[Downloaded free from http://www.nrronline.org on Sunday, February 13, 2022, IP: 90.162.46.151] Perspective Modulation of brainstem reflexes volitionally activated masseter muscle at 10% of maximum force. This silent period was shorter than the duration of significant stretch induced by non-invasive brain reflex suppression. The authors concluded that TMS-induced corticobulbar activity acts stimulation: is there a future? on brainstem interneurons that either inhibit masseter motoneurons or increase pre-synaptic inhibition of Ia-afferents. In healthy subjects, slow (1 Hz) sub-threshold Hatice Kumru*, Markus Kofler, Josep Valls-Sole rTMS over the hand motor cortex suppressed Kumru et al. (2019) have recently reported responses are conveyed through a complex the excitability recovery of the R2 component of significant reduction of the R2 component chain of interneurons at the pontomedullary the blink reflex. Significant inhibition occurred of the trigeminal blink reflex following high- level, whose excitability is under the control as early as 30 s following rTMS (De Vito et al., frequency (20 Hz) repetitive transcranial of supranuclear structures, including the 2009). Possibly, long-lasting reduction of blink magnetic stimulation (rTMS) over the vertex basal ganglia and the cerebral cortex. Blink reflex excitability might be a consequence of in both, healthy subjects and in patients reflex excitability is known to be altered reduced cortical excitability and of subsequently with spinal cord injury (SCI) (Figure 1). The in disorders such as Parkinson’s disease, reduced descending cortico-nuclear facilitation modulatory influence of non-invasive brain stroke, spinal cord injury, and others, in of the blink reflex-mediating interneuronal stimulation (NIBS) on brainstem reflexes has which therapy-oriented NIBS has shown network (De Vito et al., 2009). In another study been only scarcely studied. some symptomatic improvement. Therefore, in healthy subjects, Cabib et al. (2016) reported an eventual correlation with therapeutical enhanced excitability of trigemino-facial reflex NIBS is currently used as an add-on treatment circuits induced by bi-hemispheric tDCS, the benefits would enable using data on brainstem in various neurological disorders, based on opposite of what was reported with rTMS. The reflex excitability as a quantifiable surrogate stimulation-induced neuroplasticity. In a broad finding by these authors of larger ipsilateral measure of clinical change. Unfortunately, sense, neural plasticity can be understood as though, various NIBS methods have been than contralateral effects of tDCS with unilateral the mechanisms enabling the nervous system used in the few studies reported so far on that stimulation suggested that sensitization through to adapt to environment- or lesion-induced topic, but their consistency remains unclear. cutaneous trigeminal afferents added to other changes. rTMS and transcranial direct current We considered appropriate to review what possible mechanisms such as activation of stimulation (tDCS) are the two most commonly is known at present about NIBS-induced cortico-nuclear or cortico-reticular connections. used NIBS methods. rTMS acts by discharging modulation of brainstem reflex excitability and The possibility of peripheral mechanisms intense electrical currents into an insulated coil put forward a challenge in further research in contributing to changes in brainstem reflexes (magnetic coil), which generates a magnetic this area. after NIBS may also be present with rTMS. field that in turn induces electrical currents in No effects of high frequency (20 Hz) vertex electrically excitable structures. Depending on Effects of NIBS on brainstem reflexes in rTMS on the blink reflex excitability recovery stimulation parameters, rTMS can upregulate healthy subjects and in patients: The effects curve to paired stimuli were reported in a or downregulate to different extents the of single pulse TMS on blink reflexes has been sham-controlled study by Kumru et al. (2019). excitability of the neural structures beneath scarcely studied. Leis et al. (1993) studied the However, using TBS of the motor cortex, Suppa the stimulating coil, inducing long-lasting relationship between trigeminal blink reflex et al. (2014) showed modulation of the R2 trans-synaptic changes in the descending and cortical silent period. They observed component of the blink reflex, which increased corticospinal tract and spinal cord circuits. suppression of the R2 component but no with facilitatory iTBS and decreased with High-frequency rTMS (≥ 5 Hz) increases cortical change in R1 (or a trend toward potentiation) inhibitory cTBS. Nardone et al. (2019) found excitability, whereas low-frequency rTMS (≤ when TMS preceded supraorbital nerve also a bimodal effect of prefrontal TBS on the 1 Hz) decreases cortical excitability. A faster stimulus by 90–100 ms with subjects at rest. acquisition of the classical conditioned eyeblink modulation of motor cortex excitability can A clear R1 facilitation was observed when the responses, i.e., enhanced acquisition with iTBS be reached with a form of rTMS, theta burst supraorbital nerve stimulus was applied in the and reduced acquisition with cTBS. The effects stimulation (TBS), in which bursts of 3 pulses middle of the silent period induced by TMS on conditioned eyeblink responses have also are repeated at 50 Hz every 200 ms. This is in the volitionally activated orbicularis oculi been examined with cerebellar TBS by Hoffland known to lead to an increase of excitability muscle while the R2 component was inhibited. et al. (2012) and with tDCS by Zuchowski when administered intermittently (iTBS) and to These findings imply that the blink reflex circuit et al. (2014), who both found reduction in a decrease in excitability when administered mediating R1 remains excitable during the the acquisition of conditioned responses, continuously (cTBS). tDCS delivers a continuous cortical silent period which originates mostly concurring with the known inhibitory effect of current (1–2 mA) over the scalp, through in the cerebral cortex. Suppression of the R2 the cerebellum on the motor cortex. Finally, anodal and cathodal contacts, which does not component and concomitant facilitation of R1 Bocci et al. (2018) reported on modulatory produce action potentials in cortical neurons with preceding single pulse TMS may at least effects of cerebellar tDCS on the hand-blink but modifies the discharge rate of already in part be explained by mechanisms related reflex, suggesting a role of the cerebellum in active neurons. The anodal contact increases to prepulse modulation. Two possible sensory the control of protective reflexes within the firing by hyperpolarizing the dendrites and modalities may contribute to such a prepulse defensive peripersonal space in humans. depolarizing the cell body, whereas the cathode effect: the auditory click, unavoidably linked Only a few studies have been carried out induces the opposite effect. The stimulation- with TMS, and the possible TMS-induced in patients: Kumru et al. (2019) found a induced neuroplasticity is the basis for the activation of corticobulbar pathways leading significant decrease of the R2 component in therapy-oriented use of NIBS, as it leads to to engagement of prepulse circuits at the patients with SCI using high frequency vertex neural changes akin to those known as long- subcortical level. rTMS. Interestingly, patients with SCI had term potentiation and long-term depression, In another study, focal TMS was used to enhanced blink reflexes to supraorbital nerve observed in laboratory preparations. condition masseter stretch reflexes at different stimulation, which was rapidly normalized Studies on brainstem reflexes have provided conditioning–testing intervals (Sowman et al., after intrathecal baclofen, in parallel to the important information on the functional 2008). Masseter reflexes were elicited by a clinical effect (Kumru et al., 2011). Suppa et al. integrity of suprasegmental structures servo-controlled electromagnetic device that (2014) found absence of a modulatory effect influencing reflex excitability. The blink reflex imposed a controlled displacement of the lower of TBS on the R2 component of the blink reflex is doubtless the most extensively studied jaw in healthy subjects at rest. Masseter stretch in patients with Tourette’s syndrome, which brainstem reflex. When elicited by electrical reflexes were suppressed when TMS was the authors interpreted as a sign of reduced stimulation of the supraorbital nerve, the applied between 75 ms before the stretch and plasticity in relation to the pathophysiology blink reflex recorded in the orbicularis oculi 2 ms afterwards. TMS of the same intensity did of Tourette’s syndrome. In patients with muscles is composed of two components: not evoke a motor evoked potential in masseter blepharospasm, low frequency rTMS induced an ipsilateral R1 and a bilateral R2. These muscle at rest but induced a silent period in an immediate decrease of the enhanced blink 2004 ｜NEURAL REGENERATION RESEARCH｜Vol 16｜No. 10｜October 2021 [Downloaded free from http://www.nrronline.org on Sunday, February 13, 2022, IP: 90.162.46.151] EMG Unit, Neurology, Hospital Clinic-IDIBAPS- Barcelona, Spain (Valls-Sole J) *Correspondence to: Hatice Kumru, MD, PhD, hkumru@guttmann.com. https://orcid.org/0000-0002-0501-1660 (Hatice Kumru) Date of submission: September 20, 2020 Date of decision: November 30, 2020 Date of acceptance: December 22, 2020 Date of web publication: February 19, 2021 https://doi.org/10.4103/1673-5374.308083 How to cite this article: Kumru H, Kofler M, Valls- Sole J (2021) Modulation of brainstem reflexes induced by non-invasive brain stimulation: is there a future? Neural Regen Res 16(10):2004-2005. Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication. Figure 1 ｜ Representative example of blink reflex recordings in a male patient with spinal cord injury Plagiarism check: Checked twice by iThenticate. before and after real repetitive transcranial magnetic stimulation (rTMS) at 20 Hz over the vertex. Peer review: Externally peer reviewed. Open access statement: This is an open access journal, and articles are distributed under the reflex excitability recovery characteristic for this neurodegenerative diseases. The brainstem terms of the Creative Commons Attribution- condition, in parallel with clinical improvement is the main hub of many important functions. NonCommercial-ShareAlike 4.0 License, which (Kranz et al., 2010). Likely, the supranuclear control of those allows others to remix, tweak, and build upon the functions entails a fine regulation of work non-commercially, as long as appropriate Future research: The topic of modulating interneuronal excitability, which is often altered credit is given and the new creations are licensed brainstem reflexes with NIBS is one of the least in neurological disorders. Most reported effects under the identical terms. explored in neurophysiology. There are many of rTMS on the excitability of the blink reflex are gaps in our knowledge of how therapy-oriented inhibitory (save those induced by iTBS on the NIBS works, but neurophysiological recording of size of the R2 component or on the acquisition References the effects in brainstem and spinal cord circuits of conditioned eyeblink responses). In contrast, Bocci T, Ferrucci R, Barloscio D, Parenti L, Cortese F, is certainly feasible. Various questions may Priori A, Sartucci F (2018) Cerebellar direct current most of the effects reported for tDCS are stimulation modulates hand blink reflex: implications direct future research in this area: facilitatory. for defensive behavior in humans. Physiol Rep Clinical correlation of the effects of NIBS on 6:e13471. T h e re s u l t s o b ta i n e d s o fa r w i t h N I B S Cabib C, Cipullo F, Morales M, Valls-Solé J (2016) brainstem reflexes. It is always challenging to modulation of the blink reflex should be Transcranial direct current stimulation (tDCS) enhances seek a clinical correlation in neurophysiological expanded using different stimulation technics the excitability of trigemino-facial reflex circuits. Brain findings. They are usually better correlated with and different stimulation frequencies. The Stimul 9:218-224. the pathophysiological mechanisms leading to De Vito A, Gastaldo E, Tugnoli V, Eleopra R, Casula A, Tola studies should cover also blink reflexes MR, Granieri E, Quatrale R (2009) Effect of slow rTMS clinical expressions. This is not different for the elicited with other stimulus modalities, e.g., of motor cortex on the excitability of the blink reflex: a abnormalities reported in brainstem reflexes in the acoustic blink reflex, which would avoid study in healthy humans. Clin Neurophysiol 120:174- patients with various disorders. Interestingly, interference from peripheral trigeminal 180. however, the changes induced in brainstem stimulation. Comparison of the effects of rTMS Hoffland BS, Bologna M, Kassavetis P, Teo JT, Rothwell JC, reflexes by NIBS parallel in most instances Yeo CH, van de Warrenburg BP, Edwards MJ (2012) and tDCS applied over different cortical regions, Cerebellar theta burst stimulation impairs eyeblink the changes in the clinical context (Kranz et such as the facial and supplementary motor classical conditioning. J Physiol 590:887-897. al., 2010; Kumru et al., 2019). This raises the Kranz G, Shamim EA, Lin PT, Kranz GS, Hallett M (2010) areas, cingulate cortex, and brainstem would be question whether changes in the blink reflex Transcranial magnetic brain stimulation modulates useful. It would be also adequate to compare blepharospasm: a randomized controlled study. may have clinical relevance as a consequence, the effects of rTMS and tDCS on blink reflex Neurology 5:1465-1471. or vice versa, whether clinical changes may excitability in the same subjects. Kumru H, Kofler M, Valls-Sole J, Vidal J (2019) Brainstem serve to explain subsequent changes in the reflex excitability after high-frequency repetitive blink reflex. In conclusion, we need to better understand transcranial magnetic stimulation in healthy and spinal Other brainstem reflexes and functions apart the mechanisms of reorganization of neural cord injury subjects. Brain Res Bull 147:86-91. pathways at different levels of the central Kumru H, Stetkarova I, Schindler C, Vidal J, Kofler M (2011) of the blink reflex may be relevant for clinical Neurophysiological evidence for muscle tone reduction correlation of NIBS benefit but have not nervous system following injury. Based on by intrathecal baclofen at the brainstem level. Clin been studied so far. One such example is the such knowledge, we may be able to apply Neurophysiol 122:1229-1237. startle reaction, which reveals activation of different types of NIBS in order to promote Leis AA, Kofler M, Stokic DS, Grubwieser GJ, Delapasse JS controlled and thoughtful neuromodulation in (1993) Effect of the inhibitory phenomenon following the bulbopontine reticular formation and the magnetic stimulation of cortex on brainstem motor reticulospinal tract. Since excitability of the preserved and undamaged neural pathways. neuron excitability and on the cortical control of startle circuits is abnormal in many neurological Ultimately, we should strive to develop brainstem reflexes. Muscle Nerve 16:1351-1358. conditions, it would be worth knowing if NIBS better neurophysiological strategies aiming Nardone R, Langthaler PB, Höller Y, Golaszewski S, Versace at implementing neuronal reorganization into V, Sebastianelli L, Brigo F, Saltuari L, Trinka E (2019) can cause any modulation of the startle reflex. Role of human prefrontal cortex in the modulation The same could be said of other functions carefully planned therapy. of conditioned eyeblink responses. Behav Brain Res with a strong link to the brainstem such as the 374:112027. control of pain, sleep, respiration, etc. Hatice Kumru*, Markus Kofler, Sowman PF, Flavel SC, McShane CL, Miles TS, Nordstrom MA (2008) Transcranial magnetic stimulation reduces Targeting brainstem reflex excitability with Josep Valls-Sole masseter motoneuron pool excitability throughout Institut Guttmann, Institut Universitari de the cortical silent period. Clin Neurophysiol 119:1119- therapy-oriented NIBS. With the increasingly Neurorehabilitació adscrit a la UAB, 089M6 re c o g n i ze d ro l e o f p l a st i c i t y i n s p i n a l 1129. Badalona – Barcelona, Spain (Kumru H) Suppa A, Marsili L, Di Stasio F, Berardelli I, Roselli V, and supraspinal neuronal networks, the Univ Autonoma de Barcelona, 08M93 Bellaterra Pasquini M, Cardona F, Berardelli A (2014) Cortical current challenge is to effectively integrate (Cerdanyola del Vallès), Spain (Kumru H) and brainstem plasticity in Tourette syndrome and neurophysiological techniques that modulate Fundació Institut d’Investigació en Ciències de la obsessive-compulsive disorder. Mov Disord 29:1523- intrinsic sensorimotor processing in the 1531. Salut Germans Trias i Pujol, Badalona, Barcelona, Zuchowski ML, Timmann D, Gerwig M (2014) Acquisition neurorehabilitation setting in order to regain Spain (Kumru H) of conditioned eyeblink responses is modulated by functional recovery following neurological Department of Neurology, Hochzirl Hospital, Zirl, cerebellar tDCS. Brain Stimul 7:525-531. injury or to maintain the residual function in Austria (Kofler M) C-Editors: Zhao M, Wang L; T-Editor: Jia Y NEURAL REGENERATION RESEARCH｜Vol 16｜No. 10｜October 2021｜2005