Clinical impact of intraoperative CCEP monitoring in evaluating the dorsal language white matter pathway

In order to preserve postoperative language function, we recently proposed a new intraoperative method to monitor the integrity of the dorsal language pathway (arcuate fasciculus; AF) using cortico–cortical evoked potentials (CCEPs). Based on further investigations (20 patients, 21 CCEP investigations), including patients who were not suitable for awake surgery (five CCEP investigations) or those without preoperative neuroimaging data (eight CCEP investigations including four with untraceable tractography due to brain edema), we attempted to clarify the clinical impact of this new intraoperative method. We monitored the integrity of AF by stimulating the anterior perisylvian language area (AL) by recording CCEPs from the posterior perisylvian language area (PL) consecutively during both general anesthesia and awake condition. After tumor resection, single‐pulse electrical stimuli were also applied to the floor of the removal cavity to record subcortico‐cortical evoked potentials (SCEPs) at AL and PL in 12 patients (12 SCEP investigations). We demonstrated that (1) intraoperative dorsal language network monitoring was feasible even when patients were not suitable for awake surgery or without preoperative neuroimaging studies, (2) CCEP is a dynamic marker of functional connectivity or integrity of AF, and CCEP N1 amplitude could even become larger after reduction of brain edema, (3) a 50% CCEP N1 amplitude decline might be a cut‐off value to prevent permanent language dysfunction due to impairment of AF, (4) a correspondence (<2.0 ms difference) of N1 onset latencies between CCEP and the sum of SCEPs indicates close proximity of the subcortical stimulus site to AF (<3.0 mm). Hum Brain Mapp 38:1977–1991, 2017 . © 2017 Wiley Periodicals, Inc.     

Parieto-frontal network in humans studied by cortico-cortical evoked potential

Parieto‐frontal network is essential for sensorimotor integration in various complex behaviors, and its disruption is associated with pathophysiology of apraxia and visuo‐spatial disorders. Despite advances in knowledge regarding specialized cortical areas for various sensorimotor transformations, little is known about the underlying cortico‐cortical connectivity in humans. We investigated inter‐areal connections of the lateral parieto‐frontal network in vivo by means of cortico‐cortical evoked potentials (CCEPs). Six patients with epilepsy and one with brain tumor were studied. With the use of subdural electrodes implanted for presurgical evaluation, network configuration was investigated by tracking the connections from the parietal stimulus site to the frontal site where the maximum CCEP was recorded. It was characterized by (i) a near‐to‐near and distant‐to‐distant, mirror symmetric configuration across the central sulcus, (ii) preserved dorso‐ventral organization (the inferior parietal lobule to the ventral premotor area and the superior parietal lobule to the dorsal premotor area), and (iii) projections to more than one frontal cortical sites in 56% of explored connections. These findings were also confirmed by the standardized parieto‐frontal CCEP connectivity map constructed in reference to the Jülich cytoarchitectonic atlas in the MNI standard space. The present CCEP study provided an anatomical blueprint underlying the lateral parieto‐frontal network and demonstrated a connectivity pattern similar to non‐human primates in the newly developed inferior parietal lobule in humans. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Tuning face perception with electrical stimulation of the fusiform gyrus

The fusiform gyrus (FG) is an important node in the face processing network, but knowledge of its causal role in face perception is currently limited. Recent work demonstrated that high frequency stimulation applied to the FG distorts the perception of faces in human subjects (Parvizi et al. [ 2012 ]: J Neurosci 32:14915–14920). However, the timing of this process in the FG relative to stimulus onset and the spatial extent of FG's role in face perception are unknown. Here, we investigate the causal role of the FG in face perception by applying precise, event‐related electrical stimulation (ES) to higher order visual areas including the FG in six human subjects undergoing intracranial monitoring for epilepsy. We compared the effects of single brief (100 μs) electrical pulses to the FG and non‐face‐selective visual areas on the speed and accuracy of detecting distorted faces. Brief ES applied to face‐selective sites did not affect accuracy but significantly increased the reaction time (RT) of detecting face distortions. Importantly, RT was altered only when ES was applied 100ms after visual onset and in face‐selective but not place‐selective sites. Furthermore, ES applied to face‐selective areas decreased the amplitude of visual evoked potentials and high gamma power over this time window. Together, these results suggest that ES of face‐selective regions within a critical time window induces a delay in face perception. These findings support a temporally and spatially specific causal role of face‐selective areas and signify an important link between electrophysiology and behavior in face perception. Hum Brain Mapp 38:2830–2842, 2017. © 2017 Wiley Periodicals, Inc.     

Anomia produced by direct cortical stimulation of the pre‐supplementary motor area in a patient undergoing preoperative language mapping

There is sparse data on the analysis of supplementary motor area in language function using direct cortical stimulation of the supplementary motor area. Here, we report a patient who experienced isolated anomia during stimulation of the anterior supplementary motor area and discuss the role of the supplementary motor area in speech production. The role of the pre‐supplementary motor area in word selection, observed in fMRI studies, can be confirmed by direct cortical stimulation.     

Sleep modulates cortical connectivity and excitability in humans: Direct evidence from neural activity induced by single‐pulse electrical stimulation

Sleep‐induced changes in human brain connectivity/excitability and their physiologic basis remain unclear, especially in the frontal lobe. We investigated sleep‐induced connectivity and excitability changes in 11 patients who underwent chronic implantation of subdural electrodes for epilepsy surgery. Single‐pulse electrical stimuli were directly injected to a part of the cortices, and cortico‐cortical evoked potentials (CCEPs) and CCEP‐related high‐gamma activities (HGA: 100–200 Hz) were recorded from adjacent and remote cortices as proxies of effective connectivity and induced neuronal activity, respectively. HGA power during the initial CCEP component (N1) correlated with the N1 size itself across all states investigated. The degree of cortical connectivity and excitability changed during sleep depending on sleep stage, approximately showing dichotomy of awake vs. non‐rapid eye movement (REM) [NREM] sleep. On the other hand, REM sleep partly had properties of both awake and NREM sleep, placing itself in the intermediate state between them. Compared with the awake state, single‐pulse stimulation especially during NREM sleep induced increased connectivity (N1 size) and neuronal excitability (HGA increase at N1), which was immediately followed by intense inhibition (HGA decrease). The HGA decrease was temporally followed by the N2 peak (the second CCEP component), and then by HGA re‐increase during sleep across all lobes. This HGA rebound or re‐increase of neuronal synchrony was largest in the frontal lobe compared with the other lobes. These properties of sleep‐induced changes of the cortex may be related to unconsciousness during sleep and frequent nocturnal seizures in frontal lobe epilepsy. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc .     

Structural and functional integration between dorsal and ventral language streams as revealed by blunt dissection and direct electrical stimulation

The most accepted framework of language processing includes a dorsal phonological and a ventral semantic pathway, connecting a wide network of distributed cortical hubs. However, the cortico‐subcortical connectivity and the reciprocal anatomical relationships of this dual‐stream system are not completely clarified. We performed an original blunt microdissection of 10 hemispheres with the exposition of locoregional short fibers and six long‐range fascicles involved in language elaboration. Special attention was addressed to the analysis of termination sites and anatomical relationships between long‐ and short‐range fascicles. We correlated these anatomical findings with a topographical analysis of 93 functional responses located at the terminal sites of the language bundles, collected by direct electrical stimulation in 108 right‐handers. The locations of phonological and semantic paraphasias, verbal apraxia, speech arrest, pure anomia, and alexia were statistically analyzed, and the respective barycenters were computed in the MNI space. We found that terminations of main language bundles and functional responses have a wider distribution in respect to the classical definition of language territories. Our analysis showed that dorsal and ventral streams have a similar anatomical layer organization. These pathways are parallel and relatively segregated over their subcortical course while their terminal fibers are strictly overlapped at the cortical level. Finally, the anatomical features of the U‐fibers suggested a role of locoregional integration between the phonological, semantic, and executive subnetworks of language, in particular within the inferoventral frontal lobe and the temporoparietal junction, which revealed to be the main criss‐cross regions between the dorsal and ventral pathways. Hum Brain Mapp 37:3858–3872, 2016. © 2016 Wiley Periodicals, Inc.     

Test–retest reliability of wide‐pulse high‐frequency neuromuscular electrical stimulation evoked force

Introduction: We compare forces evoked by wide‐pulse high‐frequency (WPHF) neuromuscular electrical stimulation (NMES) delivered to a nerve trunk versus muscle belly and assess their test–retest intraindividual and interindividual reliability. Methods: Forces evoked during 2 sessions with WPHF NMES delivered over the tibial nerve trunk and 2 sessions over the triceps surae muscle belly were compared. Ten individuals participated in 4 sessions involving ten 20‐s WPHF NMES contractions interspaced by 40‐s recovery. Mean evoked force and force time integral of each contraction were quantified. Results: For both nerve trunk and muscle belly stimulation, intraindividual test–retest reliability was good (intraclass correlation coefficient > 0.9), and interindividual variability was large (coefficient of variation between 140% and 180%). Nerve trunk and muscle belly stimulation resulted in similar evoked forces. Discussion: WPHF NMES locations might be chosen by individual preference because intraindividual reliability was relatively good for both locations. Muscle Nerve 57 : E70–E77, 2018.     

Anomalous single‐subject based morphological cortical networks in drug‐naive,first‐episode major depressive disorder

Major depressive disorder (MDD) has been associated with disruptions in the topological organization of brain morphological networks in group‐level data. Such disruptions have not yet been identified in single‐patients, which is needed to show relations with symptom severity and to evaluate their potential as biomarkers for illness. To address this issue, we conducted a cross‐sectional structural brain network study of 33 treatment‐naive, first‐episode MDD patients and 33 age‐, gender‐, and education‐matched healthy controls (HCs). Weighted graph‐theory based network models were used to characterize the topological organization of brain networks between the two groups. Compared with HCs, MDD patients exhibited lower normalized global efficiency and higher modularity in their whole‐brain morphological networks, suggesting impaired integration and increased segregation of morphological brain networks in the patients. Locally, MDD patients exhibited lower efficiency in anatomic organization for transferring information predominantly in default‐mode regions including the hippocampus, parahippocampal gyrus, precuneus and superior parietal lobule, and higher efficiency in the insula, calcarine and posterior cingulate cortex, and in the cerebellum. Morphological connectivity comparisons revealed two subnetworks that exhibited higher connectivity strength in MDD mainly involving neocortex‐striatum‐thalamus‐cerebellum and thalamo‐hippocampal circuitry. MDD‐related alterations correlated with symptom severity and differentiated individuals with MDD from HCs with a sensitivity of 87.9% and specificity of 81.8%. Our findings indicate that single subject grey matter morphological networks are often disrupted in clinically relevant ways in treatment‐naive, first episode MDD patients. Circuit‐specific changes in brain anatomic network organization suggest alterations in the efficiency of information transfer within particular brain networks in MDD. Hum Brain Mapp 38:2482–2494, 2017. © 2017 Wiley Periodicals, Inc.     

Probabilistic mapping of language networks from high frequency activity induced by direct electrical stimulation

Direct electrical stimulation (DES) at 50 Hz is used as a gold standard to map cognitive functions but little is known about its ability to map large‐scale networks and specific subnetwork. In the present study, we aim to propose a new methodological approach to evaluate the specific hypothesis suggesting that language errors/dysfunction induced by DES are the result of large‐scale network modification rather than of a single cortical region, which explains that similar language symptoms may be observed after stimulation of different cortical regions belonging to this network. We retrospectively examined 29 patients suffering from focal drug‐resistant epilepsy who benefitted from stereo‐electroencephalographic (SEEG) exploration and exhibited language symptoms during a naming task following 50 Hz DES. We assessed the large‐scale language network correlated with behavioral DES‐induced responses (naming errors) by quantifying DES‐induced changes in high frequency activity (HFA, 70–150 Hz) outside the stimulated cortical region. We developed a probabilistic approach to report the spatial pattern of HFA modulations during DES‐induced language errors. Similarly, we mapped the pattern of after‐discharges (3–35 Hz) occurring after DES. HFA modulations concurrent to language symptoms revealed a brain network similar to our current knowledge of language gathered from standard brain mapping. In addition, specific subnetworks could be identified within the global language network, related to different language processes, generally described in relation to the classical language regions. Spatial patterns of after‐discharges were similar to HFA induced during DES. Our results suggest that this new methodological DES‐HFA mapping is a relevant approach to map functional networks during SEEG explorations, which would allow to shift from “local” to “network” perspectives.     

Long‐lasting enhancements of memory and hippocampal‐cortical functional connectivity following multiple‐day targeted noninvasive stimulation

Noninvasive stimulation can alter the function of brain networks, although the duration of neuroplastic changes are uncertain and likely vary for different networks and stimulation parameters. We have previously shown that multiple‐day repetitive transcranial magnetic stimulation can influence targeted hippocampal‐cortical networks, producing increased functional MRI connectivity of these networks and concomitant improvements in memory that outlast stimulation by ～24 h. Here, we present new analyses showing that multiple‐day targeted stimulation of hippocampal‐cortical networks produces even longer‐lasting enhancement. The ability to learn novel, arbitrary face‐word pairings improved over five consecutive daily stimulation sessions, and this improvement remained robust at follow‐up testing performed an average of 15 days later. Furthermore, stimulation increased functional MRI connectivity of the targeted portion of the hippocampus with distributed regions of the posterior hippocampal‐cortical network, and these changes in connectivity remained robust at follow‐up testing. Neuroplastic changes of hippocampal‐cortical networks caused by multiple‐day noninvasive stimulation therefore persist for extended periods. These findings have implications for the design of multiple‐day stimulation experiments and for the development of stimulation‐based interventions for memory disorders. © 2015 Wiley Periodicals, Inc.     

Mapping language with resting‐state functional magnetic resonance imaging: A study on the functional profile of the language network

Resting‐state functional magnetic resonance imaging (rsfMRI) is a promising technique for language mapping that does not require task‐execution. This can be an advantage when language mapping is limited by poor task performance, as is common in clinical settings. Previous studies have shown that language maps extracted with rsfMRI spatially match their task‐based homologs, but no study has yet demonstrated the direct participation of the rsfMRI language network in language processes. This demonstration is critically important because spatial similarity can be influenced by the overlap of domain‐general regions that are recruited during task‐execution. Furthermore, it is unclear which processes are captured by the language network: does it map rather low‐level or high‐level (e.g., syntactic and lexico‐semantic) language processes? We first identified the rsfMRI language network and then investigated task‐based responses within its regions when processing stimuli of increasing linguistic content: symbols, pseudowords, words, pseudosentences and sentences. The language network responded only to language stimuli (not to symbols), and higher linguistic content elicited larger brain responses. The left fronto‐parietal, the default mode, and the dorsal attention networks were examined and yet none showed language involvement. These findings demonstrate for the first time that the language network extracted through rsfMRI is able to map language in the brain, including regions subtending higher‐level syntactic and semantic processes.     

From “rest” to language task: Task activation selects and prunes from broader resting‐state network

Resting‐state networks (RSNs) show spatial patterns generally consistent with networks revealed during cognitive tasks. However, the exact degree of overlap between these networks has not been clearly quantified. Such an investigation shows promise for decoding altered functional connectivity (FC) related to abnormal language functioning in clinical populations such as temporal lobe epilepsy (TLE). In this context, we investigated the network configurations during a language task and during resting state using FC. Twenty‐four healthy controls, 24 right and 24 left TLE patients completed a verb generation (VG) task and a resting‐state fMRI scan. We compared the language network revealed by the VG task with three FC‐based networks (seeding the left inferior frontal cortex (IFC)/Broca): two from the task (ON, OFF blocks) and one from the resting state. We found that, for both left TLE patients and controls, the RSN recruited regions bilaterally, whereas both VG‐on and VG‐off conditions produced more left‐lateralized FC networks, matching more closely with the activated language network. TLE brings with it variability in both task‐dependent and task‐independent networks, reflective of atypical language organization. Overall, our findings suggest that our RSN captured bilateral activity, reflecting a set of prepotent language regions. We propose that this relationship can be best understood by the notion of pruning or winnowing down of the larger language‐ready RSN to carry out specific task demands. Our data suggest that multiple types of network analyses may be needed to decode the association between language deficits and the underlying functional mechanisms altered by disease. Hum Brain Mapp 38:2540–2552, 2017. © 2017 Wiley Periodicals, Inc.     

A single dose of lorazepam reduces paired‐pulse suppression of median nerve evoked somatosensory evoked potentials

Paired‐pulse behaviour in the somatosensory cortex is an approach to obtain insights into cortical processing modes and to obtain markers of changes of cortical excitability attributable to learning or pathological states. Numerous studies have demonstrated suppression of the response to the stimulus that follows a first one after a short interval, but the underlying mechanisms remain elusive, although there is agreement that GABAergic mechanisms seem to play a crucial role. We therefore aimed to explore the influence of the GABA_A agonist lorazepam on paired‐pulse somatosensory evoked potentials (SEPs). We recorded and analysed SEPs after paired median nerve stimulation in healthy individuals before and after they had received a single dose of 2.5 mg of lorazepam as compared with a control group receiving placebo. Paired‐pulse suppression was expressed as a ratio of the amplitudes of the second and the first peaks. We found that, after lorazepam application, paired‐pulse suppression of the cortical N20 component remained unchanged, but suppression of the N20–P25 complex was significantly reduced, indicative of GABAergic involvement in intracortical processing. Our data suggest that lorazepam most likely enhances inhibition within the cortical network of interneurons responsible for creating paired‐pulse suppression, leading to reduced inhibitory drive with a subsequently reduced amount of suppression. The results provide further evidence that GABA_A‐mediated mechanisms are involved in the generation of median nerve evoked paired‐pulse suppression.     

Inhibition of acid‐sensing ion channels by levo‐tetrahydropalmatine in rat dorsal root ganglion neurons

Levo‐tetrahydropalmatine (l‐THP), a main bioactive Chinese herbal constituent from the genera Stephania and Corydalis, has been in use in clinical practice for years in China as a traditional analgesic agent. However, the mechanism underlying the analgesic action of l‐THP is poorly understood. This study shows that l‐THP can exert an inhibitory effect on the functional activity of native acid‐sensing ion channels (ASICs), which are believed to mediate pain caused by extracellular acidification. l‐THP dose dependently decreased the amplitude of proton‐gated currents mediated by ASICs in rat dorsal root ganglion (DRG) neurons. l‐THP shifted the proton concentration–response curve downward, with a decrease of 40.93% ± 8.45% in the maximum current response to protons, with no significant change in the pH_0.5 value. Moreover, l‐THP can alter the membrane excitability of rat DRG neurons to acid stimuli. It significantly decreased the number of action potentials and the amplitude of the depolarization induced by an extracellular pH drop. Finally, peripherally administered l‐THP inhibited the nociceptive response to intraplantar injection of acetic acid in rats. These results indicate that l‐THP can inhibit the functional activity of ASICs in dissociated primary sensory neurons and relieve acidosis‐evoked pain in vivo, which for the first time provides a novel peripheral mechanism underlying the analgesic action of l‐THP. © 2014 Wiley Periodicals, Inc.     

Aberrations in the arcuate fasciculus are associated with auditory verbal hallucinations in psychotic and in non‐psychotic individuals

The pathophysiology of auditory verbal hallucinations (AVH) is still unclear. Cognitive as well as electrophysiological studies indicate that a defect in sensory feedback (corollary discharge) may contribute to the experience of AVH. This could result from disruption of the arcuate fasciculus, the major tract connecting frontal and temporo‐parietal language areas. Previous diffusion tensor imaging studies indeed demonstrated abnormalities of this tract in schizophrenia patients with AVH. It is, however, difficult to disentangle specific associations with AVH in this patient group as many other factors, such as other positive and negative symptoms, medication or halted education could likewise have affected tract integrity. We therefore investigated AVH in relative isolation and studied a group of non‐psychotic individuals with AVH as well as patients with AVH and non‐hallucinating matched controls. We compared tract integrity of the arcuate fasiculus and of three other control tracts, between 35 non‐psychotic individuals with AVH, 35 schizophrenia patients with AVH, and 36 controls using diffusion tensor imaging and magnetization transfer imaging. Both groups with AVH showed an increase in magnetization transfer ratio (MTR) in the arcuate fasciculus, but not in the other control tracts. In addition, a general decrease in fractional anisotropy (FA) for almost all bundles was observed in the patient group, but not in the non‐psychotic individuals with AVH. As increased MTR in the arcuate fasciculus was present in both hallucinating groups, a specific association with AVH seems plausible. Decreases in FA, on the other hand, seem to be related to other disease processes of schizophrenia. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Brain‐derived neurotrophic factor exerts antinociceptive effects by reducing excitability of colon‐projecting dorsal root ganglion neurons in the colorectal distention‐evoked visceral pain model

The mechanism underlying visceral pain is still largely unclear. Recently, much attention has focused on a potential modulatory role of brain‐derived neurotrophic factor (BDNF) in visceral pain. In the present study, we investigated the expression of BDNF in dorsal root ganglia (DRG) primary sensory neurons and its role in a colorectal distention (CRD)‐induced model of visceral pain. Results obtained from enzyme‐linked immunosorbant assay (ELISA) revealed that BDNF protein was upregulated after CRD. An abdominal withdrawal reflex (AWR) assay confirmed that BDNF played an antinociceptive role in this model. Application of BDNF directly to DRG neurons decreased their hypersensitivity when evoked by CRD. Pretreatment with k252a partially blocked the effect of BDNF. These findings suggest that BDNF might be a novel analgesic agent for the treatment of visceral pain. © 2012 Wiley Periodicals, Inc.     

Altered topological properties of the cortical motor‐related network in patients with subcortical stroke revealed by graph theoretical analysis

Cerebral neuroplasticity after stroke has been elucidated by functional neuroimaging. However, little is known concerning how topological properties of the cortical motor‐related network evolved following subcortical stroke. In the present study, we investigated 24 subcortical stroke patients with only left motor pathway damaged and 24 matched healthy controls. A cortical motor‐related network consisting of 20 brain regions remote from the primary lesion was constructed using resting‐state functional MRI datasets. We subsequently used graph theoretical approaches to analyze the topological properties of this network in both stroke patients and healthy controls. In addition, we divided the stroke patients into two subgroups according to their outcomes in hand function to explore relationships between topological properties of this network and outcomes in hand function. Although we observed that the cortical motor‐related network in both healthy controls and stroke patients exhibited small‐world topology, the local efficiency of this network in stroke patients is higher than and global efficiency is lower than those in healthy controls. In addition, striking alterations in the betweenness centrality of regions were found in stroke patients, including the contralesional supplementary motor area, dorsolateral premotor cortex, and anterior inferior cerebellum. Moreover, we observed significant correlations between betweenness centrality of regions and Fugl‐Meyer assessment scores. A tendency for the cortical motor‐related network to be close to a regular configuration and altered betweenness centrality of regions were demonstrated in patients with subcortical stroke. This study provided insight into functional organization after subcortical stroke from the viewpoint of network topology. Hum Brain Mapp 35:3343–3359, 2014. © 2013 Wiley Periodicals, Inc .