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.     

Vagus nerve stimulation: a new form of therapeutic brain stimulation

Although the vagus nerve has traditionally been considered to perform efferent functions, in reality it performs significant afferent functions as well, carrying information from the body, head, and neck to the brain. Preliminary studies examining this afferent activity led to the theory that vagus nerve stimulation (VNS) could successfully control seizure activity in persons who are refractory to antiepileptic medications. Unlike other forms of brain stimulation, VNS is unable to directly stimulate multiple discrete areas of the brain; however, through several pathways, it is able to relay sensory information to higher brain regions. An implantable VNS device known as the VNSTM NeuroCybernetic Prosthesis (NCP) System has been used in approximately 9,000 epilepsy patients in Europe and the United States since 1994. The implant has reduced seizure frequency by an average of 25% to 30%, with minimal side effects. Studies underway are also showing some degree of success in the management of treatment-refractory depression. The future efficacy of the implantable system in other disorders may depend on whether the implant can be more precisely focused to affect different brain regions. Research in this area is underway.     

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。     

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.     

Facilitation of seizures in limbic epileptic rats by complex 1 microTesla magnetic fields

On three separate sessions 24 male rats with histories of limbic epilepsy were exposed to 10 temporal configurations for 5 min. each of one of two patterns of magnetic fields. Their intensities averaged about 1 microTesla (microT). The numbers of Level 5 (Racine) seizures, inferred by the rat's rearing, rapid forelimb clonus, and falling, were statistically more frequent for the frequency-modulated (Thomas) pattern when its pixel duration and interstimulus presentation were 3 msec. The effectiveness of this temporal configuration was replicated in a second within-subjects experiment (n = 9) that directly compared the numbers of seizures during exposures to each of the two patterns and to a sham-field. These results suggest that brains with sensitive limbic systems might respond to weak magnetic fields, generated from multiple overlapping fields from communication and computer systems whose temporal derivatives emerge as complex sequences with pixel durations within the millisecond range.     

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.     

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.     

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.     

Comparison between two opposite homicidal syndromes (Syndrome e vs. limbic psychotic trigger reaction)

Two syndromes with opposite kinds of homicidal acts also implicate opposite activation of frontal lobe and limbic systems. I. Fried's “Syndrome E” refers to planned, ideologically-motivated mass murders, committed in groups and accompanied by “elation.” Implicated are heightened functioning of certain frontal lobe regions with certain reduced limbic involvement . In contrast, A. A. Pontius' “Limbic Psychotic Trigger Reaction” delineates unplanned, motiveless homicidal acts (so far 17 cases) committed by a single loner with flat affect, implicating a partial limbic seizure hyperactivation with fleeting psychosis and brief secondary dysfunctioning of certain frontal regions.     

A neurophysiologic model for aggressive behavior in the cat

A neurophysiologic model for aggessive behavior in the cat is proposed. Stimulus-bound and seizure-bound aggression was evaluated in relation to limbic and basal ganglia induced seizures (after-discharges). Electrically induced limbic and basal ganglia afterdischarges were used because they are known to implicate septohypothalamic sites from which aggression can be elicited by direct stimulation. The occurrence of behavioral aggression is correlated with the discharge characteristics of a single discharging system and with two interacting discharging systems. Aggression is composed of autonomic and somato-motor components which poses relatively low and high thresholds, respectively, for their activation. Aggression occurring during a combined septum and amygdala discharge was more intense and prolonged than with a septum discharge alone. Participation of a slow frequency discharging basal ganglia system activated seizurebound aggression in an otherwise nonaggressive limbic seizure. The limbic and basal ganglia stimulations and after-discharges lowered the excitability threshold of the aggression system and made it more vulnerable to being activated by external stimuli, such as visual and auditory stimuli. These observations are reminiscent of patients with aggressive behavior associated with psychomotor seizures.     

No country for girly men: High instrumentality men express empathic concern when caring is “manly”

Two studies explored the relationship between men’s gender role identity (as measured by the Bem Sex Role Inventory) and their experience of empathic concern (situational empathy). In both, participants read of a man coping with his friend’s death while being exposed to one of three subliminal primes: “real men care”/“caring is strength,” “girly men care”/“caring is weakness,” or “people are walking.” Congruent with previous research, higher femininity (expressivity) predicted greater empathic concern irrespective of prime. The real men/strength primes tended to: (1) increase empathic concern among high instrumentality men; and (2) link empathic concern to predominantly positive projected coping responses when participants thought of themselves in the survivor’s situation, consistent with the broaden-and-build theory of positive emotions. Thus, subtly framing empathic concern as a positive emotional response that is congruent with an agentic self-appraisal seems to boost traditionally masculine men’s willingness to experience it.     

Retention of orienting reaction habituation in patients with epileptogenic cerebral tumors

An electrographic study on habituation of the somatic (EMG), autonomic (finger plethysmogram, galvanic skin reaction, respiration, pulse) and EEG (acoustic evoked potential and EEG-blocking reaction) components of the orienting reaction elicited by a repetitive auditory stimulus during successive (weekly) sessions was performed in 41 patients with epileptogenic cerebral tumors (ECT) and in 128 control subjects. The study evidenced significant retention disturbances of orienting reaction habituation (i.e., of learning), the “saving” of stimulations, achieved from one session to the other to obtain the habituation criterion, being lesser in ECT patients than in control subjects. The severity of habituation retention disturbances depended on the tumor site and size, as well as on the electro-clinical form and frequency of seizures. Thus, the most marked habituation retention disturbances were found in patients with temporal or predominantly temporal epileptogenic tumors, in cases with large hemispheric epileptogenic tumors (over 6 cm), in patients with generalized or generalized plus partial seizures, as well as in those with frequent (daily) seizures.     

Stimulus characteristics that can enhance or decrease aggression: Associations with prior positive or negative reinforcements for aggression

To establish an analogue of the “weapons effect,” male university subjects were required to use a distinctive apparatus in delivering noxious sounds to a peer in an adjoining room, and then were either (a) positively reinforced, or (b) negatively reinforced, or (c) not given any reaction by the experimenter, for what they had done. Immediately after this, each person had to administer other noise blasts to someone else in a different manner, but with the previous noise machines (the fist “weapon”) being either present or not present. The initial “weapon's” presence augmented the effects of the prior reinforcement; the second victim was attacked most strongly after the men had been positively reinforced and the earlier “weapon” was nearby, whereas he received the fewest blasts if the subjects had been negatively reinforced and the earlier noise machine was present. Other evidence indicates (1) that the aggressive cue, the “weapon,” had not affected the subjects' aggressive intentions, (2) the results are not due simply to differences in moods or general arousal, and (3) the subjects were not aware of the hypothesis regarding the interaction of reinforcement and cue presence.     

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.     

Communication Styles,Cultural Values,and Counseling Effectiveness With Asian Americans

This study examined counseling intervention designed for Asian Americans. Participants (N = 158) rated session effectiveness after viewing a videotape of a counselor using a culturally congruent or incongruent communication style. Analyses of variance showed that the incongruent style was viewed as more satisfying and credible than the congruent style. Factor analysis showed that participants perceived “being direct” and “maintaining harmony” styles, and multiple regression analyses revealed that these perceptions had a positive relationship with effectiveness.     

The influence of spatial representation on valence judgements: An event-related potential study

The present study used event-related potentials (ERPs) to explore the nature of space-valence congruency effects. We presented participants with up or down arrows at the centre of the screen and then asked participants to identify whether the following target words had the emotional valence. The target words included positive emotional words (e.g., “happy” and “delight”), negative emotional words (e.g., “sad” and “depressive”) and neutral words (e.g., “history” and “country”). Behavioural data showed that the positive targets were identified faster when they are primed by up arrows than when primed by down arrows, whereas the negative targets were identified faster when they are primed by down arrows than when primed by up arrows. The ERP analysis showed larger P2 amplitudes were found in the congruent condition (i.e., the positive targets following up arrows or the negative targets following down arrows) than in the incongruent condition (i.e., the positive targets following down arrows or the negative targets following up arrows). Furthermore, larger N400 amplitudes were found in the incongruent condition compared with the congruent condition. Moreover, larger LPC amplitudes were found in the congruent condition compared with the incongruent condition. Therefore, in addition to replicating the space-valence congruency effects in a neutral/emotional judgement task, our study also extended previous studies by showing that spatial information modulates the processing of the emotional words at multiple stages.     

Delayed effects of practiced versus unpracticed responses after observation of movie violence

University men participating in an ostensible study of “impression formation” first received either an insulting or neutral evaluation of themselves from their supposed partner and then watched either a prize fight or an exciting but nonaggressive scene. After this, they either had an opportunity to evaluate their partner right away or they had to wait an hour before evaluating him. On scoring the subjects' written statements about the partner (to be seen by him and the experimenter), it was found that (1) for those given the immediate opportunity to be aggressive, the violent movie increased the strength of the angered subjects' initial attack on their partner over that displayed by the similarly insulted men shown the nonaggressive film; (2) if the angry subjects had to wait an hour before evaluating their partner, there was no difference between the aggressive and nonaggressive movie groups; (3) the aggression-heightening effect of the violent scene did carry over the intervening hour, however, if the insulted men had been given the earlier opportunity to evaluate their partner. It is suggested that the performance of an aggressive response soon after seeing an aggressive film increases the persistence of the aggressive reactions over time.     

Blinding integrity of dorsomedial prefrontal intermittent theta burst stimulation in depression

BackgroundThe antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) is partly placebo, making blinding integrity important. Blinding of high-frequency rTMS and intermittent theta burst stimulation (iTBS) has been reported as successful at study end. However, blinding integrity at study start is rarely reported. The aim of this study was to investigate blinding integrity during a treatment course of iTBS over the dorsomedial prefrontal cortex (DMPFC) in depression.MethodsForty-nine patients with depression from a double-blind-designed randomized controlled trial (NCT02905604) were included. Patients received either active or sham iTBS over the DMPFC with a placebo coil. The sham group received iTBS-synchronized transcutaneous electrical nerve stimulation.ResultsAfter one session, 74% of participants were able to correctly guess their treatment allocation. This was above chance level (p = 0.001). The percentage dropped to 64% and 56% after the fifth and last sessions. Belonging to the active group influenced the choice to guess “active” (odds ratio: 11.7, 95% CI 2.5–53.7). A higher treatment intensity of the sham treatment increased the probability to guess “active”, but pain did not influence the choice.ConclusionsBlinding integrity in iTBS trials must be investigated at study start to avoid uncontrolled confounding. Better sham methods are needed.     

Relationship between types of humour and stress response and well‐being among children in Japan

This study examined the relationship between three types of children's humour (aggressive, self‐defeating, and playful) and the children's stress response and well‐being in the Japanese context, where a collectivistic culture is prevalent. To do so, 500 study participants (250 elementary and 250 junior high school students) were recruited. The participants reported the types of humour, stress responses, and level of well‐being that they experienced. After correlation analysis, aggressive humour and playful humour showed a positive correlation with stress responses; in addition, aggressive humour showed a negative correlation with well‐being. Self‐defeating humour showed a negative correlation with stress responses and a positive correlation with well‐being. We also conducted a cluster analysis using the scores for the three types of humour, analysing four groups: “aggressive humourists” (respondents who demonstrated above‐average aggressive humour and scored average for all other humours), “nonhumourists” (below‐average humour in all areas), “self‐deprecating humourists” (above‐average self‐defeating humour, below‐average aggressive humour, and average playful humour), and “multiple humourists” (above‐average humour in all areas). Upon comparing the results of stress responses and well‐being scores among the four groups, we found that self‐deprecating humourists reported the highest level of well‐being. These results show that in collectivistic cultures, self‐defeating humour may be adaptive.