Luis Garcia-Larrea

• MD, PhD
• Research Director at INSERM and Claude Bernard University Lyon 1

Background and Objectives: The activity profile of the posterior insula in neuropathic pain (NeP) remains largely unexplored. To address this and examine its modulation by somatosensory stimulation, we recorded local field potentials (LFP) in awake patients with NeP undergoing deep brain stimulation (DBS) electrode implantation to the posterior-sup...

Background Pain is the leading cause of disability and reduced quality of life worldwide. Despite the increasing burden for patients and healthcare systems, pain research remains underfunded and under focused. Having stakeholders identify and prioritize areas that need urgent attention in the field will help focus funding topics, reduce ‘research w...

During paradoxical sleep (PS, aka REM sleep) the cerebral cortex displays rapid electroencephalographic activity similar to that of wakefulness, whereas in the posterior associative thalamus, rapid activity is interrupted by frequent periods of slow‐wave (delta) oscillations at 2–3 Hz, thereby dissociating the intrinsic frequency in thalamus and co...

Objective: To assess the value of combining brain and autonomic measures to discriminate the subjective perception of pain from other sensory-cognitive activations. Methods: 20 healthy individuals received 2 types of tonic painful stimulation delivered to the hand: electrical stimuli and immersion in 10 Celsius degree (°C) water, which were contra...

Contextual pain conditioning is the process of associating a specific painful experience to its emotional and environmental context. Although pain conditioning is suggested to play a key role in the development and maintenance of chronic pain, there is still paucity of studies and protocols specifically devoted to better understanding its underlyin...

Memories of painful events constitute the basis for assessing patients' pain. This study explores the brain oscillatory activity during short‐term memorization of a nociceptive stimulus. High‐density EEG activity (128 electrodes) was recorded in 13 healthy subjects during a match‐to‐sample sensory discrimination task, whereby participants compared...

Background and Objective Functional magnetic resonance imaging, in conjunction with models of peripheral and/or central sensitization, has been used to assess analgesic efficacy in healthy humans. This review aims to summarize the use of these techniques to characterize brain mechanisms of hyperalgesia/allodynia and to evaluate the efficacy of anal...

Introduction The ability of repetitive transcranial magnetic stimulation (rTMS) to deliver a magnetic field (MF) in deep brain targets is debated and poorly documented. Objective To quantify the decay of MF in the human brain. Methods Magnetic field was generated by single pulses of TMS delivered at maximum intensity using a flat or angulated coi...

The conscious perception of pain is the result of dynamic interactions of neural activities from local brain regions to distributed brain networks. Mapping out the networks of functional connections between brain regions that form and disperse when an experimental participant received nociceptive stimulations allow to characterize the pattern of ne...

Background This study investigates the functional brain connectivity in patients with anterior knee pain (AKP). While biomechanical models are frequently employed to investigate AKP, it is important to recognize that pain can manifest even in the absence of structural abnormalities. Leveraging the capabilities of functional magnetic resonance imagi...

Background and objective: Repetitive transcranial magnetic stimulation (rTMS) applied to the motor cortex provides supplementary relief for some individuals with chronic pain who are refractory to pharmacological treatment. As rTMS slowly enters treatment guidelines for pain relief, its starts to be confronted with challenges long known to pharmac...

Purpose of review: Neuromodulation techniques are being increasingly used to alleviate pain and enhance quality of life. Non-invasive cortical stimulation was originally intended to predict the efficacy of invasive (neurosurgical) techniques, but has now gained a place as an analgesic procedure in its own right. Recent findings: Repetitive trans...

Background: Innocuous cooling of the skin activates cold-specific Aδ fibres, and hence, the recording of cold-evoked potentials (CEPs) may improve the objective assessment of human thermo-nociceptive function. While the feasibility of CEP recordings in healthy humans has been reported, their reliability and diagnostic use in clinical conditions ha...

Background and purpose: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). Methods: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative se...

The interruption of sleep by a nociceptive stimulus is favoured by an increase in the pre‐stimulus functional connectivity between sensory and higher‐level cortical areas. In addition, stimuli inducing arousal also trigger a widespread EEG response reflecting the coordinated activation of a large cortical network. Since functional connectivity betw...

La stimulation épidurale du cortex moteur (eMCS) a été conçue dans les années 1990 et a maintenant largement supplanté la stimulation thalamique pour soulager la douleur neuropathique. Ses mécanismes d’action impliquent l’activation de multiples zones cortico-sous-corticales via une activation initiée dans le thalamus, avec implication des opioïdes...

While high-frequency transcranial magnetic stimulation (HF-rTMS) is now included in the armamentarium to treat chronic neuropathic pain (NP), direct-current anodal stimulation (a-tDCS) to the same cortical targets may represent a valuable alternative in terms of feasibility and cost. Here we performed a head-to-head, randomized, single-blinded, cro...

Background Pain is a private experience, whose assessment relies on subjective self-reporting. Inaccurate communication renders pain evaluation unreliable in individuals with alteration of consciousness, lack of verbal interaction, cognitive dysfunction or simple malingering, hence the importance of developing reliable objective assessment tools....

Background IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem a...

Activation of the spinothalamic system does not always result in a subjective pain perception. While the cerebral network processing nociception is relatively well known, the one underlying its transition to conscious pain remains poorly described. We used intracranial electroencephalography in epileptic patients to investigate whether the amplitud...

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets a...

Central post-stroke pain affects up to 12% of stroke survivors and is notoriously refractory to treatment. However, stroke patients often suffer from other types of pain of non- neuropathic nature (musculoskeletal, inflammatory, complex regional) and no head-to-head comparison of their respective clinical and somatosensory profiles has been perform...

Epidural stimulation of the motor cortex (eMCS) was devised in the 1990s, and has now largely supplanted thalamic stimulation for neuropathic pain relief. Its mechanisms of action involve activation of multiple cortico-subcortical areas initiated in the thalamus, with involvement of endogenous opioids and descending inhibition toward the spinal cor...

La prise en charge en urgence d'une hypertension intracrânienne idiopatique et un suivi multidisciplinaire sur 5 ans. A propos d'un cas Idiopathic Intracranial Hypertension: Emergency Treatment and a 5-year Follow-Up.

The functional roles of the insula diverge between its posterior portion (PI), mainly connected with somato-sensory and motor areas, and its anterior section (AI) connected with the frontal, limbic, and cingulate regions. We report intracranial recordings of local field evoked potentials from PI, AI, and the visual fusiform gyrus to a full array of...

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization ind...

Objective In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. Methods In 26 healthy p...

Objectives Although somatosensory evoked potentials (SEPs) after median nerve stimulation are widely used in clinical practice, the dorsal horn generator of the N13 SEP spinal component is not clearly understood. To verify whether wide dynamic range neurons in the dorsal horn of the spinal cord are involved in the generation of the N13 SEP, we test...

Transcranial Direct Current Stimulation (tDCS) over the primary motor cortex (M1) and the Dorsolateral Prefrontal Cortex (DLPFC) seem to improve pain and other symptoms of fibromyalgia (FM), although the evidence on the effectiveness of tDCS and the optimal stimulation target is not robust enough. Our main objective was to establish the optimal are...

Poststroke pain (PSP) is a heterogeneous term encompassing both central neuropathic (ie, central poststroke pain [CPSP]) and nonneuropathic poststroke pain (CNNP) syndromes. Central poststroke pain is classically related to damage in the lateral brainstem, posterior thalamus, and parietoinsular areas, whereas the role of white matter connecting the...

Background IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nocicept...

Objective High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent “theta-burst” stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two mo...

Nociceptive stimuli disrupt sleep, but may, or may not, entail an arousal. While arousal reactions go along with the activation of a widespread cortical network, the factors enabling such activation remain unknown. Here we used intracranial EEG in humans to test the relation between the cortical activity immediately preceding a noxious stimulus and...

Background As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock‐like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and...

Objective Suppression of alpha and enhancement of gamma electroencephalographic (EEG) power have both been suggested as objective indicators of cortical pain processing. While gamma activity has been emphasized as the best potential marker, its spectral overlap with pain-related muscular responses is a potential drawback. Since muscle contractions...

Background The posterior insula (PI) has been proposed as a potential neurostimulation target for neuropathic pain relief as it represents a key‐structure in pain processing. However, currently available data remain inconclusive as to efficient stimulation parameters. Objective As frequency was shown to be the most correlated parameter to pain rel...

Intracranial EEG (iEEG) studies have suggested that the conscious perception of pain builds up from successive contributions of brain networks in less than one second. However, the functional organization of cortico-subcortical connections at the multi-second time scale, and its accordance with iEEG models, remains unknown. Here, we used graph theo...

Background: Previous studies have reported the pain-relieving effect of chronic electrical motor cortex stimulation (eMCS) in various types of neuropathic pain. Objective: The study aimed to explore the potential relationship between the clinical efficacy of eMCS for the treatment of chronic neuropathic pain and the precise localization of the c...

Background Central post‐stroke pain (CPSP) can arise after lesions anywhere in the central somatosensory pathways, essentially within the spinothalamic system (STS). Although the STS can be selectively injured in the mesencephalon, CPSP has not been described in pure midbrain infarcts. Methods Out of more than 300 CPSP consecutive cases, we descri...

Key points Sleep spindles have recently been shown to occur not only across multiple neocortical regions but also locally in restricted cortical areas. Here we show that local spindles are indeed present in the human posterior thalamus. Thalamic local spindles had lower spectral power than non‐local ones. While non‐local thalamic spindles had equal...

“Asymbolia for pain” has shown the potentiality of diseased insular networks to dissociate sensory from affective-behavioral dimensions of pain, resulting in the lack of appropriate motor and affective responses despite preserved sensory aspect of pain. Here, we describe 4 patients with an inverse phenomenon of asymbolia for pain, namely an isolate...

We aimed at measuring the impact of a school-based sleep education program (ENSOM: 'EN' for 'ENfant' and SOM for 'SOMmeil' in French) on sleep, cognitive functioning and academic performance in children. In contrast with existing sleep education programs, ENSOM was designed by sleep experts with the intent of being autonomously achieved by teachers...

Résumé L’enregistrement des réponses cérébrales à une douleur expérimentale, chez des patients épileptiques avec des électrodes implantées dans différentes zones de la matrice douleur, plaide pour des réponses précoces préconscientes : les réponses insulaires postérieures et amygdaliennes avant 200 ms précèdent les réponses conscientes de la matric...

Observing pain in others can enhance our own pain. Two aspects of this effect remain unknown or controversial: first, whether it depends on the ‘painfulness’ of the visual stimulus; second, whether it reflects a genuine bias in perception or rather a bias in the memory encoding of the percept. Pain ratings and vegetative skin responses were recorde...

Objective: Vestibular afferents converge with nociceptive ones within the posterior insula, and can therefore modulate nociception. Consistent with this hypothesis, caloric vestibular stimulation (CVS) has been shown to reduce experimental and clinical pain. Since CVS can induce undesirable effects in a proportion of patients, here we explored an...

Empathetic verbal feedback from others has been shown to alleviate the intensity of experimental pain. To investigate the brain changes associated with this effect, we conducted 3T-fMRI measurements in 30 healthy subjects who received painful thermal stimuli on their left hand while overhearing empathetic, neutral or unempathetic comments, supposed...

The clinical use of noninvasive cortical stimulation procedures is hampered by the limited duration of the analgesic effects and the need to perform stimulation in hospital settings. Here, we tested the feasibility and pilot efficacy of an internet-based system for at-home, long-duration, medically controlled transcranial motor cortex stimulation (...

Objective: To compare the analgesic effects of stimulation of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep (d) repetitive (r) transcranial magnetic stimulation (TMS) in patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-...

Objectif Des stimuli nociceptifs phasiques délivrés au cours du sommeil provoquent dans environ 1/3 des cas une réaction d’éveil (RE). La présence de cette réaction semble favorisée par un sommeil plus léger et une plus grande connectivité fonctionnelle cérébrale avant le stimulus. Le but de notre étude est de caractériser le traitement cérébral ap...

Lenoir et al. [1] recently reported two cases of epileptic seizures as adverse events of continuous theta burst stimulation.They targeted the dorsal-posterior operculo-insular cortex in order to modulate somatosensory sensations in healthy volunteers, including those mediated by thermo-nociceptive input received by this region. Although the princip...

Electrophysiological techniques demonstrate abnormalities in somatosensory transmission, hence providing objective evidence of 'somatosensory lesion or disease’ which is crucial to the diagnosis of neuropathic pain (NP). Since most instances of NP result from damage to thermo-nociceptive pathways (thin fibres and spino-thalamo-cortical systems), sp...

Two parallel di-synaptic routes convey nociceptive input to the telencephalon: the spino-thalamic system projecting principally to the posterior insula, and the spino-parabrachial pathway reaching the amygdalar nucleus. Interplay between the two systems underlies the sensory and emotional aspects of pain, and was explored here in humans with simult...

INTRODUCTION The aim of this study was to search the relationship between the anatomical location and the eventual analgesic effect of each contact. METHODS Twenty-two patients (14 men and 8 women) suffering from central and/or peripheral neuropathic pain were implanted with stimulation of the precentral cortex. The implantation of the electrodes...

Intra-epidermal electrical stimulation (IEES) has been shown to activate selectively Aδ fibers subserving spinothalamic-mediated sensations. Owing to electrically induced highly synchronous afferent volleys, IEES induces Aδ-mediated evoked potentials at nonpainful intensities, contrasting with thermo-nociceptive laser pulses which entail painful pr...

Although modulation of cardiac activity may be influenced by several factors, interaction between autonomic nociceptive responses and the high-level of cortical processes is not clearly understood. Here, we studied in 26 subjects whether empathetic or unempathetic contexts could interact with autonomic pain responses. RR intervals variability was u...

Objectif Des stimulations nociceptives délivrées au cours du sommeil provoquent dans 1/3 des cas une réaction d’éveil qui suit une réponse cérébrale de type cognitif (Bastuji et al., 08) [1]. L’hypothèse de ce travail est que la présence ou l’absence de réaction d’éveil serait modulée par le profil d’activité cérébrale avant le stimulus nociceptif....

Background: Amitriptyline has well-established efficacy in several chronic pain conditions. While optimal treatment for chronic neck pain (CNP) remains controversial, amitriptyline was not tested for CNP. We evaluated the effect of bedtime amitriptyline in the management of CNP. Methods: 220 patients suffering from idiopathic CNP were randomized...

Pain was considered to be integrated subcortically during most of the 20thcentury, and it was not until 1956 that focal injury to the parietal opercular-insular cortex was shown to produce selective loss of pain senses. The parietal operculum and adjacent posterior insula are the main recipients of spinothalamic afferents in primates. The innermost...

Introduction L’objectif de cette étude est de localiser les contacts des électrodes en regard du cortex cérébral moteur et chercher la relation entre la localisation anatomique et l’effet antalgique de stimulation électrique de chaque contact. Matériaux et méthodes Vingt-deux patients (14 hommes et 8 femmes) sont victimes de douleurs neuropathique...

Background: The therapeutic influence of somatotopic matching between pain topography and motor cortex stimulation site for neuropathic pain (NP) remains controversial. Methods: Thirty-two patients suffering from NP involving the upper limb (n = 20) or the face (n = 12) received two high-frequency rTMS neuronavigated sessions targeting hand and...

We have all experienced that time seems stretched during unpleasant situations. While there is evidence of subjective time overestimation when perceiving external unpleasant stimuli, no study has measured the dilation of time when individuals experience an unpleasant situation in their own body. Here we measured the time dilation induced by a painf...

Cortical electrical stimulation (CES) has shown to be an effective therapeutic alternative for neuropathic pain refractory to pharmacological treatment. The primary motor cortex(M1) was the main cortical target used in the vast majority of both invasive and non-invasive studies. Despite positive results M1-based approaches still fail to relieve pai...

The aversive experience we call "pain" results from the coordinated activation of multiple brain areas, commonly described as a "pain matrix". This is not a fixed arrangement of structures but rather a fluid system composed of several interacting networks: A 'nociceptive matrix' includes regions receiving input from ascending nociceptive systems, a...

Neurophysiological techniques are useful to diagnose, predict and treat chronic pain, in particular of neuropathic origin. In this talk we shall succinctly review these different approaches, as well as the possibility they open to «back translation» of results gathered in humans to animal models. Diagnosis Definite diagnosis of neuropathic pain (N...

Objectives Intra-epidermal electrical stimulation (IES) is considered to stimulate selectively and directly Aδ fibres, by-passing the heat-mediated receptor process of laser stimulation. However, there has been only extra-cranial data to argue such fiber selectivity. Here, we recorded intracranial responses to IE and laser stimulations, to assess w...

Background: Motor Cortex Stimulation (MCS) was introduced in the early 1990's by Tsubokawa and his group for patients diagnosed with drug-resistant, central neuropathic pain. Inconsistencies concerning the details of this therapy and its outcomes and poor methodology of most clinical essays, divide the neuromodulation society worldwide in "believe...

The physiological and behavioural effects of empathy for other's pain have been widely investigated, while the opposite situation, i.e. the influence on one's pain of empathetic feedback from others, remains largely unexplored. Here, we assessed whether and how empathetic and unempathetic comments from observers modulate pain and associated vegetat...

Background: Source modeling of EEG traditionally relies on interplay between physiological hypotheses and mathematical estimates. We propose to optimize the process by using evidence gathered from brain imaging and intracortical recordings. Methods: We recorded laser-evoked potentials in 18 healthy participants, using high-density EEG. Brain sou...

Although motor cortex stimulation (MCS) is being increasingly used to treat chronic refractory neuropathic pain in humans, its mechanisms of action remain elusive. Studies in animals have suggested the involvement of subcortical structures, in particular the thalamus. Most of these studies have been carried out in rats, a species presenting signifi...

Objectif Alors que les fuseaux de sommeil ont longtemps ete consideres comme des elements inhibiteurs de l’information sensorielle durant le sommeil lent, nous avons montre l’absence de cet effet inhibiteur sur le traitement de l’information nociceptive, aussi bien en termes de reponse corticale que de reaction d’eveil (Claude et al., 2015). Le but...

Objectif D’apres le modele felin de Steriade, les fuseaux du sommeil lent, generes dans les noyaux reticulaires du thalamus, sont transmis de facon synchrone dans la boucle thalamo-corticale. Des donnees recentes, obtenues chez l’homme, ont montre qu’ils different en terme de frequence, plus lents dans les regions frontales que parietales, et de lo...

Objective: For a decade it has been known that the insular lobe epilepsy can mimic frontal lobe epilepsy. We aimed to clarify the pattern of functional coupling occurring during the frontal presentation. Methods: We analyzed five insular lobe epilepsy patients. Frontal semiology was predominant for three of them, whereas insular semiology was pr...

A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson’s disease, other movement d...

Objective Chronic neuropathic pain is difficult to treat. Recently, a novel target for neuromodulation, the DRG, has been shown to be effective in managing neuropathic pain. However, the mechanisms underlying the impact of DRG stimulation are not well established. Therefore, we want to assess LEP’s for the quantification of the effects of DRG stimu...

Background and purpose: Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Eval...