Cognitive Functions following Trigeminal Neuromodulation.

Vast scientific effort in recent years have been focused on the search for effective and safe treatments for cognitive decline. In this regard, non-invasive neuromodulation has gained increasing attention for its reported effectiveness in promoting the recovery of multiple cognitive domains after central nervous system damage. In this short review, we discuss the available evidence supporting a possible cognitive effect of trigeminal nerve stimulation (TNS). In particular, we ask that, while TNS has been widely and successfully used in the treatment of various neuropsychiatric conditions, as far as research in the cognitive field is concerned, where does TNS stand? The trigeminal nerve is the largest cranial nerve, conveying the sensory information from the face to the trigeminal sensory nuclei, and from there to the thalamus and up to the somatosensory cortex. On these bases, a bottom-up mechanism has been proposed, positing that TNS-induced modulation of the brainstem noradrenergic system may affect the function of the brain networks involved in cognition. Nevertheless, despite the promising theories, to date, the use of TNS for cognitive empowering and/or cognitive decline treatment has several challenges ahead of it, mainly due to little uniformity of the stimulation protocols. However, as the field continues to grow, standardization of practice will allow for data comparisons across studies, leading to optimized protocols targeting specific brain circuitries, which may, in turn, influence cognition in a designed manner.

ERP and attachment dimensions as predictors of seeking care or food comfort in stressful situations.

In this study, we aimed to test the association of the Late Positive Potential (LPP) response and attachment dimensions in the choice of care/food pictures and its reaction time (RT) in threatening versus neutral conditions. Fifty-two participants (38 females, Mage 22.62) responded to the ECR questionnaire and were exposed to adequate visual stimuli, during EEG recording. Results showed that threatening stimuli increase the choice of care, decrease RT, and increase LPP magnitude in centro-parietal areas (Cpz, Pz, P3 and P4). Food choice was lower, with increased RT. Furthermore, larger LPP magnitude in centro-parietal cluster was associated with increased RT in the choice of care. Considering the dimensions of attachment, in threatening conditions, while anxiety was not associated with RT and care/food choice, avoidance was associated with an increase in care choice and RT. In conclusion, the specific association of increased RT in care choice with high LPP magnitude centro-parietal cluster may be explained in terms of a functional interference of these areas in the choice of care, but not of food. Further, we postulate that the increased RT of avoidant individuals may reflect a more articulated choice process.

Short-term transcutaneous trigeminal nerve stimulation does not affect visual oddball task and paired-click paradigm ERP responses in healthy volunteers.

Recent research suggests that transcutaneous trigeminal nerve stimulation (TNS) may positively affect cognitive function. However, no clear-cut evidence is available yet, since the majority of it derives from clinical studies, and the few data on healthy subjects show inconsistent results. In this study, we report the effects of short-term TNS on event-related potentials (ERP) recorded during the administration of a simple visual oddball task and a paired-click paradigm, both considered useful for studying brain information processing functions. Thirty-two healthy subjects underwent EEG recording before and after 20 min of sham- or real-TNS, delivered bilaterally to the infraorbital nerve. The amplitude and latency of P200 and P300 waves in the simple visual oddball task and P50, N100 and P200 waves in the paired-click paradigm were measured before and after treatment. Our results show that short-term TNS did not alter any of the ERP parameters measured, suggesting that in healthy subjects, short-term TNS may not affect brain processes involved in cognitive functions such as pre-attentional processes, early allocation of attention and immediate memory. The perspective of having an effective, non-pharmacological, non-invasive, and safe treatment option for cognitive decline is particularly appealing; therefore, more research on the positive effects on cognition of TNS is definitely needed.

Adult Avoidant Attachment, Attention Bias, and Emotional Regulation Patterns: An Eye-Tracking Study.

Proximity-seeking in distress situations is one of attachment theory's primary strategies; insecure individuals often also develop secondary strategies. The mechanisms implied in attachment deactivation constitute a key issue in the current debate related to their role in support-seeking. The main aim of this study is to investigate the attachment deactivation strategy and the processes of proximity/support-seeking under distress conditions by analyzing the attentional processes (i.e., an essential emotion-regulation strategy), using eye-tracking techniques. Seventy-two participants (45 female; Mage 23.9 ± 3.97) responded to the ECR-R questionnaire in order to identify their attachment style. They participated in an experimental situation in which they had to choose between pictures of care or pictures of food, following the presentation of threatening or neutral prime conditions (via the pictures' stimuli). Results showed that a care-consistency response pattern was the most frequent pattern of response, particularly under a threatening condition; on the contrary, only avoidant individuals showed a lower care-consistency response pattern by choosing food pictures. The overall findings demonstrate that avoidant individuals used the deactivation strategy to process comfort-related attachment pictures, suggesting that they considered these stimuli to be threatening. The implications for attachment theory and particularly for avoidant strategies are discussed.

SPECT imaging of cerebral blood flow changes induced by acute trigeminal nerve stimulation in drug-resistant epilepsy. A pilot study.

OBJECTIVE: To explore the cortical areas targeted by acute transcutaneous trigeminal nerve stimulation (TNS) in patients with drug-resistant epilepsy (DRE) using single photon emission computed tomography (SPECT). METHODS: Ten patients with DRE underwent brain SPECT at baseline and immediately after a 20-minute TNS (0.25 ms; 120 Hz; 30 s ON and 30 s OFF) applied bilaterally to the infraorbital nerve. The French Color Standard International Scale was used for qualitative analyses and z-scores were used to calculate the Odds Ratio (OR). RESULTS: At baseline global hypoperfusion (mainly in temporo-mesial, temporo-parietal and fronto-temporal and temporo-occipital areas) was detected in all patients. Following TNS, a global increase in cortical tracer uptake and a significant decrease in median hypoperfusion score were observed. A significant effect favoring a general TNS-induced increase in cortical perfusion (OR = 4.96; p = 0.0005) was detected in 70% of cases, with significant effects in the limbic (p = 0.003) and temporal (p = 0.003) lobes. Quantitative analyses of z-scores confirmed significant TNS-induced increases in perfusion in the temporal (+0.59 SDs; p = 0.001), and limbic (+0.43 SDs; p = 0.03) lobes. CONCLUSION: Short-term TNS is followed a global increase in cortical perfusion, namely in the temporal and limbic lobes. SIGNIFICANCE: The TNS-induced perfusion increase may reflect neurons' activity changes in cortical areas implicated in the epilepsy network.

Transcutaneous trigeminal nerve stimulation modulates the hand blink reflex.

The hand-blink reflex (HBR) is a subcortical response, elicited by the electrical stimulation of the median nerve, whose magnitude is specifically modulated according to the spatial properties of the defensive peripersonal space (DPPS) of the face. For these reasons, the HBR is commonly used as a model to assess the DPPS of the face. Little is known on the effects induced by the activation of cutaneous afferents from the face on the DPPS of the face. Therefore, we tested the effect of non-painful transcutaneous trigeminal nerve stimulation (TNS) on the amplitude of the HBR. Fifteen healthy participants underwent HBR recording before and after 20 min of sham- and real-TNS delivered bilaterally to the infraorbital nerve in two separate sessions. The HBR was recorded bilaterally from the orbicularis oculi muscles, following non-painful median nerve stimulation at the wrist. The HBR amplitude was assessed in the "hand-far" and "hand-near" conditions, relative to the hand position in respect to the face. The amplitudes of the hand-far and hand-near HBR were measured bilaterally before and after sham- and real-TNS. Real-TNS significantly reduced the magnitude of the HBR, while sham-TNS had no significant effect. The inhibitory effect of TNS was of similar extent on both the hand-far and hand-near components of the HBR, which suggests an action exerted mainly at brainstem level.

Role of cutaneous and proprioceptive inputs in sensorimotor integration and plasticity occurring in the facial primary motor cortex.

KEY POINTS: Previous studies investigating the effects of somatosensory afferent inputs on cortical excitability and neural plasticity often used transcranial magnetic stimulation (TMS) of hand motor cortex (M1) as a model, but in this model it is difficult to separate out the relative contribution of cutaneous and muscle afferent input to each effect. In the face, cutaneous and muscle afferents are segregated in the trigeminal and facial nerves, respectively. We studied their relative contribution to corticobulbar excitability and neural plasticity in the depressor anguli oris M1. Stimulation of trigeminal afferents induced short-latency (SAI) but not long-latency (LAI) afferent inhibition of face M1, while facial nerve stimulation evoked LAI but not SAI. Plasticity induction was observed only after a paired associative stimulation protocol using the facial nerve. Physiological differences in effects of cutaneous and muscle afferent inputs on face M1 excitability suggest they play separate functional roles in behaviour. ABSTRACT: The lack of conventional muscle spindles in face muscles raises the question of how sensory input from the face is used to control muscle activation. In 16 healthy volunteers, we probed sensorimotor interactions in face motor cortex (fM1) using short-afferent inhibition (SAI), long-afferent inhibition (LAI) and LTP-like plasticity following paired associative stimulation (PAS) in the depressor anguli oris muscle (DAO). Stimulation of low threshold afferents in the trigeminal nerve produced a clear SAI (P < 0.05) when the interval between trigeminal stimulation and transcranial magnetic stimulation (TMS) of fM1 was 15-30 ms. However, there was no evidence for LAI at longer intervals of 100-200 ms, nor was there any effect of PAS. In contrast, facial nerve stimulation produced significant LAI (P < 0.05) as well as significant facilitation 10-30 minutes after PAS (P < 0.05). Given that the facial nerve is a pure motor nerve, we presume that the afferent fibres responsible were those activated by the evoked muscle twitch. The F-wave in DAO was unaffected during both LAI and SAI, consistent with their presumed cortical origin. We hypothesize that, in fM1, SAI is evoked by activity in low threshold, presumably cutaneous afferents, whereas LAI and PAS require activity in (higher threshold) afferents activated by the muscle twitch evoked by electrical stimulation of the facial nerve. Cutaneous inputs may exert a paucisynaptic inhibitory effect on fM1, while proprioceptive information is likely to target inhibitory and excitatory polysynaptic circuits involved in LAI and PAS. Such information may be relevant to the physiopathology of several disorders involving the cranio-facial system.

Effect of short-term transcutaneous trigeminal nerve stimulation on EEG activity in drug-resistant epilepsy.

BACKGROUND: Transcutaneous trigeminal nerve stimulation (TNS) has antiepileptic effects in patients with drug-resistant epilepsy (DRE). However, whether and how TNS is able to modulate the electroencephalogram (EEG) background activity in patients with DRE is still unknown. OBJECTIVES: To investigate the effect of short-term TNS on EEG background activity in DRE by qualitative and quantitative analyses. METHODS: Twenty-nine DRE patients participated in the study. Twenty-two were randomly divided into a "sham-TNS" or "real-TNS" group; seven patients underwent stimulation of the median nerve (MNS) at the wrist. Real-TNS was delivered bilaterally to the infraorbital nerve (trains of 1-20 mA, 120 Hz, cyclic modality for 20 min). The sham-TNS protocol mimicked the real-TNS one but at a zero intensity. For MNS, the same parameters as real-TNS were used. EEG was continuously acquired for 40 min: 10' pre, 20' during and 10' post stimulation. EEG was visually inspected for interictal epileptiform discharge (IEDs) changes and processed by spectral analysis for changes in mean frequency and absolute power of each frequency band. RESULTS: A significant increase of EEG absolute alpha power was observed during real-TNS compared with the sham-TNS (F34,680 = 1.748; p = 0.006). Conversely, no significant effects were noticed either for quantitative analysis of other frequency bands or for IEDs detection. MNS proved unable to modulate EEG activity. CONCLUSIONS: Short-term TNS induces an acute and specific effect on background EEG of DRE by increasing the absolute alpha band power. EEG alpha rhythm enhancement may index a cortical functional inhibition and act as a seizure-preventing mechanism.

Vestibular Evoked Myogenic Potentials Are Abnormal in Idiopathic REM Sleep Behavior Disorder.

Objectives: To investigate brainstem function in idiopathic REM sleep Behavior Disorder (iRBD), a condition occurring as a result of a derangement of connections within brainstem structures, with a battery of Vestibular Evoked Myogenic Potentials (VEMPs), neurophysiological tools suited for the functional investigation of the brainstem. Neurophysiological data were correlated with clinical characteristics of patients. Methods: Twenty patients with iRBD and 22 healthy controls underwent cervical (cVEMP), masseter (mVEMP) and ocular (oVEMP) VEMP recording. Patients were assessed clinically according to presence of motor as well as non-motor symptoms such as constipation, depression, and hyposmia. Also, they were screened for postural instability through the Berg Balance Scale (BBS). VEMPs were categorized as for increasing degrees of abnormalities, namely latency delay, amplitude reduction and absence; a VEMP score was built accordingly. Results: Compared with controls, iRBD had higher rates of abnormalities both in the VEMP battery (iRBD 75%, Controls 23%; p < 0.01) as well as in each single VEMP (cVEMP: 45 vs. 5%; mVEMP: 65 vs. 13.6%; oVEMP: 50 vs. 5%; p < 0.01), which exhibited significantly lower amplitudes (cVEMP and oVEMP: p < 0.0001; mVEMP: p = 0.001) in iRBD. Within altered reflexes, absence was predominant in oVEMP (81%), amplitude reduction in mVEMP (50%) and cVEMP (70%). Severity of VEMP alterations was significantly higher in iRBD compared with controls (p < 0.05 for all VEMPs), as indicated by the larger VEMP scores in the former. The oVEMP score correlated inversely with poor performances on the BBS. Conclusion: VEMPs unveil consistent and extensive brainstem abnormalities in iRBD patients. Further studies are warranted for testing the potential of VEMPs in the monitoring of the evolution of iRBD over time.

Effects of acute trigeminal nerve stimulation on rest EEG activity in healthy adults.

Trigeminal nerve stimulation (TNS) is a non-invasive neuromodulation method which is increasingly used for its beneficial effects on symptoms of several neuropsychiatric disorders such as drug-resistant epilepsy. Sites and mechanisms of its action are still unknown. The present study was aimed at investigating the physiological effects of acute TNS on rest electroencephalographic (EEG) activity. EEG was recorded with a 19-channel EEG system from 18 healthy adults who underwent 20 min of sham- and real-TNS (cycles of 30 s ON and 30 s OFF) in two separate sessions. EEG was continuously acquired in the 10-min preceding TNS, during TNS in the "OFF" period and throughout 10 min after TNS. Mean frequency, total power over the 0.5-48 Hz frequency range and absolute power for delta, theta, alpha, beta and gamma bands were analyzed by a discrete Fast Fourier Transform algorithm. Interhemispheric and intrahemispheric coherences were also analyzed for each band at different time points. Intra- and interhemispheric coherences were significantly reduced for the beta frequencies only during real-TNS (p = 0.002 and p = 0.006, respectively). No TNS effect on the power spectra of any band was detected. A trend of increase in the mean EEG frequency total power during real-TNS (p = 0.03) and of decrease in interhemispheric gamma coherence after real-TNS (p = 0.01) was observed. Acute TNS may induce a spatially diffuse desynchronization of fast EEG rhythms in healthy adults, this desynchronization may underpin the antiepileptic effect of TNS described by clinical studies.

Anatomo-Physiologic Basis for Auricular Stimulation.

Introduction: Stimulation of cranial nerves modulates central nervous system (CNS) activity via the extensive connections of their brainstem nuclei to higher-order structures. Clinical experience with vagus-nerve stimulation (VNS) demonstrates that it produces robust therapeutic effects, however, posing concerns related to its invasiveness and side-effects. Discussion: Trigeminal nerve stimulation (TNS) has been recently proposed as a valid alternative to VNS. The ear presents afferent vagus and trigeminal-nerve distribution; its innervation is the theoretical basis of different reflex therapies, including auriculotherapy. An increasing number of studies have shown that several therapeutic effects induced by invasive VNS and TNS, can be reproduced by noninvasive auricular-nerve stimulation. However, the sites and neurobiologic mechanisms by which VNS and TNS produce their therapeutic effects are not clear yet. Conclusions: Accumulating evidence suggests that VNS and TNS share multiple levels and mechanisms of action in the CNS.

Auricular Neuromodulation: The Emerging Concept beyond the Stimulation of Vagus and Trigeminal Nerves.

Neuromodulation, thanks to intrinsic and extrinsic brain feedback loops, seems to be the best way to exploit brain plasticity for therapeutic purposes. In the past years, there has been tremendous advances in the field of non-pharmacological modulation of brain activity. This review of different neurostimulation techniques will focus on sites and mechanisms of both transcutaneous vagus and trigeminal nerve stimulation. These methods are scientifically validated non-invasive bottom-up brain modulation techniques, easily implemented from the outer ear. In the light of this, auricles could transpire to be the most affordable target for non-invasive manipulation of central nervous system functions.

Trigeminal nerve stimulation induces Fos immunoreactivity in selected brain regions, increases hippocampal cell proliferation and reduces seizure severity in rats.

Sites and mechanisms by which trigeminal nerve stimulation (TNS) exerts beneficial effects on symptoms of drug-resistant epilepsy and depression are still unknown. Effects of short-term TNS on brain regions involved in the physiopathology of these disorders were investigated in this study. Forty male rats were assigned to three groups: TNS (undergoing electrical stimulation of the left infraorbitary nerve via surgically implanted cuff electrodes); Sham (undergoing surgical procedure but without a stimulation); Naïve rats. The effects of TNS (3-hour session; 30-s ON, 5-min OFF; 30Hz; 500µs; 2mA) were evaluated on: (i) behavioral pattern of pentylenetetrazole (PTZ)-induced seizures as measured by the Racine scale; (ii) c-Fos-like immunoreactivity in discrete brain areas; (iii) hippocampal cell proliferation by bromodeoxyuridine (BrdU)-like immunoreactivity. In comparison with Sham groups, TNS significantly decreased the duration of PTZ-induced seizures (p<0.05) and promoted a faster recovery (p<0.001) by reducing the most severe seizure types. In the TNS group the number of c-Fos-labeled cells was significantly increased (p<0.001) in the trigeminal nuclear complex, nucleus of the solitary tract, locus coeruleus, dorsal raphe nucleus, hippocampus, amygdala, endopiriform nucleus, entorhinal cortex and sensorimotor cortex. In the TNS group the number of BrdU-positive cells in the dentate gyrus was significantly greater with respect to both Naïve and Sham groups. Data show that acute TNS effectively counteracted PTZ-induced seizures and boosted hippocampal cell proliferation in rats. TNS increased c-Fos-like immunoreactivity in brainstem and forebrain structures which play a pivotal role in the physiopathology of epilepsy and depression.

Resistance Training for Muscle Weakness in Multiple Sclerosis: Direct Versus Contralateral Approach in Individuals With Ankle Dorsiflexors' Disparity in Strength.

OBJECTIVE: To compare effects of contralateral strength training (CST) and direct strength training of the more affected ankle dorsiflexors on muscle performance and clinical functional outcomes in people with multiple sclerosis (MS) exhibiting interlimb strength asymmetry. DESIGN: Randomized controlled trial. SETTING: University hospital. PARTICIPANTS: Individuals with relapsing-remitting MS (N=30) and mild-to-moderate disability (Expanded Disability Status Scale score ≤6) presenting with ankle dorsiflexors' strength disparity. INTERVENTIONS: Participants were randomly assigned to a CST (n=15) or direct strength training (n=15) group performing 6 weeks of maximal intensity strength training of the less or more affected dorsiflexors, respectively. MAIN OUTCOME MEASURES: Maximal strength, endurance to fatigue, and mobility outcomes were assessed before, at the intervention end, and at 12-week follow-up. Strength and fatigue parameters were measured after 3 weeks of training (midintervention). RESULTS: In the more affected limb of both groups, pre- to postintervention significant increases in maximal strength (P≤.006) and fatigue endurance (P≤.04) were detected along with consistent retention of these improvements at follow-up (P≤.04). At midintervention, the direct strength training group showed significant improvements (P≤.002), with no further increase at postintervention, despite training continuation. Conversely, the CST group showed nonsignificant strength gains, increasing to significance at postintervention (P≤.003). In both groups, significant pre- to postintervention improvements in mobility outcomes (P≤.03), not retained at follow-up, were observed. CONCLUSIONS: After 6 weeks of training, CST proved as effective as direct strength training in enhancing performance of the more affected limb with a different time course, which may have practical implications in management of severely weakened limbs where direct strength training is not initially possible.

Transcutaneous trigeminal nerve stimulation induces a long-term depression-like plasticity of the human blink reflex.

The beneficial effects of trigeminal nerve stimulation (TNS) on several neurological disorders are increasingly acknowledged. Hypothesized mechanisms include the modulation of excitability in networks involved by the disease, and its main site of action has been recently reported at brain stem level. Aim of this work was to test whether acute TNS modulates brain stem plasticity using the blink reflex (BR) as a model. The BR was recorded from 20 healthy volunteers before and after 20 min of cyclic transcutaneous TNS delivered bilaterally to the infraorbital nerve. Eleven subjects underwent sham-TNS administration and were compared to the real-TNS group. In 12 subjects, effects of unilateral TNS were tested. The areas of the R1 and R2 components of the BR were recorded before and after 0 (T0), 15 (T15), 30 (T30), and 45 (T45) min from TNS. In three subjects, T60 and T90 time points were also evaluated. Ipsi- and contralateral R2 areas were significantly suppressed after bilateral real-TNS at T15 (p = 0.013), T30 (p = 0.002), and T45 (p = 0.001), while R1 response appeared unaffected. The TNS-induced inhibitory effect on R2 responses lasted up to 60 min. Real- and sham-TNS protocols produced significantly different effects (p = 0.005), with sham-TNS being ineffective at any time point tested. Bilateral TNS was more effective (p = 0.009) than unilateral TNS. Acute TNS induced a bilateral long-lasting inhibition of the R2 component of the BR, which resembles a long-term depression-like effect, providing evidence of brain stem plasticity produced by transcutaneous TNS. These findings add new insight into mechanisms of TNS neuromodulation and into physiopathology of those neurological disorders where clinical benefits of TNS are recognized.

Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression.

Chronic ethanol consumption causes structural and functional reorganization in the hippocampus and induces alterations in the gene expression of gamma-aminobutyric acid type A receptors (GABAARs). Distinct forced intermittent exposure models have been used previously to investigate changes in GABAAR expression, with contrasting results. Here, we used repeated cycles of a Chronic Intermittent Ethanol paradigm to examine the relationship between voluntary, dependence-associated ethanol consumption, and GABAAR gene expression in mouse hippocampus. Adult male C57BL/6J mice were exposed to four 16-h ethanol vapor (or air) cycles in inhalation chambers alternated with limited-access two-bottle choice between ethanol (15%) and water consumption. The mice exposed to ethanol vapor showed significant increases in ethanol consumption compared to their air-matched controls. GABAAR alpha4 and delta subunit gene expression were measured by qRT-PCR at different stages. There were significant changes in GABAAR delta subunit transcript levels at different time points in ethanol-vapor exposed mice, while the alpha4 subunit levels remained unchanged. Correlated concurrent blood ethanol concentrations suggested that GABAAR delta subunit mRNA levels fluctuate depending on ethanol intoxication, dependence, and withdrawal state. Using a vapor-based Chronic Intermittent Ethanol procedure with combined two-bottle choice consumption, we corroborated previous evidences showing that discontinuous ethanol exposure affects GABAAR delta subunit expression but we did not observe changes in alpha4 subunit. These findings indicate that hippocampal GABAAR delta subunit expression changes transiently over the course of a Chronic Intermittent Ethanol paradigm associated with voluntary intake, in response to ethanol-mediated disturbance of GABAergic neurotransmission.

Acute restraint stress prevents nicotine-induced mesolimbic dopaminergic activation via a corticosterone-mediated mechanism: a microdialysis study in the rat.

BACKGROUND: Stress affects the responsiveness to nicotine (NIC), by increasing drug use, facilitating relapse and reinstating NIC self administration even after prolonged abstinence. In turn, high corticosterone (CORT) blood levels induced by stress may alter the neurobiological properties of NIC by acting on the dopamine (DA) mesolimbic system. METHODS: In this study, we evaluated the effect of exposure to acute restraint stress on NIC-induced stimulation of the mesolimbic DA system of the rat, by studying extracellular DA levels in the nucleus accumbens shell (NAccs) with microdialysis. RESULTS: NIC intravenous administration (130 µg/kg) increased DA levels in the NAccs in control rats but not in subjects exposed to stress; this latter phenomenon was prevented by blockade of CORT effects with the inhibitor of corticosterone synthesis metirapone (100 mg/kg) or the glucorticoid receptor antagonist mifepristone (150 µmol/kg). CONCLUSIONS: These observations show that exposure to acute stress inhibits the stimulatory response of the mesolimbic DA system to NIC and suggest that this effect is mediated by circulating CORT acting on its receptors. These results may bear relevance in explaining the role played by stressful stimuli in NIC-seeking and taking behavior.