Aberrantly Expressed Hsa_circ_0060762 and CSE1L as Potential Peripheral Blood Biomarkers for ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive adult-onset neurodegenerative disease that is often diagnosed with a delay due to initial non-specific symptoms. Therefore, reliable and easy-to-obtain biomarkers are an absolute necessity for earlier and more accurate diagnostics. Circular RNAs (circRNAs) have already been proposed as potential biomarkers for several neurodegenerative diseases. In this study, we further investigated the usefulness of circRNAs as potential biomarkers for ALS. We first performed a microarray analysis of circRNAs on peripheral blood mononuclear cells of a subset of ALS patients and controls. Among the differently expressed circRNA by microarray analysis, we selected only the ones with a host gene that harbors the highest level of conservation and genetic constraints. This selection was based on the hypothesis that genes under selective pressure and genetic constraints could have a major role in determining a trait or disease. Then we performed a linear regression between ALS cases and controls using each circRNA as a predictor variable. With a False Discovery Rate (FDR) threshold of 0.1, only six circRNAs passed the filtering and only one of them remained statistically significant after Bonferroni correction: hsa_circ_0060762 and its host gene CSE1L. Finally, we observed a significant difference in expression levels between larger sets of patients and healthy controls for both hsa_circ_0060762 and CSE1L. CSE1L is a member of the importin ß family and mediates inhibition of TDP-43 aggregation; the central pathogenicity in ALS and hsa_circ_0060762 has binding sites for several miRNAs that have been already proposed as biomarkers for ALS. In addition, receiver operating characteristics curve analysis showed diagnostic potential for CSE1L and hsa_circ_0060762. Hsa_circ_0060762 and CSE1L thus represent novel potential peripheral blood biomarkers and therapeutic targets for ALS.

Awake craniotomy for operative treatment of brain gliomas - experience from University Medical Centre Ljubljana.

BACKGROUND: Awake craniotomy is a neurosurgical technique that allows neurophysiological testing with patient cooperation during the resection of brain tumour in regional anaesthesia. This allows identification of vital functional (i.e. eloquent) brain areas during surgery and avoidance of their injury. The aim of the study was to present clinical experience with awake craniotomy for the treatment of gliomas at the University Medical Centre Ljubljana from 2015 to 2019. PATIENTS AND METHODS: Awake craniotomy was considered in patients with a gliomas near or within the language brain areas, in all cases of insular lesions and selected patients with lesions near or within primary motor brain cortex. Each patient was assessed before and after surgery. RESULTS: During the 5-year period, 24 awake craniotomies were performed (18 male and 6 female patients; average age 41). The patient's cooperation, discomfort and perceived pain assessed during the awake craniotomy were in majority of the cases excellent, slight, and moderate, respectively. After surgery, mild neurological worsening was observed in 13% (3/24) of patients. Gross total resection, in cases of malignant gliomas, was feasible in 60% (6/10) and in cases of low-grade gliomas in 29% (4/14). The surgery did not have important negative impact on functional status or quality of life as assessed by Karnofsky score and Short-Form 36 health survey, respectively (p > 0.05). CONCLUSIONS: The results suggest that awake craniotomy for treatment of gliomas is feasible and safe neurosurgical technique. The proper selection of patients, preoperative preparation with planning, and cooperation of medical team members are necessary for best treatment outcome.

Cone-beam computed tomography guided nusinersen administrations in adult spinal muscular atrophy patients with challenging access: a single- center experience.

BACKGROUND: The challenging anatomic predispositions in adult patients with spinal muscular atrophy (SMA) preclude the conventional lumbar punctures. Consequently, an introduction of alternative method for intrathecal delivery of nusinersen is required. Cone-beam CT (CBCT) allows volumetric display of the area of interest, pre-procedural planning and real time needle guidance which results in accurate anatomic navigation. The aim of the study was to evaluate technical success, safety, and feasibility of CBCT lumbar intrathecal delivery of nusinersen in the adult SMA patients with challenging anatomical access. PATIENTS AND METHODS: Thirty-eight adult SMA patients were treated in our institution. Patients with challenging access were selected by multidisciplinary board for image guided administration of nusinersen either due to implantation of the posterior fusion instrumentation, severe scoliosis defined as Cobb's angle > 40º or body mass index over 35. Technical success, radiation exposure and occurrence of adverse events were assessed. RESULTS: Twenty patients were selected, and 108 CBCT-guided procedures were performed. Each patient underwent at least 4 administrations. Transforaminal approach was performed in 82% of patients. The technical success was 100%, with primary success of 93.5%. The median radiation effective dose of the administrations was 5 mSv, the mean value equalled 10 mSv. Only mild adverse events were reported in the study. CONCLUSIONS: CBCT-guided lumbar intrathecal administrations of nusinersen in an adult SMA population with challenging access was feasible and safe image guided method.

Genetic Variability of Inflammation and Oxidative Stress Genes Affects Onset, Progression of the Disease and Survival of Patients with Amyotrophic Lateral Sclerosis.

Inflammation and oxidative stress are recognized as important contributors to amyotrophic lateral sclerosis (ALS) disease pathogenesis. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on ALS susceptibility and modification. One-hundred-and-eighty-five ALS patients and 324 healthy controls were genotyped for nine polymorphisms in seven antioxidant and inflammatory genes using competitive allele-specific PCR. Logistic regression; nonparametric tests and survival analysis were used in the statistical analysis. Investigated polymorphisms were not associated with ALS susceptibility. Carriers of at least one polymorphic SOD2 rs4880 T or IL1B rs1071676 C allele more often had bulbar ALS onset (p = 0.036 and p = 0.039; respectively). IL1B rs1071676 was also associated with a higher rate of disease progression (p = 0.015). After adjustment for clinical parameters; carriers of two polymorphic IL1B rs1071676 C alleles had shorter survival (HR = 5.02; 95% CI = 1.92-13.16; p = 0.001); while carriers of at least one polymorphic CAT rs1001179 T allele had longer survival (HR = 0.68; 95% CI = 0.47-0.99; p = 0.046). Our data suggest that common genetic variants in the antioxidant and inflammatory pathways may modify ALS disease. Such genetic information could support the identification of patients that may be responsive to the immune or antioxidant system-based therapies.

Shaky hands are a part of motor neuron disease phenotype: clinical and electrophysiological study of 77 patients.

BACKGROUND: In the sharp contrast with the existing literature, we frequently observe minipolymyoclonus, tremor and pseudodystonic thumb posturing in patients with motor neuron disease. We conducted a clinical and electrophysiological study to describe phenomenology, prevalence and pathophysiology of involuntary movements in motor neuron disease. METHODS: We included 77 consecutive patients. Involuntary movements were assessed at rest and on action. Patients were videotaped. Arm muscle tone, power and deep tendon reflexes were evaluated. Accelerometry with electromyography was recorded in a subset of patients. RESULTS: Involuntary movements were observed in 68.9% of patients and could be separated into rest minipolymyoclonus, thumb tremor, pseudodystonic thumb posture, action minipolymyoclonus, and action tremor. One-third of patients reported negative impact of involuntary movements on hand use. Logistic regression showed that rest minipolymyoclonus and thumb tremor were more likely to occur in patients with more prominent distal muscle weakness and less spasticity. Similarly, action involuntary movements were more likely to appear in weaker patients. Patients with brisk tendon reflexes were more likely to display action tremor than action minipolymyoclonus. Action tremor was characterized by accelerometer and corresponding electromyography peak frequency, which decreased with mass loading, suggesting a mechanical-reflex tremor. CONCLUSIONS: Involuntary movements are common, but poorly recognized feature of motor neuron disease that may add to functional impairment. Results of our study suggest that involuntary movements are likely of peripheral origin, with a non-fused contraction of enlarged motor units being a common driving mechanism. Minipolymyoclonus appears if no synchronization of motor units occurs. When synchronization occurs via stretch reflex, mechanical-reflex tremor is generated.

Axonal Polyneuropathy in 2 Brothers With a Homozygous Missense Variant in the First Catalytic Domain of PCYT2.

BACKGROUND AND OBJECTIVES: To expand the phenotype and genotype associated with PCYT2-related disorder. METHODS: Exome sequencing data from a patient with molecularly undiagnosed complex spastic paraplegia and axonal motor and sensory polyneuropathy were analyzed. Clinical data and nerve conduction studies of the patient and his affected brother were collected, and their phenotype and genotype were compared with previously reported patients with PCYT2-related disorder. RESULTS: A novel homozygous missense variant in PCYT2 (NM_001184917.2) c.88T>G; p.(Cys30Gly) was identified. This variant is located in a highly conserved tyrosine kinase site and is predicted damaging by several variant annotation tools. Both patients reported here and the previously published patients share several phenotypic features, including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline. Axonal polyneuropathy, diagnosed in both brothers, was not previously reported. DISCUSSION: This family with a novel PCYT2 variant expands the clinical spectrum of PCYT2-related disorder to include axonal motor and sensory polyneuropathy and the genetic spectrum to include the variant located in the first catalytic domain, whereas all previously reported variants are located in the second catalytic domain. Further research is required to disentangle the underlying pathophysiologic mechanisms, leading to the complex phenotype of PCYT2-related disorder.

Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Cholinergic basal forebrain and hippocampal structure influence visuospatial memory in Parkinson's disease.

Visuospatial impairment in Parkinson's disease (PD) heralds the onset of a progressive dementia syndrome and might be associated with cholinergic dysfunction. It remains unclear however, whether degeneration of the cholinergic basal forebrain is directly related to cognitive decline, or whether relationships between this region and cognitive function are mediated by closely related brain structures such as those in the medial temporal lobe. To evaluate relationships between structure of the cholinergic basal forebrain, medial temporal lobe and cognition, 27 PD patients without dementia and 20 controls underwent neuropsychological assessment and MRI. Volumes of the cholinergic basal forebrain nuclei, the entorhinal cortex, the hippocampus and its subfields were measured. Regression models utilised basal forebrain and hippocampal volumetric measures to predict cognitive performance. In PD, visuospatial memory (but not verbal memory or executive function) was correlated with hippocampal volume, particularly CA2-3, and basal forebrain subregion Ch1-2, but not Ch4. In addition, hippocampal volume was correlated with Ch1-2 in PD. The relationship between Ch1-2 and visuospatial memory was mediated by CA2-3 integrity. There were no correlations between cognitive and volumetric measures in controls. Our data imply that the integrity of the cholinergic basal forebrain is associated with subregional hippocampal volume. Additionally, a relationship between visuospatial function and cholinergic nuclei does exist, but is fully mediated by variations in hippocampal structure. These findings are consistent with the recent hypothesis that forebrain cholinergic system degeneration results in cognitive deficits via cholinergic denervation, and subsequent structural degeneration, of its target regions.

Preserved cholinergic forebrain integrity reduces structural connectome vulnerability in mild cognitive impairment.

Neurodegeneration leads to redistribution of processing, which is reflected in a reorganisation of the structural connectome. This might affect its vulnerability to structural damage. Cortical acetylcholine allows favourable adaptation to pathology within the memory circuit. However, it remains unclear if it acts on a broader scale, affecting reconfiguration of whole-brain networks. To investigate the role of the cholinergic basal forebrain (CBFB) in strategic lesions, twenty patients with mild cognitive impairment (MCI) and twenty elderly controls underwent magnetic resonance imaging. Whole-brain tractograms were represented as network graphs. Lesions of individual nodes were simulated by removing a node and its connections from the graph. The impact of simulated lesions was quantified as the proportional change in global efficiency. Relationships between subregional CBFB volumes, global efficiency of intact connectomes and impacts of individual simulated lesions of network nodes were assessed. In MCI but not controls, larger CBFB volumes were associated with efficient network topology and reduced impact of hippocampal, thalamic and entorhinal lesions, indicating a protective effect against the global impact of simulated strategic lesions. This suggests that the cholinergic system shapes the configuration of the connectome, thereby reducing the impact of localised damage in MCI.

Improvements in the multidisciplinary care are beneficial for survival in amyotrophic lateral sclerosis (ALS): experience from a tertiary ALS center.

Objective: The Ljubljana ALS Centre, established in 2002, is the only tertiary center for amyotrophic lateral sclerosis (ALS) in Slovenia. The aim of our study was to evaluate the impact of therapeutic interventions and improvements in the multidisciplinary care on the survival of our patients.Methods: All patients diagnosed with ALS at our center during years 2003-2005 (early group) and 2011-2012 (late group) were included in this retrospective cohort study (n = 124). Kaplan-Meier survival analysis and multiple regression analysis with Cox proportional hazards model were performed to compare survival and to evaluate the differences between the two cohorts.Results: Median survival from the time of diagnosis was 13.0 (95% CI 10.2-15.8) months in the early group and 21.8 (95% CI 17.2-26.4) months in the late group (p = 0.005). In the Cox proportional hazards analysis, the late group of patients was associated with better survival independently of all other prognostic factors (hazard ratio (HR)=0.51, 95% CI = 0.32-0.81, p = 0.004). Survival was also associated with patients' age, use of noninvasive ventilation (NIV) and gastrostomy. The model fit significantly improved when the interaction between the NIV use and the observed time period was added to the model (HR = 0.34, 95% CI = 0.12-0.96, p = 0.041).Conclusions: Our findings suggest that improvements in the multidisciplinary care were beneficial for survival of our patients with ALS. The survival benefit in the late group of our patients could be partially explained by the improvements in the NIV use at our center.

Continuous Dynamic Mapping of the Corticospinal Tract in Motor Eloquent Tumor Surgery: Our Experience and Evaluation of the Method.

OBJECTIVE: The aim of this article is to present our experience with continuous dynamic mapping (CDM) of the corticospinal tract (CST) when removing tumors in motor eloquent regions. METHODS: We studied 44 patients with a brain tumor adjacent to the CST where CDM was used. The mapping probe was integrated at the tip of the suction device. Thresholds for eliciting MEPs were recorded. In all patients, along with CDM, MEPs to direct cortical stimulation were also monitored throughout the operation. Motor function was assessed preoperatively, after the procedure and on discharge. RESULTS: In the series, there were 37 patients with gliomas, six with brain metastasis, and one with cavernoma. The threshold to elicit MEPs in CDM was >20 mA in 17 cases, 16-20 mA in six cases, 11-15 mA in six cases, 6-10 mA in nine cases and 2-5 mA in six cases. MEPs to direct cortical stimulation were preserved in all patients. In three cases a new temporary motor deficit was noted. No new permanent motor deficit occurred. Gross total resection was reached in 57% of cases. CONCLUSIONS: From our experience, the combined use of CDM and MEPs to direct cortical stimulation improves the safety of surgery in the proximity of the CST, and at the same time offers the possibility of higher rates of gross total resection.

IMG-01 The spectrum of involuntary movements in patients with motor neuron disease: a cross-sectional study.

Background: We have commonly observed involuntary jerks and tremor in patients with motor neuron disease (MND), even though these features are not considered typical for the disease.Objectives: We conducted prospective clinical and electrophysiological study to explore the prevalence, phenomenology and pathophysiology of involuntary movements in MND.Methods: Seventy-four consecutive patients were clinically examined and video-recorded. Based on regularity and distribution, movements observed at rest position were classified as minipolymyoclonus (MPMC) or rest thumb tremor (RTT) and movements present during action as action MPMC or action tremor. In 11 patients with tremor, accelerometry was recorded at (a) rest position, (b) with arms outstretched (postural condition) and (c) at postural condition with 500 g mass attached to the hand.Results: Involuntary movements were present in 54 patients (73%). Rest MPMC was present in 26 patients (35%), RTT in 22 patients (31%), action MPMC in 22 patients (30%) and action tremor in 20 patients (27%), with some overlap. Sixteen patients (22%) reported negative impact of involuntary movements on their ability to use hands. Regression model showed that lower distal muscle power and less prominent upper motor neuron involvement significantly increased the odds of MND patient having involuntary movements. Sex, age and disease duration did not significantly predict the occurrence of involuntary movements. At rest, tremor frequency ranged from 5.2 to 8.2 Hz, at postural position from 4.9 Hz to 7.6 Hz and during postural position with mass attached from 3.6 Hz to 7.6 Hz. On the group level, tremor peak frequency statistically significantly decreased from 6.1 Hz to 5 Hz without versus with loading.Discussion and conclusions: Involuntary movements are very common yet largely overlooked feature of MND that may also have negative impact on patient's functional abilities. Lower distal muscle power increases and the presence of upper motor neuron signs decreases the probability of involuntary movements. Together with finding of decrease in tremor frequency with mass loading, these results suggest that generation of involuntary movements is of peripheral origin.

Circular RNAs as Potential Blood Biomarkers in Amyotrophic Lateral Sclerosis.

Circular RNAs (circRNAs) are emerging as a novel, yet powerful player in many human diseases. They are involved in several cellular processes and are becoming a noteworthy type of biomarkers. Among other functions, circRNAs can serve as RNA sponges or as scaffolds for RNA-binding proteins. Here, we investigated a microarray expression profile of circRNAs in leukocyte samples from ALS patients and age- and sex-matched healthy controls to identify differentially expressed circRNAs. We selected 10 of them for a qPCR validation of expression on a larger set of samples, identification of their associations with clinical parameters, and evaluation of their diagnostic potential. In total, expression of 7/10 circRNAs was significant in a larger cohort of ALS patients, compared with age- and sex-matched healthy controls. Three of them (hsa_circ_0023919, hsa_circ_0063411, and hsa_circ_0088036) showed the same regulation as in microarray results. These three circRNAs also had AUC > 0.95, and sensitivity and specificity for the optimal threshold point > 90%, showing their potential for using them as diagnostic biomarkers.

Differential Expression of Several miRNAs and the Host Genes AATK and DNM2 in Leukocytes of Sporadic ALS Patients.

Genetic studies have managed to explain many cases of familial amyotrophic lateral sclerosis (ALS) through mutations in several genes. However, the cause of a majority of sporadic cases remains unknown. Recently, epigenetics, especially miRNA studies, show some promising aspects. We aimed to evaluate the differential expression of 10 miRNAs, including miR-9, miR-338, miR-638, miR-663a, miR-124a, miR-143, miR-451a, miR-132, miR-206, and let-7b, for which some connection to ALS was shown previously in ALS culture cells, animal models or patients, and in three miRNA host genes, including C1orf61 (miR-9), AATK (miR-338), and DNM2 (miR-638), in leukocyte samples of 84 patients with sporadic ALS. We observed significant aberrant dysregulation across our patient cohort for miR-124a, miR-206, miR-9, let-7b, and miR-638. Since we did not use neurological controls we cannot rule out that the revealed differences in expression of investigated miRNAs are specific for ALS. Nevertheless, the group of these five miRNAs is worth of additional research in leukocytes of larger cohorts from different populations in order to verify their potential association to ALS disease. We also detected a significant up-regulation of the AAKT gene and down-regulation of the DNM2 gene, and thus, for the first time, we connected these with sporadic ALS cases. These findings open up new research toward miRNAs as diagnostic biomarkers and epigenetic processes involved in ALS. The detected significant deregulation of AAKT and DNM2 in sporadic ALS also represents an interesting finding. The DNM2 gene was previously found to be mutated in Charcot-Marie-Tooth neuropathy-type CMT2M and centronuclear myopathy (CNM). In addition, as recent studies connected AATK and frontotemporal dementia (FTD) and DNM2 and hereditary spastic paraplegia (HSP), these two genes together with our results genetically connect, at least in part, five diseases, including FTD, HSP, Charcot-Marie-Tooth (type CMT2M), CNM, and ALS, thus opening future research toward a better understanding of the cell biology involved in these partly overlapping pathologies.

Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls.

Amyotrophic lateral sclerosis is a late-onset disorder primarily affecting motor neurons and leading to progressive and lethal skeletal muscle atrophy. Small RNAs, including microRNAs (miRNAs), can serve as important regulators of gene expression and can act both globally and in a tissue-/cell-type-specific manner. In muscle, miRNAs called myomiRs govern important processes and are deregulated in various disorders. Several myomiRs have shown promise for therapeutic use in cellular and animal models of ALS; however, the exact miRNA species differentially expressed in muscle tissue of ALS patients remain unknown. Following small RNA-Seq, we compared the expression of small RNAs in muscle tissue of ALS patients and healthy age-matched controls. The identified snoRNAs, mtRNAs and other small RNAs provide possible molecular links between insulin signaling and ALS. Furthermore, the identified miRNAs are predicted to target proteins that are involved in both normal processes and various muscle disorders and indicate muscle tissue is undergoing active reinnervation/compensatory attempts thus providing targets for further research and therapy development in ALS.

Electrophysiological Studies to Detect Peripheral Neuropathy in Children Treated With Vincristine.

Patients treated with vincristine predictably develop peripheral neuropathy. The aim of our study was to investigate the pattern of vincristine-induced neuropathy in children by nerve conduction studies and somatosensory-evoked potentials (SSEPs). We included data from 39 children who received vincristine for various pediatric malignancies, and we performed initial and follow-up (after a minimum of 4 doses of vincristine 1.5 mg/m) conduction studies in 27 patients and SSEPs studies in 34 patients. On follow-up the most prevalent symptoms were paresthesias (44%) and constipation (22%), and the most common neurological sign was impaired myotatic reflexes (89%). Performing nerve conduction studies we found that significant reductions were measured for distal amplitudes, distal latencies were prolonged, and conduction velocities were relatively preserved. The most pronounced differences in amplitudes and distal latencies were measured in the peroneal nerves. Changes of SSEPs studies were subtle. Vincristine-induced neuropathy presents with primary axonal involvement and is more pronounced on motor neurons. We found a trend between higher age and higher dose and the degree of neuropathy in our group of patients.

Beyond aphasia: Altered EEG connectivity in Broca's patients during working memory task.

Broca's region and adjacent cortex presumably take part in working memory (WM) processes. Electrophysiologically, these processes are reflected in synchronized oscillations. We present the first study exploring the effects of a stroke causing Broca's aphasia on these processes and specifically on synchronized functional WM networks. We used high-density EEG and coherence analysis to map WM networks in ten Broca's patients and ten healthy controls during verbal WM task. Our results demonstrate that a stroke resulting in Broca's aphasia also alters two distinct WM networks. These theta and gamma functional networks likely reflect the executive and the phonological processes, respectively. The striking imbalance between task-related theta synchronization and desynchronization in Broca's patients might represent a disrupted balance between task-positive and WM-irrelevant functional networks. There is complete disintegration of left fronto-centroparietal gamma network in Broca's patients, which could reflect the damaged phonological loop.

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

The electrophysiological correlates of the working memory subcomponents: evidence from high-density EEG and coherence analysis.

Synchronization between prefrontal (executive) and posterior (association) cortices seems a plausible mechanism for temporary maintenance of information. However, while EEG studies reported involvement of (pre)frontal midline structures in synchronization, functional neuroimaging elucidated the importance of lateral prefrontal cortex (PFC) in working memory (WM). Verbal and spatial WM rely on lateralized subsystems (phonological loop and visuospatial sketchpad, respectively), yet only trends for hemispheric dissociation of networks supporting rehearsal of verbal and spatial information were identified by EEG. As oscillatory activity is WM load dependent, we applied an individually tailored submaximal load for verbal (V) and spatial (S) task to enhance synchronization in the relevant functional networks. To map these networks, we used high-density EEG and coherence analysis. Our results imply that the synchronized activity is limited to highly specialized areas that correspond well with the areas identified by functional neuroimaging. In both V and S task, two independent networks of theta synchronization involving dorsolateral PFC of each hemisphere were revealed. In V task, left prefrontal and left parietal areas were functionally coupled in gamma frequencies. Theta synchronization thus provides the necessary interface for storage and manipulation of information, while left-lateralized gamma synchronization could represent the EEG correlate of the phonological loop.