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Sites and mechanisms of trigeminal nerve stimulation: a human and animal study
Get PDFTrigeminal nerve stimulation (TNS) has proven efficacious in the treatment of several neurological disorders, but sites and mechanisms of action are still unknown. TNS effects were investigated on: intracortical circuits and sensorimotor integration at cortical level (Study 1), brainstem excitability and plasticity (Study 2), in healthy subjects; hippocampal neurogenesis (Study 3), in rats. TNS consisted of 20min bilateral stimulation of the infraorbital nerve.Study 1: Short- and long-interval intracortical inhibition, intracortical facilitation, short- and long-afferent inhibition were assessed using transcranial magnetic stimulation in 17 volunteers before and after TNS.Study 2: The R1 and R2 areas of the blink reflex (BR) were measured before and after 0, 15, 30, 45min from TNS delivery.Study 3: Hippocampal neurogenesis was evaluated in 18 male Sprague-Dawley rats after 24h from TNS, through immunohistochemical labeling of newly formed brain cells.Results.Study 1: cortical excitability and sensorimotor integration were unaltered by TNS.Study 2: The R2 area of the BR was significantly reduced after TNS at all time points tested. By contrast, R1 area was unaffected.Study 3: The number of newly formed cells in the dentate gyrus was significantly increased after TNS.These data suggest that TNS mainly acts on brainstem polysynaptic circuits with a minor role in modifying the activity of higher-level structures. Acute TNS induces a long-lasting inhibition of the R2 component of the BR, which resembles a long-term depression-like effects. In the rat TNS promotes new cell proliferation in the hippocampus, which supports the notion of an involvement of hippocampal plasticity in the TNS effects described in several neurological conditions
Short-term transcutaneous trigeminal nerve stimulation does not affect visual oddball task and paired-click paradigm ERP responses in healthy volunteers
No full textRecent 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
Auricular Neuromodulation: The Emerging Concept beyond the Stimulation of Vagus and Trigeminal Nerves
No full textNeuromodulation, 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
Cognitive Functions following Trigeminal Neuromodulation
No full textVast 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
Exploring Numeracy Development Across the Lifespan: Comparing Symbolic and Non-Symbolic Representations
No full textResearch on numeracy development is increasingly relevant due to its importance across the lifespan, impacting academic achievement in children, work success in adults, and managing everyday demands in elders. Despite this, few studies directly address the issue. To investigate numeracy development, we administered a PC-presented parity judgment (PJ) task to children, young adults, and elderly participants, collecting response accuracy and reaction time (RT). Our task included Arabic digits (symbolic), dots (non-symbolic), and finger-based representations, as numeracy may be associated with both symbolic and non-symbolic formats. Fingers promote numerical skills development from early childhood (e.g. Noel, 2005), and several studies highlight a physiological association between fingers and number representations even in adults (e.g. Rusconi et al., 2005). By including finger-based numerical representation we aimed to verify whether access to quantity representation conveyed by fingers follows the same pattern as non-symbolic numerical format (dots) or is closer to Arabic symbols. The research sample consisted of 96 participants: 22 8-year-old children (17F), 21 10-year-old children (13F), 22 elderly participants (10F; M= 68.5 years; range 62-79); 31 young adults (16F; M= 24.13 years; range 19-37). Analyses were conducted using Mixed Effects Models. For accuracy, results showed a main effect of Age and Condition (Arabic, fingers, dots): 8-year-olds performed significantly lower than young adults and the elderly (p < .001), and 10-year-old children performed similarly to adults and the elderly. Regarding Condition, dot performance was significantly lower than that with Arabic digits (p < .001) while correct responses with fingers and Arabic digits did not differ. For RTs, the main factor Age was significant: 8-year-olds had significantly longer RTs than other groups in all conditions, while 10-year-old children did not differ from young adults and the elderly. In conclusion, a developmental trend regarding accuracy aligns performances when presented with stimuli represented by fingers and Arabic digits, supporting the hypothesis of a stronger association between hands and numbers compared to dots. RTs, however, do not seem to support this finding as no differences were found between the different stimulus presentation modalities. Limitation: small sample size
Transcutaneous trigeminal nerve stimulation induces a long-term depression-like plasticity of the human blink reflex.
No full textThe 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
Acute restraint stress prevents nicotine-induced mesolimbic dopaminergic activation via a corticosterone-mediated mechanism: A microdialysis study in the rat
No full textBackground: 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 (CURT) 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 mu g/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 CURT effects with the inhibitor of corticosterone synthesis metirapone (100 mg/Kg) or the glucorticoid receptor antagonist mifepristone (150 mu mol/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 CURT acting on its receptors. These results may bear relevance in explaining the role played by stressful stimuli in NIC-seeking and taking behavior
Symbolic and non-symbolic numerical representations in old and young subjects. An exploratory EEG study
No full textNumeracy has significant implications throughout the lifecourse. Its age-induced
decline represents a vulnerability factor in elderly populations when it comes to solving everyday
tasks. However, the reasons behind age-induced decline in numeracy are still unclear. In this
study, we used a parity judgment task to study variations in number cognition between old and
young participants. Since numeracy is associated with both symbolic and non-symbolic
representations, three numerical formats were used: arabic digits (N), finger representations (F),
and dots (D). Fifty-three healthy subjects joined the study: 31 young (24.1±4.73 y.o.) and 22 old
(68.8±4.38 y.o.). EEG (64 channels) was recorded during the task. Mixed Effects Models
analysis showed that performance accuracy for D was significantly lower than for N and F (p =
.02). There were significant main effects for reaction time for Group (old, young), Condition (N,
F, D) and Gender. Notably, old adults responded slower than young adults (p < .001) and both
groups performed significantly faster in the task for N compared to F and D (p < .001).
Significant interaction effects showed that performance between males and females were
comparable for arabic digits (p = .14), with females showing significantly slower response for
non-symbolic stimuli than males (F, p = 0.04; D, p = .007). In sensor space, multivariate pattern
analysis shows that the neural correlates supporting the different number representations can be
classified as categorically separate, with an early dissociation (~200 ms) between N, F, and D
stimuli when compared to each other. This provides provisional evidence that symbolic and non-
symbolic representations recruit functionally distinct neuronal processes. Subjects in the old
group showed a slight reduction in decoding and an increase in its latency. Numerical cognition
involves a highly-integrated network, with a key role of the intraparietal sulcus and fusiform
gyrus. In source space, we found reduced activation levels and increased latency of response in
the primary cortical areas involved in numerical cognition in the old group. In the same group,
all stimuli also induced a wider cortical response with respect to young subjects. We hypothesize
that the reduced activity of the main cortical areas may contribute to the age-induced decay in
numeracy and that the recruitment of other cortical areas may serve as a compensatory
mechanism. The results of this exploratory study provide further evidence for the multifaceted
processes involved in numerical reasoning and its age-related decline, with a potentially distinct
neural network for symbolic and non-symbolic numerical representations
Effects of acute trigeminal nerve stimulation on rest EEG activity in healthy adults
No full textTrigeminal 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
Symbolic and non-symbolic numerical representations in old and young subjects: an exploratory EEG study
No full textNumeracy has significant implications throughout the life course. Its agei nduced
decline represents a vulnerability factor in elderly populations when it comes to solving everyday tasks. However, the reasons behind age-induced decline in numeracy are still unclear. In this study, we used a parity judgment task to study variations in number cognition between old and young participants. Since numeracy is associated with both symbolic and nonsymbolic representations, three numerical formats were used: arabic digits (N), finger representations (F), and dots (D). Fifty-three healthy subjects joined the study: 31 young (24.1±4.73 y.o.) and 22 old (68.8±4.38 y.o.). EEG (64 channels) was recorded during the task. Mixed Effects Models analysis showed that performance accuracy for D was significantly lower than for N and F (p = .02).
There were significant main effects for reaction time for Group (old, young), Condition (N, F, D) and Gender. Notably, old adults responded slower than
young adults (p < .001) and both groups performed significantly faster in the
task for N compared to F and D (p < .001). Significant interaction effects showed that performance between males and females were comparable for arabic digits (p = .14), with females showing significantly slower response for non-symbolic stimuli than males (F, p = 0.04; D, p = .007). In sensor space, multivariate pattern analysis shows that the neural correlates supporting the different number representations can be classified as categorically separate, with an early dissociation (~200 ms) between N, F, and D stimuli when compared to each other. This provides provisional evidence that symbolic and non-symbolic representations recruit functionally distinct neuronal processes.
Subjects in the old group showed a slight reduction in decoding and an
increase in its latency. Numerical cognition involves a highly-integrated
network, with a key role of the intraparietal sulcus and fusiform gyrus. In
source space, we found reduced activation levels and increased latency of
response in the primary cortical areas involved in numerical cognition in the
old group. In the same group, all stimuli also induced a wider cortical response
with respect to young subjects. We hypothesize that the reduced activity of the
main cortical areas may contribute to the age-induced decay in numeracy and
that the recruitment of other cortical areas may serve as a compensatory
mechanism. The results of this exploratory study provide further evidence for
the multifaceted processes involved in numerical reasoning and its age-related
decline, with a potentially distinct neural network for symbolic and nonsymbolic
numerical representations
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