David E Linden

The current study aims to characterize brain morphology of pain as reported by small fiber neuropathy (SFN) patients with or without a gain-of-function variant involving the SCN9A gene and compare these with findings in healthy controls without pain. The Neuropathic Pain Scale was used in patients with idiopathic SFN (N = 20) and SCN9A-associated SFN (N = 12) to capture pain phenotype. T1-weighted, structural magnetic resonance imaging (MRI) data were collected in patients and healthy controls (N = 21) to 1) compare cortical thickness and subcortical volumes and 2) quantify the association between severity, quality, and duration of pain with morphological properties. SCN9A-associated SFN patients showed significant (P < .017, Bonferroni corrected) higher cortical thickness in sensorimotor regions, compared to idiopathic SFN patients, while lower cortical thickness was found in more functionally diverse …

BackgroundCarriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.MethodsMagnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference.ResultsFor the 1q21.1 distal deletion carriers, cortical …

Although many genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10–17 years old. Resting-state oscillatory activity and …

BackgroundDeep brain stimulation (DBS) is an effective intervention for refractory obsessive-compulsive disorder (OCD). Although treatment success is measured by a decrease in the severity of core symptoms, this procedure can have broader psychological and physical effects. The field regrettably still lacks knowledge and tools allowing an adequate understanding and assessment of the full range of experiences that accompany DBS treatment. We aimed to describe possible side effects of DBS treatment as experienced by patients, beyond specific changes in OCD core symptoms.MethodsWe interviewed 16 patients and 7 of their relatives from two independent cohorts, receiving stimulation in different anatomical locations. We conducted semi-structured interviews, then transcribed at verbatim. Inductive content analysis was performed to code and group common themes.ResultsWe categorized a variety of …

Habituation to pain is a fundamental learning process and important adaption. Yet, a comprehensive review of the current state of the field is lacking. Through a systematic search, 63 studies were included. Results address habituation to pain in healthy individuals based on self-report, electroencephalography, or functional magnetic resonance imaging. Our findings indicate a large variety in methods, experimental settings, and contexts, making habituation a ubiquitous phenomenon. Habituation to pain based on self-report studies shows a large influence of expectations, as well as the presence of individual differences. Furthermore, widespread neural effects, with sometimes opposing effects in self-report measures, are noted. Electroencephalography studies showed habituation of the N2-P2 amplitude, whereas functional magnetic resonance imaging studies showed decreasing activity during painful repeated …

ObjectiveTo evaluate whether psychological and social factors complement biomedical factors in understanding post-COVID-19 fatigue and cognitive complaints. Additionally, to incorporate objective (neuro-cognitive) and subjective (patient-reported) variables in identifying factors related to post-COVID-19 fatigue and cognitive complaints.DesignProspective, multicenter cohort study.SettingSix Dutch hospitals.Participants205 initially hospitalized (March-June 2020), confirmed patients with SARS-CoV-2, aged ≥18 years, physically able to visit the hospital, without prior cognitive deficit, magnetic resonance imaging (MRI) contraindication, or severe neurologic damage post-hospital discharge (N=205).InterventionsNot applicable.Main Outcome MeasuresNine months post-hospital discharge, a 3T MRI scan and cognitive testing were performed and patients completed questionnaires. Medical data were retrieved from …

BACKGROUNDNeurological complications in COVID-19 patients admitted to an intensive care unit (ICU) have been previously reported. As the pandemic progressed, therapeutic strategies were tailored to new insights. This study describes the incidence, outcome, and types of reported neurological complications in invasively mechanically ventilated (IMV) COVID-19 patients in relation to three periods during the pandemic.METHODSIMV COVID-19 ICU patients from the Dutch Maastricht Intensive Care COVID (MaastrICCht) cohort were included in a single-center study (March 2020 – October 2021). Demographic, clinical, and follow-up data were collected. Electronic medical records were screened for neurological complications during hospitalization. Three distinct periods (P1, P2, P3) were defined, corresponding to periods with high hospitalization rates. ICU survivors with and without reported neurological …

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in …

ObjectiveHuntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which to our knowledge has never been measured before.MethodsWe recruited 20 manifest, 13 premanifest HD gene expansion carriers (HDGECs) and 20 age-matched controls. All patients underwent detailed assessments, including Unified Huntington’s Disease Rating Scale (UHDRS) total motor score (TMS) and total function capacity score. Tear fluid was collected using paper Schirmer’s strips. The level of tear mHTT was determined using the Single Molecule Counting SMCxPRO technology.ResultsAverage tear mHTT levels in manifest (67,223±80,360 fM) and premanifest patients (55,561±45,931 fM) were significantly higher than in controls (1622±2179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length,‘estimated years to diagnosis’, disease burden score and UHDRS TMS and TFC. The ROC curve demonstrated an almost perfect score (AUC= 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cut-off value to distinguish between controls and manifest patients was 4544 fM, whereas it was 6596 fM for the distinction between controls and premanifest patients.ConclusionsTear mHTT levels have the potential for early and non-invasive detection of alterations in HD and could be integrated into …

The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remains a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 CNV containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models we show that 15q11.2 deletion and CYFIP1-LoF leads to premature neuronal differentiation while CYFIP1-GoF favors neural progenitor maintenance. CYFIP1 dosage changes led to dysregulated cholesterol metabolism and altered levels of 24S,25-epoxycholesterol, which can mimic the 15q11.2del and CYFIP1-LoF phenotype by promoting cortical neuronal differentiation and restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of LXR while compound deletion of LXR in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2CNV and provides a potential target for therapeutic strategies for associated disorders.

In population-based cohort studies, magnetic resonance imaging (MRI) is vital for examining brain structure and function. Advanced MRI techniques, such as diffusion-weighted MRI (dMRI) and resting-state functional MRI (rs-fMRI), provide insights into brain connectivity. However, biases in MRI data acquisition and processing can impact brain connectivity measures and their associations with demographic and clinical variables. This study, conducted with 5110 participants from The Maastricht Study, explored the relationship between brain connectivity and various image quality metrics (e.g., signal-to-noise ratio, head motion, and atlas–template mismatches) that were obtained from dMRI and rs-fMRI scans. Results revealed that in particular increased head motion (R2 up to 0.169, p < 0.001) and reduced signal-to-noise ratio (R2 up to 0.013, p < 0.001) negatively impacted structural and functional brain connectivity, respectively. These image quality metrics significantly affected associations of overall brain connectivity with age (up to −59%), sex (up to −25%), and body mass index (BMI) (up to +14%). Associations with diabetes status, educational level, history of cardiovascular disease, and white matter hyperintensities were generally less affected. This emphasizes the potential confounding effects of image quality in large population-based neuroimaging studies on brain connectivity and underscores the importance of accounting for it.

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as …

Aberrant movement-related cortical activity has been linked to impaired motor function in Parkinson’s disease (PD). Dopaminergic drug treatment can restore these, but dosages and long-term treatment are limited by adverse side-effects. This experiment reports the first study of home-based electroencephalographic (EEG) neurofeedback training as a non-pharmacological candidate treatment for PD. Sixteen people with PD received six home visits comprising symptomology self-reports, a standardised motor assessment, and a precision handgrip force production task while EEG was recorded (visits 1, 2 and 6); and 3 × 1-hr EEG neurofeedback training sessions to reduce EEG high-alpha power before initiating handgrip movements (visits 3 to 5). Participants successfully learned to self-regulate movement-related alpha rhythms, and this appeared to expedite the initiation of precision movements. There was no evidence of wider symptomology reduction. Interviews indicated that the intervention was well-received. We conclude that home-based neurofeedback for people with PD is feasible and warrants further research.

22q11. 2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11. 2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (ie, loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these …

Task-free brain activity exhibits spontaneous fluctuations between functional states, characterized by synchronized activation patterns in distributed resting-state (RS) brain networks. The temporal dynamics of the networks’ electrophysiological signatures reflect individual variations in brain activity and connectivity linked to mental states and cognitive functions and can predict or monitor vulnerability to develop psychiatric or neurological disorders. In particular, RS alpha fluctuations modulate perceptual sensitivity, attentional shifts, and cognitive control, and could therefore reflect a neural correlate of increased vulnerability to sensory distortions, including the proneness to hallucinatory experiences. We recorded 5 min of RS EEG from 33 non-clinical individuals varying in hallucination proneness (HP) to investigate links between task-free alpha dynamics and vulnerability to hallucinations. To this end, we used a …

ObjectiveIn the current study, we assess the role of the peripheral and central adrenergic system in this respect.MethodsHealthy volunteers underwent a double inhalation of 35% CO 2, which is a well-validated procedure to induce an intense emotion, namely panic. In a randomized, cross-over design, 34 participants received either a β 1-blocker acting selectively in the peripheral nervous system (atenolol), a β 1-blocker acting in the peripheral and central nervous system (metoprolol), or a placebo before the CO 2 inhalation.ResultsHeart rate and systolic blood pressure were reduced in both β-blocker conditions compared to placebo, showing effective inhibition of the adrenergic tone. Nevertheless, the subjective experience of the induced panic was the same in all conditions, as measured by self-reported fear, discomfort, and panic symptom ratings.ConclusionsThese results indicate that information from the …

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1‐weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source‐based morphometry (SBM) pipeline (SS‐Detect) to generate structural brain patterns (SBPs) that capture co‐varying GMV. We investigated the impact of the 22q11.2 deletion …

Objectives: Schizophrenia genetics is complex, and the contribution of common and rare variants are not fully understood. Several specific copy number variations (CNVs) confer increased risk, and the study of their effects is central to molecular models of mental disorders. However, these CNVs are spread across the genome and differ in the number of genes affected and classes of coded proteins. This diversity suggests that we need to look beyond the deleted or duplicated genes, to their interaction partners and involved molecular pathways.Methods: In this study, we developed machine-readable interactive pathways to enable analysis of functional effects of genes within CNV loci and identify ten common pathways across CNVs with high schizophrenia risk using the WikiPathways database, schizophrenia risk gene collections from GWAS studies, and a gene-disease association database.Results: For CNVs that …

Working memory (WM) represents a building-block of higher cognitive functions and a wide range of mental disorders are associated with WM impairments. Initial studies have shown that several sessions of functional near-infrared spectroscopy (fNIRS) informed real-time neurofeedback (NF) allow healthy individuals to volitionally increase activity in the dorsolateral prefrontal cortex (DLPFC), a region critically involved in WM. For the translation to therapeutic or neuroenhancement applications, however, it is critical to assess whether fNIRS-NF success transfers into neural and behavioral WM enhancement in the absence of feedback. We therefore combined single-session fNIRS-NF of the left DLPFC with a randomized sham-controlled design (N = 62 participants) and a subsequent WM challenge with concomitant functional MRI. Over four runs of fNIRS-NF, the left DLPFC NF training group demonstrated …

INTRODUCTION Late-onset Alzheimers disease (LOAD) has been associated with alterations in the morphology of multiple brain structures and it is likely that disease mechanisms differ between brain regions. Coupling genetic determinants of LOAD with measures of brain morphology could localize and identify primary causal neurobiological pathways. METHODS Mediation and Mendelian randomization (MR) analysis were performed using common genetic variation, T1 MRI and clinical data collected by UK Biobank and Alzheimers Disease Neuroimaging Initiative. RESULTS Thickness of the entorhinal cortex and the volumes of the hippocampus, amygdala, choroid plexus and inferior lateral ventricle mediated the effect of APOE E4 on LOAD. MR showed that a thinner entorhinal cortex, a smaller hippocampus and amygdala, and a larger volume of the choroid plexus and inferior lateral ventricles, increased the risk of LOAD as well as vice versa. DISCUSSION Combining neuroimaging and genetic data can give insight into the causal neuropathological pathways of LOAD.