首都医科大学三博脑科医院 李天富 高青 栾国明

While the efficacy of vagus nerve stimulation (VNS) to reduce seizures and improve comorbidities associated with pharmacoresistant epilepsy including mood as well as quality of life is clinically proven, the exact mechanism of VNS remains unclear. VNS exerts antiepileptic or antiepileptogenic effect possibly through i) neuromodulation of release of noradrenaline from locus coeruleus; ii) induced profound changes in brain blood flow; iii) immunomodulation or anti-neuroinflammation; iv) change EEG brain function-al connectivity; v) modification of the proteome of excitatory synapses of amyg-daloid/piriform cortex; vi) modulation of adenosine system and DNA methyla- tion. Beyond epilepsy, VNS is also under investigation for the treatment of epilep-sy associated comorbidities including cognitive comorbidities and psychiatric comorbidities. Of importance, progression in VNS clinical efficacy over time suggests an underlying disease-modifying neuromodulation, which is an emerging field in pharmacoresistant epilepsy. With bidirectional potential clinical efficacy of VNS in epilepsy, a prototype neuropsychiatric illness, further research on the solid mechanisms of VNS for epilep-sy and associated comorbidities is encouraging.

Key words: epilepsy, comorbidity, vagus nerve stimulation, neuromodulation.

Introduction

Up to 30 percent of patients with epilepsy is pharmacoresistant , and apart from those who are candidates for resective surgery, most will continue to have disabling seizures and the poor quality of life with a wide range of cognitive and psychiatric symptoms . Epilepsy may be regarded as prototype neuropsychiatric illness with interface of neurology and psychiatry, and treatment of comorbidity is likely to improve the overall course of illness as well as quality of life. Therefore, new therapies aim to modify the progression of epilepsy (disease modification) and concomitant comorbidities through by targeting the disease process. Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as a palliative ther- apy for patients with pharmacoresistant epilepsy who are not suitable candidates for resective brain surgery or for whom surgery has failed . VNS is also a possible treatment option for treatment of epilep-sy associated comorbidities including cognitive comorbidities and psychiatric comorbidities. VNS has been proved to be effective in the treatment epileptic seizures, improve quality of life as well as progres-sion in VNS clinical efficacy over time . Currently, most of the VNS studies in epilepsy mainly focused on VNS effectiveness in seizure control. Several studies demonstrated that the mechanism of action might be related to neuromodulation of release of noradrenaline from locus coeruleus , induced hippo-campal decreases in glucose metabolism and blood flow, immunomodulation or anti-neuroinflamma-tion, change EEG brain functional connectivity as well as modification of neuronal activity and the proteome of excitatory synapses of amygdaloid/piriform cortex, and possible modulation of adenosine system and DNA methylation .

Comorbidities in epilepsy represent a major conceptual and therapeutic challenge. Currently, the bidi-rectional relation between epilepsy and associated comorbidities has been paid more and more atten-tions , and advances on the overlap of psychiatric / cognitive and neurologic symptoms from a patho-physiologic and phenomenologic perspective are becoming a hot topic in epilepsy. Depressive disorders are the most common type of psychiatric comorbidity in patients with epilepsy , especially in individu-als suffering from refractory temporal lobe epilepsy. Several mechanisms of primary depressive disor-ders such as endocrine abnormalities, structural and functional abnormalities of cortical and subcortical structures, neurotransmitter abnormalities and immunological inflammation abnormalities, have an effect on cortical hyperexcitability and the epileptogenic process. The mechanism of VNS to treat epilepsy associated comorbidities might be through the mechanisms mentioned above . Of scientific interesting, progression in VNS clinical efficacy over time and chronic VNS clearly induces long-last- ing changes in the neuronal network involved in epileptogenesis , indicating that long term use of VNS modify the progression of epilepsy (disease modification or antiepileptogenesis) , and that the earlier this is done, the better the outcome for seizures and associated comorbidities control. In this review, we will focus on the mechanisms of action of VNS for epilepsy and associated comorbidities.

Mechanisms of action of VNS for epilepsy

Serotonin as a mediator of the antiepileptic effects of VNS Recent study provided convincing evidence for the existence of a strong causal link between increased noradrenergic signaling and the anticonvulsant effect of VNS. Increased in extracellular hippocampal noradrenaline (NE), but not of dopamine, serotonin and GABA, has been indicated to be responsible for its seizure-suppressing effect in a model for limbic seizures, and regarded as a potential biomarker for the efficacy of VNS in temporal lobe epilepsy . Selective a2-adrenoreceptor antagonism in proximity of the seizure focus abolishes the seizure-suppressing effect of VNS . The locus coeruleus, the most important source of NE in the brain , appears to be crucial for the anticonvulsive effects of VNS since seizure-suppressive effects of VNS were prevented by LC lesioning . Serotonergic transmission may also play a role since basal firing rates of serotonergic neurons in the dorsal raphe nucleus significantly increased after chronic VNS. However, this effect seems to be NE-dependent since selective lesioning of the locus coeruleus prevented this enhancement of serotonin neuron firing .

Induced profound changes in brain blood

flowPositron-emission tomography and functional magnetic resonance imaging of the effects of VNS in human beings have confirmed the influence the vagus nerve on higher brain structures. Stimulation of VNS causes increases in cerebral blood flow and can alter electroencephalographic patterns. Clinical studies with positron-emission tomography demonstrated that VNS increased blood flow to the right thalamus, the right posterior temporal cortex, the left putamen, and the left inferior cerebellum at inter- ictal stage of seizures ; Clinical studies with functional magnetic resonance imaging indicated that the areas of significant activation in response to VNS were the bilateral orbitofrontal and parieto-occipital cortex, the left temporal cortex, and the left amygdala at interictal stage of seizures . Animal study demonstrated that VNS can arrest ongoing seizure activity (ictal stage of seizures) by ultimately decreasing hippocampal blood flow .

Anti-neuroinflammation or immunomodulation

Extensive experimental and clinical evidence supports a link between inflammation and epilepsy, both in terms of epileptogenesis and the long-term consequences of seizures, which indicates that activation of inflammatory processes in the brain is a common feature of various epileptic disorders . With an intact vagal-immune network, VNS can dampen inflammatory response. The vagus nerve is implicated in immunomodulation as efferent vagus nerve fibres systemically inhibit pro-inflammatory cytokine release . In addition, VNS activates the hypothalamic-pituitary-adrenal axis. Animal research has demonstrated that VNS-induced increased hippocampal expression of corticotrophin releasing factor and increased plasma levels of adrenocorticotropic hormone and corticosteron , which support the role of the VNS in immunomodulation or anti-neuroinflammation.

Change EEG brain functional connectivity

EEG brain functional connectivity is a way to study brain function through the study of pair-wise correlations, and reflects how different brain areas coordinate their activities. Estimating changes of EEG brain functional connectivity is indicated as a promising tool for predicting response to VNS . The effect of VNS on functional connectivity has been studied using scalp EEG demonstrated that functional connectivity tended to be lower in the on period, and that this effect was maximal for responder patients . More recently, study investigated the impact of VNS on brain functional connectivity with stereotactic EEG signals . The results demonstrated that VNS can decrease or increase the functional connectivity changes with variable effect from patient to patient, and clinical responder with decreased functional connectivity .

Modification the proteome of excitatory synapses of amygdaloid/piriform cortex

The molecular mechanisms underlying VNS for epilepsy are overall unclear. Plasticity of excitatory synapses is thought to contribute to the hyperexcitability of epilepsy . The postsynaptic density (PSD) is a membrane specialization of the postsynaptic component of excitatory synapses in the CNS and the protein composition of the PSD is regulated by neuronal activity . Recent study demonstrated that VNS modifies both neuronal activity in amygdala and hippocampus and the composition of excitatory synapses in the CNS , which suggested that activity-dependent formation of excitatory synapses might be molecular targets of VNS for epilepsy.

Modulation of adenosine system and DNA methylation.

Adenosine is an inhibitory modulator of brain activity, and its anticonvulsant and seizure terminating effects, mediated by both receptor-dependent and receptor–independent pathways, have been illustrated in a wide range of experimental models of epilepsy and clinical studies . Therapeutic adenosine augmentation is a powerful therapeutic strategy to suppress epileptic seizures and epileptogenesis . Neurostimulation has been indicated to increase the extracellular adenosine concentration in the brain to enhance adenosine signaling and adenosine A1 receptor-dependent activation. On the other hand, increase of adenosine levels in the brain might also exert receptor-independent effects in DNA methyla- tion homeostasis to reduce DNA methylation . There is every indication that agents able to increase adenosine availability may have a place in the future treatment of epilepsy via adenosine receptor-de-pendent pathway and adenosine receptor-independent pathway . How the VNS modulated adenosine system and exert its efficacy in the treatment of epilepsy and modification the progression of epilepsy needs further investigation in the future.

Mechanisms of action of VNS for comorbidities associated with epilepsy

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition .Up to 30 percent of patients with epilepsy is pharmacoresistant , and apart from those who are candi-dates for resective surgery, most will continue to have disabling seizures and the poor quality of life with a wide range of cognitive and psychiatric symptoms . Recurrent seizures induced the reorganization of neural circuits and activities in the brain, therefore, patients frequently experience cognitive, psychiatric and mood disorders . On the other hand, the most recent research indicates that some neurocognitive and psychological comorbidities as well as structural brain changes predate the onset of seizures, with the early cognitive compromise being further magnified by the onset of epileptogenesis, and later on, by the chronicity of seizures . Epilepsy, being regarded as a prototype of neuropsychiatric /neurocognitive and illness, epilepsy and associated comorbidities are usually frequent and share common underlying mech-anisms with epilepsy. Currently, the bidirectional relation between epilepsy and associated comorbidi-ties has been paid much more attentions . Currently, mechanisms of dysregulation of the hypothala-mus–pituitary–adrenal (HPA) axis, and compromised raphe-hippocampal serotonergic transmission are well accepted behind epilepsy and neuropsychiatric disorders . VNS has been proved to increase the basal firing rates of serotonergic neurons in the dorsal raphe nucleus, thus plays a role in both seizures and associated comorbidities.

Recently, adenosine dysfunction has been indicated as the underlying mechanism for comorbidities associated with epilepsy and that therapeutic adenosine augmentation might be effective for the treat- ment of epilepsy and comorbid symptoms in epilepsy . Clinical as well as experimental data suggest that a triad of synaptotoxicity, astrogliosis, and overexpression of ADK, resulting in a deficiency of homeo-static adenosine can directly cause a wide range of cognitive and psychiatric symptoms commonly seen as comorbidities in epilepsy as follows:

i) Adenosine and epilepsy.

As introduced above, extensive experimental and clinical evidence demonstrated that dysfunctional astrocytic adenosine homeostasis as one of the early pathophysiologic mechanisms of epilepsy, and therapeutic adenosine augmentation exerts anticonvulsant and seizure terminating effects, mediated by both receptor-dependent and receptor–independent pathways .

ii) Adenosine and cognition.

Adenosine affects cognitive processes on several mechanistic levels through locally refined neuronal and astroglial A2AR signaling effects and modulation of glutamatergic, dopaminergic, GABAergic, and BDNF-dependent mechanisms . Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to cognitive impairment . Adenosine augmentation to the hippocampus can improve cognitive function . These findings suggest that therapeutic adenosine augmentation might constitute a promising approach for the treatment of comorbid depression in a wide range of neurological and neuro-psychiatric disorders.

iii) Adenosine and depression.

Recent study demonstrated that astrocytic signaling to adenosine A1 receptor was required for the robust reduction of depressive-like behaviors in mice following 12 h of sleep deprivation . Approaches known to increase adenosine level such as exercise , sleep deprivation , acupuncture , deep brain stimulation ,or ketogenic diet have demonstrated antidepressive effects. S-adenosylhomocysteine, a precursor of adenosine, has been used for the treatment of major depression . VNS, the most commonly used neuro-modulation for pharmacoresistant epilepsy, might constitute a promising approach for the treatment of epilepsy associated comorbidities as well through adenosine system.

Concluding remarks

Advances on the overlap of psychiatric and neurologic symptoms from a pathophysiologic and phenom- enologic perspective are becoming a hot topic in epilepsy. New therapies aim to modify the progression of epilepsy and concomitant comorbidities through by targetting the disease process. VNS has demon-strated its potential in pharmacoresistant epilepsy and comorbidities associated with epilepsy, and enhanced VNS efficacy over time clearly reflects a its disease modification effects. It is crucial to identi-fify and validate the biomarkers for the VNS therapy that track with disease progression and comorbidi-ties, and predict therapeutic outcome. In the future, research will focus on how to combine neurocogni-tive and neuropsychiatric markers, allowing systematic advances in our understanding of the natural history of cognitive and behavioral disturbances in the epilepsies relative to the onset and progression of seizures.

Acknowledgements

We are grateful to the outstanding contributions of the authors for their efforts and collaboration to submit their manuscripts to this special issue. We acknowledge the financial support from national natu-ral science foundation of China (81571275), BIBD-PXM2013_014226_07_000084, National Key Tech-nology R&D Program of China (2012BAI03B02), Scientific Research Common Program of Beijing

Commission of Education (KM201410025027), Capital Characteristic Clinical Application Research (Z131107002213169), the capital health research and development of special(2016-4-8011)

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