Phosphenes are commonly evoked by transcranial magnetic stimulation (TMS) to study the functional organization, connectivity, and excitability of the human visual brain. For years, phosphenes have been documented only from stimulating early visual areas (V1–V3) and a handful of specialized visual regions (V4, V5/MT+) in occipital cortex. Recently, phosphenes were reported after applying TMS to a region of posterior parietal cortex involved in the top-down modulation of visuo-spatial processing. In the present study, we systematically characterized parietal phosphenes to determine if they are generated directly by local mechanisms or emerge through indirect activation of other visual areas. Using technology developed in-house to record the subjective features of phosphenes, we found no systematic differences in the size, shape, location, or frame-of-reference of parietal phosphenes when compared to their occipital counterparts. In a second experiment, discrete deactivation by 1 Hz repetitive TMS yielded a double dissociation: phosphene thresholds increased at the deactivated site without producing a corresponding change at the non-deactivated location. Overall, the commonalities of parietal and occipital phosphenes, and our ability to independently modulate their excitability thresholds, lead us to conclude that they share a common neural basis that is separate from either of the stimulated regions.
Citation: Fried PJ, Elkin-Frankston S, Rushmore RJ, Hilgetag CC, Valero-Cabre A (2011) Characterization of Visual Percepts Evoked by Noninvasive Stimulation of the Human Posterior Parietal Cortex. PLoS ONE 6(11): e27204. https://doi.org/10.1371/journal.pone.0027204
Editor: Chris I. Baker, National Institute of Mental Health, United States of America
Received: August 3, 2011; Accepted: October 12, 2011; Published: November 8, 2011
Copyright: © 2011 Fried et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The contributions of PJF and SEF were funded through the Graduate Program in Neuroscience at Boston University, via the National Institutes of Health (MH020064-09) and the Department of Anatomy and Neurobiology at Boston University School of Medicine. The work of RJR and AVC was supported by the Spivak Foundation, the National Institutes of Health (NSS062317), and FP6& ANR project eraNET-NEURON BEYONDVIS (AV-C). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Phosphenes are brief visual percepts caused by mechanically or electrically induced depolarization of cells in the retina or visual brain . Cortically evoked phosphenes were first elicited in humans by applying alternating electrical currents through scalp electrodes . More recently, transcranial magnetic stimulation (TMS) has been used to safely, painlessly and noninvasively evoke phosphenes in the human occipital cortex . TMS works on the principles of electromagnetic induction : current is passed briefly through a coil held against the scalp, generating a rapidly changing electromagnetic field; this noninvasive field induces a brief focal electrical current in the underlying cortex, which in turn produces a synchronous depolarization of neurons in the target region (for a review, see ).
TMS-evoked phosphenes are a straightforward means to map the functional organization of visual cortical areas in both intact humans ,  and those with blindness or blindsight , . In addition, phosphenes have been widely used to characterize cortico-cortical interactions underlying visual awareness and visuo-spatial attention –. More recently, phosphenes have proved instrumental in demonstrating the state-dependent nature of neurostimulation methods –.
Phosphenes are also used to assess the relative excitability of visual cortex , . By convention, this measure is quantified as the phosphene threshold, and corresponds to the magnetic field intensity (measured as a % of the maximum stimulator output) that elicits a positive report of a perceived phosphene in approximately 50% of pulses. Under normal conditions, the phosphene threshold is a very stable measure of excitability that can be followed longitudinally across time or experimental conditions in both healthy individuals and patients –. Consequently, phosphene thresholds have been widely used to assess the outcome of rTMS and other neuromodulation regimes , , monitor cortical plasticity induced by light deprivation –, and increase our understanding of certain neurological disorders, such as migraine –.
Phosphenes have traditionally been studied in early visual areas (V1–V3) of occipital cortex, where they tend to appear as small stationary blobs or shapes (wedges, crescents, ellipses, etc.) . Regardless of appearance, all occipital TMS phosphenes share three essential characteristics: they are perceived regardless of whether the participant's eyes are open or closed; they appear contralateral to the stimulated hemisphere; and their perceived position in visual space predictably changes with the location of fixation , . Changing the coil position also alters phosphene location, reflecting the point-to-point retinotopic organization of early visual areas , , . In later visual areas (i.e., V4, V5/MT+), where neurons have broader receptive fields and process specific features, TMS produces phosphenes that tend to be larger, display a coarser retinotopic organization, and even adopt qualities such as motion, texture or color , , , . Together, these observations suggest that the characteristics of phosphenes are closely related to the function and receptive field organization of the stimulated neurons.
Recently, Marzi et al.  published the first documentation of phosphene-like percepts resulting from parietal TMS. In the context of investigating parietal/occipital differences in interhemispheric transfer time, the authors reported that stimulation of the left and right intraparietal sulcus (IPS) evoked visual percepts that were similar to occipital phosphenes in many respects. While this study was instrumental in establishing the existence of parietal phosphenes, the authors did not perform a more systematic characterization of their features. Thus it remains unclear whether parietal phosphenes have properties that reflect the intrinsic function of local IPS neurons.
The IPS is a region of visual association cortex located fairly rostrally along the dorsal visual stream. As such, it receives visual input through the slow retino-geniculo-striate pathway, via extastriate areas, as well as the fast retino-tectal pathway, via the pulvinar and other thalamic nuclei –. Within the IPS region, neurons are organized into rough visual maps representing the contralateral hemifield , . These neurons have larger receptive fields than in early visual areas ,  and are thought to incorporate a frame-of-reference representing egocentric or global rather than retinocentric space –. On the basis of these regional differences in neuronal properties, we hypothesized that phosphenes induced by TMS of the IPS would display distinct features from those evoked in early visual areas. Specifically, we predicted that parietal phosphenes would appear larger than occipital phosphenes and less anchored to eye movements.
In addition to receiving feed-forward visual input, the IPS has feedback projections onto multiple cortical and subcortical visual structures , . Through these connections, the IPS exerts a strong top-down modulatory effect on the activity in early (V1–V3) and later (V4, V5/MT+) visual areas , , , . Given the functional connectivity between the IPS region and early visual areas, it is reasonable to presume that parietal and occipital phosphenes might depend in some way on activity in the corresponding region. If this is the case, then altering the excitability of one region should produce a corresponding change in the phosphene threshold measured at the other site.
The broad goal of the present study was to determine whether parietal phosphenes are generated directly by local mechanisms or emerge through indirect activation of other visual areas. To accomplish this goal, we directly compared phosphenes evoked in two discrete regions of visual cortex: the intraparietal sulcus in right posterior parietal cortex and early visual areas of the right occipital pole. In the first of two experiments, we used a custom-made documentation system, developed in-house to electronically record the subjective features of phosphenes evoked as participants fixated in different locations. In the second experiment, we examined the interdependence of parietal and occipital phosphenes using low frequency (1 Hz) repetitive TMS (rTMS) to temporarily deactivate each site in separate sessions , . This combined approach allowed us to systematically characterize parietal phosphenes and elucidate their neural basis.
All participants (n = 23) consistently reported phosphenes following single pulse TMS to early visual areas in right occipital cortex and the intraparietal sulcus region in right posterior parietal cortex. At both locations, phosphenes conformed to inclusionary criteria: they appeared in the side of visual space contralateral to the stimulated hemisphere and were perceived regardless of whether participants' eyes were opened or closed. Importantly, phosphenes were not systematically reported following sham stimulation of phosphene regions or real TMS of non-phosphene regions.
Results from Experiment 1
As illustrated in Figure 1C, the two-tailed paired-samples t-test for phosphene thresholds (mean ± SEM: % of maximum stimulator output) demonstrated it took significantly greater intensity to consistently elicit parietal (60.7±2) than occipital phosphenes (50.4±2), t(8) = −3.71, p<0.01.
Phosphenes were reliably elicited in all participants (n = 9) at both occipital (OCC) and posterior parietal (PPC) locations. A. With stimulation intensity set to 110% of phosphene threshold, there were no significant differences (all p's>0.1) in area with regard to either the location of TMS (OCC, PPC) or the direction of fixation (center, 45° up, 45° right). B. For the subset of phosphenes that were perceived (and drawn) as lines rather than enclosed shapes, there was no significant difference (p>0.5) with regard to the location of TMS (OCC, PPC). C. There were significantly higher stimulation thresholds for parietal phosphenes than their occipital counterparts (p<0.01). Error bars represent SEM.
Considering phosphene size, the 2 (TMS site)×3 (fixation location) ANOVA for area (mean ± SEM: square degrees of visual angle), indicated no significant main effects of the phosphene site or the fixation location and no significant interaction, all F's<1.2, all p's>0.1. As depicted in Figure 1A, planned pairwise comparisons using two-tailed paired-samples t-tests revealed no significant difference between the area of occipital (281.4±81) and parietal phosphenes (192.1±55), t(8) = 1.025, p>0.1. Figure 1B illustrates that for the subset of phosphenes perceived as straight lines (mean ± SEM: degrees of visual angle), two-tailed paired-samples t-test showed no significant difference in the length of occipital (27.1±7) and parietal phosphenes (25.1±9), t(6) = 0.17, p>0.5. In sum, while occipital phosphenes tended to be larger than parietal ones, no significant group-level differences were observed with regard to either measure of phosphene size, area or length.
Finally, a qualitative examination of drawings made by participants using the Laser Tracking and Painting (LTaP) system  revealed that parietal phosphenes, like their occipital counterparts, were perceived in the visual field contralateral to the TMS location, typically below the horizontal meridian. Moreover, as illustrated in Figure 2, this position reliably and predictably changed according to the location of fixation and indicates parietal phosphenes are perceived in a retinocentric frame-of-reference. A number of different shapes were depicted including wedges, ellipses, circles, bars, and lines. These varied, both within and across participants, but no obvious differences in geometry were found between the two stimulation sites. When prompted to compare the two, participants tended to report that parietal phosphenes appeared less vivid than and not as sharply demarcated as occipital ones.
Each graph represents LTaP data from a single participant. Bubbles represent phosphene size (area of bubble = phosphene area) and position (center of bubble = phosphene center-of-gravity) for all six conditions: two stimulation sites (OCC, PPC)×three fixations (center, 45° up, 45° right). Axes are in degrees of visual angle.
Results from Experiment 2
The 2 (rTMS target)×2 (phosphene site)×3 (time) repeated measures ANOVA revealed a significant main effect for site of phosphene induction (TMS), F(1,19) = 34.851, p<0.001; and time of stimulation (Time), F(1.7,31.7) = 4.586, p<0.05. These results demonstrate that the intensity required to elicit phosphenes (i.e., the threshold) was different for occipital and parietal stimulation and also varied with time (baseline, post-rTMS and recovery). In addition, the ANOVA revealed a significant interaction between the rTMS target and phosphene site, F(1,19) = 8.642, p<0.01) and between rTMS target, phosphene site, and time, F(2,38) = 19.729, p<0.001. This suggests that 1 Hz rTMS produces discrete and temporary changes in phosphene thresholds relative to the site of stimulation.
Figure 3A illustrates that, in accordance with Experiment 1, the two-tailed z-test revealed baseline phosphene thresholds (mean ± SEM: % of maximum stimulator output) were significantly higher for parietal (53.1±8) than occipital (46.2±7), z(38) = −4.17, p<0.001. As depicted in Figure 4C–D, post-hoc comparisons using two-tailed t-tests demonstrated that immediately after rTMS was applied to the parietal target, we observed a significant increase in the parietal phosphene threshold, t(19) = −3.89, p<0.001; as well as a slight decrease in the occipital threshold, which was not significant after correcting for multiple comparisons, t(19) = 2.27, p>0.01. By comparison, Figure 4A–B illustrates that immediately after rTMS was applied to the occipital target, we found a significant increase in the occipital phosphene threshold, t(19) = −4.11, p<0.001, and no change for parietal threshold, t(19) = −0.3, p>0.1. Regardless of the rTMS condition and site of induction, all thresholds measured 60 minutes after rTMS were not statistically different from baseline, all t's<2.3, all p's>0.01. Finally, as depicted in Figure 3B, a Pearson's correlation test indicated that occipital and parietal thresholds were strongly correlated with each other, r(20) = 0.581, p<0.01, indicating the response of these regions to TMS is governed by related factors. On the other hand, neither occipital nor parietal phosphene thresholds were correlated with motor thresholds, all r's<0.24, all p's>0.1, reflecting differences in the response to TMS between motor and visual cortices.
A. As with Experiment 1, phosphenes elicited from posterior parietal cortex (PPC) had higher thresholds than those from occipital cortex (OCC; P<0.00005). B. There was a significant positive correlation (r = 0.581) between thresholds of PPC and OCC phosphenes (P<0.01). Error bars represent SEM.
A–B. In session A, suppressing excitability in right occipital cortex (OCC) with 1 Hz rTMS produced a significant increase in the OCC phosphene threshold (p<0.001), but did not change the phosphene threshold (p>0.1) assessed in right posterior parietal cortex (PPC). When re-assessed one hour later, thresholds at both sites were statistically unchanged from baseline (p's>0.1). C–D. In session B, 1 Hz rTMS of PPC produced a similar increase in phosphene thresholds observed at that site (p<0.001), while OCC thresholds were statistically unchanged from baseline (p>0.01). When re-assessed one hour later, both OCC and PPC phosphene thresholds were statistically unchanged from baseline (p's>0.01). Error bars represent SEM.
These results confirmed our findings from Experiment 1 of higher thresholds for parietal than occipital phosphenes. Moreover, the results from Experiment 2 demonstrated that reducing excitability at either cortical location exclusively elevated the threshold from the site receiving rTMS, but did not significantly modulate phosphene thresholds elicited from the non-stimulated site. Thus, in spite of the similarities of occipital and parietal percepts documented in Experiment 1, these results indicate that at both sites, local mechanisms contributing to phosphene generation are independent.
In accordance with the results of Marzi et al. , we found no systematic differences in size, shape or location between parietal and occipital phosphenes. In addition, phosphene location was just as dependent on gaze fixation for parietal as occipital phosphenes. Thus, phosphenes evoked by TMS of IPS were not found to exhibit the unique properties associated with neurons in that region and were no different in most measures from occipital phosphenes. However, parietal phosphenes did have a significantly higher threshold than occipital phosphenes. Anatomical studies have shown the distance between the scalp and cortical surface is greater for parietal than for occipital cortex , . Therefore, higher parietal thresholds are likely due to physical rather than neural differences. This interpretation is reinforced by strong correlations between the phosphene thresholds in the two regions. Overall, these findings lead us to conclude that parietal and occipital phosphenes have similar qualities and likely share a common neural basis.
The driving hypothesis of this study was that phosphenes induced by TMS should reflect the intrinsic attributes of the neurons being stimulated , , , . In contrast, phosphenes perceived following IPS stimulation had no distinct features from those evoked in occipital cortex. The functional organization of neurons in the IPS region has been well characterized in both humans and non-human primates; for reviews, see  and . Notably, neurons in the IPS have larger receptive fields than in early visual areas ,  and given the role of this region in the allocation of attention to extrapersonal space –, IPS neurons are thought to incorporate a frame-of-reference representing egocentric or global rather than retinocentric space –, . Based on these properties, IPS phosphenes were predicted to be larger and less anchored to eye movements than those evoked from stimulation of early visual areas. Instead, phosphenes from both sites were of equivalent size and similarly changed location with fixation. Thus parietal phosphenes appear to reflect features attributed to early visual areas, rather than those associated exclusively with the IPS region.
These results cast doubt on the neural basis of parietal phosphenes. It has been suggested that phosphenes might be generated by stimulation of the optic radiations , . However, given the close anatomical relationship of the optic radiations to the lateral ventricles , it is unlikely that parietal TMS (even at suprathreshold intensities) could penetrate deep enough to reach them. The most parsimonious explanation for the current findings is that stimulation of the IPS indirectly activates early visual areas. Connections between the IPS region and early visual areas consist of both feed-forward visual input as well as feedback projections , . In particular, the latter pathways facilitate the robust top-down influence of the IPS region on early visual areas , , , , Therefore, it is feasible that TMS induced depolarization of IPS could propagate (either antidromically or orthodromically) to early visual areas, where the awareness of the percept could occur.
To investigate this hypothesis, the parietal phosphene threshold was measured before and immediately after deactivating the occipital phosphene site with 1 Hz rTMS. If the generation of parietal phosphenes depends on activity in early visual areas, suppression of occipital excitability should alter the parietal phosphene threshold. In contrast, the results show that deactivation of the occipital phosphene site temporarily increased the phosphene threshold at that location, but did not change the threshold for parietal phosphenes. This indicates that parietal phosphenes are not dependent on activity in the occipital phosphene site. The inverse of this relationship produced the opposite results: applying 1 Hz rTMS to the IPS region increased the threshold for parietal, but not occipital phosphenes. Overall, these results demonstrate that parietal and occipital phosphenes are functionally independent from each other, and that the source of parietal phosphenes is not the region of early visual cortex we targeted for occipital phosphenes.
A reconciliation of the commonalities of parietal and occipital phosphenes with their functional independence is possible if neither of the stimulated areas generates the perception of the phosphene. In this view, both the occipital and parietal phosphene sites represent independent nodes that, when stimulated by suprathreshold TMS, direct the activation of a common third region or network on which the two systems might converge. Thus each phosphene is the product of activity of local circuits as well as neurons in the third region. The former govern factors such as the excitability threshold and can be independently modulated by rTMS, while the latter confer features upon phosphenes based on intrinsic neural properties and are not susceptible to the effects of remotely applied rTMS.
In support of such a hypothesis, Taylor et al.  evoked phosphenes in the occipital pole while simultaneously recording the EEG of participants. With stimulation intensity set to the 50% occurrence threshold, participants were asked to respond whether or not they perceived a phosphene. The only difference in EEG evoked activity between positive and negative phosphene reports occurred relatively late (160–200 ms) after delivery of the TMS pulse. This implication of this study is that conscious perception of a phosphene only occurs after substantial processing of neural activity induced by the TMS pulse. Therefore, if the awareness of a phosphene and its associated TMS induced depolarization are decoupled in time, it is reasonable to presume they also occur in different brain regions.
The region most likely to serve as the source of phosphene awareness is the primary visual cortex (V1). Lesions of V1 (or its input) result in the loss of conscious perception of incoming visual stimuli. Even in the absence of V1, some retinal input makes its way to higher visual areas (e.g., V5/MT+, IPS) via the tecto-pulvinar pathway, however this information does not reach the level of awareness, hence the term blindsight . The same is true for TMS-induced activity: several studies , ,  of blind, blindsighted, and intact individuals have shown V1 activity is necessary for the awareness of phosphenes evoked by stimulating V5/MT+. In the present study, the fact that there was no change in the ability to induce parietal phosphenes following deactivation of the occipital phosphene site would suggest that the latter did not correspond to V1. The scalp locations used to target occipital stimulation in this and similar studies ,  lie at least 2 cm laterally from the midline. Given the retinotopic position of the phosphenes in the lower contralateral visual field, it is probable that the associated neural representation of V1 is in fact within the calcarine sulcus on the medial surface of the brain and thus poorly accessible to the currents induced by focal TMS. As such, it is more likely that occipital stimulation targeted some combination of V2 and V3 and activated projections to V1.
In sum, this study provides confirmation that stimulation of a region near the intraparietal sulcus in posterior parietal cortex reliably produces genuine phosphenes. Rather than adopting features associated with the intrinsic attributes of IPS neurons, these percepts appear similar to those evoked from stimulating visual areas V2–V3 in occipital cortex. Despite these commonalities, deactivation of the occipital and parietal sites revealed their functional independence. Thus we conclude that the perception of IPS and V2–V3 phosphenes occurs not from local TMS-induced activity, but rather from indirect activation of a common third region. Given its preeminent role in visual awareness and functional connectivity with both of the targeted regions, the strongest and most compatible interpretation is that V1 is the locus of phosphene perception for both IPS and V2–V3 stimulation.
Materials and Methods
The present study comprised two independent experiments. Experiment 1 consisted of a single session per participant and compared the characteristic features of phosphenes induced in posterior parietal cortex to those generated by stimulating the pole of the occipital cortex. Experiment 2 required two sessions per participant and explored the functional dependence of the same two locations by using 1 Hz rTMS to modulate phosphene thresholds.
All forms and procedures used in the study received approval by the Institutional Review Board at Boston University School of Medicine. All participants provided written consent upon enrollment in the study, and were thoroughly screened for exclusion criteria with regards to the risks of TMS  prior to each experimental session. Participants were compensated for their time at the end of each experimental session.
A total of 23 healthy adults (15 male, 8 female) of mean age 27.9 years (range = 21.8–45.5) with no known history of neurological disease participated in one or both experiments of the present study (see Table 1 for demographic information).
Transcranial Magnetic Stimulation
In both experiments, phosphenes and motor responses were induced by TMS using a Magstim 200 monophasic stimulator attached to a standard 70 mm diameter figure-of-eight coil for focal stimulation (Magstim Co. Ltd., Dyfeld, Wales, UK). The coil was held against the scalp with the center tangential to the site of stimulation and pulses were delivered either by stepping on a pneumatic foot switch or by pressing the trigger button on the front of the stimulator. Pulses were spaced at least 5–10 seconds apart (≤0.2 Hz); this rate served both to limit the temporal predictability of pulse onset and to avoid the lasting cumulative effects of rTMS . Sham TMS was performed at the same locations by positioning the edge of the coil tangentially at 90° against the scalp, and discharging pulses at 80% of stimulator output, thus eliciting similar accompanying acoustic and somatosensory sensations, without inducing significant currents in the brain. Given the inherently subjective nature of phosphene perception, we randomly interposed catch trials, consisting of sham pulses delivered to phosphene sites, as well as real pulses delivered to non-phosphene areas (e.g., scalp vertex, primary motor cortex, etc.), to further assess participants' reliability in reporting the presence or absence of phosphenes.
In Experiment 2, rTMS was applied using an air-cooled 70 mm figure-of-eight focal coil (Magstim) attached to a Magstim SuperRapid biphasic stimulator. The coil was kept fixed in place for the duration of stimulation with the assistance of a multi-joint adjustable Magic Arm (Manfrotto, Italy). The sequence of pulses was programmed and initiated using Magstim Rapid Session Software (v 4.0). The pattern of stimulation consisted of one pulse per second (1 Hz) for 15 minutes (900 pulses total) at 90% of the local phosphene threshold value, which was determined separately from baseline threshold using the air-cooled coil and SuperRapid stimulator. Based on prior research ,  and our own preliminary data, this rTMS pattern should result in a period of reduced excitability lasting at least 10 minutes, thus providing sufficient time to assess phosphene thresholds at both locations. During rTMS, participants were seated comfortably against a portable massage chair, with their face in a headrest, and were instructed to keep their eyes open as much as possible to avoid any confounding effects of light deprivation.
TMS was directed to scalp locations overlying three cortical sites: the pole of the right occipital cortex, corresponding most likely to early visual areas V2–V3, although stimulation of V1 cannot be ruled out ; borders of the IPS within the right posterior parietal cortex; and the region of primary motor cortex (M1) representing either the abductor pollicis brevis muscle (thumb) or first dorsal interosseous muscle (index finger). This last site served both to index the excitability of non-visual cortex for comparison with phosphene thresholds (Experiment 2) as well as to confirm the reliability of phosphene reports in an area that should not induce such percepts (Experiment 1 & 2). These three areas of stimulation were determined initially using anatomical skull landmarks and the “International 10–20 system” for EEG electrode placement. The position of the coil was then fine adjusted until a reliable behavioral response (i.e., an unambiguous phosphene report or a visual muscle twitch) was evoked. These sites were then marked on a snug-fitting Lycra™ swim cap worn by the participant. The approximate location (and orientation) of the TMS coil for each of these stimulation sites was as follows: 4–5 cm laterally from the vertex (EEG coordinate CZ) for M1 (handle pointing medial to lateral, away from CZ); 2 cm dorsally and 2 cm laterally from the inion for V2–V3 (handle pointing medial to lateral, away from the inion), and directly over EEG coordinate P4 for the IPS region (handle pointing ventromedial to dorsolateral, away from the inion). The use of EEG coordinates to guide TMS placement over functional brain areas represents an economical and practical tradeoff over more precise neuroimaging-based methods. With consequence for the present study, the relationship of P4 to the right IPS has been validated by several studies , . All three of the aforementioned sites are common starting points when using TMS to measure cortico-spinal excitability from primary motor cortex , elicit retinotopically organized phosphenes from occipital cortex , or interact with visuo-spatial processes in posterior parietal cortex . Similarly, these coil orientations have been shown to produce the optimal stimulation of the intended region, while minimizing stimulation of other significant cortical areas or musculature of the neck and face , , .
Phosphenes and Motor Responses to TMS
We used the following established inclusion criteria for occipital phosphenes: a brief and spatially circumscribed visual percept, appearing in the left visual hemifield (contralateral to the stimulated hemisphere), immediately following real TMS only, and occurring regardless of whether the participant's eyes were opened or closed. The inclusion criteria for parietal phosphenes were the same as for occipital, although we would accept percepts that were less circumscribed and without restriction on visual field location, since there is some debate as to whether neurons in the human right IPS have bilateral or purely contralateral representations of visual space. A small number of potential participants (n = 3) were not included in the study on for the following reasons: an inability to perceive phosphenes in either of the two locations; reporting visual percepts following TMS that did not adhere to the aforementioned criteria or proved highly inconsistent; or reporting visual percepts following sham TMS to visual regions or real TMS to non-visual regions.
In both experiments we measured phosphene thresholds for the occipital and parietal sites. Additionally, in Experiment 2, we assessed the motor threshold at M1. Regardless of site, the same protocol was used at all times: with intensity initially set at 50–60% of the maximum stimulator output, we applied a series of at least 5 pulses at a maximum of 0.2 Hz and recorded whether each pulse produced a visible muscle twitch of the contralateral thumb or index finger (TMS to M1) or the unambiguous report of a qualified phosphene (TMS to V2–V3 and IPS). When assessing the occurrence of phosphenes, participants were instructed to respond verbally by stating “yes” if they definitely perceived a phosphene, “no” if they definitely did not perceive a phosphene, or “maybe” if they perceived something, but were unsure if it was a phosphene or some other sensation such as an eye blink. A “maybe” response was not counted as a positive or negative report, but instead initiated a follow-up pulse. Based on these responses, the stimulation intensity was subsequently adjusted using the following algorithm: if at least four consecutive pulses resulted in a “no” response, the stimulation intensity was increased by 10%; if at least four successive pulses resulted in a “yes” response, stimulation intensity was decreased by 10%; otherwise, if the series of pulses resulted in a mixture of “yes” and “no” responses, stimulation intensity was adjusted in smaller increments (1–5%). This process was repeated until reaching the minimum intensity value that resulted in positive reports from 50% of at least 10 delivered pulses. If no single intensity resulted in an occurrence of exactly 50%, we used the criteria of at least 40%, but no more than 60% positive reports. The advantage of this approach, which is similar to methods used in other phosphene studies , , , , , , is that it can be performed in approximately 2–4 minutes and thus works within the constraints imposed by the rapidly decaying effects of rTMS. Furthermore, a reliability study (data not shown) confirmed this method of assessing phosphene thresholds produces comparable results to more rigorous (and therefore longer) techniques based on randomized sampling , .
Detailed Methods for Experiment 1
A subgroup of nine adults (seven males, two females) of mean age 26.4 years (range = 22.5–32.0) with no known history of neurological disease, including one of the co-authors of the study (PJF), participated in this experiment. Seven out of the nine participants were naïve to TMS-induced phosphenes, nonetheless they did not require significant training to consistently perceive and report them. The aim of this experiment was to characterize phosphenes evoked from applying TMS to the IPS region of posterior parietal cortex and compare their features (size, shape, location, and frame-of-reference) to those induced by stimulating early visual areas of the right occipital cortex.
Experiment 1 consisted of a single session for each participant divided into two parts. In the first part, occipital and parietal phosphene sites were identified for each participant and marked on his or her swim cap. Using these locations, we determined the phosphene thresholds. Next, participants were seated in a dimly lit (∼0.5 cd/m2) room, at a distance of approximately 45 cm (measured from nasion) in front of a dual-sided projection screen (Da-View fast-fold® deluxe, Warsaw IN, USA) so that it filled their entire visual field, and given a modified green laser pointer (532 nm, 50 mW) that was held in their dominant hand. The participant was instructed to fixate on a point at the center of the projection screen while single pulses were delivered to occipital and parietal locations at 110% of the phosphene threshold recorded for each site. After each pulse, participants were asked whether they perceived a phosphene and if so, to trace the outline on the screen using the laser pointer. The Laser Tracking and Painting (LTaP) system (Laboratory of Cerebral Dynamics, Plasticity and Rehabilitation, Boston, MA, USA) documented the path of the laser pointer as X–Y coordinates and briefly displayed the outlined shape of the phosphene for near-instantaneous feedback (for a complete and detailed description of the LTaP system, see ). Once 5 phosphenes were successfully recorded in this manner, the process was repeated with the participant fixating on a point located 45° above, and then, 45° to the right of the center of the screen. As illustrated in Figure 5, a total of 30 phosphenes were collected for each participant: 5 phosphenes per fixation×3 locations of fixation (center, 45° up, 45° right) per stimulation site×2 stimulation sites (occipital and parietal).
Upper panel. LTaP output from one participant when TMS was applied to the pole of the right occipital cortex (OCC) during three fixation conditions (center, 45° up, 45° right). Lower panel. LTaP output from the same participant when TMS was applied to the right posterior parietal cortex (PPC) during the same three fixation conditions. Axes, numbers, and concentric circles were not visible on the screen during the experiment.
We recorded the following data for each participant: two phosphene thresholds (measured as a % of maximal stimulator output) and 30 arrays of X–Y coordinates, each corresponding to the outline of a single perceived phosphene. Each X and Y value was transformed from a pixel value to a degree of visual angle using the following formula:(1)Where (X,Y)degree is the transformed value, (X,Y)pixel is the native value obtained from the LTaP system, R is the ratio of the resolution output of the projector to the size of the projected image (12.5 pixels/cm) and D is the distance between the participant and the projection screen (45 cm). These transformed, standardized coordinates allowed us to calculate the area of phosphenes (in square degrees of visual angle). These data were averaged by participant, TMS site, and fixation location and entered into a 2 (TMS site: occipital and parietal)×3 (fixation location: center, 45° up, 45° right) repeated-measures analysis of variance (ANOVA) with a 95% confidence interval (α = 0.05). Mauchly's test indicated that the assumption of sphericity had been violated for the main effect of Fixation location, χ2(2) = 7.59, p<0.05), therefore degrees of freedom were corrected using Huynh-Feldt estimates of sphericity (ε = .6). For all other effects and interactions, the assumption of sphericity was met, all χ2's<2, all p's>0.1, allowing us to use uncorrected degrees of freedom. Pair-wise comparisons were computed using two-tailed paired-samples t-tests, with a more conservative 99% confidence interval (α = 0.01) to account for multiple comparisons. In addition, occipital and parietal phosphene thresholds were compared using a two-tailed paired-samples t-test.
A low number of phosphenes (12 occipital and 19 parietal) were perceived as straight lines rather than enclosed shapes, thus their extent could only be measured in terms of total length. These data were averaged for each participant independent of gaze direction due to the small number of samples and compared using a two-tailed independent-samples t-test. A small number of phosphenes (6 occipital and 1 parietal) were excluded from all analyses because a software error resulted in a truncated recording.
Detailed Methods for Experiment 2
A subgroup of 20 adults (13 males, 7 females) of mean age 28.2 years (range = 21.8–45.5) with no known history of neurological disease, including three co-authors of the study (PJF, CCH and AV-C), participated in the experiment. An additional five had participated in the previous experiment, while nine were naïve to TMS-induced phosphenes. As with the previous experiment, participants required only minimal training to consistently perceive and report phosphenes. The aim of this experiment was to determine whether parietal and occipital phosphenes were independent and generated by local mechanisms, or interdependent, reflecting a common neural basis.
As illustrated in Figure 6, Experiment 2 consisted of two sessions per participant. Individual sessions were counterbalanced against order bias and separated by at least seven days to minimize the likelihood of carryover effects from the previous session. Both sessions began by assessing the motor threshold followed by baseline threshold values for occipital and parietal phosphenes. Next, 15 minutes of 1 Hz rTMS was applied to one of the two sites, and immediately thereafter, we again assessed the phosphene threshold at both locations. Since 1 Hz rTMS is known to temporarily reduce excitability at the stimulated region , , , , we predicted that this manipulation would increase the magnetic field intensity required to elicit phosphenes (i.e., the phosphene threshold) for the site that received rTMS. Furthermore, we hypothesized that any change in thresholds for the site that did not receive rTMS would be evidence of a functional dependency, thus indicating some link or common origin. Following the post-rTMS thresholds, participants took a break for approximately 60 minutes to allow the effects of the rTMS to completely wear off before both phosphenes thresholds were measured for a third and final time. For all time-points, we first assessed the threshold at the site that did not receive rTMS, so that a null change in the threshold measured at the non-rTMS site could not be simply attributed to the effects of rTMS wearing off before we had finished collecting both post-stimulation thresholds.
Each session in Experiment 2 lasted approximately two hours and involved 15 minutes of suppressive 1 Hz repetitive transcranial magnetic stimulation (rTMS) applied to either the pole of the right occipital cortex (OCC) or the right posterior parietal cortex (PPC). At the start of each session, motor and phosphene thresholds were collected to establish baseline excitability. Phosphene thresholds were reassessed immediately following rTMS as well as after a 60-minute break to allow the effects of the rTMS to wear off. Phosphene thresholds were always assessed first at the site that did not receive rTMS, that way a finding of “no change” could not simply be attributed to the effects wearing off.
Data collected for each participant consisted of one motor threshold and three pairs of phosphene thresholds per session. To assess the effect of 1 Hz rTMS, phosphene thresholds were entered into a 2 (rTMS target: occipital, parietal)×2 (phosphene threshold site: occipital, parietal)×3 (time: baseline, post-rTMS, recovery) repeated-measures ANOVA with a 95% confidence interval (α = 0.05). Mauchly's test indicated that the assumption of sphericity had been violated for the main effect of Time, χ2(2) = 6.06, p<0.05), therefore degrees of freedom were corrected using Huynh-Feldt estimates of sphericity (ε = .83). For all other effects and interactions, the assumption of sphericity was met, all χ2's<5, all p's>0.1, allowing us to use uncorrected degrees of freedom. Post-hoc and planned pair-wise comparisons were computed using z-tests (for n≥30) and paired-samples t-tests (for n<30), using a more conservative 99% confidence interval (α = 0.01) to account for multiple comparisons. In addition, we used a Pearson's coefficient (r) to examine the correlations between baseline motor and phosphene thresholds, with a 95% confidence interval.
Conceived and designed the experiments: PJF SEF RJR CCH AVC. Performed the experiments: PJF SEF. Analyzed the data: PJF SEF. Contributed reagents/materials/analysis tools: SEF RJR AVC. Wrote the paper: PJF RJR AVC CCH SEF. Designed software used in data acquisition: SEF.
- 1. Marg E (1991) Magnetostimulation of vision: direct noninvasive stimulation of the retina and the visual brain. Optom Vis Sci 68: 427–440.E. Marg1991Magnetostimulation of vision: direct noninvasive stimulation of the retina and the visual brain.Optom Vis Sci68427440
- 2. Merton PA, Morton HB (1980) Stimulation of the cerebral cortex in the intact human subject. Nature 285: 227.PA MertonHB Morton1980Stimulation of the cerebral cortex in the intact human subject.Nature285227
- 3. Marg E, Rudiak D (1994) Phosphenes induced by magnetic stimulation over the occipital brain: description and probable site of stimulation. Optom Vis Sci 71: 301–311.E. MargD. Rudiak1994Phosphenes induced by magnetic stimulation over the occipital brain: description and probable site of stimulation.Optom Vis Sci71301311
- 4. Barker A (1985) Non-invasive Magnetic Stimulation of Human Motor Cortex. The Lancet 325: 1106–1107.A. Barker1985Non-invasive Magnetic Stimulation of Human Motor Cortex.The Lancet32511061107
- 5. Pascual-Leone A, Walsh V, Rothwell JC (2000) Transcranial magnetic stimulation in cognitive neuroscience–virtual lesion, chronometry, and functional connectivity. Curr Opin Neurobiol 10: 232–237.A. Pascual-LeoneV. WalshJC Rothwell2000Transcranial magnetic stimulation in cognitive neuroscience–virtual lesion, chronometry, and functional connectivity.Curr Opin Neurobiol10232237
- 6. Kammer T (1999) Phosphenes and transient scotomas induced by magnetic stimulation of the occipital lobe: their topographic relationship. Neuropsychologia 37: 191–198.T. Kammer1999Phosphenes and transient scotomas induced by magnetic stimulation of the occipital lobe: their topographic relationship.Neuropsychologia37191198
- 7. Kammer T, Puls K, Erb M, Grodd W (2005) Transcranial magnetic stimulation in the visual system. II. Characterization of induced phosphenes and scotomas. Exp Brain Res 160: 129–140.T. KammerK. PulsM. ErbW. Grodd2005Transcranial magnetic stimulation in the visual system. II. Characterization of induced phosphenes and scotomas.Exp Brain Res160129140
- 8. Cowey A, Walsh V (2000) Magnetically induced phosphenes in sighted, blind and blindsighted observers. Neuroreport 11: 3269–3273.A. CoweyV. Walsh2000Magnetically induced phosphenes in sighted, blind and blindsighted observers.Neuroreport1132693273
- 9. Silvanto J, Cowey A, Lavie N, Walsh V (2007) Making the blindsighted see. Neuropsychologia 45: 3346–3350.J. SilvantoA. CoweyN. LavieV. Walsh2007Making the blindsighted see.Neuropsychologia4533463350
- 10. Bestmann S, Ruff CC, Blakemore C, Driver J, Thilo KV (2007) Spatial attention changes excitability of human visual cortex to direct stimulation. Curr Biol 17: 134–139.S. BestmannCC RuffC. BlakemoreJ. DriverKV Thilo2007Spatial attention changes excitability of human visual cortex to direct stimulation.Curr Biol17134139
- 11. Boulay C, Paus T (2005) Modulation of phosphene perception during saccadic eye movements: a transcranial magnetic stimulation study of the human visual cortex. Exp Brain Res 167: 297–300.C. BoulayT. Paus2005Modulation of phosphene perception during saccadic eye movements: a transcranial magnetic stimulation study of the human visual cortex.Exp Brain Res167297300
- 12. Pascual-Leone A, Walsh V (2001) Fast backprojections from the motion to the primary visual area necessary for visual awareness. Science 292: 510–512.A. Pascual-LeoneV. Walsh2001Fast backprojections from the motion to the primary visual area necessary for visual awareness.Science292510512
- 13. Silvanto J, Lavie N, Walsh V (2006) Stimulation of the human frontal eye fields modulates sensitivity of extrastriate visual cortex. J Neurophysiol 96: 941–945.J. SilvantoN. LavieV. Walsh2006Stimulation of the human frontal eye fields modulates sensitivity of extrastriate visual cortex.J Neurophysiol96941945
- 14. Silvanto J, Muggleton N, Lavie N, Walsh V (2009) The perceptual and functional consequences of parietal top-down modulation on the visual cortex. Cereb Cortex 19: 327–330.J. SilvantoN. MuggletonN. LavieV. Walsh2009The perceptual and functional consequences of parietal top-down modulation on the visual cortex.Cereb Cortex19327330
- 15. Brighina F, Piazza A, Daniele O, Fierro B (2002) Modulation of visual cortical excitability in migraine with aura: effects of 1 Hz repetitive transcranial magnetic stimulation. Exp Brain Res 145: 177–181.F. BrighinaA. PiazzaO. DanieleB. Fierro2002Modulation of visual cortical excitability in migraine with aura: effects of 1 Hz repetitive transcranial magnetic stimulation.Exp Brain Res145177181
- 16. Silvanto J, Muggleton N, Cowey A, Walsh V (2007) Neural adaptation reveals state-dependent effects of transcranial magnetic stimulation. Eur J Neurosci 25: 1874–1881.J. SilvantoN. MuggletonA. CoweyV. Walsh2007Neural adaptation reveals state-dependent effects of transcranial magnetic stimulation.Eur J Neurosci2518741881
- 17. Silvanto J, Cattaneo Z (2010) Transcranial magnetic stimulation reveals the content of visual short-term memory in the visual cortex. Neuroimage 50: 1683–1689.J. SilvantoZ. Cattaneo2010Transcranial magnetic stimulation reveals the content of visual short-term memory in the visual cortex.Neuroimage5016831689
- 18. Gerwig M (2003) Evaluation of cortical excitability by motor and phosphene thresholds in transcranial magnetic stimulation. Journal of the Neurological Sciences 215: 75–78.M. Gerwig2003Evaluation of cortical excitability by motor and phosphene thresholds in transcranial magnetic stimulation.Journal of the Neurological Sciences2157578
- 19. Meyer B-U, Diehl R, Steinmetz H, Britton TC, Benecke R (1991) Magnetic stimuli applied over motor and visual cortex: influence of coil position and field polarity on motor responses, phosphenes, and eye movements. Electroencephalogr Clin Neurophysiol Suppl 43: 121–134.B-U MeyerR. DiehlH. SteinmetzTC BrittonR. Benecke1991Magnetic stimuli applied over motor and visual cortex: influence of coil position and field polarity on motor responses, phosphenes, and eye movements.Electroencephalogr Clin Neurophysiol Suppl43121134
- 20. Antal A, Arlt S, Nitsche MA, Chadaide Z, Paulus W (2006) Higher variability of phosphene thresholds in migraineurs than in controls: a consecutive transcranial magnetic stimulation study. Cephalalgia 26: 865–870.A. AntalS. ArltMA NitscheZ. ChadaideW. Paulus2006Higher variability of phosphene thresholds in migraineurs than in controls: a consecutive transcranial magnetic stimulation study.Cephalalgia26865870
- 21. Boroojerdi B, Meister IG, Foltys H, Sparing R, Cohen LG, et al. (2002) Visual and motor cortex excitability: a transcranial magnetic stimulation study. Clin Neurophysiol 113: 1501–1504.B. BoroojerdiIG MeisterH. FoltysR. SparingLG Cohen2002Visual and motor cortex excitability: a transcranial magnetic stimulation study.Clin Neurophysiol11315011504
- 22. Stewart L, Walsh V, Rothwell JC (2001) Motor and phosphene thresholds: a transcranial magnetic stimulation correlation study. Neuropsychologia 39: 415–419.L. StewartV. WalshJC Rothwell2001Motor and phosphene thresholds: a transcranial magnetic stimulation correlation study.Neuropsychologia39415419
- 23. Boroojerdi B, Prager A, Muellbacher W, Cohen LG (2000) Reduction of human visual cortex excitability using 1-Hz transcranial magnetic stimulation. Neurology 54: 1529–1531.B. BoroojerdiA. PragerW. MuellbacherLG Cohen2000Reduction of human visual cortex excitability using 1-Hz transcranial magnetic stimulation.Neurology5415291531
- 24. Lang N, Siebner HR, Chadaide Z, Boros K, Nitsche MA, et al. (2007) Bidirectional modulation of primary visual cortex excitability: a combined tDCS and rTMS study. Invest Ophthalmol Vis Sci 48: 5782–5787.N. LangHR SiebnerZ. ChadaideK. BorosMA Nitsche2007Bidirectional modulation of primary visual cortex excitability: a combined tDCS and rTMS study.Invest Ophthalmol Vis Sci4857825787
- 25. Boroojerdi B, Bushara KO, Corwell B, Immisch I, Battaglia F, et al. (2000) Enhanced excitability of the human visual cortex induced by short-term light deprivation. Cereb Cortex 10: 529–534.B. BoroojerdiKO BusharaB. CorwellI. ImmischF. Battaglia2000Enhanced excitability of the human visual cortex induced by short-term light deprivation.Cereb Cortex10529534
- 26. Fierro B, Brighina F, Vitello G, Piazza A, Scalia S, et al. (2005) Modulatory effects of low- and high-frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation. J Physiol (Lond.) 565: 659–665.B. FierroF. BrighinaG. VitelloA. PiazzaS. Scalia2005Modulatory effects of low- and high-frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation.J Physiol (Lond.)565659665
- 27. Pitskel NB, Merabet LB, Ramos-Estebanez C, Kauffman T, Pascual-Leone A (2007) Time-dependent changes in cortical excitability after prolonged visual deprivation. Neuroreport 18: 1703–1707.NB PitskelLB MerabetC. Ramos-EstebanezT. KauffmanA. Pascual-Leone2007Time-dependent changes in cortical excitability after prolonged visual deprivation.Neuroreport1817031707
- 28. Afra J, Mascia A, Phy PG, Noordhout AM de, Schoenen J (1998) Interictal cortical excitability in migraine: A study using transcranial magnetic stimulation of motor and visual cortices. Annals of Neurology 44: 209–215.J. AfraA. MasciaPG Phyde Noordhout AMJ. Schoenen1998Interictal cortical excitability in migraine: A study using transcranial magnetic stimulation of motor and visual cortices.Annals of Neurology44209215
- 29. Aurora SK, Ahmad BK, Welch KM, Bhardhwaj P, Ramadan NM (1998) Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine. Neurology 50: 1111–1114.SK AuroraBK AhmadKM WelchP. BhardhwajNM Ramadan1998Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine.Neurology5011111114
- 30. Fierro B, Ricci R, Piazza A, Scalia S, Giglia G, et al. (2003) 1 Hz rTMS enhances extrastriate cortex activity in migraine: evidence of a reduced inhibition? Neurology 61: 1446–1448.B. FierroR. RicciA. PiazzaS. ScaliaG. Giglia20031 Hz rTMS enhances extrastriate cortex activity in migraine: evidence of a reduced inhibition?Neurology6114461448
- 31. Gothe J, Brandt SA, Irlbacher K, Röricht S, Sabel BA, et al. (2002) Changes in visual cortex excitability in blind subjects as demonstrated by transcranial magnetic stimulation. Brain 125: 479–490.J. GotheSA BrandtK. IrlbacherS. RörichtBA Sabel2002Changes in visual cortex excitability in blind subjects as demonstrated by transcranial magnetic stimulation.Brain125479490
- 32. Khedr EM, Ahmed MA, Mohamed KA (2006) Motor and visual cortical excitability in migraineurs patients with or without aura: transcranial magnetic stimulation. Neurophysiol Clin 36: 13–18.EM KhedrMA AhmedKA Mohamed2006Motor and visual cortical excitability in migraineurs patients with or without aura: transcranial magnetic stimulation.Neurophysiol Clin361318
- 33. Hotson J, Braun D, Herzberg W, Boman D (1994) Transcranial magnetic stimulation of extrastriate cortex degrades human motion direction discrimination. Vision Res 34: 2115–2123.J. HotsonD. BraunW. HerzbergD. Boman1994Transcranial magnetic stimulation of extrastriate cortex degrades human motion direction discrimination.Vision Res3421152123
- 34. Stewart L, Battelli L, Walsh V, Cowey A (1999) Motion perception and perceptual learning studied by magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl 51: 334–350.L. StewartL. BattelliV. WalshA. Cowey1999Motion perception and perceptual learning studied by magnetic stimulation.Electroencephalogr Clin Neurophysiol Suppl51334350
- 35. Marzi CA, Mancini F, Savazzi S (2009) Interhemispheric transfer of phosphenes generated by occipital versus parietal transcranial magnetic stimulation. Exp Brain Res 192: 431–441.CA MarziF. ManciniS. Savazzi2009Interhemispheric transfer of phosphenes generated by occipital versus parietal transcranial magnetic stimulation.Exp Brain Res192431441
- 36. Chambers CD, Payne JM, Stokes MG, Mattingley JB (2004) Fast and slow parietal pathways mediate spatial attention. Nat Neurosci 7: 217–218.CD ChambersJM PayneMG StokesJB Mattingley2004Fast and slow parietal pathways mediate spatial attention.Nat Neurosci7217218
- 37. Clower DM, West RA, Lynch J, Strick PL (2001) The Inferior Parietal Lobule Is the Target of Output from the Superior Colliculus, Hippocampus, and Cerebellum. J Neurosci 21: 6283–6291.DM ClowerRA WestJ. LynchPL Strick2001The Inferior Parietal Lobule Is the Target of Output from the Superior Colliculus, Hippocampus, and Cerebellum.J Neurosci2162836291
- 38. Harting JK, Huerta MF, Frankfurter AJ, Strominger NL, Royce GJ (1980) Ascending pathways from the monkey superior colliculus: an autoradiographic analysis. J Comp Neurol 192: 853–882.JK HartingMF HuertaAJ FrankfurterNL StromingerGJ Royce1980Ascending pathways from the monkey superior colliculus: an autoradiographic analysis.J Comp Neurol192853882
- 39. Swisher JD, Halko MA, Merabet LB, McMains SA, Somers DC (2007) Visual topography of human intraparietal sulcus. J Neurosci 27: 5326–5337.JD SwisherMA HalkoLB MerabetSA McMainsDC Somers2007Visual topography of human intraparietal sulcus.J Neurosci2753265337
- 40. Orban GA, Claeys K, Nelissen K, Smans R, Sunaert S, et al. (2006) Mapping the parietal cortex of human and non-human primates. Neuropsychologia 44: 2647–2667.GA OrbanK. ClaeysK. NelissenR. SmansS. Sunaert2006Mapping the parietal cortex of human and non-human primates.Neuropsychologia4426472667
- 41. Daniel PM, Whitteridge D (1961) The representation of the visual field on the cerebral cortex in monkeys. J Physiol (Lond.) 159: 203–221.PM DanielD. Whitteridge1961The representation of the visual field on the cerebral cortex in monkeys.J Physiol (Lond.)159203221
- 42. Wandell BA, Brewer AA, Dougherty RF (2005) Visual field map clusters in human cortex. Philos Trans R Soc Lond, B, Biol Sci 360: 693–707.BA WandellAA BrewerRF Dougherty2005Visual field map clusters in human cortex.Philos Trans R Soc Lond, B, Biol Sci360693707
- 43. Mullette-Gillman OA, Cohen YE, Groh JM (2005) Eye-centered, head-centered, and complex coding of visual and auditory targets in the intraparietal sulcus. J Neurophysiol 94: 2331–2352.OA Mullette-GillmanYE CohenJM Groh2005Eye-centered, head-centered, and complex coding of visual and auditory targets in the intraparietal sulcus.J Neurophysiol9423312352
- 44. Mullette-Gillman OA, Cohen YE, Groh JM (2008) Motor-Related Signals in the Intraparietal Cortex Encode Locations in a Hybrid, rather than Eye-Centered Reference Frame. Cereb. Cortex. OA Mullette-GillmanYE CohenJM Groh2008Motor-Related Signals in the Intraparietal Cortex Encode Locations in a Hybrid, rather than Eye-Centered Reference Frame. Cereb. Cortex.PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/19068491. Accessed 23 May 2009. PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/19068491. Accessed 23 May 2009.
- 45. Pertzov Y, Avidan G, Zohary E (2011) Multiple reference frames for saccadic planning in the human parietal cortex. J Neurosci 31: 1059–1068.Y. PertzovG. AvidanE. Zohary2011Multiple reference frames for saccadic planning in the human parietal cortex.J Neurosci3110591068
- 46. Harting JK, Updyke BV, Van Lieshout DP (1992) Corticotectal projections in the cat: anterograde transport studies of twenty-five cortical areas. J Comp Neurol 324: 379–414.JK HartingBV UpdykeDP Van Lieshout1992Corticotectal projections in the cat: anterograde transport studies of twenty-five cortical areas.J Comp Neurol324379414
- 47. Lynch J, Graybiel AM, Lobeck LJ (1985) The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus. J Comp Neurol 235: 241–254.J. LynchAM GraybielLJ Lobeck1985The differential projection of two cytoarchitectonic subregions of the inferior parietal lobule of macaque upon the deep layers of the superior colliculus.J Comp Neurol235241254
- 48. Ruff CC, Bestmann S, Blankenburg F, Bjoertomt O, Josephs O, et al. (2008) Distinct causal influences of parietal versus frontal areas on human visual cortex: evidence from concurrent TMS-fMRI. Cereb Cortex 18: 817–827.CC RuffS. BestmannF. BlankenburgO. BjoertomtO. Josephs2008Distinct causal influences of parietal versus frontal areas on human visual cortex: evidence from concurrent TMS-fMRI.Cereb Cortex18817827
- 49. Ruff CC, Blankenburg F, Bjoertomt O, Bestmann S, Weiskopf N, et al. (2009) Hemispheric Differences in Frontal and Parietal Influences on Human Occipital Cortex: Direct Confirmation with Concurrent TMS-fMRI. J Cogn Neurosci 21: 1146–1161.CC RuffF. BlankenburgO. BjoertomtS. BestmannN. Weiskopf2009Hemispheric Differences in Frontal and Parietal Influences on Human Occipital Cortex: Direct Confirmation with Concurrent TMS-fMRI.J Cogn Neurosci2111461161
- 50. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, et al. (1997) Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48: 1398–1403.R. ChenJ. ClassenC. GerloffP. CelnikEM Wassermann1997Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation.Neurology4813981403
- 51. Valero-Cabré A, Payne BR, Pascual-Leone A (2007) Opposite impact on 14C-2-deoxyglucose brain metabolism following patterns of high and low frequency repetitive transcranial magnetic stimulation in the posterior parietal cortex. Exp Brain Res 176: 603–615.A. Valero-CabréBR PayneA. Pascual-Leone2007Opposite impact on 14C-2-deoxyglucose brain metabolism following patterns of high and low frequency repetitive transcranial magnetic stimulation in the posterior parietal cortex.Exp Brain Res176603615
- 52. Elkin-Frankston S, Fried P, Rushmore RJ, Valero-Cabré A (2011) From qualia to quantia: A system to document and quantify phosphene percepts elicited by non-invasive neurostimulation of the human occipital cortex. J Neurosci Methods. S. Elkin-FrankstonP. FriedRJ RushmoreA. Valero-Cabré2011From qualia to quantia: A system to document and quantify phosphene percepts elicited by non-invasive neurostimulation of the human occipital cortex.J Neurosci MethodsPubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/21419796. Accessed 13 Apr 2011. PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/21419796. Accessed 13 Apr 2011.
- 53. Stokes MG, Chambers CD, Gould IC, Henderson TR, Janko NE, et al. (2005) Simple metric for scaling motor threshold based on scalp-cortex distance: application to studies using transcranial magnetic stimulation. J Neurophysiol 94: 4520–4527.MG StokesCD ChambersIC GouldTR HendersonNE Janko2005Simple metric for scaling motor threshold based on scalp-cortex distance: application to studies using transcranial magnetic stimulation.J Neurophysiol9445204527
- 54. Stokes MG, Chambers CD, Gould IC, English T, McNaught E, et al. (2007) Distance-adjusted motor threshold for transcranial magnetic stimulation. Clin Neurophysiol 118: 1617–1625.MG StokesCD ChambersIC GouldT. EnglishE. McNaught2007Distance-adjusted motor threshold for transcranial magnetic stimulation.Clin Neurophysiol11816171625
- 55. Grefkes C, Fink GR (2005) The functional organization of the intraparietal sulcus in humans and monkeys. J Anat 207: 3–17.C. GrefkesGR Fink2005The functional organization of the intraparietal sulcus in humans and monkeys.J Anat207317
- 56. Chica A, Bartolo P, Valero-Cabre A (In press) Dorsal and Ventral Parietal Contributions to Spatial Orienting in the Human Brain. J Neurosci 31: xxx–xxx.A. ChicaP. BartoloA. Valero-CabreIn pressDorsal and Ventral Parietal Contributions to Spatial Orienting in the Human Brain.J Neurosci31xxxxxx
- 57. Corbetta M, Kincade JM, Shulman GL (2002) Neural systems for visual orienting and their relationships to spatial working memory. J Cogn Neurosci 14: 508–523.M. CorbettaJM KincadeGL Shulman2002Neural systems for visual orienting and their relationships to spatial working memory.J Cogn Neurosci14508523
- 58. Corbetta M, Tansy A, Stanley C, Astafiev S, Snyder A, et al. (2005) A functional MRI study of preparatory signals for spatial location and objects. Neuropsychologia 43: 2041–2056.M. CorbettaA. TansyC. StanleyS. AstafievA. Snyder2005A functional MRI study of preparatory signals for spatial location and objects.Neuropsychologia4320412056
- 59. Hilgetag CC, Théoret H, Pascual-Leone A (2001) Enhanced visual spatial attention ipsilateral to rTMS-induced “virtual lesions” of human parietal cortex. Nat Neurosci 4: 953–957.CC HilgetagH. ThéoretA. Pascual-Leone2001Enhanced visual spatial attention ipsilateral to rTMS-induced “virtual lesions” of human parietal cortex.Nat Neurosci4953957
- 60. Yeshurun Y, Carrasco M (1999) Spatial attention improves performance in spatial resolution tasks. Vision Res 39: 293–306.Y. YeshurunM. Carrasco1999Spatial attention improves performance in spatial resolution tasks.Vision Res39293306
- 61. Vallar G, Lobel E, Galati G, Berthoz A, Pizzamiglio L, et al. (1999) A fronto-parietal system for computing the egocentric spatial frame of reference in humans. Exp Brain Res 124: 281–286.G. VallarE. LobelG. GalatiA. BerthozL. Pizzamiglio1999A fronto-parietal system for computing the egocentric spatial frame of reference in humans.Exp Brain Res124281286
- 62. Mahaney KB, Abdulrauf SI (2008) Anatomic relationship of the optic radiations to the atrium of the lateral ventricle: description of a novel entry point to the trigone. Neurosurgery 63: 195–202; discussion 202–203.KB MahaneySI Abdulrauf2008Anatomic relationship of the optic radiations to the atrium of the lateral ventricle: description of a novel entry point to the trigone.Neurosurgery63195202; discussion 202–203
- 63. Haxby JV, Grady CL, Horwitz B, Ungerleider LG, Mishkin M, et al. (1991) Dissociation of object and spatial visual processing pathways in human extrastriate cortex. Proceedings of the National Academy of Sciences of the United States of America 88: 1621–1625.JV HaxbyCL GradyB. HorwitzLG UngerleiderM. Mishkin1991Dissociation of object and spatial visual processing pathways in human extrastriate cortex.Proceedings of the National Academy of Sciences of the United States of America8816211625
- 64. Taylor PCJ, Walsh V, Eimer M (2010) The neural signature of phosphene perception. PCJ TaylorV. WalshM. Eimer2010The neural signature of phosphene perception.Hum Brain Mapp. PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/20091790. Accessed 15 Mar 2010. Hum Brain Mapp. PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/20091790. Accessed 15 Mar 2010.
- 65. Sanders MD, Warrington EK, Marshall J, Wieskrantz L (1974) “Blindsight”: Vision in a field defect. Lancet 1: 707–708.MD SandersEK WarringtonJ. MarshallL. Wieskrantz1974“Blindsight”: Vision in a field defect.Lancet1707708
- 66. Silvanto J, Cowey A, Lavie N, Walsh V (2005) Striate cortex (V1) activity gates awareness of motion. Nat Neurosci 8: 143–144.J. SilvantoA. CoweyN. LavieV. Walsh2005Striate cortex (V1) activity gates awareness of motion.Nat Neurosci8143144
- 67. Kammer T, Beck S, Erb M, Grodd W (2001) The influence of current direction on phosphene thresholds evoked by transcranial magnetic stimulation. Clin Neurophysiol 112: 2015–2021.T. KammerS. BeckM. ErbW. Grodd2001The influence of current direction on phosphene thresholds evoked by transcranial magnetic stimulation.Clin Neurophysiol11220152021
- 68. Rossi S, Hallett M, Rossini PM, Pascual-Leone A (2009) Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. S. RossiM. HallettPM RossiniA. Pascual-Leone2009Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.Clin Neurophysiol. PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/19833552. Accessed 26 Oct 2009. Clin Neurophysiol. PubMed website. Available: http://www.ncbi.nlm.nih.gov/pubmed/19833552. Accessed 26 Oct 2009.
- 69. Pascual-Leone A, Davey N, Rothwell JC, Wasserman E, Puri BK (2002) Handbook of Transcranial Magnetic Stimulation. 1st ed. A Hodder Arnold Publication. A. Pascual-LeoneN. DaveyJC RothwellE. WassermanBK Puri2002Handbook of Transcranial Magnetic Stimulation. 1st edA Hodder Arnold Publication
- 70. Fumal A, Bohotin V, Vandenheede M, Seidel L, de Pasqua V, et al. (2003) Effects of repetitive transcranial magnetic stimulation on visual evoked potentials: new insights in healthy subjects. Exp Brain Res 150: 332–340.A. FumalV. BohotinM. VandenheedeL. SeidelV. de Pasqua2003Effects of repetitive transcranial magnetic stimulation on visual evoked potentials: new insights in healthy subjects.Exp Brain Res150332340
- 71. Kim D, Kim S, Joo E, Tae W, Choi S, et al. (2007) Cortical localization of scalp electrodes on three-dimensional brain surface using frameless stereotactic image guidance system. Neurology Asia 12: 84.D. KimS. KimE. JooW. TaeS. Choi2007Cortical localization of scalp electrodes on three-dimensional brain surface using frameless stereotactic image guidance system.Neurology Asia1284
- 72. Herwig U, Satrapi P, Schönfeldt-Lecuona C (2003) Using the international 10–20 EEG system for positioning of transcranial magnetic stimulation. Brain Topogr 16: 95–99.U. HerwigP. SatrapiC. Schönfeldt-Lecuona2003Using the international 10–20 EEG system for positioning of transcranial magnetic stimulation.Brain Topogr169599
- 73. Brasil-Neto JP, Cohen LG, Panizza M, Nilsson J, Roth BJ, et al. (1992) Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation, shape of the induced current pulse, and stimulus intensity. J Clin Neurophysiol 9: 132–136.JP Brasil-NetoLG CohenM. PanizzaJ. NilssonBJ Roth1992Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation, shape of the induced current pulse, and stimulus intensity.J Clin Neurophysiol9132136
- 74. Mills KR, Boniface SJ, Schubert M (1992) Magnetic brain stimulation with a double coil: the importance of coil orientation. Electroencephalogr Clin Neurophysiol 85: 17–21.KR MillsSJ BonifaceM. Schubert1992Magnetic brain stimulation with a double coil: the importance of coil orientation.Electroencephalogr Clin Neurophysiol851721
- 75. Kosslyn SM, Pascual-Leone A, Felician O, Camposano S, Keenan JP, et al. (1999) The role of area 17 in visual imagery: convergent evidence from PET and rTMS. Science 284: 167–170.SM KosslynA. Pascual-LeoneO. FelicianS. CamposanoJP Keenan1999The role of area 17 in visual imagery: convergent evidence from PET and rTMS.Science284167170