Beyond the treatment of epilepsy: new applications of vagus nerve stimulation in psychiatry

Vagus nerve stimulation (VNS) in humans generally refers to stimulation of the left vagus nerve at the cervical level VNS is an established treatment largely devoid of severe side effect for medically refractory partial onset seizures and has been used in more than 16,000 patients. Over the past 5 years, applications in other neuropsychiatric disorders have been investigated with a special emphasis on depression. Recent data from an open-label, multi-center pilot study involving 60 patients suggest a potential clinical usefulness in the acute and maintenance treatment of drug-resistant depressive disorder. The perspective of VNS as along-term treatment with the advantage of assured compliance makes it an interesting technique to potentially treat drug-resistant depression. However, definite therapeutic effects of clinical significance remain to be confirmed in large placebo-controlled trial. Results of clinical pilot studies involving patients suffering from obesity and Alzheimer's disease indicate that VNS might induce weight loss and improve cognition. Besides its clinical usefulness, VNS can be used as a research tool, allowing neurophysiologic investigations of the parasympathetic system and its interactions with other parts of the central nervous system.     

Putative common pathways in therapeutic brain stimulation for affective disorders

Brain stimulation methods in the treatment of affective disorder are electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Clinically, ECT is considered the strongest remedy in the treatment of severe depression, especially depression with psychotic features, and in the elderly. TMS, despite positive reports, is somewhat more controversial. VNS has, so far, only been used in treatment-resistant depression with limited results. DBS may be of potential use in rare cases of treatment-resistant cases of affective disorder. This article highlights the similarities and differences between the four stimulation methods. The main difference is the seizures necessary in ECT. A stronger involvement of the hippocampus following experimental seizures compared with effects in that region induced by TMS and VNS might explain the consistent findings of the superiority of ECT in the most severe cases of affective disorder.     

Possible involvement of the vagus nerve in monitoring plasma catecholamine levels

In their article Miyashita and Williams (Neurobiology of Learning and Memory 2006, 85, 116-124) describe the effect of peripheral administration of epinephrine on neural discharge in vagal afferent fibers. It seems that described data supports the hypothesis of the vagus nerve participation in monitoring plasma catecholamine levels and consequently modifying brain functions. However, do these results indicate indeed that afferent vagus nerve pathways are activated by circulating epinephrine? Catecholamines influence virtually all tissues and many functions. Vagus nerve participates significantly in monitoring of those effects. Therefore epinephrine-induced increases of afferent vagus nerve activity described by Miyashita and Williams may reflect not only exclusive activation of beta-adrenergic receptors but also an activation of other types of receptors on vagal sensory nerve endings, e.g., mechanosensors, chemoreceptors, and osmosensors. Discussion is focused on the possibility that the increase in afferent vagus nerve activity may reflect activation of mechanoreceptors of the vagus nerve endings in the epinephrine-activated heart.     

Aggression in temporal lobe epilepsy and limbic psychotic trigger reaction implicating vagus kindling of hippocampus/amygdala (in sinus abnormalites on MRIs)

Five aspects associated with potentially aggressive partial limbic seizures are interrelated: (1) Five out of six unselected (consecutively referred) White, male out-of-character aggressive felons (mean age 33) had histories of recurrent nasopharyngeal infections, four with congruent MRIs, two of these MRIs also showed cortical atrophy, three men had histories of various seizures, and one scalp EEG was “congruent with seizures in the temporal regions.” All men had histories of head injuries. The diagnoses of their bizarre acts during a brief psychosis were partial limbic seizures in an “exhibitionist” with temporal lobe epilepsy (TLE) and proposed limbic psychotic trigger reaction (LPTR) in four “murderers”, based on 13 specific symptoms and signs. (2) The men's nasopharyngeal (medical) conditions are hypothesized to be associated with intermittent mild stimulation of the vagus nerve. Supportive evidence shows that (3) experimental vagus stimulation has the most excitatory impact on hippocampus and amygdala, which are also (4) the most susceptible to limbic seizure kindling (by intermittent subthreshold stimuli). (5) even by contrast, high-voltage energy level and frequently applied vagus nerve stimulation (VNS), which is used as an antiepileptic treatment; however, VNS has elicited seizures in some patients.     

经皮迷走神经刺激对抑制控制的调节机制

近年众多研究表明, 经皮迷走神经刺激(tVNS)作为一种新型、非侵入式的神经调控技术对个体的抑制控制功能具有积极的调节作用。已有研究发现, tVNS对抑制控制的调节作用可能是通过调控蓝斑核-去甲肾上腺素系统(LC-NE)的活动和神经递质GABA的浓度来实现的。然而, 目前对tVNS调控抑制控制的神经机制仍存在诸多尚未明确的问题。未来研究在进一步优化tVNS的刺激参数后, 可以从tVNS对抑制控制能力受损群体的调控作用及机制、如何实现和增强tVNS长期积极效应等方面进行深入探索。     

Mechanisms and the current state of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is unique among the current brain stimulation techniques because it is relatively non-invasive. TMS markedly differs from vagus nerve stimulation, deep brain stimulation and magnetic seizure therapy, all of which require either an implanted prosthesis or general anesthesia, or both. Since its rebirth in its modern form in 1985, TMS has already shown potential usefulness in at least three important domains-as a basic neuroscience research instrument, as a potential clinical diagnostic tool, and as a therapy for several different neuropsychiatric conditions. The TMS scientific literature has now expanded beyond what a single summary article can adequately cover. This review highlights several new developments in combining TMS with functional brain imaging, using TMS as a psychiatric therapy, potentially using TMS to enhance performance, and finally recent advances in the core technology of TMS. TMS' ability to non-invasively and focally stimulate the brain of an awake human is proving to be a most important development for neuroscience in general, and neuropsychiatry in particular.     

Vagus nerve stimulation and Lennox-Gastaut syndrome: a review of the literature and data from the VNS patient registry

Lennox-Gastaut syndrome (LGS) is a severe form of childhood epilepsy that is usually refractory to medical management. When medication fails, alternative therapies are considered. Among these are two surgical options: corpus callosotomy and vagus nerve stimulation (VNS). Safety and efficacy are two important factor to consider when selecting an appropriate treatment. VNS is safer than callosotomy, but its efficacy is more difficult to assess. Available studies evaluate its effectiveness using a mixed population of patients (some with prior epilepsy surgery), a multitude of VNS settings, and variable endpoints. To estimate the efficacy of VNS in patients with LGS, a review of the medical literature and the VNS Patient Registry was performed. Within the limits of this type of study, the results showed that VNS appears to be equally as effective as callosotomy. Because VNS has a lower potential for adverse effects, these results suggest that VNS should be considered first in appropriately selected patients.     

Selective unilateral autonomic activation: implications for psychiatry

Research advances have led to three methods for selectively activating one half of the autonomic nervous system in humans. The first method is an ancient yogic technique called unilateral forced nostril breathing (UFNB) that employs forced breathing through only one nostril while closing off the other. The second method works by stimulation of an autonomic reflex point on the fifth intercostal space near the axilla. The most recent method employs unilateral vagus nerve stimulation (VNS) via the mid-inferior cervical branch and requires surgical implantation of a wire and pacemaker. UFNB is non-invasive and seems to selectively activate the ipsilateral branch of the sympathetic nervous system with a possible compensation effect leading to contralateral VNS. UFNB and VNS have been employed to treat psychiatric disorders. While UFNB has been studied for its potential effects on the endogenous ultradian rhythms of the autonomic and central nervous system, and their tightly coupled correlates, VNS has yet to be studied in this regard. This article reviews these three methods and discusses their similarities, putative mechanisms, their studied effects on the endogenous autonomic nervous system and central nervous system rhythms, and their implications for the treatment of psychiatric disorders.     

Vagus nerve stimulation therapy in a patient with treatment-resistant depression: a case report of long-term follow-up and battery end-of-service

This is the first case report of a patient who received long-term (69-month) adjunctive vagus nerve stimulation (VNS) therapy for treatment-resistant depression (TRD) and reached VNS battery end-of-service (EOS). The patient is a 41-year-old female with depression who entered a study of adjunctive VNS therapy for TRD. Her Hamilton Rating Scale for Depression (HAM-D) scores dropped from a mean of 33.5 (pre-implantation baseline period) to 16 at the end of the 12-week acute-phase treatment period, and then fluctuated from <7 (normal range) to scores in the moderately depressed range (approximately 20) during long-term follow-up. Three and one-half years after VNS implantation, the patient's HAM-D scores began to increase from a score of 18 to a peak score of 27 approximately 16 months later (5-years post-implantation). The patient subsequently reported that she could no longer feel stimulation from the device and device interrogation 2 weeks later indicated battery EOS. The patient was hospitalized due to worsened depression, the pulse generator was replaced, and medication adjusted. HAM-D scores through the subsequent 9 months of follow-up returned to a pattern of fluctuations within the range noted during the long-term follow-up period prior to VNS battery EOS.     

Epilepsy, consciousness and neurostimulation

Consciousness is often disrupted in epilepsy. This may involve altered responsiveness or changes in awareness of self and subjective experiences. Subcortical arousal systems and paralimbic fronto-parietal association cortices are thought to underpin current concepts of consciousness. The Network Inhibition Hypothesis proposes a common neuroanatomical substrate for impaired consciousness during absence, complex partial and tonic-clonic seizures. Neurostimulation in epilepsy remains in its infancy with vagal nerve stimulation (VNS) as the only firmly established technique and a series of other methods under investigation including deep brain stimulation (DBS), intracranial cortical stimulation and repetitive transcranial magnetic stimulation (rTMS). Many of these systems impact on the neural systems thought to be involved in consciousness as a continuous duty cycle although some adaptive (seizure triggered) techniques have been developed. Theoretically, fixed duty cycle neurostimulation could have profound effects on responsiveness, awareness of self and subjective experience. Animal studies suggest vagal nerve stimulation positively influences hippocampal long term potentiation. In humans, a chronic effect of increased alertness in VNS implanted subjects and acute effect on memory consolidation have been reported but convincing data on either improvements or deterioration in attention and memory is lacking. Thalamic deep brain stimulation (DBS) is perhaps the most interesting neurostimulation technique in the context of consciousness. Neither bilateral anterior or centromedian thalamic nucleus DBS seem to affect cognition. Unilateral globus pallidus internus DBS caused transient wakefulness in an anaesthetised individual. As intracranial neurostimulation, particularly thalamic DBS, becomes more established as a clinical intervention, the effects on consciousness and cognition with variations in stimulus parameters will need to be studied to understand whether these secondary effects of neurostimulation make a significant positive (or adverse) contribution to quality of life.     

大脑电刺激在听觉语言加工研究中的应用

大脑电刺激是历史悠久但近年来才广泛应用在人类被试上的实验技术。通过对颅内刺激位点进行电刺激, 并分析引发的暂时性行为功能变化和记录位点的电位活动, 大脑电刺激技术可以揭示认知加工过程中脑区内的功能作用与脑区间的有效连接。通过对听觉语言加工过程相关的丘脑、听觉皮层、高级语言皮层进行电刺激, 现有研究发现了各个脑区的不同功能特点以及不同脑区间的信息传递机制, 为进一步探索听觉语言加工的神经机制提供了新的视角。     

Epinephrine administration increases neural impulses propagated along the vagus nerve: Role of peripheral beta-adrenergic receptors

A significant number of animal and human studies demonstrate that memories for new experiences are encoded more effectively under environmental or laboratory conditions which elevate peripheral concentrations of the hormone epinephrine and in turn, induce emotional arousal. Although this phenomenon has been replicated across several learning paradigms, understanding of how this arousal related hormone affects memory processing remains obscure because epinephrine does not freely enter into the central circulation to produce any direct effects on the brain. This study examined whether epinephrine's actions on the CNS may be mediated by the initial activation of peripheral vagal fibers that project to the brain. The vagus was selected as a candidate for this role since it is densely embedded with beta-adrenergic receptors and the peripheral endings of this nerve innervate a broad spectrum of sensory organs that are directly affected by epinephrine release. Electrophysiological recordings of cervical vagal activity was measured over 110 min in urethane-anesthetized Sprague-Dawley rats given saline, epinephrine (0.3 mg/kg), the peripherally acting beta-adrenergic antagonist sotalol (2.0 mg/kg), or a combination of sotalol followed 15 min later by an injection of epinephrine. Epinephrine produced a significant increase in vagal nerve firing 10 min post-injection (p < .05) relative to controls and neural impulses recorded from the vagus remained significantly elevated for the remaining 55 min collection period. The excitatory actions of epinephrine were not observed in groups given an identical dose of the hormone after peripheral beta-adrenergic receptor blockade with sotalol. These findings demonstrate that neural discharge in vagal afferent fibers is increased by elevations in peripheral concentrations of epinephrine and the significance of these findings in understanding how epinephrine modulates brain limbic structures to encode and store new information into memory is discussed.     

Posttraining Electrical Stimulation of Vagal Afferents with Concomitant Vagal Efferent Inactivation Enhances Memory Storage Processes in the Rat

Peripherally administered or released substances that modulate memory storage, but do not freely enter the brain, may produce their effects on memory by activating peripheral receptors that send messages centrally through the vagus nerve. Indeed, vagus nerve stimulation enhances memory performance, although it is unclear whether this effect is due to the activation of vagal afferents or efferents. To eliminate the possible influence of descending fibers on memory storage processes, rats were implanted with cuff electrode/catheter systems along the left cervical vagus. Forty-eight hours following surgery, each animal received a 3.0-μl infusion (1.0 μl/min) of either lidocaine hydrochloride (75.0 mM) or isotonic saline below the point of stimulation. Animals were then trained 10 min later on an inhibitory-avoidance task with a 0.75-mA, 1.0-s foot shock. Sham stimulation or vagus nerve stimulation (0.5-ms biphasic pulses; 20.0 Hz; 30 s; 0.2, 0.4, or 0.8 mA) was administered immediately after training. Memory, tested 24 h later, was enhanced by stimulation whether descending vagus nerve fibers were inactivated or not. Both lidocaine- and saline-infused groups showed an intensity-dependent, inverted-U-shaped pattern of retention performance, with the greatest effect observed for 0.4 mA (U= 9,p< .05, andU= 7,p< .01, respectively). Additionally, animals that received lidocaine infusions, but no vagus nerve stimulation, showed impaired memory compared to the performance of saline-infused control animals (U= 11,p< .05). Together, these findings suggest that vagal afferents carry messages about peripheral states that lead to the modulation of memory storage and that the memory-enhancing effect produced by vagus nerve stimulation is not mediated via the activation of vagal efferents.     

Tactile stimulation: Psychophysical studies of receptor function

Psychometric functions for the detection of brief tactile pulses were determined at the fingertips and the dorsal forearm. Functions at both lore were shallower than those previously obtained for electrocutaneous pulses. demonstrating the different neural consequences of receptor and afferent nerve stimulation. Detection on the forearm was characterized by steeper slopes of psychometric functions and by lower rates of false alarms than on the fingertips, though absolute sensitivity was better at the latter site. An examination is made of explanations for the differential effects based on receptor type, receptor density, and static tremor.     

Cochlear implants in young children

The cochlear implant is best characterized as a device that provides access to the sound environment. The device enables the hearing pathway to respond to environmental and speech sounds, providing informational cues from the surroundings and from others that may escape visual detection. As the developmental effects of a profound hearing loss are multiple, cochlear implants have been applied to ever younger children in an attempt to promote a more normal level of developmental learning through audition. In deafness, transducer elements of the inner ear fail to trigger auditory nerve afferent nerves in the presence of sound input. However, large reserves of afferent fibers exist even in the auditory nerve of a profoundly deaf patient. Furthermore, these nerve fibers retain the ability to respond to prosthetic activation. Through developmental learning in the early, formative years, auditory centers of the brain appear capable of processing information from the implant to provide speech comprehension and oral language development. Multichannel implants have replaced original single channel designs. multichannel devices enable larger percentages of recipients to recognize the spoken word without visual cues because they provide spectral information in addition to temporal and intensity cues. Testing under conditions of auditory (implant)-only input reveals significant open-set speech understanding capabilities in more than 75% of children after three years of device use. The benefit provided by implants may vary with a number of conditions including: hearing history, age of deafness onset, age at implantation, etiology of deafness, linguistic abilities, and the presence of a motivated system of support of oral language development. Patient variables should be given individual consideration in judging candidacy for a cochlear implant and in planning rehabilitative and education services after surgery and activation of the device.     

The default mode network and altered consciousness in epilepsy

The default mode network has been hypothesized based on the observation that specific regions of the brain are consistently activated during the resting state and deactivated during engagement with task. The primary nodes of this network, which typically include the precuneus/posterior cingulate, the medial frontal and lateral parietal cortices, are thought to be involved in introspective and social cognitive functions. Interestingly, this same network has been shown to be selectively impaired during epileptic seizures associated with loss of consciousness. Using a wide range of neuroimaging and electrophysiological modalities, decreased activity in the default mode network has been confirmed during complex partial, generalized tonic-clonic, and absence seizures. In this review we will discuss these three seizure types and will focus on possible mechanisms by which decreased default mode network activity occurs. Although the specific mechanisms of onset and propagation differ considerably across these seizure types, we propose that the resulting loss of consciousness in all three types of seizures is due to active inhibition of subcortical arousal systems that normally maintain default mode network activity in the awake state. Further, we suggest that these findings support a general "network inhibition hypothesis", by which active inhibition of arousal systems by seizures in certain cortical regions leads to cortical deactivation in other cortical areas. This may represent a push-pull mechanism similar to that seen operating between cortical networks under normal conditions.     

Hippocampal stimulation disrupts spatial working memory even 8 h after acquisition

The present experiment used hippocampal stimulation to determine the temporal gradient of consolidation of spatial working memory. Rats were trained to perform a spatial working memory task on a radial maze with 12 arms. Each rat went to the ends of 6 arms to obtain a food reward. After 8 h, the rat chose among all the arms to find the ones not previously chosen (and consequently still having food). During some test sessions, the hippocampus was stimulated electrically either at a current level just high enough to produce an electrophysiological seizure, or at a current level below this seizure threshold. Stimulation occurred at one of five intervals (0 to 8 h) following the completion of the first six choices. During other test sessions, the hippocampus was not stimulated. After seizure stimulation, the number of retroactive errors (returning to arms chosen prior to stimulation) increased at all delay intervals; the number of proactive errors (returning to arms chosen after stimulation) increased only with the delay of 8 h. Subthreshold stimulation had no influence on either type of error. These results indicate that normal hippocampal function is required for the maintenance of spatial information in working memory, and that the time course of consolidation of this information is significantly greater than that seen in other types of memory, or consolidation may not take place at all.     

不同感觉功能对抑郁的影响及其神经机制

大脑通过视觉、听觉、嗅觉、味觉和触觉等感官通道接收来自外界的信息。不同感觉功能受损涉及抑郁发生的中枢机制,而基于不同感官通道进行适当刺激以及多感官联合干预也可能发挥显著的抑郁治疗作用。笔者以症状-脑区-机制-治疗为逻辑主线,首次系统梳理了五种主要感觉障碍人群的抑郁临床症状、抑郁神经机制以及基于感觉刺激的抗抑郁治疗。结果表明,不同感觉功能障碍对抑郁相关神经机制的影响可能表征了不同的抑郁病理,涉及神经元电活动(某些神经元放电和神经环路激活等)和神经生化改变(神经可塑性和神经发生、炎症免疫和HPA轴、神经激素和神经递质等),且主要发生在边缘系统及其附近脑区,涉及岛叶、颞叶、额叶等。因此,未来研究可聚焦于机体对不同感觉信息的提取,这将为人类抑郁的病因和治疗提供新的研究视角。     

The Occipital Cortex in the Blind

ABSTRACT— Studying the brains of blind individuals provides a unique opportunity to investigate how the brain changes and adapts in response to afferent (input) and efferent (output) demands. We discuss evidence suggesting that regions of the brain normally associated with the processing of visual information undergo remarkable dynamic change in response to blindness. These neuroplastic changes implicate not only processing carried out by the remaining senses but also higher cognitive functions such as language and memory. A strong emphasis is placed on evidence obtained from advanced neuroimaging techniques that allow researchers to identify areas of human brain activity, as well as from lesion approaches (both reversible and irreversible) to address the functional relevance and role of these activated areas. A possible mechanism and conceptual framework for these physiological and behavioral changes is proposed.     

The role of brain stimulation priming effects in self-deprivation

Choice of brain stimulation reward (BSR) over biologically necessary substances in some self-stimulating animals is referred to as self-deprivation. In several recent papers, it has been argued that this phenomenon is produced by the rewarding aspects of the brain stimulation. This conclusion is partially based on data showing that self-deprivation and brain stimulation reward increase and decrease in a similar manner in response to changes in the brain stimulation parameters. However, the priming aspects of the brain stimulation also fluctuate with changes in stimulation parameters. Therefore, changes in the priming rather than the rewarding aspects of the brain stimulation could be responsible for self-deprivation. To determine whether the priming effects of brain stimulation play an important role in self-deprivation, rats with bipolar stimulating electrodes were given the choice between BSR and food. Time-outs were enforced within each BSR/food competition session. Since priming effects decay over time, increasing time-out length should have decreased self-deprivation due to decay of priming. It was found that time-out length did not affect the degree of self-deprivation. It was concluded that self-deprivation is not mediated by the priming aspects of brain stimulation.