Simultaneous invasive and non-invasive recordings in humans: a novel Rosetta stone for deciphering brain activity.

Simultaneous noninvasive and invasive electrophysiological recordings provide a unique opportunity to achieve a comprehensive understanding of human brain activity, much like a Rosetta stone for human neuroscience. In this review we focus on the increasingly-used powerful combination of intracranial electroencephalography (iEEG) with scalp electroencephalography (EEG) or magnetoencephalography (MEG). We first provide practical insight on how to achieve these technically challenging recordings. We then provide examples from clinical research on how simultaneous recordings are advancing our understanding of epilepsy. This is followed by the illustration of how human neuroscience and methodological advances could benefit from these simultaneous recordings. We conclude with a call for open data sharing and collaboration, while ensuring neuroethical approaches and argue that only with a true collaborative approach the promises of simultaneous recordings will be fulfilled.

SEEG electrode shaft affects amplitude and latency of potentials evoked with single pulse electrical stimulation.

BACKGROUND: Long and thin shaft electrodes are implanted intracerebrally for stereoelectroencephalography (SEEG) in patients with pharmacoresistant focal epilepsies. Two adjacent contacts of one of such electrodes can deliver a train of single pulse electrical stimulations (SPES), and evoked potentials (EPs) are recorded on other contacts. In this study we assess if stimulating and recording on the same shaft, as opposed to different shafts, has an impact on common EP features. NEW METHOD: We leverage the large volume of SEEG data gathered in the F-TRACT database and analyze data from nearly one thousand SEEG implantations in order to verify whether stimulation and recording from the same shaft influence the EP pattern. RESULTS: We found that when the stimulated and the recording contacts were located on the same shaft, the mean and median amplitudes of an EP are greater, and its mean and median latencies are smaller than when the contacts were located on different shafts. This effect is small (Cohen's d ∼ 0.1), but robust (p-value < 10-3) across the SEEG database. COMPARISON WITH EXISTING METHOD(S): Our study is the first one to address this question. Due to the choice of commonly used EP features, our method is congruent with other studies. CONCLUSIONS: The magnitude of the reported effect does not obligate all standard analyses to correct for it, unless they aim at high precision. The source of the effect is not clear. Manufacturers of SEEG electrodes could examine it and potentially minimize the effect in their future products.

Comparison of hemodynamic response functions obtained from resting-state functional MRI and invasive electrophysiological recordings in rats.

Resting-state functional MRI (rs-fMRI) is a popular technology that has enriched our understanding of brain and spinal cord functioning, including how different regions communicate (connectivity). But fMRI is an indirect measure of neural activity capturing blood hemodynamics. The hemodynamic response function (HRF) interfaces between the unmeasured neural activity and measured fMRI time series. The HRF is variable across brain regions and individuals, and is modulated by non-neural factors. Ignoring this HRF variability causes errors in FC estimates. Hence, it is crucial to reliably estimate the HRF from rs-fMRI data. Robust techniques have emerged to estimate the HRF from fMRI time series. Although such techniques have been validated non-invasively using simulated and empirical fMRI data, thorough invasive validation using simultaneous electrophysiological recordings, the gold standard, has been elusive. This report addresses this gap in the literature by comparing HRFs derived from invasive intracranial electroencephalogram recordings with HRFs estimated from simultaneously acquired fMRI data in six epileptic rats. We found that the HRF shape parameters (HRF amplitude, latency and width) were not significantly different (p>0.05) between ground truth and estimated HRFs. In the single pathological region, the HRF width was marginally significantly different (p=0.03). Our study provides preliminary invasive validation for the efficacy of the HRF estimation technique in reliably estimating the HRF non-invasively from rs-fMRI data directly. This has a notable impact on rs-fMRI connectivity studies, and we recommend that HRF deconvolution be performed to minimize HRF variability and improve connectivity estimates.

Evoked responses to single pulse electrical stimulation reveal impaired striatal excitability in a rat model of Parkinson's disease.

BACKGROUND: Sensorimotor beta oscillations are increased in Parkinson's disease (PD) due to the alteration of dopaminergic transmission. This electrophysiological read-out is reported both in patients and in animal models such as the 6-OHDA rat model obtained with unilateral nigral injection of 6-hydroxydopamine (6-OHDA). Current treatments, based on dopaminergic replacement, transiently normalize this pathological beta activity and improve patients' quality of life. OBJECTIVES: We wanted to assess in vivo whether the abnormal beta oscillations can be correlated with impaired striatal or cortical excitability of the sensorimotor system and modulated by the pharmacological manipulation of the dopaminergic system. METHODS: In the unilateral 6-OHDA rat model and control animals, we used intra-striatal and intra-cortical single-pulse electrical stimulation (SPES) and concurrent local field potentials (LFP) recordings. In the two groups, we quantified basal cortico-striatal excitability from time-resolved spectral analyses of LFP evoked responses induced remotely by intracerebral stimulations. The temporal dependance of cortico-striatal excitability to dopaminergic transmission was further tested using electrophysiological recordings combined with levodopa injection. RESULTS: LFP evoked responses after striatal stimulation showed a transient reduction of power in a large time-frequency domain in the 6-OHDA group compared to the sham group. This result was specific to the striatum, as no significant difference was observed in cortical LFP evoked responses between the two groups. This impaired striatal excitability in the 6-OHDA group was observed in the striatum at least during the first 3 months after the initial lesion. In addition, the striatum responses to SPES during a levodopa challenge showed a transient potentiation of the decrease of responsiveness in frequencies below 40 Hz. CONCLUSION: The spectral properties of striatal responses to SPES show high sensitivity to dopaminergic transmission in the unilateral 6-OHDA rat model. We thus propose that this approach could be used in preclinical models as a time-resolved biomarker of impaired dopaminergic transmission capable of monitoring progressive neurodegeneration and/or challenges to drug intake.

Altered parabrachial nucleus nociceptive processing may underlie central pain in Parkinson's disease.

The presence of central neuropathic pain in Parkinson's disease suggests that the brain circuits that allow us to process pain could be dysfunctional in the disorder. However, there is to date no clear pathophysiological mechanism to explain these symptoms. In this work, we present evidence that the dysfunction of the subthalamic nucleus and/or substantia nigra pars reticulata may impact nociceptive processing in the parabrachial nucleus (PBN), a low level primary nociceptive structure in the brainstem, and induce a cellular and molecular neuro-adaptation in this structure. In rat models of Parkinson's disease with a partial dopaminergic lesion in the substantia nigra compacta, we found that the substantia nigra reticulata showed enhanced nociceptive responses. Such responses were less impacted in the subthalamic nucleus. A total dopaminergic lesion produced an increase in the nociceptive responses as well as an increase of the firing rate in both structures. In the PBN, inhibited nociceptive responses and increased expression of GABAA receptors were found following a total dopaminergic lesion. However, neuro-adaptations at the level of dendritic spine density and post-synaptic density were found in both dopaminergic lesion groups. These results suggest that the molecular changes within the PBN following a larger dopaminergic lesion, such as increased GABAA expression, is a key mechanism to produce nociceptive processing impairment, whilst other changes may protect function after smaller dopaminergic lesions. We also propose that these neuro-adaptations follow increased inhibitory tone from the substantia nigra pars reticulata and may represent the mechanism generating central neuropathic pain in Parkinson's disease.

Multi-scale and cross-dimensional TMS mapping: A proof of principle in patients with Parkinson's disease and deep brain stimulation.

Introduction: Transcranial magnetic stimulation (TMS) mapping has become a critical tool for exploratory studies of the human corticomotor (M1) organization. Here, we propose to gather existing cutting-edge TMS-EMG and TMS-EEG approaches into a combined multi-dimensional TMS mapping that considers local and whole-brain excitability changes as well as state and time-specific changes in cortical activity. We applied this multi-dimensional TMS mapping approach to patients with Parkinson's disease (PD) with Deep brain stimulation (DBS) of the sub-thalamic nucleus (STN) ON and OFF. Our goal was to identifying one or several TMS mapping-derived markers that could provide unprecedent new insights onto the mechanisms of DBS in movement disorders. Methods: Six PD patients (1 female, mean age: 62.5 yo [59-65]) implanted with DBS-STN for 1 year, underwent a robotized sulcus-shaped TMS motor mapping to measure changes in muscle-specific corticomotor representations and a movement initiation task to probe state-dependent modulations of corticospinal excitability in the ON (using clinically relevant DBS parameters) and OFF DBS states. Cortical excitability and evoked dynamics of three cortical areas involved in the neural control of voluntary movements (M1, pre-supplementary motor area - preSMA and inferior frontal gyrus - IFG) were then mapped using TMS-EEG coupling in the ON and OFF state. Lastly, we investigated the timing and nature of the STN-to-M1 inputs using a paired pulse DBS-TMS-EEG protocol. Results: In our sample of patients, DBS appeared to induce fast within-area somatotopic re-arrangements of motor finger representations in M1, as revealed by mediolateral shifts of corticomuscle representations. STN-DBS improved reaction times while up-regulating corticospinal excitability, especially during endogenous motor preparation. Evoked dynamics revealed marked increases in inhibitory circuits in the IFG and M1 with DBS ON. Finally, inhibitory conditioning effects of STN single pulses on corticomotor activity were found at timings relevant for the activation of inhibitory GABAergic receptors (4 and 20 ms). Conclusion: Taken together, these results suggest a predominant role of some markers in explaining beneficial DBS effects, such as a context-dependent modulation of corticospinal excitability and the recruitment of distinct inhibitory circuits, involving long-range projections from higher level motor centers and local GABAergic neuronal populations. These combined measures might help to identify discriminative features of DBS mechanisms towards deep clinical phenotyping of DBS effects in Parkinson's Disease and in other pathological conditions.

Communication dynamics in the human connectome shape the cortex-wide propagation of direct electrical stimulation.

Communication between gray matter regions underpins all facets of brain function. We study inter-areal communication in the human brain using intracranial EEG recordings, acquired following 29,055 single-pulse direct electrical stimulations in a total of 550 individuals across 20 medical centers (average of 87 ± 37 electrode contacts per subject). We found that network communication models-computed on structural connectivity inferred from diffusion MRI-can explain the causal propagation of focal stimuli, measured at millisecond timescales. Building on this finding, we show that a parsimonious statistical model comprising structural, functional, and spatial factors can accurately and robustly predict cortex-wide effects of brain stimulation (R2=46% in data from held-out medical centers). Our work contributes toward the biological validation of concepts in network neuroscience and provides insight into how connectome topology shapes polysynaptic inter-areal signaling. We anticipate that our findings will have implications for research on neural communication and the design of brain stimulation paradigms.

Neocortical and medial temporal seizures have distinct impacts on brain responsiveness.

Focal epileptic seizures are characterized by abnormal neuronal discharges that can spread to other cortical areas and interfere with brain activity, thereby altering the patient's experience and behavior. The origin of these pathological neuronal discharges encompasses various mechanisms that converge toward similar clinical manifestations. Recent studies have suggested that medial temporal lobe (MTL) and neocortical (NC) seizures are often underpinned by two characteristic onset patterns, which, respectively, affect and spare synaptic transmission in cortical slices. However, these synaptic alterations and their effects have never been confirmed or studied in intact human brains. To fill this gap, we here evaluate whether responsiveness of MTL and NC are differentially affected by focal seizures, using a unique data set of cortico-cortical evoked potentials (CCEPs) collected during seizures triggered by single-pulse electrical stimulation (SPES). We find that responsiveness is abruptly reduced by the onset of MTL seizures, despite increased spontaneous activity, whereas it is preserved in the case of NC seizures. The present results provide an extreme example of dissociation between responsiveness and activity and show that brain networks are diversely affected by the onset of MTL and NC seizures, thus extending at the whole brain level the evidence of synaptic alteration found in vitro.

Excessive daytime sleepiness in a model of Parkinson's disease improved by low-frequency stimulation of the pedunculopontine nucleus.

Patients with Parkinson's disease often complain of excessive daytime sleepiness which negatively impacts their quality of life. The pedunculopontine nucleus, proposed as a target for deep brain stimulation to improve freezing of gait in Parkinson's disease, is also known to play a key role in the arousal system. Thus, the putative control of excessive daytime sleepiness by pedunculopontine nucleus area stimulation merits exploration for treating Parkinson's disease patients. To this end, two adult nonhuman primates (macaca fascicularis) received a deep brain stimulation electrode implanted into the pedunculopontine nucleus area along with a polysomnographic equipment. Stimulation at low frequencies and high frequencies was studied, in healthy and then MPTP-treated nonhuman primates. Here, we observed that MPTP-treated nonhuman primates suffered from excessive daytime sleepiness and that low-frequency stimulation of the pedunculopontine nucleus area was effective in reducing daytime sleepiness. Indeed, low-frequency stimulation of the pedunculopontine nucleus area induced a significant increase in sleep onset latency, longer continuous periods of wakefulness and thus, a partially restored daytime wake architecture. These findings may contribute to the development of new therapeutic strategies in patients suffering from excessive daytime sleepiness.

Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338).

BACKGROUND: Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18-34 kg/m2) with stable health and diet. The study comprised seven treatment groups (Cohorts 1-7). Participants received bimagrumab or placebo treatment every 4 weeks for three doses (Cohorts 1 [700 mg] and 2 [210 mg] intravenous infusion; Cohorts 3 [1500 mg] and 4 [525 mg] subcutaneous infusion), or every week for 12 doses (Cohorts 5 [300 mg], 6 [150 mg], and 7 [52.5 mg] subcutaneous bolus injection) and were followed up until week 20. Blood samples were collected for bimagrumab PK analysis. PD were assessed by dual energy X-ray absorptiometry to quantify the change from baseline in lean body mass (LBM) and fat body mass (FBM) compared with placebo. Safety was assessed throughout the study. RESULTS: Eighty-four of 91 (92.3%) randomized participants (mean age 74.5 years; BMI 28.0 kg/m2) completed the study. Demographic characteristics were generally balanced across the groups. A target-mediated drug disposition profile was observed following both intravenous and subcutaneous administration. The absolute subcutaneous bioavailability was estimated at approximately 40%. LBM increased by 4-6% (1.5-2 kg) from baseline throughout the treatment period for intravenous and subcutaneous regimens, except for the 52.5 mg subcutaneous dose, which did not differ from placebo. Concurrently, there was a decrease in FBM (approximately 2-3 kg) for all intravenous and subcutaneous regimens. Bimagrumab was generally safe and well tolerated; adverse events were mostly mild to moderate in severity. CONCLUSIONS: Dose levels of bimagrumab administered weekly subcutaneously resulted in PK profiles and PD effects comparable with monthly intravenous dosing, which supports the feasibility of the subcutaneous route of administration for bimagrumab for future clinical development.

Variability of Single Pulse Electrical Stimulation Responses Recorded with Intracranial Electroencephalography in Epileptic Patients.

Cohort studies of brain stimulations performed with stereo-electroencephalographic (SEEG) electrodes in epileptic patients allow to derive large scale functional connectivity. It is known, however, that brain responses to electrical or magnetic stimulation techniques are not always reproducible. Here, we study variability of responses to single pulse SEEG electrical stimulation. We introduce a second-order probability analysis, i.e. we extend estimation of connection probabilities, defined as the proportion of responses trespassing a statistical threshold (determined in terms of Z-score with respect to spontaneous neuronal activity before stimulation) over all responses and derived from a number of individual measurements, to an analysis of pairs of measurements.Data from 445 patients were processed. We found that variability between two equivalent measurements is substantial in particular conditions. For long ( > ~ 90 mm) distances between stimulating and recording sites, and threshold value Z = 3, correlation between measurements drops almost to zero. In general, it remains below 0.5 when the threshold is smaller than Z = 4 or the stimulating current intensity is 1 mA. It grows with an increase of either of these factors. Variability is independent of interictal spiking rates in the stimulating and recording sites.We conclude that responses to SEEG stimulation in the human brain are variable, i.e. in a subject at rest, two stimulation trains performed at the same electrode contacts and with the same protocol can give discrepant results. Our findings highlight an advantage of probabilistic interpretation of such results even in the context of a single individual.

Early onset of sleep/wake disturbances in a progressive macaque model of Parkinson's disease.

Parkinsonian patients often experience sleep/wake disturbances, which may appear at an early stage of the disease; however, these disturbances have not been fully described. To better understand the evolution of these disturbances with respect to disease progression, we aimed to characterize these clinical signs in a progressive nonhuman primate model of Parkinson's disease. Three adult macaques (Macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of sleep/wake behavior via long-term neurophysiological recordings and underwent a modified multiple sleep latency test. Experiments were first performed in a healthy state and then during the progressive induction of a parkinsonian syndrome by intramuscular injections of low doses of MPTP. We observed an early onset of significant sleep/wake disturbances (i.e., before the appearance of motor symptoms). These disturbances resulted in (i) a disorganization of nighttime sleep with reduced deep sleep quality and (ii) an excessive daytime sleepiness characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day. The present study suggests that nighttime and daytime sleep/wake disturbances may appear early in the disease and should be considered in the development of biomarkers in further studies.

Brain mapping of auditory hallucinations and illusions induced by direct intracortical electrical stimulation.

BACKGROUND: The exact architecture of the human auditory cortex remains a subject of debate, with discrepancies between functional and microstructural studies. In a hierarchical framework for sensory perception, simple sound perception is expected to take place in the primary auditory cortex, while the processing of complex, or more integrated perceptions is proposed to rely on associative and higher-order cortices. OBJECTIVES: We hypothesize that auditory symptoms induced by direct electrical stimulation (DES) offer a window into the architecture of the brain networks involved in auditory hallucinations and illusions. The intracranial recordings of these evoked perceptions of varying levels of integration provide the evidence to discuss the theoretical model. METHODS: We analyzed SEEG recordings from 50 epileptic patients presenting auditory symptoms induced by DES. First, using the Juelich cytoarchitectonic parcellation, we quantified which regions induced auditory symptoms when stimulated (ROI approach). Then, for each evoked auditory symptom type (illusion or hallucination), we mapped the cortical networks showing concurrent high-frequency activity modulation (HFA approach). RESULTS: Although on average, illusions were found more laterally and hallucinations more posteromedially in the temporal lobe, both perceptions were elicited in all levels of the sensory hierarchy, with mixed responses found in the overlap. The spatial range was larger for illusions, both in the ROI and HFA approaches. The limbic system was specific to the hallucinations network, and the inferior parietal lobule was specific to the illusions network. DISCUSSION: Our results confirm a network-based organization underlying conscious sound perception, for both simple and complex components. While symptom localization is interesting from an epilepsy semiology perspective, the hallucination-specific modulation of the limbic system is particularly relevant to tinnitus and schizophrenia.

Exploring the spatial resolution of TMS-EEG coupling on the sensorimotor region.

The use of TMS-EEG coupling as a neuroimaging tool for the functional exploration of the human brain recently gained strong interest. If this tool directly inherits the fine temporal resolution from EEG, its spatial counterpart remains unknown. In this study, we explored the spatial resolution of TMS-EEG coupling by evaluating the minimal distance between two stimulated cortical sites that would significantly evoke different response dynamics. TMS evoked responses were mapped on the sensorimotor region in twenty participants. The stimulation grid was composed of nine targets separated between 10 and 15 mm on average. The dynamical signatures of TMS evoked activity were extracted and compared between sites using both local and remote linear regression scores and spatial generalized mixed models. We found a significant effect of the distance between stimulated sites on their dynamical signatures, neighboring sites showing differentiable response dynamics. Besides, common dynamical signatures were also found between sites up to 25-30 mm from each other. This overlap in dynamical properties decreased with distance and was stronger between sites within the same Brodmann area. Our results suggest that the spatial resolution of TMS-EEG coupling might be at least as high as 10 mm. Furthermore, our results reveal an anisotropic spatial resolution that was higher across than within the same Brodmann areas, in accordance with the TMS induced E-field modeling. Common cytoarchitectonic leading to shared dynamical properties within the same Brodmann area could also explain this anisotropy. Overall, these findings suggest that TMS-EEG benefits from the spatial resolution of TMS, which makes it an accurate technique for meso-scale brain mapping.

Somatomotor or somatosensory facial manifestations in patients with temporobasal epilepsies.

OBJECTIVE: The semiology of temporo-basal epilepsy has rarely been analysed in the literature. In this paper, we report three patients with proven basal temporal epilepsy with somatomotor or somatosensory facial ictal semiology, highly suggestive of insulo-opercular onset. METHODS: The three patients had a temporobasal lesion and their drugresistant epilepsy was cured with resection of the lesion (follow-up duration: 7-17 years). We reviewed the medical charts, non-invasive EEG data as well as the stereoelectroencephalography (SEEG) performed in two patients. Quantitative analysis of ictal fast gamma activity was performed for one patient. RESULTS: Early ictal features were orofacial, either somatomotor in two patients or ipsilateral somatosensory in one. The three patients had prior sensations compatible with a temporal lobe onset. Interictal and ictal EEG pointed to the temporal lobe. The propagation of the discharge to the insula and operculum before the occurrence of facial features was seen on SEEG. Facial features occurred 7-20 seconds after electrical onset. Quantitative analysis of six seizures in one patient confirmed the visual analysis, showing statistically significant fast gamma activity originating from basal areas and then propagating to insuloopercular regions after a few seconds. SIGNIFICANCE: We report three cases of lesional temporo-basal epilepsy responsible for orofacial semiology related to propagation of insulo-opercular ictal discharge. In MRI-negative patients with facial manifestations, this origin should be suspected when EEG is suggestive. These observations may contribute to our understanding of brain networks.

A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials.

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.

Making Chiral Salen Complexes Work with Organocatalysts.

Bisimine derivatives of salicylaldehyde with chiral diamines (salens) are privileged ligands in asymmetric organometallic catalysis, which can be used in cooperation with organocatalysts as additives. The latter can be a modifier of the metal reactivity by liganding or a true co-catalyst working in tandem or in a dual system. All scenarios encountered in the literature are reviewed and classified according to the organocatalyst. In each case, mechanistic and physical-organic chemistry considerations are discussed to better understand the gears of these complex catalytic settings.

Tinnitus Perception in Light of a Parietal Operculo-Insular Involvement: A Review.

In tinnitus literature, researchers have increasingly been advocating for a clearer distinction between tinnitus perception and tinnitus-related distress. In non-bothersome tinnitus, the perception itself can be more specifically investigated: this has provided a body of evidence, based on resting-state and activation fMRI protocols, highlighting the involvement of regions outside the conventional auditory areas, such as the right parietal operculum. Here, we aim to conduct a review of available investigations of the human parietal operculo-insular subregions conducted at the microscopic, mesoscopic, and macroscopic scales arguing in favor of an auditory-somatosensory cross-talk. Both the previous literature and new results on functional connectivity derived from cortico-cortical evoked potentials show that these subregions present a dense tissue of interconnections and a strong connectivity with auditory and somatosensory areas in the healthy brain. Disrupted integration processes between these modalities may thus result in erroneous perceptions, such as tinnitus. More precisely, we highlight the role of a subregion of the right parietal operculum, known as OP3 according to the Jülich atlas, in the integration of auditory and somatosensory representation of the orofacial muscles in the healthy population. We further discuss how a dysfunction of these muscles could induce hyperactivity in the OP3. The evidence of direct electrical stimulation of this area eliciting auditory hallucinations further suggests its involvement in tinnitus perception. Finally, a small number of neuroimaging studies of therapeutic interventions for tinnitus provide additional evidence of right parietal operculum involvement.

Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis.

BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses. OBJECTIVES: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose. METHODS: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses. RESULTS: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels. CONCLUSION: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.

Optimization of sampling designs for pedigrees and association studies.

In many studies, related individuals are phenotyped in order to infer how their genotype contributes to their phenotype, through the estimation of parameters such as breeding values or locus effects. When it is not possible to phenotype all the individuals, it is important to properly sample the population to improve the precision of the statistical analysis. This article studies how to optimize such sampling designs for pedigrees and association studies. Two sampling methods are developed, stratified sampling and D optimality. It is found that it is important to take account of mutation when sampling pedigrees with many generations: as the size of mutation effects increases, optimized designs sample more individuals in late generations. Optimized designs for association studies tend to improve the joint estimation of breeding values and locus effects, all the more as sample size is low and the genetic architecture of the trait is simple. When the trait is determined by few loci, they are reminiscent of classical experimental designs for regression models and tend to select homozygous individuals. When the trait is determined by many loci, locus effects may be difficult to estimate, even if an optimized design is used.