Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Invited Review: The spectrum of neuropathology in COVID-19.

There is increasing evidence that patients with Coronavirus disease 19 (COVID-19) present with neurological and psychiatric symptoms. Anosmia, hypogeusia, headache, nausea and altered consciousness are commonly described, although there are emerging clinical reports of more serious and specific conditions such as acute cerebrovascular accident, encephalitis and demyelinating disease. Whether these presentations are directly due to viral invasion of the central nervous system (CNS) or caused by indirect mechanisms has yet to be established. Neuropathological examination of brain tissue at autopsy will be essential to establish the neuro-invasive potential of the SARS-CoV-2 virus but, to date, there have been few detailed studies. The pathological changes in the brain probably represent a combination of direct cytopathic effects mediated by SARS-CoV-2 replication or indirect effects due to respiratory failure, injurious cytokine reaction, reduced immune response and cerebrovascular accidents induced by viral infection. Further large-scale molecular and cellular investigations are warranted to clarify the neuropathological correlates of the neurological and psychiatric features seen clinically in COVID-19. In this review, we summarize the current reports of neuropathological examination in COVID-19 patients, in addition to our own experience, and discuss their contribution to the understanding of CNS involvement in this disease.

Hippocampal subfield segmentation in temporal lobe epilepsy: Relation to outcomes.

OBJECTIVE: To investigate the clinical and surgical outcome correlates of preoperative hippocampal subfield volumes in patients with refractory temporal lobe epilepsy (TLE) using a new magnetic resonance imaging (MRI) multisequence segmentation technique. METHODS: We recruited 106 patients with TLE and hippocampal sclerosis (HS) who underwent conventional T1-weighted and T2 short TI inversion recovery MRI. An automated hippocampal segmentation algorithm was used to identify twelve subfields in each hippocampus. A total of 76 patients underwent amygdalohippocampectomy and postoperative seizure outcome assessment using the standardized ILAE classification. Semiquantitative hippocampal internal architecture (HIA) ratings were correlated with hippocampal subfield volumes. RESULTS: Patients with left TLE had smaller volumes of the contralateral presubiculum and hippocampus-amygdala transition area compared to those with right TLE. Patients with right TLE had reduced contralateral hippocampal tail volumes and improved outcomes. In all patients, there were no significant relationships between hippocampal subfield volumes and clinical variables such as duration and age at onset of epilepsy. There were no significant differences in any hippocampal subfield volumes between patients who were rendered seizure free and those with persistent postoperative seizure symptoms. Ipsilateral but not contralateral HIA ratings were significantly correlated with gross hippocampal and subfield volumes. CONCLUSIONS: Our results suggest that ipsilateral hippocampal subfield volumes are not related to the chronicity/severity of TLE. We did not find any hippocampal subfield volume or HIA rating differences in patients with optimal and unfavorable outcomes. In patients with TLE and HS, sophisticated analysis of hippocampal architecture on MRI may have limited value for prediction of postoperative outcome.

Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study.

BACKGROUND: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. MATERIALS AND METHODS: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. RESULTS: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. CONCLUSION: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics.

Spontaneous and TMS-related EEG changes as new biomarkers to measure anti-epileptic drug effects.

Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

Patients self-mastery of wearable devices for seizure detection: A direct user-experience.

PURPOSE: wearable devices aimed at detecting seizures are rapidly emerging. Continuous collection and optimal data quality are paramount to guarantee the acquisition of clinically meaningful data. It is still unknown how successfully patients can self-manage new technologies and which factors have an impact on this. We assessed the performance of patients managing a wrist-worn device. METHOD: patients wearing a wrist-worn device received a single training session to perform 5 tasks: (1) fitting the device correctly; (2) switching the device on and off; (3) charging the device on a daily basis; (4) pairing the device with a phone or tablet; (5) seeking assistance. Participants were then reviewed every 24 h and, at the end of the study, a Wearable technology Self-management Score (WSS) was calculated according to their performance in the different tasks (0-12). The association between WSS, seizure capture, demographics and clinical characteristics was analysed. RESULTS: Thirty patients were included. The mean WSS score was 9.4 ± 2.1 points. The task more often performed inaccurately was pairing the device with a phone or tablet, followed by performing charging procedures. A strong association was found between WSS and seizure capture (p = 0.019), with higher scores strongly associated with more seizures captured. A WSS of ≥9 was the minimum value of WSS that allowed the device to record all the seizures. Number of AEDs and illness-perception related factors (perceived disease timeline and personal control) were significantly associated with WSS. CONCLUSIONS: Overall, participants demonstrated good performances in self-managing a wrist-worn device. Digital inequalities may extend to variations in how different individuals feel about their own disease and, consequently, manage the technology. These aspects should be addressed when technological solutions are delivered to users.

Imaging epilepsy in larval zebrafish.

Our understanding of the genetic aetiology of paediatric epilepsies has grown substantially over the last decade. However, in order to translate improved diagnostics to personalised treatments, there is an urgent need to link molecular pathophysiology in epilepsy to whole-brain dynamics in seizures. Zebrafish have emerged as a promising new animal model for epileptic seizure disorders, with particular relevance for genetic and developmental epilepsies. As a novel model organism for epilepsy research they combine key advantages: the small size of larval zebrafish allows high throughput in vivo experiments; the availability of advanced genetic tools allows targeted modification to model specific human genetic disorders (including genetic epilepsies) in a vertebrate system; and optical access to the entire central nervous system has provided the basis for advanced microscopy technologies to image structure and function in the intact larval zebrafish brain. There is a growing body of literature describing and characterising features of epileptic seizures and epilepsy in larval zebrafish. Recently genetically encoded calcium indicators have been used to investigate the neurobiological basis of these seizures with light microscopy. This approach offers a unique window into the multiscale dynamics of epileptic seizures, capturing both whole-brain dynamics and single-cell behaviour concurrently. At the same time, linking observations made using calcium imaging in the larval zebrafish brain back to an understanding of epileptic seizures largely derived from cortical electrophysiological recordings in human patients and mammalian animal models is non-trivial. In this review we briefly illustrate the state of the art of epilepsy research in zebrafish with particular focus on calcium imaging of epileptic seizures in the larval zebrafish. We illustrate the utility of a dynamic systems perspective on the epileptic brain for providing a principled approach to linking observations across species and identifying those features of brain dynamics that are most relevant to epilepsy. In the following section we survey the literature for imaging features associated with epilepsy and epileptic seizures and link these to observations made from humans and other more traditional animal models. We conclude by identifying the key challenges still facing epilepsy research in the larval zebrafish and indicate strategies for future research to address these and integrate more directly with the themes and questions that emerge from investigating epilepsy in other model systems and human patients.

Tensor decomposition of TMS-induced EEG oscillations reveals data-driven profiles of antiepileptic drug effects.

Transcranial magnetic stimulation combined with electroencephalography is a powerful tool to probe human cortical excitability. The EEG response to TMS stimulation is altered by drugs active in the brain, with characteristic "fingerprints" obtained for drugs of known mechanisms of action. However, the extraction of specific features related to drug effects is not always straightforward as the complex TMS-EEG induced response profile is multi-dimensional. Analytical approaches can rely on a-priori assumptions within each dimension or on the implementation of cluster-based permutations which do not require preselection of specific limits but may be problematic when several experimental conditions are tested. We here propose an alternative data-driven approach based on PARAFAC tensor decomposition, which provides a parsimonious description of the main profiles underlying the multidimensional data. We validated reliability of PARAFAC on TMS-induced oscillations before extracting the features of two common anti-epileptic drugs (levetiracetam and lamotrigine) in an integrated manner. PARAFAC revealed an effect of both drugs, significantly suppressing oscillations in the alpha range in the occipital region. Further, this effect was stronger under the intake of levetiracetam. This study demonstrates, for the first time, that PARAFAC can easily disentangle the effects of subject, drug condition, frequency, time and space in TMS-induced oscillations.

Preoperative fMRI predicts memory decline following anterior temporal lobe resection.

BACKGROUND: Anterior temporal lobe resection (ATLR) benefits many patients with refractory temporal lobe epilepsy (TLE) but may be complicated by material specific memory impairments, typically of verbal memory following left ATLR, and non-verbal memory following right ATLR. Preoperative memory functional MRI (fMRI) may help in the prediction of these deficits. OBJECTIVE: To assess the value of preoperative fMRI in the prediction of material specific memory deficits following both left- and right-sided ATLR. METHODS: We report 15 patients with unilateral TLE undergoing ATLR; eight underwent dominant hemisphere ATLR and seven non-dominant ATLR. Patients performed an fMRI memory paradigm which examined the encoding of words, pictures and faces. RESULTS: Individual patients with relatively greater ipsilateral compared with contralateral medial temporal lobe activation had greater memory decline following ATLR. This was the case for both verbal memory decline following dominant ATLR and for non-verbal memory decline following non-dominant ATLR. For verbal memory decline, activation within the dominant hippocampus was predictive of postoperative memory change whereas activation in the non-dominant hippocampus was not. CONCLUSION: These findings suggest that preoperative memory fMRI may be a useful non-invasive predictor of postoperative memory change following ATLR and provide support for the functional adequacy theory of hippocampal function. They also suggest that fMRI may provide additional information, over that provided by neuropsychology, for use in the prediction of postoperative memory decline.

Estimation of brain network ictogenicity predicts outcome from epilepsy surgery.

Surgery is a valuable option for pharmacologically intractable epilepsy. However, significant post-operative improvements are not always attained. This is due in part to our incomplete understanding of the seizure generating (ictogenic) capabilities of brain networks. Here we introduce an in silico, model-based framework to study the effects of surgery within ictogenic brain networks. We find that factors conventionally determining the region of tissue to resect, such as the location of focal brain lesions or the presence of epileptiform rhythms, do not necessarily predict the best resection strategy. We validate our framework by analysing electrocorticogram (ECoG) recordings from patients who have undergone epilepsy surgery. We find that when post-operative outcome is good, model predictions for optimal strategies align better with the actual surgery undertaken than when post-operative outcome is poor. Crucially, this allows the prediction of optimal surgical strategies and the provision of quantitative prognoses for patients undergoing epilepsy surgery.

Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome.

OBJECTIVE: A previous study showed no effect of 1Hz repetitive transcranial magnetic stimulation (rTMS) on tics in Gilles de la Tourette Syndrome (GTS). We modified the rTMS protocol in order to investigate some of the possible methodological reasons for the negative outcome in that study. METHODS: In a single blinded placebo-controlled cross-over study in five GTS patients without obsessive compulsive disorder we probed whether longer trains (1800 stimuli) of 1 Hz pre-motor cortex rTMS at 80% of active motor threshold and application to both hemispheres can improve tics in GTS. This was measured with the Yale Global Tic severity rating scale, the MOVES self-rating scale and video analysis. RESULTS: We found no significant effect of either left pre-motor cortex stimulation alone, or left pre-motor followed by right pre-motor cortex stimulation. CONCLUSIONS: These results suggest that the rTMS protocol used in this study is not useful for the treatment of tics in GTS. SIGNIFICANCE: rTMS protocols need to be modified substantially in order to explore their potential for the treatment of tics in GTS.

Molecular cloning and characterization of a highly conserved human 67-kDa laminin receptor pseudogene mapping to Xq21.3.

A highly conserved laminin receptor processed pseudogene (LAMRL5) that has been isolated from a fetal brain cDNA library is described. The pseudogene is a complete copy (97.9% identical) of the transcribed laminin receptor (LAMR1) with all the introns precisely removed. The sequence has direct repeats of 18 bp at either end. It has an 885 nucleotide open reading frame from the start methionine codon to the stop codon that contains no deletions, additions or premature stop codons relative to the expressed LAMR1 gene and has the coding potential for a protein of 295 amino acids. Although TATA and CAAT boxes exist in the region 5' to the open reading frame and a polyadenylation signal is present in the 3' region, no evidence could be obtained either by reverse transcriptase-polymerase chain reaction (RT-PCR) or in the expressed sequence tag (EST) database that LAMRL5 is expressed in vivo. If not expressed, it is estimated that this LAMRL5 pseudogene was incorporated into the human genome approximately 3.5-5 million years ago.

11C-flumazenil PET in neocortical epilepsy.

OBJECTIVE: To investigate focal cortical abnormalities of gamma-aminobutyric acid type A-central benzodiazepine receptors (GABA(A)-cBZRs) in patients with extratemporal partial seizures with acquired lesions and in patients with normal high-resolution MRI. METHODS: Six patients with acquired lesions and 18 patients with normal high-resolution MRI and extratemporal partial seizures, as well as 24 normal controls, were studied with 11C-flumazenil (FMZ) PET to produce voxel-by-voxel images of FMZ volume of distribution (FMZVD), which reflects density of GABA(A)-cBZRs. These images were analyzed using Statistical Parametric Mapping (SPM). Each patient was compared with the control group to reveal regions with abnormal FMZVD at p < 0.001 uncorrected, corrected to p < 0.05 for the whole brain volume. Each normal control was compared with the remaining controls in the same manner. RESULTS: All six patients with acquired lesions had a single region of reduced FMZVD. Thirteen of 18 patients with normal MRI had regions of abnormal cortical FMZVD: 10 had regions of increased FMZVD, 6 had regions of decreased FMZVD, and 3 had both regions of increased and decreased FMZVD. Seven patients had an abnormality in the lobe and 12 in the hemisphere of presumed seizure origin. CONCLUSIONS: FMZ PET analyzed with SPM is an automated, objective, sensitive, and specific means for detecting regional cortical abnormalities of GABA(A)-cBZRs in patients with partial seizures. This technique may be useful in the evaluation of patients with refractory partial seizures for surgical treatment, particularly in those patients with normal MRI.

11C-flumazenil PET, volumetric MRI, and quantitative pathology in mesial temporal lobe epilepsy.

BACKGROUND: Using statistical parametric mapping and 11C-flumazenil (FMZ) PET we have previously shown reduction of central benzodiazepine receptor (cBZR) binding restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) due to hippocampal sclerosis (HS). The limited spatial resolution of PET, however, results in partial-volume averaging that affects quantitative analysis of cBZR density. METHOD: We determined hippocampal volume loss and reduction in cBZR binding using an MRI-based method for partial-volume effect correction of 11C-FMZ volume of distribution (FMZ-Vd) in 17 patients with refractory mTLE and an MRI diagnosis of HS that was subsequently histologically verified in all cases. Quantitative neuropathology was performed with assessment of neuron density in 14 of the 17 patients. Absolute FMZ-Vd and asymmetry indices (FMZ-AI) were compared before and after partial-volume effect correction with MRI-determined hippocampal volumes (HCV), hippocampal T2 measurements, and, if available, neuronal cell densities. RESULTS: Compared with 15 age-matched healthy volunteers, significant reductions of absolute hippocampal FMZ-Vd were found before correction for partial-volume effects in 11 of 17 patients (65%) and only abnormal FMZ-AI in the other six patients. After partial-volume effects correction all 17 patients (100%) showed both significant unilateral reduction of absolute FMZ-Vd and abnormal FMZ-AI. There was no correlation between corrected absolute FMZ-Vd and HCV or neuronal cell density. After correction for partial-volume effect we found a mean 38% reduction of FMZ-Vd in the sclerosed hippocampus, over and above the reduction of HCV. CONCLUSION: Correction for partial-volume effect allows absolute quantitation of FMZ-PET and increases its sensitivity for detecting abnormalities in TLE due to HS. The lack of correlation between cBZR binding and neuronal density implies that atrophy with neuron loss is not the sole determinant of reduced cBZR binding in patients with mTLE and hippocampal sclerosis.

A simple flow cytometry assay using dihydrorhodamine for the measurement of the neutrophil respiratory burst in whole blood: comparison with the quantitative nitrobluetetrazolium test.

The neutrophil respiratory burst is essential for the host's ability to kill ingested microorganisms. Several flow cytometric assays have recently been developed to measure this process. These assays are largely unvalidated. In this study a whole blood flow cytometry assay using dihydrorhodamine 123 (DHR) as a substrate was compared with the quantitative nitrobluetetrazolium (NBT) test, an accepted measure of the earliest events in the respiratory burst. Because whole blood is used, the new assay is quicker and simpler than existing flow cytometry assays. Specimens as small as 0.1 ml can be used which makes the assay ideal for use in neonates and young children. There was a high degree of correlation between the DHR assay and the quantitative NBT test (r(s) = 0.76, P < 0.01). It is concluded that the whole blood DHR assay is an accurate and sensitive measure of the respiratory burst.

Molecular cloning and genomic structure of a gene encoding interferon regulatory factor in the pufferfish (Fugu rubripes).

Interferon regulatory factors (IRFs) are a large family of transcription factors involved in regulating the transcriptional response of vertebrates to interferons and viral infection. In this report we describe the cloning and genomic organization of an IRF gene from the pufferfish (Fugu rubripes). The fugu IRF gene spans 2.7 kb from the transcription start site to the polyadenylation signal. It consists of 10 exons and 9 introns and encodes a protein of 296 amino acids. The overall amino acid sequence of fugu IRF displays 55% identity to flounder IRF and approximately 44% identity to avian and mammalian IRF-1 and IRF-2. On the basis of the genomic structure and the absence of a transcriptional repression domain, we conclude that the fugu IRF is a member of the IRF-1 family. The fugu IRF gene is expressed in a wide range of tissues. While a single transcript of 1.4 kb was detected in most tissues, several larger transcripts generated using alternative polyadenylation signals were found in the gills.

CPD - education and self-assessment: functional imaging in epilepsy.

Functional imaging plays a growing role in the clinical assessment and research investigation of patients with epilepsy. This article reviews the literature on functional MRI (fMRI) investigation of EEG activity, fMRI evaluation of cognitive and motor functions, magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT) and positron emission tomography (PET) in epilepsy. The place of these techniques in clinical evaluation and their contribution to a better neurobiological understanding of epilepsy are discussed.

Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole.

HIV positive women of reproductive age are increasingly treated with a combination of antiretroviral agents, with effects on the developing human fetus that are largely unknown. We report two cases of severe spinal malformations in the fetuses of women treated with combination antiretroviral therapy and co-trimoxazole.

Oculo-auriculo-vertebral spectrum with vascular ring and other unusual anomalies.

An infant with the oculo-auriculo-vertebral (OAV) spectrum is described with the previously unreported association of rectal agenesis with recto-urethral fistula. The patient died at the age of 14 weeks from respiratory obstruction. Autopsy revealed the cause of death to be tracheal compression from a pulmonary artery sling. Previous reports of vascular rings within the OAV spectrum are reviewed, and it is concluded that these malformations are an uncommon, but clinically important, complication of the disorder.

Acute otitis media and otitis media with effusion in children with bacterial meningitis.

Acute otitis media and otitis media with effusion (OME) have often been observed in children with bacterial meningitis. OME has also been proposed as the mechanism of reversible hearing loss after meningitis. In this controlled study, children with acute bacterial meningitis were studied using auditory brainstem responses (ABR), otoacoustic emissions, tympanometry and otoscopy. An age- and sex-matched control was recruited for each patient and the incidence of acute otitis media and OME was compared between the two groups. One hundred and twenty-four children with meningitis were studied. Ninety-two children (74 per cent) had meningococcal meningitis. Five patients (4 per cent) had conductive hearing loss (ABR threshold > or = 30 dB HL) at the time of discharge from hospital. None of the patients or controls had acute otitis media. Patients and controls were well matched for risk factors for OME and the prevalence of middle ear effusion in patients and controls was 7.2 per cent and 11.3 per cent respectively. The relative risk of OME in the children with meningitis was 0.64 (95 per cent confidence interval 0.29 to 1.42). After nine months, three of the five children with meningitis and conductive hearing loss had regained normal hearing. In contrast to previous reports, there was no relationship between bacterial meningitis and acute otitis media or OME in this study. Nevertheless, coincidental conductive hearing defects were identified as the cause of reversible hearing loss in three patients.