Local field potential activity dynamics in response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Local field potentials (LFPs) may afford insight into the mechanisms of action of deep brain stimulation (DBS) and potential feedback signals for adaptive DBS. In Parkinson's disease (PD) DBS of the subthalamic nucleus (STN) suppresses spontaneous activity in the beta band and drives evoked resonant neural activity (ERNA). Here, we investigate how STN LFP activities change over time following the onset and offset of DBS. To this end we recorded LFPs from the STN in 14 PD patients during long (mean: 181.2 s) and short (14.2 s) blocks of continuous stimulation at 130 Hz. LFP activities were evaluated in the temporal and spectral domains. During long stimulation blocks, the frequency and amplitude of the ERNA decreased before reaching a steady state after ~70 s. Maximal ERNA amplitudes diminished over repeated stimulation blocks. Upon DBS cessation, the ERNA was revealed as an under-damped oscillation, and was more marked and lasted longer after short duration stimulation blocks. In contrast, activity in the beta band suppressed within 0.5 s of continuous DBS onset and drifted less over time. Spontaneous activity was also suppressed in the low gamma band, suggesting that the effects of high frequency stimulation on spontaneous oscillations may not be selective for pathological beta activity. High frequency oscillations were present in only six STN recordings before stimulation onset and their frequency was depressed by stimulation. The different dynamics of the ERNA and beta activity with stimulation imply different DBS mechanisms and may impact how these activities may be used in adaptive feedback.

Discrimination of physiological tremor from pathological tremor using accelerometer and surface EMG signals.

BACKGROUND AND OBJECTIVE: Although careful clinical examination and medical history are the most important steps towards a diagnostic separation between different tremors, the electro-physiological analysis of the tremor using accelerometry and electromyography (EMG) of the affected limbs are promising tools. METHODS: A soft-decision wavelet-based decomposition technique is applied with 8 decomposition stages to estimate the power spectral density of accelerometer and surface EMG signals (sEMG) sampled at 800 Hz. A discrimination factor between physiological tremor (PH) and pathological tremor, namely, essential tremor (ET) and the tremor caused by Parkinson's disease (PD), is obtained by summing the power entropy in band 6 (B6: 7.8125-9.375 Hz) and band 11 (B11: 15.625-17.1875 Hz). RESULTS: A discrimination accuracy of 93.87% is obtained between the PH group and the ET & PD group using a voting between three results obtained from the accelerometer signal and two sEMG signals. CONCLUSION: Biomedical signal processing techniques based on high resolution wavelet spectral analysis of accelerometer and sEMG signals are implemented to efficiently perform classification between physiological tremor and pathological tremor.

Hypercalcemia as an Early Finding of Opportunistic Fungal Pneumonia in Renal Transplantation: A Case Series Report.

BACKGROUND: Pneumonia caused by opportunistic fungi is a serious complication in immunocompromised patients. Hypercalcemia has been described in renal transplantation associated with Pneumocystis jirovecii (PJP) or Histoplasma capsulatum (HCP) pneumonia. METHODS: We describe 5 patients who underwent kidney transplant between 2014 and 2019 and developed hypercalcemia before the diagnosis of pulmonary fungal infection: 4 patients with PJP and 1 with HCP. We assessed calcium metabolism and kidney function by total and ionized calcium, phosphorus, intact parathormone (iPTH), 25-OH vitamin D, 1,25(OH)2 vitamin D, and serum creatinine levels. RESULTS: Mean albumin-corrected calcium and ionized calcium were 12.56 mg/dL (range, 10.8-13.8 mg/dL) and 1.57 mmol/L (range, 1.43-1.69 mmol/L). Patients were normocalcemic, at 10.12 mg/dL (range, 9.6-10.5 mg/dL), before diagnosis and resolved hypercalcemia after antifungal treatment, at 8.86 mg/dL (range, 8.0-9.5 mg/dL). All patients had low or normal iPTH values, at 29.1 pg/mL (range, <3-44 pg/mL), with higher PTH levels 3 months before diagnosis and after treatment, at 147.3 pg/mL (range, 28.1-479 pg/mL) and 117.5 pg/mL (range, 18.2-245 pg/mL), respectively. The mean value for 25-OH vitamin D was 30.8 ng/mL (range, 14.6-62.8 ng/mL). This supports a PTH-independent mechanism, and we postulated an extrarenal production of 1,25(OH)2 vitamin D. CONCLUSION: In kidney transplant patients, hypercalcemia independent of PTH and refractory to treatment should alert for the possibility of opportunistic fungal pneumonia.

Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi-allelic mutations in NKX6-2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6-2 mutations in a multicentre setting is described. Then, all reported NKX6-2 mutations and those identified in this study were combined and an in-depth analysis of NKX6-2-related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6-2 were identified, evidencing a high NKX6-2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6-2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6-2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Evidence for a white matter lesion size threshold to support the diagnosis of relapsing remitting multiple sclerosis.

BACKGROUND: The number of white matter lesions (WML) in brain MRI is the most established paraclinical tool to support the diagnosis of multiple sclerosis (MS) and to monitor its course. Diagnostic criteria have stipulated a minimum detectable diameter of 3 mm per WML, although this threshold is not evidence-based. We aimed to provide a rationale for a WML size threshold for three-dimensional MRI sequences at 3 T by comparing patients with relapsing-remitting MS (RRMS) to control subjects (CS). METHODS: We analyzed MR images from two cohorts, obtained at scanners from two different vendors, each comprising patients with RRMS and CS. Both cohorts were examined with FLAIR and T1w sequences. In total, 232 patients with RRMS (Expanded Disability Status Scale: mean = 1.6 ± 1.2; age: mean = 36 ± 10) as well as 116 age- and sex-matched CS were studied. We calculated odds ratios across WML volumes. The WML size threshold, which discriminated best between patients and CS, was estimated with receiver operating characteristic curve analysis. RESULTS: In both cohorts, odds ratios increased continuously with increasing WML volumes, and discriminative power was highest at a WML size threshold corresponding to a diameter of about 3 mm. CONCLUSION: The stipulated WML size threshold of 3 mm in diameter for the diagnostic criteria of MS seems a reasonable choice for three-dimensional MRI sequences at 3 T.

Transcranial magnetic stimulation in migraine prophylaxis.

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation method used worldwide to make causality-based inferences about brain-behavior interactions, assess cortical reactivity, and map functionally relevant brain regions inducing a controlled current pulse in a specific cortical area. Clinical applications of TMS have shown promising results in the treatment of a vast number of psychiatric and neurological conditions such as headache disorders - migraine being one of the most encountered. In patients with migraine, the pharmacologic therapy is divided in urgent/ abortive treatment of the attack and prophylactic one. As first-line drugs simple analgesics and non-steroidal inflammatory are preferred. Nevertheless, many individuals continue to have attacks refractory to various prophylactic and/or abortive therapies, while others are at high risk of developing medication overuse headache. Among non-pharmacologic therapies TMS has been broadly studied as a preventive migraine treatment with good outcome results. Abbreviations: DLPFC - Dorsolateral prefrontal cortex, FDA - United States Food and Drug Administration, HF-TMS - High frequency transcranial magnetic stimulation, TMS - Transcranial magnetic stimulation, rTMS - Repetitive transcranial magnetic stimulation.

Single-Center Long-Term Follow-Up of Kidney Donors in Argentina (Hospital Italiano de Buenos Aires).

INTRODUCTION: Living kidney donor (LKD) transplantation is increasing due to organ shortage. Clinical studies have shown that the risk of developing end-stage renal disease (ESRD) in donors is similar to that in the general population. Our goal was to evaluate postdonation renal outcomes assessed by glomerular filtration rate (GFR), proteinuria, and blood pressure. METHODS: A total of 210 LKD transplants were performed at Hospital Italiano de Buenos Aires between 2000 and 2014. Postdonation outcomes were analyzed in 109 donors. GFR was assessed by 24-hour creatinine clearance (as 24-hour ClCr) and estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Additionally, we correlated the predonation renal functional reserve (RFR) with postdonation GFR. Donor results were compared to the expected GFR (adjusted to age and single kidney). Other renal outcome indicators measured were albuminuria and blood pressure, and they were compared (predonation and postdonation) using univariate analysis. RESULTS: A total of 109 patients were followed up for 47 ± 34 months (range, 12-168): 70% were female, age at donation was 48.58 years (range, 25-70), and predonation serum creatinine was 0.85 ± 0.17 mg/dL. Postnephrectomy GFR (24-hour ClCr) was significantly lower compared to predonation GFR (105.38 ± 21.78 mL/min/1.73 m2 vs 90.14 ± 17.78 mL/min/1.73 m2). However, postdonation GFR was not significantly different compared to the expected GFR. No differences were found for blood pressure or albuminuria. Age >50 and an RFR (<20%) was associated with a lower GFR. CONCLUSIONS: In this population of LKD, renal outcome (24-hour CrCl, albuminuria, and blood pressure) was within the expected outcome for healthy individuals after uninephrectomy.

[Pathophysiology of tremor]. / Pathophysiologie des Tremors.

Tremor is clinically defined as a rhythmic, oscillating movement of parts of the body, which functionally leads to impairment of the coordination and execution of targeted movements. It can be a symptom of a primary disease, such as resting tremor in Parkinson's disease or occur as an independent disease, such as essential or orthostatic tremor. For the development of tremor, cerebral components as well as mechanisms at the spinal and muscular level play an important role. This review presents the results of new imaging and electrophysiological studies that have led to important advances in our understanding of the pathophysiology of tremor. We discuss pathophysiological models for the development of resting tremor in Parkinson's disease, essential and orthostatic tremor. We describe recent developments starting from the classical generator model, with an onset of pathological oscillations in distinct cerebral regions, to a network perspective in which tremor arises and spreads through existing anatomical or newly emerged pathological brain networks. In particular translational approaches are presented and discussed. These could serve in the future as a basis for the development of new therapeutic strategies.

Establishing and validating a new source analysis method using phase.

Electroencephalogram (EEG) measures the brain oscillatory activity non-invasively. The localization of deep brain generators of the electric fields is essential for understanding neuronal function in healthy humans and for damasking specific regions that cause abnormal activity in patients with neurological disorders. The aim of this study was to test whether the phase estimation from scalp data can be reliably used to identify the number of dipoles in source analyses. The steps performed included: i) modeling different phasic oscillatory signals using auto-regressive processes at a particular frequency, ii) simulation of two different noises, namely white and colored noise, having different signal-to-noise ratios, iii) simulation of dipoles at different areas in the brain and iv) estimation of the number of dipoles by calculating the phase differences of the simulated signals. Moreover we applied this method of source analysis on real data from temporal lobe epilepsy (TLE) patients. The analytical framework was successful in identifying the sources and their orientations in the simulated data and identified the epileptogenic area in the studied patients which was confirmed by pathological studies after TLE surgery.

Comparison Between CKD-EPI Creatinine and MDRD Equations to Estimate Glomerular Filtration Rate in Kidney Transplant Patients.

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) equation is widely used to estimate glomerular filtration rate (eGFR) in kidney transplant (KT) patients. The novel Chronic Kidney Disease-Epidemiology Collaboration equation (CKD-EPI) could improve accuracy of GFR estimation. Our aim was to compare both equations for staging of CKD in KT patients. METHODS: In a cohort of KT patients, correlation of eGFR according to MDRD and CKD-EPI with 24-hour creatinine clearance (24h-CrCl) was evaluated. Concordance between both equations for CKD staging was performed. MDRD was used for initial CKD staging. The mean difference of GFR between 24h-CrCl and each equation was calculated and Bland-Altman analysis applied. RESULTS: A cohort of 463 KT patients were studied: 67% female, overall average age 46 ± 14 years, 41% living donor, mean time of transplantation 71 months (3-95), and mean serum creatinine 1.68 ± 1.03 mg/dL. For the whole cohort (all CKD stages), eGFR by CKD-EPI was 5.33 mL/min/1.73 m(2) higher than by MDRD (P < .01). For CKD stages 1, 2, and 3A, the mean eGFR differences (CKD-EPI - MDRD) were 13.98 ± 3.27, 8.2 ± 1.98, and 5.34 ± 1.32 mL/min/1,73 m(2), respectively. The percentage of patients with eGFR <60 mL/min/1.73 m(2) decreased from 63.8% according to MDRD to 53.9% with the use of CKD-EPI. In women and patients ≤65 years old, eGFR by CKD-EPI was 5.98 and 5.81 mL/min/1.73 m(2) higher, respectively, than by MDRD (P < .01). CONCLUSIONS: The novel CKD-EPI reduces the number of patients with eGFR <60 mL/min/1.73 m(2) and consequently assigns lower CKD stages to our KT population.

Functional connectivity analysis using whole brain and regional network metrics in MS patients.

In the present study we investigated brain network connectivity differences between patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HC) as derived from functional resonance magnetic imaging (fMRI) using graph theory. Resting state fMRI data of 18 RRMS patients (12 female, mean age ± SD: 42 ± 12.06 years) and 25 HC (8 female, 29.2 ± 5.38 years) were analyzed. In order to obtain information of differences in entire brain network, we focused on both, local and global network connectivity parameters. And the regional connectivity differences were assessed using regional network parameters. RRMS patients presented a significant increase of modularity in comparison to HC, pointing towards a network structure with densely interconnected nodes within one module, while the number of connections with other modules outside decreases. This higher decomposable network favours cost-efficient local information processing and promotes long-range disconnection. In addition, at the regional anatomical level, the network parameters clustering coefficient and local efficiency were increased in the insula, the superior parietal gyrus and the temporal pole. Our study indicates that modularity as derived from fMRI can be seen as a characteristic connectivity feature that is increased in MS patients compared to HC. Furthermore, specific anatomical regions linked to perception, motor function and cognition were mainly involved in the enhanced local information processing.

Network effects and pathways in Deep brain stimulation in Parkinson's disease.

Deep brain stimulation of subthalamic nucleus (STN-DBS) became a standard therapeutic option in Parkinson's disease (PD), even though the underlying modulated network of STN-DBS is still poorly described. Probabilistic tractography and connectivity analysis as derived from diffusion tensor imaging (DTI) were performed together with modelling of implanted electrode positions and linked postoperative clinical outcome. Fifteen patients with idiopathic PD without dementia were selected for DBS treatment. After pre-processing, probabilistic tractography was run from cortical and subcortical seeds of the hypothesized network to targets represented by the positions of the active DBS contacts. The performed analysis showed that the projections of the stimulation site to supplementary motor area (SMA) and primary motor cortex (M1) are mainly involved in the network effects of STN-DBS. An involvement of the "hyperdirected pathway" and a clear delimitation of the cortico-spinal tract were demonstrated. This study shows the effects of STN-DBS in PD distinctly rely on the network connections of the stimulated region to M1 and SMA, motor and premotor regions.

Testing the effects of pre-processing on voxel based morphometry analysis.

Voxel based morphometry (VBM) is an automated analysis technique which allows voxel-wise comparison of mainly grey-matter volumes between two magnetic resonance images (MRI). Two main analysis processes in VBM are possible. One is cross-sectional data analysis, where one group is compared with another to depict see the regions in the brain, which show changes in their grey-matter volume. Second is longitudinal data analysis, where MRIs, taken at different time points, are compared to see the regions in the brain that show changes in their grey matter volume for one time point with respect to another time point. Both types of analyses require pre-processing steps before performing the statistical analysis. In this study, we examined grey matter differences for patients with blepharospasmus (BFS) before and after treatment, at two different time points. The main evidence base therapy for this condition is the "botulinum toxin" injection in the respective muscles. The main aim of this study was to look at the effects of different pre-processing steps, namely, normalization and smoothing on the results of the longitudinal data analysis. A second aim was to analyze structural grey-matter differences before and after the treatment. Our results showed that the DARTEL normalization and the lower width for smoothing as preprocessing steps delivered pathophysiological plausible results. The longitudinal analysis revealed significant temporal differences after the injection of the botulinum toxin injection mainly in patients with BFS.

Testing different ICA algorithms and connectivity analyses on MS patients.

Multiple sclerosis (MS) is a progressive neurological disorder that affects the central nervous system. Functional magnetic resonance imaging (fMRI) has been employed to track the course and disease progression in patients with MS. The two main aims of this study were to apply in a data-driven approach the independent component analysis (ICA) in the spatial domain to depict the active sources and to look at the effective connectivity between the identified spatial sources. Several ICA algorithms have been proposed for fMRI data analysis. In this study, we aimed to test two well characterized algorithms, namely, the fast ICA and the complex infomax algorithms, followed by two effective connectivity algorithms, namely, Granger causality (GC) and generalized partial directed coherence (GPDC), to illustrate the connections between the spatial sources in patients with MS. The results obtained from the ICA analyses showed the involvement of the default mode network sources. The connectivity analyses depicted significant changes between the two applied algorithms. The significance of this study was to demonstrate the robustness of the analyzed algorithms in patients with MS and to validate them before applying them on larger datasets of patients with MS.

The cortical and sub-cortical network of sensory evoked response in healthy subjects.

The aim of this study was to find the cortical and sub-cortical network responsible for the sensory evoked coherence in healthy subjects during electrical stimulation of right median nerve at wrist. The multitaper method was used to estimate the power and coherence spectrum followed by the source analysis method dynamic imaging of coherent sources (DICS) to find the highest coherent source for the basic frequency 3 Hz and the complete cortical and sub-cortical network responsible for the sensory evoked coherence in healthy subjects. The highest coherent source for the basic frequency was in the posterior parietal cortex for all the subjects. The cortical and sub-cortical network comprised of the primary sensory motor cortex (SI), secondary sensory motor cortex (SII), frontal cortex and medial pulvinar nucleus in the thalamus. The cortical and sub-cortical network responsible for the sensory evoked coherence was found successfully with a 64-channel EEG system. The sensory evoked coherence is involved with a thalamo-cortical network in healthy subjects.

Proteinuria/creatininuria index and its correlation with the 24-hour proteinuria in renal transplanted patients.

BACKGROUND: Proteinuria (P) is a early sign of inflammation and renal damage. It has an important role in the detection, diagnosis, and monitoring of renal disease in transplanted patients. The aim of this study was to examine the correlation between random urinary proteinuria/creatininuria index (P/CI) and 24-hour total protein excretion among stable renal transplant patients. MATERIALS AND METHODS: We obtained 1511 samples of 24-hour protein excretion (24-hr P) with corresponding P/CI were obtained from 197 adult patients beyond 6 months post-transplantation between 2009 and 2011. The population was divided into 2 groups: One to obtain a population of justification (755) and another, of validation (755). A scatter graft yielded was obtained by Pearson's coefficient of correlation. A "receiver operater characteristic curve" analysis was carried out to evaluate the sensitivity and specifity of PCI and 24hr-P, showing a cutoff of 0.15 for PCI. RESULTS: The PCI and 24 hr P Pearson's correlation was significant (r = 0.89; P = .0001). The sensitivities of the P/CI for the justification and the validation samples were 97% and 94%, respectively; the a cutoff was 0.15. Their negative predictive values for P/CI were 92% and 84% respectively (cutoff, 0.15). The specificity was below 50% in both groups. CONCLUSIONS: We observed a significant correlation between P/CI and 24 hr P. The sensitivity was slightly higher than the specificity (50%) but the negative predictive value was >92%. The use of P/CI seemed to be adequate for screening of protein excretion during renal transplant recipient follow-up.

A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee.

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

Locating the STN-DBS electrodes and resolving their subsequent networks using coherent source analysis on EEG.

The deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most effective surgical therapy for Parkinson's disease (PD). The first aim of the study was to locate the STN-DBS electrode by applying source analysis on EEG. Secondly, to identify tremor related areas which are associated with the STN. The Dynamic imaging of coherent sources (DICS) was used to find the coherent sources in the brain. The capability of the source analysis to detect deep sources like STN in the brain using EEG data was tested with two model dipole simulations. The simulations were concentrated on two aspects, the angle of the dipole orientation and the disturbance of the cortical areas on locating subcortical regions. In all the DBS treated Parkinsonian tremor patients the power spectrum showed a clear peak at the stimulated frequency and followed by there harmonics. The DBS stimulated frequency constituted a network of primary sensory motor cortex, supplementary motor area, prefrontal cortex, diencephalon, cerebellum and brainstem. Thus the STN was located in the region of the diencephalon. The resolved network may give better understanding to the pathophysiology of the effected tremor network in PD patients with STN-DBS.

A novel DCC mutation and genetic heterogeneity in congenital mirror movements.

OBJECTIVE: DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the body's midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. METHODS: We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. RESULTS: The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. CONCLUSION: DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity.