- and white matter injury in this cohort.