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Treating Chronic Migraine With Neuromodulation: The Role of Neurophysiological Abnormalities and Maladaptive Plasticity.

ABSTRACT: Chronic migraine (CM) is the most disabling form of migraine, because pharmacological treatments have low efficacy and cumbersome side effects. New evidence has shown that migraine is primarily a disorder of brain plasticity and migraine chronification depends on a maladaptive process favoring the development of a brain state of hyperexcitability. Due to the ability to induce plastic changes in the brain, researchers started to look at Non-Invasive Brain Stimulation (NIBS) as a possible therapeutic option in migraine field. On one side, NIBS techniques induce changes of neural plasticity that outlast the period of the stimulation (a fundamental prerequisite of a prophylactic migraine treatment, concurrently they allow targeting neurophysiological abnormalities that contribute to the transition from episodic to CM. The action may thus influence not only the cortex but also brainstem and diencephalic structures. Plus, NIBS is not burdened by serious medication side effects and drug-drug interactions. Although the majority of the studies reported somewhat beneficial effects in migraine patients, no standard intervention has been defined. This may be due to methodological differences regarding the used techniques (e.g., transcranial magnetic stimulation, transcranial direct current stimulation), the brain regions chosen as targets, and the stimulation types (e.g., the use of inhibitory and excitatory stimulations on the basis of opposite rationales), and an intrinsic variability of stimulation effect. Hence, it is difficult to draw a conclusion on the real effect of neuromodulation in migraine. In this article, we first will review the definition and mechanisms of brain plasticity, some neurophysiological hallmarks of migraine, and migraine chronification-related (dys)plasticity. Secondly, we will review available results from therapeutic and physiological studies using neuromodulation in CM. Lastly we will discuss the results obtained in these preventive trials in the light of a possible effect on brain plasticity.

SUBMITTER: Vigano A

PROVIDER: S-EPMC6370938 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Treating Chronic Migraine With Neuromodulation: The Role of Neurophysiological Abnormalities and Maladaptive Plasticity.

Viganò Alessandro A Toscano Massimiliano M Puledda Francesca F Di Piero Vittorio V

Frontiers in pharmacology 20190205

Chronic migraine (CM) is the most disabling form of migraine, because pharmacological treatments have low efficacy and cumbersome side effects. New evidence has shown that migraine is primarily a disorder of brain plasticity and migraine chronification depends on a maladaptive process favoring the development of a brain state of hyperexcitability. Due to the ability to induce plastic changes in the brain, researchers started to look at Non-Invasive Brain Stimulation (NIBS) as a possible therapeu ...[more]

PMID: 30804782

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Project description:IntroductionRemote electrical neuromodulation (REN) is a novel acute treatment of migraine. Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. The REN device (Nerivio®, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. The current study assessed the consistency of response over multiple migraine attacks in people with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans.MethodsThis was an open-label, single-arm, dual-center study conducted on adults with chronic migraine. Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 min within 1 h of attack onset. Pain levels were recorded at baseline, 2 h, and 24 h post-treatment. Efficacy outcomes (pain relief and pain-free responses at 2 h, sustained pain relief and sustained pain-free responses at 24 h) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50% of the treatments.ResultsForty-two participants were enrolled, and 38 participants were evaluable for analyses; 73.7% (28/38) achieved pain relief at 2 h, 26.3% (10/38) were pain-free at 2 h, 84.4% (27/32) had sustained pain relief response at 24 h and 45.0% (9/20) had sustained pain relief response at 24 h in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent. The incidence of device-related adverse events was low (1.8%).ConclusionsREN used for a series of migraine attacks was effective and well tolerated across attacks. REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine.Trial registrationClinicalTrials.gov identifier, NCT04161807. Retrospectively registered on November 13, 2019.

Project description:Tinnitus is a phantom auditory sensation experienced by up to 14% of the United States population with a smaller percentage experiencing decreased quality of life. A compelling hypothesis is that tinnitus results from a maladaptive plastic net down-regulation of inhibitory amino acid neurotransmission in the central auditory pathway. This loss of inhibition may be a compensatory response to loss of afferent input such as that caused by acoustic insult and/or age-related hearing loss, the most common causes of tinnitus in people. Compensatory plastic changes may result in pathologic neural activity that underpins tinnitus. The neural correlates include increased spontaneous spiking, increased bursting and decreased variance of inter-spike intervals. This review will examine evidence for chronic plastic neuropathic changes in the central auditory system of animals with psychophysically-defined tinnitus. Neurochemical studies will focus on plastic tinnitus-related changes of inhibitory glycinergic neurotransmission in the adult dorsal cochlear nucleus (DCN). Electrophysiological studies will focus on functional changes in the DCN and inferior colliculus (IC). Tinnitus was associated with increased spontaneous activity and altered response properties of fusiform cells, the major output neurons of DCN. Coincident with these physiologic alterations were changes in glycine receptor (GlyR) subunit composition, its anchoring/trafficking protein, gephyrin and the number and affinity of membrane GlyRs revealed by receptor binding. In the IC, the primary afferent target of DCN fusiform cells, multi-dimensional alterations in unit-spontaneous activity (rate, burst rate, bursting pattern) were found in animals with behavioral evidence of chronic tinnitus more than 9 months following the acoustic/cochlear insult. In contrast, immediately following an intense sound exposure, acute alterations in IC spontaneous activity resembled chronic tinnitus-related changes but were not identical. This suggests that long-term neuroplastic changes responsible for chronic tinnitus are likely to be responsible for its persistence. A clear understanding of tinnitus-related plasticity in the central auditory system and its associated neurochemistry may help define unique targets for therapeutic drug development.

Project description:BACKGROUND:There is a significant unmet need for new, effective and well tolerated acute migraine treatments. A recent study has demonstrated that a novel remote electrical neuromodulation (REN) treatment provides superior clinically meaningful pain relief with a low rate of device-related adverse events. The results reported herein compare the efficacy of REN with current standard of care in the acute treatments of migraine. METHODS:We performed a post-hoc analysis on a subgroup of participants with migraine from a randomized, double-blind, parallel-group, sham-controlled, multicenter study on acute care. The original study included a 2-4?weeks run-in phase, in which migraine attacks were treated according to patient preference (i.e., usual care) and reported in an electronic diary; next, participants entered a double-blind treatment phase in which they treated the attacks with an active or sham device. The efficacy of REN was compared to the efficacy of usual care or pharmacological treatments in the run-in phase in a within-subject design that included participants who treated at least one attack with the active REN device and reported pain intensity at 2?h post-treatment. RESULTS:Of the 252 patients randomized, there were 99 participants available for analysis. At 2?h post-treatment, pain relief was achieved in 66.7% of the participants using REN versus 52.5% participants with usual care (p?<?0.05). Pain relief at 2?h in at least one of two attacks was achieved by 84.4% of participants versus 68.9% in usual care (p?<?0.05). REN and usual care were similarly effective for pain-free status at 2?h. The results also demonstrate the non-inferiority of REN compared with acute pharmacological treatments and its non-dependency on preventive medication use. CONCLUSION:REN is an effective acute treatment for migraine with non-inferior efficacy compared to current acute migraine therapies. Together with a very favorable safety profile, these findings suggest that REN may offer a promising alternative for the acute treatment of migraine and could be considered first line treatment in some patients. TRIAL REGISTRATION:ClinicalTrials.gov NCT03361423 . Registered 18 November 2017.

Project description:Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adkfl/fl mice. These Adk?brain mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A1 receptor (A1R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A2A receptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2A receptor activity in Adk?brain mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion of Adk (Adk?brain). Similar to ADK-deficient patients, Adk?brain mice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A2A receptor (A2AR)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.

Dataset Information

Treating Chronic Migraine With Neuromodulation: The Role of Neurophysiological Abnormalities and Maladaptive Plasticity.

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Treating Chronic Migraine With Neuromodulation: The Role of Neurophysiological Abnormalities and Maladaptive Plasticity.

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