Yuliya Nigmatullina

Left Cathodal Trans-Cranial Direct Current Stimulation of the Parietal Cortex Leads to an Asymmetrical Modulation of the Vestibular-Ocular Reflex

Multi-sensory visuo-vestibular cortical areas within the parietal lobe are important for spatial orientation and possibly for descending modulation of the vestibular-ocular reflex (VOR). Functional imaging and lesion studies suggest that vestibular cortical processing is localized primarily in the non-dominant parietal lobe. However, the role of inter-hemispheric parietal balance in vestibular processing is poorly understood. Therefore, we tested whether experimentally induced asymmetries in right versus left parietal excitability would modulate vestibular function. VOR function was assessed in right-handed normal subjects during caloric ear irrigation (30 °C), before and after trans-cranial direct current stimulation (tDCS) was applied bilaterally over the parietal cortex. Bilateral tDCS with the anode over the right and the cathode over the left parietal region resulted in significant asymmetrical modulation of the VOR, with highly suppressed responses during the right caloric irrigation (i.e. rightward slow phase nystagmus). In contrast, we observed no VOR modulation during either cathodal stimulation of the right parietal cortex or SHAM tDCS conditions. Application of unilateral tDCS revealed that the left cathodal stimulation was critical in inducing the observed modulation of the VOR. We show that disruption of parietal inter-hemispheric balance can induce asymmetries in vestibular function. This is the first report using neuromodulation to show right hemisphere dominance for vestibular cortical processing.

Temporoparietal encoding of space and time during vestibular-guided orientation

The cardinal features of vestibular dysfunction are illusory self-motion (vertigo) and spatial disorientation. Testing 18 acute focal cortical lesion patients, Kaski et al. show that temporoparietal junction lesions impair vestibular-guided spatial orientation but not self-motion perception. Distinct cortical substrates thus mediate the vestibular percepts of spatial orientation and self-motion.

Bidirectional Modulation of Numerical Magnitude

Numerical cognition is critical for modern life; however, the precise neural mechanisms underpinning numerical magnitude allocation in humans remain obscure. Based upon previous reports demonstrating the close behavioral and neuro-anatomical relationship between number allocation and spatial attention, we hypothesized that these systems would be subject to similar control mechanisms, namely dynamic interhemispheric competition. We employed a physiological paradigm, combining visual and vestibular stimulation, to induce interhemispheric conflict and subsequent unihemispheric inhibition, as confirmed by transcranial direct current stimulation (tDCS). This allowed us to demonstrate the first systematic bidirectional modulation of numerical magnitude toward either higher or lower numbers, independently of either eye movements or spatial attention mediated biases. We incorporated both our findings and those from the most widely accepted theoretical framework for numerical cognition to present a novel unifying computational model that describes how numerical magnitude allocation is subject to dynamic interhemispheric competition. That is, numerical allocation is continually updated in a contextual manner based upon relative magnitude, with the right hemisphere responsible for smaller magnitudes and the left hemisphere for larger magnitudes.

Right hemisphere dominance directly predicts both baseline V1 cortical excitability and the degree of top-down modulation exerted over low-level brain structures

Highlights • Line bisection predicts V1 excitability.• Line bisection predicts degree of VOR modulation.• Line bisection correlates with tDCS-mediated vestibular-nystagmus suppression.• Degree of nystagmus suppression is a bio-marker of right hemisphere dominance.

Separate attentional components modulate early visual cortex excitability.

Disruption of the right lateralised fronto-parietal attentional network using neuro-modulation techniques has been shown to induce both functional and perceptual modulation of early visual cortex (Silvanto, Muggleton, Lavie, & Walsh, 2009). Such modulation is suggested to be mediated by interhemispheric competition (Silvanto et al., 2009). To date in neurologically normal subjects no behavioural demonstration of such modulation exists. In this study, we stimulated the vestibular system duringperformanceof anattentional task. Aprevious studyhas demonstrated that passive rotation combined with performance of a visual attentional task results in asymmetric modulation of the brainstemmediated vestibulo-ocular reflex (VOR) (Arshad, Nigmatullina, & Bronstein, 2013). The modulation of the VOR is suggested to occur as a result of activating overlapping cortical networks responsible for processing both vestibular information and the attentional task in the right parietal lobe (Corbetta & Shulman, 2002; Dieterich et al., 2003; Miller et al., 2000; Van Elk & Blanke, 2012), resulting in inhibition of the left hemisphere via interhemispheric competition (Arshad et al., 2013; Miller et al., 2000). This hypothesis was directly tested in a recent study where transcranial direct current stimulation of the parietal cortex was employed to assess the effect upon the VOR (Arshad, Nigmatullina, Roberts et al., 2013), with the largest modulation of the VOR observed during cathodal stimulation of left parietal cortex. Thus in this study, we combined caloric stimulationwith a visual attention task to disrupt parietal interhemispheric balance in normal subjects, and measured the possible effect on V1/V2 excitability. Moreover, for the first time we delineate the specific contributions of spatial versus non-spatial attentional networks in modulating early visual cortex. We assessed V1 excitability using phosphenes, elicited by briefly stimulating the visual cortex using single pulse transcranial magnetic stimulation (TMS), with the intensity required to elicit a phosphene reflecting the underlying cortical excitability (Marg & Rudiak, 1994). Eighteen righthanded participants (male 14, mean age 1⁄4 24; range 20e33) gave written informed consent as approved by the local research ethics committee. Subjects were blindfolded and were seated on a chair fitted with a fixed magnetic coil and head restraint system. The head was inclined 30 from the horizontal plane for maximal horizontal canal caloric stimulation. Firstly, V1 stimulation site was localised using a functional method by placing the coil centrally over the inion then moving it dorsally until the brightest stationary phosphene percept is observed in the centre of the visual field (Walsh, Pascual-Leone, & Kosslyn, 2003). Secondly, the threshold was established according to a modified binary staircase algorithm (Tyrrell & Owens, 1988) previously described (Seemungal et al., 2013). Subjects were trained to rate the intensity of the perceived phosphene on a scale from 0 (no phosphene, below threshold) to 5 (maximumbrightness, 100% maximum stimulator output). We then used the established clinical approach for coldwater (30 C) caloric irrigation (left or right ear, randomised order) for 40 sec to activate the vestibular system. The irrigations were separated by a period of 5 minutes to allow for any after effects to subside. Following each irrigation we immediately measured visual cortical excitability using 20 single TMS pulses (GuzmanLopez, Silvanto, & Seemungal, 2011) applied at 20% above phosphene threshold for each individual, with each pulse separated by 3 sec. Subjects responded verbally and rated

How imagery changes self-motion perception.

Highlights • Imagined self-motion differentially modulates vestibular processing.• Differential modulation affects both high- and low-order vestibular processing.• Congruent and incongruent imagery have opposing effects.• Modulation reported is specific to mental imagery and not an attentional bias.

Applications of neuromodulation to explore vestibular cortical processing; new insights into the effects of direct current cortical modulation upon pursuit, VOR and VOR suppression

Functional imaging, lesion studies and behavioural observations suggest that vestibular processing is lateralised to the non-dominant hemisphere. Moreover, disruption of interhemispheric balance via inhibition of left parietal cortex using transcranial direct current stimulation (tDCS) has been associated with an asymmetric suppression of the vestibulo-ocular reflex (VOR). However, the mechanism by which the VOR was modulated remains unknown. In this paper we review the literature on non-invasive brain stimulation techniques which have been used to probe vestibular function over the last decade. In addition, we investigate the mechanisms whereby tDCS may modulate VOR, e.g. by acting upon pursuit, VOR suppression mechanisms or direct VOR modulation. We applied bi-hemispheric parietal tDCS in 11 healthy subjects and only observed significant effects on VOR gain (tdcs * condition p=0.041) - namely a trend for VOR gain increase with right anodal/left cathodal stimulation, and a decrease with right cathodal/left anodal stimulation. Hence, we suggest that the modulation of the VOR observed both here and in previous reports, is directly caused by top-down cortical control of the VOR as a result of disruption to interhemispheric balance, likely parietal.

Lateralisation of the Vestibular Cortex Is More Pronounced in Left-Handers

Visual acuity during head perturbations is maintained by the brainstem mediated vestibular-ocular reflex (VOR), which can be artificially elicited via caloric vestibular stimulation. We have recently probed cortical influences upon the VOR by applying transcranial direct current stimulation (tDCS) over the posterior parietal cortex (PPC) (implicated in vestibular cortical processing [1]) and subsequently assessed the degree of VOR modulation during cold water irrigations [2]. In right-handed individuals, we found that cathodal stimulation over the left PPC suppressed both left and rightear cold-water irrigations [2]. However, a significantly more marked suppression was observed upon left-beating vestibular nystagmus, elicited during right-sided cold irrigations [2], which in righthanders are predominantly processed by the left hemisphere [3]. Conversely, in left-handed individuals, we found that cathodal stimulation of the right hemisphere resulted in suppression of only rightear cold irrigations [4] that are predominantly processed by the right hemisphere. However, to date it remains unknown whether cathodal tDCS applied over the PPC can modulate vestibular nystagmus that is elicited during warm water irrigations? This is an important and relevant question given that our recent behavioural study has indirectly suggested that differences present in the degree of lateralisation for the cortical processing of cold and warm water irrigations that preferentially activate the same hemisphere. That is, left-ear warm water irrigations appear to be more lateralised to the left hemisphere in comparison to right-ear cold water irrigations, in right handers [5]. Herewith, we directly address this question by assessing any VORmodulation during warm water irrigations, following either left or right hemisphere cathodal tDCS over the PPC, in both right and left handed individuals respectively. If cortical lateralisation of cold andwarmwater irrigations differs, then cathodal tDCS will differentially modulate the VOR during cold and warm irrigations. However, an identical modulatory effect upon the VOR will be observed following cathodal tDCS, if cold and warm water irrigations are similarly lateralised. Twenty right-handed subjects (11 male, mean age 22.6, range 19–25; >40 on the Edinburgh handedness inventory [6]) and twelve left-handed subjects (9 male, mean age 23.1, range 20–26; <–40) without brain stimulation contraindications nor any history or active neurological, ophthalmological, psychiatric or otological disorders participated in this study. Subjects provided written informed consent. A battery-driven stimulator (neuroConn GMBH, Ilmenau, Germany) was used to deliver the stimulation-current, which had a ramp up time of 10 s at which point a constant current of 1.5 mA was applied for a duration of 15 min, which then ramped down in a 10 s fade out period. The tDCS montage is identical to that previously implemented in our earlier studies [2,4,7,8] (Fig. 1). In righthanders, either left cathodal (session 1; test condition) or left anodal (session 2; control condition) stimulation was applied over P3 (Fig. 1A). In left-handers, either right cathodal (session 1; test condition) or right anodal (session 2; control condition) stimulation was applied over P4 (Fig. 1A). Each session was separated by 1 week to avoid any possible tDCS carry-over effects [Electrode placement area 25 cm2; Electrode-position was defined using 10–20 internationalEEG electrode placement co-ordinates; Electrodes were held in place with EEG cap). The reference electrode was always placed over the deltoid muscle on the ipsilateral shoulder [2,4,8]. Participants lay supine on a couch with the head tilted up by 30° in order to obtain maximal horizontal semi-circular canal activation. Eye movements were recorded using a head mounted infrared binocular video-oculography (VOG) system, and were analysed using a computerised automatic analysis program (CHARTR VNG; ICS medical) that removed the fast phases of the vestibular nystagmus and plotted each individual slow phase velocity over 100 s. Response intensity was determined by identifying the peak slow phase eye velocity (SPV). The experimental protocol involved subjects undergoing either right or left-ear warm water (randomisedorder) caloric stimulation (44 °C, flow-rate; 500 ml/min, 40 s duration) to establish pre-tDCS peak SPV. Irrigations were separated by 7min, avoiding vestibular carry-over effects. Following the establishment of the pre-tDCS peak SPV, tDCSwas applied for 15min, as detailed above. Following tDCS, irrigations were repeated to establish the post-tDCS peak SPV [2,4,7,8]. In right-handers, left hemisphere cathodal stimulation induced asymmetrical VOR modulation as shown in Fig. 1B. 2 × 2 × 2 repeated measures ANOVA with factors ‘stimulation’ (two levels; tDCS, no tDCS), ‘laterality’ (two levels; right ear, left ear) and ‘polarity’ (two levels; anodal, cathodal) revealed a significant main effect of ‘laterality’ (F(1,19) = 11.9, P < 0.01), no main effect of ‘stimulation’ (F(1,19) = 0.318, P > 0.05), and no main effect of ‘polarity’ (F(1,19) = 0.84, P > 0.05). We found a significant three-way interaction between laterality*stimulation*polarity (F(1,19) = 27.4, P < 0.001). Post-hoc paired t-tests revealed significant differences for left (P < 0.001 paired t-test Bonferroni corrected) but not right ear (P > 0.05 paired t-test Bonferroni corrected) warm irrigations following left cathodal stimulation. No VORmodulation was observed upon either left or right ear irrigations following left anodal stimulation (P > 0.05 paired t-test; Fig. 1B). In left-handers, right hemisphere cathodal stimulation induced asymmetrical VOR modulation as shown in Fig. 1C. 2 × 2 × 2 repeated measures ANOVA with factors ‘stimulation’ (two levels; tDCS, no tDCS), ‘laterality’ (two levels; right ear, left ear) and ‘polarity’ (two levels; anodal, cathodal) revealed a significant main effect for both ‘laterality’ (F(1,11) = 9.8, P < 0.03), and ‘stimulation’ ARTICLE IN PRESS

ELECTROCORTICAL THERAPY FOR MOTION SICKNESS

Given a sufficiently provocative stimulus, almost everyone can be made motion sick, with approximately one-third experiencing significant symptoms on long bus trips, on ships, or in light aircraft.1–4 Current countermeasures are either behavioral or pharmacologic. Behavioral measures include habituation/desensitization treatment protocols5 as well as positioning the head in alignment with the direction of the gravito-inertial force and maintaining a stable horizontal reference frame.5 Pharmacologic measures include antimuscarinics, H1 antihistamines, and sympathomimetics, which all detrimentally impact upon cognitive function, rendering them inappropriate for occupational use.5 All current therapies are only partially effective.

Perceived state of self during motion can differentially modulate numerical magnitude allocation.

Although a direct relationship between numerical allocation and spatial attention has been proposed, recent research suggests that these processes are not directly coupled. In keeping with this, spatial attention shifts induced either via visual or vestibular motion can modulate numerical allocation in some circumstances but not in others. In addition to shifting spatial attention, visual or vestibular motion paradigms also (i) elicit compensatory eye movements which themselves can influence numerical processing and (ii) alter the perceptual state of ‘self’, inducing changes in bodily self‐consciousness impacting upon cognitive mechanisms. Thus, the precise mechanism by which motion modulates numerical allocation remains unknown. We sought to investigate the influence that different perceptual experiences of motion have upon numerical magnitude allocation while controlling for both eye movements and task‐related effects. We first used optokinetic visual motion stimulation (OKS) to elicit the perceptual experience of either ‘visual world’ or ‘self’‐motion during which eye movements were identical. In a second experiment, we used a vestibular protocol examining the effects of perceived and subliminal angular rotations in darkness, which also provoked identical eye movements. We observed that during the perceptual experience of ‘visual world’ motion, rightward OKS‐biased judgments towards smaller numbers, whereas leftward OKS‐biased judgments towards larger numbers. During the perceptual experience of ‘self‐motion’, judgments were biased towards larger numbers irrespective of the OKS direction. Contrastingly, vestibular motion perception was found not to modulate numerical magnitude allocation, nor was there any differential modulation when comparing ‘perceived’ vs. ‘subliminal’ rotations. We provide a novel demonstration that numerical magnitude allocation can be differentially modulated by the perceptual state of self during visual but not vestibular mediated motion.