Hemispheric asymmetry in cortical control of memory-guided saccades. A transcranial magnetic stimulation study

To study the temporal organisation of memory-guided saccade control we used single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal (PPC) and prefrontal cortex (PFC) in eight healthy subjects. TMS was applied either following presentation of a visual target, i.e. 160, 260, and 360 ms after the flashed point, or during the period of memorisation, i.e. between 700 and 1500 ms, or finally 100 ms after extinguishing of the central fixation point (i.e. 2100 ms after the target presentation). Latency of memory-guided saccades and the percentage of error in amplitude (PEA) was measured and compared with results without stimulation.TMS over the left PPC 100 ms after the extinguishing of the central fixation point significantly increased memory-guided saccade latency bilaterally. Furthermore, stimulation over the left PFC had a significant effect on the PEA of contralateral memory-guided saccades when applied during the period of memorisation, i.e. between 700 and 1500 ms.In a previous study using identical methodology [13: Müri RM, Vermersch SI, Rivaud S, Gaymard B, Pierrot-Deseilligny C. Effects of single-pulse transcranial magnetic stimulation over the prefrontal and posterior parietal cortices during memory-guided saccades in humans. Journal of Neurophysiology 1996;76:2102-2106], we found that TMS over the right PPC increased the contralateral PEA when applied 260 ms after the flash, the effects on saccade latency after right PPC stimulation or on the PEA after right PFC stimulation being similar to those observed here. Taken together, these results show that (1) a hemispheric asymmetry in the preparation of memory-guided saccade amplitude during the early phase of sensorimotor integration exists, (2) memory-guided saccade triggering is controlled by PPC on both sides, and (3) PFC on both sides are involved in spatial working memory performance.     

Interhemispheric imbalance during visuospatial attention investigated by unilateral and bilateral TMS over human parietal cortices

We used single-pulse transcranial magnetic stimulation (TMS) to study visuospatial attention. TMS was applied over one hemisphere, or simultaneously over both the right and left posterior parietal cortex (PPC), at two different interstimulus intervals (ISI) during a visual detection task. Unilateral TMS over the right and left PPC, respectively, impaired detection of contralateral presented visual stimuli at an ISI of 150 ms. By contrast, simultaneous biparietal TMS induced no significant changes in correct stimulus detection. TMS at an ISI of 250 ms evoked no changes for magnetic stimulation over either the right or the left parietal cortex. These results suggest that both PPC play a crucial role at a relatively early stage in the widely distributed brain network of visuospatial attention. The abolition of behavioral deficits during simultaneous biparietal TMS underlines the common hypothesis that an interhemispheric imbalance might underlie the disorders of neglect and extinction seen following unilateral brain damage.     

The role of the left posterior parietal lobule in top-down modulation on space-based attention: a transcranial magnetic stimulation study

Converging evidence from neuroimaging as well as lesion and transcranial magnetic stimulation (TMS) studies has been obtained for the involvement of right ventral posterior parietal cortex (PPC) in exogenous orienting. However, the contribution of dorsal PPC to attentional orienting, particularly endogenous orienting, is still under debate. In an informative peripheral cueing paradigm, in which the exogenous and endogenous orienting can be studied in relative isolation within a single task, we applied TMS over sub-regions of dorsal PPC to explore their possible distinct involvement in exogenous and endogenous processes. We found that disruption of the left posterior intraparietal sulcus (pIPS) weakened the attentional effects of endogenous orienting, but did not affect exogenous processes. In addition, TMS applied over the right superior parietal lobule (SPL) resulted in an overall increase in reaction times. The present study provides the causal evidence that the left pIPS plays a crucial role in voluntary orienting of visual attention, while right SPL is involved in the processing of arousal and/or vigilance.     

Time-course of posterior parietal and occipital cortex contribution to sound localization

It has been suggested that both the posterior parietal cortex (PPC) and the extrastriate occipital cortex (OC) participate in the spatial processing of sounds. However, the precise time-course of their contribution remains unknown, which is of particular interest, considering that it could give new insights into the mechanisms underlying auditory space perception. To address this issue, we have used event-related transcranial magnetic stimulation (TMS) to induce virtual lesions of either the right PPC or right OC at different delays in subjects performing a sound lateralization task. Our results confirmed that these two areas participate in the spatial processing of sounds. More precisely, we found that TMS applied over the right OC 50 msec after the stimulus onset significantly impaired the localization of sounds presented either to the right or to the left side. Moreover, right PPC virtual lesions induced 100 and 150 msec after sound presentation led to a rightward bias for stimuli delivered on the center and on the left side, reproducing transiently the deficits commonly observed in hemineglect patients. The finding that the right OC is involved in sound processing before the right PPC suggests that the OC exerts a feedforward influence on the PPC during auditory spatial processing.     

Short-term cortical reorganization by deafferentation of the contralateral sensory cortex

The topographic arrangement of the human primary somatosensory cortex following deafferentation of the contralateral cortex has been investigated by means of dipole source analysis. Somatosensory-evoked potentials were obtained by electrical stimulation of digit 1 and digit 5 of the left hand before and after anesthesia of digits 2-4 of the right hand during different terms of attention. Anesthesia induced an expansion of the three-dimensional distance between digits 1 and 5. This suggests intercortical plasticity modulated between bilateral primary somatosensory cortical areas, which is unaffected by spatial attention. These changes occur rapidly and are probably mediated by disinhibition of intercortical connections, leading to hyperexcitability of the primary sensory cortex that is contralateral to the region undergoing deafferentation.     

Effects of rTMS conditioning over the fronto-parietal network on motor versus visual attention

Many studies have shown that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. Rushworth et al. [Rushworth, M. F., Krams, M., & Passingham, R. E. The attentional role of the left parietal cortex: The distinct lateralization and localization of motor attention in the human brain. Journal of Cognitive Neuroscience, 13, 698-710, 2001] have recently provided evidence for a left-lateralized network of parietal areas involved in motor attention. Using two variants of a cued reaction time (RT) task, we set out to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS; 5 Hz) delivered "off-line" in a virtual lesion paradigm over the right or left dorsolateral prefrontal cortex (DLPFC) or the posterior parietal cortex (PPC) would affect performance in a motor versus a visual attention task. Although rTMS over the DLPFC on either side did not affect RT performance on a spatial orienting task, it did lead to an increase in the RTs of invalidly cued trials in a motor attention task when delivered to the left DLPFC. The opposite effect was found when rTMS was delivered to the PPC: In this case, conditioning the right PPC led to increased RTs in invalidly cued trials located in the left hemispace, in the spatial orienting task. rTMS over the PPC on either side did not affect performance in the motor attention task. This double dissociation was evident in the first 10 min after rTMS conditioning. These results enhance our understanding of the networks associated with attention. They provide evidence of a role for the left DLPFC in the mechanisms of motor preparation, and confirm Mesulam's original proposal for a right PPC dominance in spatial attention [Mesulam, M. M. A cortical network for directed attention and unilateral neglect. Annals of Neurology, 10, 309-325, 1981].     

Interaction between space and number representations during motor preparation in manual aiming

The existence of a spatial component in the representation of number magnitude has been repeatedly supported by the demonstration that the left hand responds faster to smaller numbers, whereas the right hand responds faster to larger numbers. These results support the view that the 'mental number line' is oriented such that smaller numbers are associated with the left side of space while larger numbers are associated with the right side. We investigated whether the link between spatial and number processing arises from a continuous or categorical mapping between space and number representations. The investigation was designed to study all aspects of the motor act, including both planning and execution phases. For this purpose we measured reaction times (RTs), movement times (MTs), spatial accuracy, and endpoint pressure of manual aiming, while subjects reached with the right hand towards the location of a visual digit target. Five different digits were equiprobably presented at five positions along the horizontal axis. A GO/NO-GO choice task paradigm was used to ensure that digit parity (i.e., odd/even) was being processed. Analyses of MT, accuracy, and pressure data showed no digit effects. However, two number-related effects were observed on RTs. First, shorter RTs were obtained for smaller digits independent of target location, despite the use of the right hand. Second, an interaction was observed between target location and number magnitude whereby relative RTs were shortest when there was a congruity between target magnitude and location. These results imply that motor preparation is contaminated both by the direct activation of number magnitude and by the congruity between the spatial location of a target number and its magnitude. We conclude that continuous mapping intervenes between mental number representation and physical space.     

Cerebellar transcranial magnetic stimulation impairs verbal working memory

Previous functional magnetic resonance imaging and patient studies indicate cerebellar participation in verbal working memory. In particular, event-related functional magnetic resonance imaging showed superior cerebellar activation during the initial encoding phase of the Sternberg task. This study used functional magnetic resonance imaging-guided transcranial magnetic stimulation (TMS) to test whether disruption of the right superior cerebellum (hemispheric lobule VI/Crus I) impairs verbal working memory performance. Single-pulse TMS was administered immediately after letter presentation during the encoding phase on half the trials. Sham TMS and a Motor Control task were included to test for general distraction and nonmemory-related motor effects. Results showed no effects of TMS on accuracy, but reaction times (RTs) on correct trials were significantly increased on TMS relative to non-TMS trials for the Verbal Working Memory and Motor Control tasks. Additional analyses showed that the increased RT was significantly greater for Verbal Working Memory than for the motor task, suggesting that the effect on working memory was not caused by interference with finger responses. Sham TMS did not affect RTs, indicating that the potentially distracting effects of the postencoding click did not contribute to the increase in RT. The observed effects from cerebellar disruption are consistent with proposed cerebrocerebellar involvement in verbal working memory.     

Modulation of upper extremity motor evoked potentials by cutaneous afferents in humans.

The excitability of motoneurons controlling upper limb muscles in humans may vary with cutaneous nerve stimulation. We investigated the effect of noxious and non-noxious conditioning stimuli applied to right and left digit II and right digit V on motor evoked potentials (MEPs) recorded from right thenar eminence, abductor digiti minimi, biceps and triceps brachii muscles in twelve healthy subjects. Transcranial magnetic stimulation (TMS) was applied at interstimulus intervals (ISI) ranging from 40 to 160 ms following conditioning distal digital stimulation. TMS and transcranial electrical stimulation (TES) were compared at ISI 80 ms. Painful digital stimulation caused differential MEP amplitude modulation with an early maximum inhibition in hand muscles and triceps brachii followed by a maximum facilitation in arm muscles. Stimulation of different digits elicited a similar pattern of MEP modulation, which largely paralleled the behavior of cutaneous silent periods in the same muscles. Contralateral digital stimulation was less effective. MEPs following TMS and TES did not differ in their response to noxious digital stimulation. MEP latencies were shortened by cutaneous stimuli. The observed effects were stimulus intensity dependent. We conclude that activation of A-alpha and A-delta fibers gives rise to complex modulatory effects on upper limb motoneuron pools. A-delta fibers initiate a spinal reflex resulting in MEP amplitude reduction in muscles involved in reaching and grasping, and MEP amplitude facilitation in muscles involved in withdrawal. These findings suggest a protective reflex mediated by A-delta fibers that protects the hand from harm. A-alpha fibers induce MEP latency shortening possibly via a transcortical excitatory loop.     

Differential effects of transcranial magnetic stimulation of left and right posterior parietal cortex on mental rotation tasks

A recently published study used the interference strategy of transcranial magnetic stimulation (TMS) to demonstrate the role of the right posterior parietal cortex (PPC) in the mental rotation of alphanumeric stimuli. We used similar stimulation parameters over the same left and right PPC regions, and examined the ability to rotate more complex 3D Shepard and Metzler (1971) images. There was reduced accuracy of performance with both right and left PPC stimulation for different angles of rotation of the visual stimuli. Right PPC stimulation led to reduced accuracy to rotate stimuli by 1200, whereas left PPC stimulation affected 180 degrees C rotation. We hypothesise that the two hemispheres make different contributions to the processing underlying visuospatial mental imagery: the right PPC is important for spatial rotations through smaller angles; the left hemisphere has a unique role when the stimuli to be compared are rotated through 180 degrees C, a task that engages verbal strategies due to the well-documented special nature of enantiomorphs.     

Dual-site TMS demonstrates causal functional connectivity between the left and right posterior temporal sulci during facial expression recognition

BackgroundNeuroimaging studies suggest that facial expression recognition is processed in the bilateral posterior superior temporal sulcus (pSTS). Our recent repetitive transcranial magnetic stimulation (rTMS) study demonstrates that the bilateral pSTS is causally involved in expression recognition, although involvement of the right pSTS is greater than involvement of the left pSTS.Objective/Hypothesis: In this study, we used a dual-site TMS to investigate whether the left pSTS is functionally connected to the right pSTS during expression recognition. We predicted that if this connection exists, simultaneous TMS disruption of the bilateral pSTS would impair expression recognition to a greater extent than unilateral stimulation of the right pSTS alone.MethodsParticipants attended two TMS sessions. In Session 1, participants performed an expression recognition task while rTMS was delivered to the face-sensitive right pSTS (experimental site), object-sensitive right lateral occipital complex (control site) or no rTMS was delivered (behavioural control). In Session 2, the same experimental design was used, except that continuous theta-burst stimulation (cTBS) was delivered to the left pSTS immediately before behavioural testing commenced. Session order was counter-balanced across participants.ResultsIn Session 1, rTMS to the rpSTS impaired performance accuracy compared to the control conditions. Crucially in Session 2, the size of this impairment effect doubled after cTBS was delivered to the left pSTS.ConclusionsOur results provide evidence for a causal functional connection between the left and right pSTS during expression recognition. In addition, this study further demonstrates the utility of the dual-site TMS for investigating causal functional links between brain regions.     

Interference with vision by TMS over the occipital pole: a fourth period

We investigated the effect of single-pulse transcranial magnetic stimulation (TMS) over the occipital pole on a forced-choice visual letter-identification task. Magnetic stimuli were applied on the midline but with the initial current directed pseudorandomly toward either left or right hemisphere; visual stimuli were presented randomly in either left or right hemifield; magnetic-visual stimulus onset asynchrony varied randomly between 12 values: -500 ms and from -50 ms to +50 ms in 10 ms steps. The data revealed the existence of a hitherto unknown fourth task-interfering TMS effect that was maximal at -10 ms and specific for magnetic stimulus polarity and visual stimulus location. This -10 ms effect cannot be explained by reflex blinking (as the -50 ms effect can) and direct disruption of letter-induced activity (as the +20 ms and +100 ms effects can), but it could be explained by direct disruption of pre-letter activity or indirect disruption of letter-induced activity.     

TMS of the posterior parietal cortex delays the latency of unpredictable saccades but not when they are combined with predictable divergence

This study tests the influence of transcranial magnetic stimulation (TMS) of the posterior parietal cortex (PPC) on the initiation of horizontal and vertical saccades, alone or combined with a predictable divergence. A gap paradigm was used; TMS was applied 100 ms after target onset. TMS of the left PPC increased the latency of unpredictable rightward saccades, while TMS of the right PPC increased the latency of unpredictable downward saccades. Yet, when unpredictable saccades were combined with predictable divergence, neither component was affected. We suggest that in the latter case, the initiation of both components was taken in charge by another area, e.g. frontal. Thus, even when one component was predictable, a common mechanism controls the initiation of both components. The results confirm that TMS only modifies the latency when the cortical area stimulated is involved in the triggering of the eye movement.     

Reflexive and preparatory selection and suppression of salient information in the right and left posterior parietal cortex

Attentional cues can trigger activity in the parietal cortex in anticipation of visual displays, and this activity may, in turn, induce changes in other areas of the visual cortex, hence, implementing attentional selection. In a recent TMS study [Mevorach, C., Humphreys, G. W., & Shalev, L. Opposite biases in salience-based selection for the left and right posterior parietal cortex. Nature Neuroscience, 9, 740-742, 2006b], it was shown that the posterior parietal cortex (PPC) can utilize the relative saliency (a nonspatial property) of a target and a distractor to bias visual selection. Furthermore, selection was lateralized so that the right PPC is engaged when salient information must be selected and the left PPC when the salient information must be ignored. However, it is not clear how the PPC implements these complementary forms of selection. Here we used on-line triple-pulse TMS over the right or left PPC prior to or after the onset of global/local displays. When delivered after the onset of the display, TMS to the right PPC disrupted the selection of the more salient aspect of the hierarchical letter. In contrast, left PPC TMS delivered prior to the onset of the stimulus disrupted responses to the lower saliency stimulus. These findings suggest that selection and suppression of saliency, rather than being "two sides of the same coin," are fundamentally different processes. Selection of saliency seems to operate reflexively, whereas suppression of saliency relies on a preparatory phase that "sets up" the system in order to effectively ignore saliency.     

Repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex disrupts digit span task performance

The digit span task measures the maintenance of information in short-term memory, and is one of the most widely used tests in clinical and experimental neuropsychology. Functional imaging studies have suggested a role of the right dorsolateral prefrontal cortex (DLPFC) in digit span performance. It remains unclear however, whether activation of this area is critical for task performance. Using repetitive transcranial magnetic stimulation (rTMS) over the right DLPFC in a sham-controlled design, we tested the hypothesis of the involvement of the right DLPFC in digit span task performance. We observed a significant disruption of digit span performance in healthy subjects in the real rTMS condition as compared to the sham condition. This effect of rTMS did not differ between digits forward and digits backward. Our results suggest that the right DLPFC is critical for central executive processes utilized by the digits forward and backward tasks.     

The cortical representation of foveal stimuli: evidence from quadrantanopia and TMS-induced suppression

To address the extent to which the visual foveal representation is split, we examined a 29-year-old patient with a lower right quadrantanopia following surgical removal of the left occipital cortex above the calcarine sulcus and compared her performance with subjects receiving transcranial magnetic stimulation (TMS) over the occipital lobes. In a letter/digit classification task, the patient responded accurately to targets presented in the upper visual field, for all horizontal eccentricities. In the lower visual field, she failed to discriminate letters from digits when targets were presented in the right, but not the left visual field (RVF and LVF, respectively). This pattern was also true for the foveal targets, with poor performance to foveal-RVF (0.5 degrees to the right of fixation) but not foveal-LVF (0.5 degrees to the left of fixation) targets. Similar patterns of normal performance to LVF but not RVF or foveal-RVF targets were observed in a group of nine normal observers when TMS was applied over their left occipital cortex. Complementary impairments to LVF and foveal-LVF target classification were induced with TMS over the right occipital cortex. Thus, we have induced an hemianopic pattern in normal observers contralateral to the magnetically stimulated hemisphere. This correspondence between real and TMS-induced visual field defects is further evidence, in neurologically intact subjects, that the cortical representation of the fovea is split between the two hemispheres along the vertical meridian.     

Working memory load modulation of parieto-frontal connections: evidence from dynamic causal modeling

Previous neuroimaging studies have shown that working memory load has marked effects on regional neural activation. However, the mechanism through which working memory load modulates brain connectivity is still unclear. In this study, this issue was addressed using dynamic causal modeling (DCM) based on functional magnetic resonance imaging (fMRI) data. Eighteen normal healthy subjects were scanned while they performed a working memory task with variable memory load, as parameterized by two levels of memory delay and three levels of digit load (number of digits presented in each visual stimulus). Eight regions of interest, i.e., bilateral middle frontal gyrus (MFG), anterior cingulate cortex (ACC), inferior frontal cortex (IFC), and posterior parietal cortex (PPC), were chosen for DCM analyses. Analysis of the behavioral data during the fMRI scan revealed that accuracy decreased as digit load increased. Bayesian inference on model structure indicated that a bilinear DCM in which memory delay was the driving input to bilateral PPC and in which digit load modulated several parieto‐frontal connections was the optimal model. Analysis of model parameters showed that higher digit load enhanced connection from L PPC to L IFC, and lower digit load inhibited connection from R PPC to L ACC. These findings suggest that working memory load modulates brain connectivity in a parieto‐frontal network, and may reflect altered neuronal processes, e.g., information processing or error monitoring, with the change in working memory load. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc     

Interhemispheric balance of overt attention: a theta burst stimulation study

Interhemispheric imbalance is discussed as a pathophysiological mechanism in visuospatial neglect. It is suggested that after a lesion of the right hemisphere the mutual transcallosal inhibition is impaired, resulting in an increased activity of the left hemisphere. We investigated the interhemispheric balance of attention in healthy subjects by using a free visual exploration task and by interfering with the neural activity of the posterior parietal cortex (PPC) of either hemisphere using an inhibitory transcranial magnetic stimulation routine with theta burst stimulation (TBS). Subjects explored colour photographs of real-life scenes presented on a computer screen under four conditions: (i) without TBS; (ii) after TBS over the right PPC; (iii) after TBS over the left PPC; and (iv) after TBS over the right PPC and, after the first half of the task, over the left PPC. Eye movements were measured, and distribution of mean cumulative fixation duration over screen halves was analyzed. TBS over the right PPC resulted in a significant rightward shift of mean cumulative fixation duration of ∼30 min. The shift could be reversed when a subsequent train of TBS was applied over the left PPC. However, left PPC stimulation alone had no significant effect on visual exploration behaviour. The present study shows that the effect of TBS on the PPC depends on which hemisphere is stimulated and on the state of the contralateral homologue area. These findings are in accordance with the predictions of the interhemispheric rivalry model in neglect.     

Double dissociation of working memory load effects induced by bilateral parietal modulation

Transcranial magnetic stimulation and neuroimaging data have revealed bilateral posterior parietal cortex (PPC) involvement during verbal n-back working memory (WM). In this task as n (i.e., WM load) increases, subjects show poorer behavioral performance as well as greater activation of this brain area. Moreover, there is evidence that a brief period of practice or even increased familiarity with the task can improve WM performance and lead to activation changes in the PPC. The aim of this study was to investigate, using transcranial direct current stimulation (tDCS), the effects on WM load performance induced by different PPC modulation after increased familiarity with the task. After a short practice, we tested verbal WM using an n-back task (1-back vs. 2-back) before and after the application of bilateral tDCS over PPCs (left anodal-right cathodal, left cathodal-right anodal or sham). ANOVA showed a significant interaction between tDCS and task. In the 1-back task, left anodal-right cathodal modulation abolished improvement in reaction times observed in the other two modulation conditions. Conversely, in the 2-back task the same effect was observed after left cathodal-right anodal modulation relative to the other two modulation conditions. This double dissociation demonstrates either a differential engagement of each PPC or changes in the interhemispheric balance of activity across this brain region. Neuroimaging studies show parametric activation of the PPC as difficulty increases, but activation does not switch sides. Thus, our observed effects cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we suggest that these findings reflect the use of different processing strategies to perform these two tasks. In conclusion, after increased familiarity with the task, different tDCS modulations lead to changes in a task-related region depending on differences in processing strategies in 1-back vs. 2-back.     

Effects of transcranial magnetic stimulation of the posterior parietal cortex on saccades and vergence.

Previous studies showed that transcranial magnetic stimulation (TMS) of the posterior parietal cortex (PPC) prolongs the latency of intentional saccades. We examined whether a similar effect exists for reflexive saccades and vergence. To elicit reflexive movements, a gap paradigm was used; lateral saccades and vergence along the median plane were interleaved. TMS was applied on the right PPC 80 ms after target onset. Blocks without TMS were performed and a control experiment with TMS over the primary motor cortex. The latter had no effect on the latency of any type of movements. In contrast, stimulation of the PPC increased the latency of both saccades and vergence, suggesting that the PPC is involved in the triggering of reflexive movements both in direction and in depth.