New approaches to the study of human brain networks underlying spatial attention and related processes
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- Driver, J., Blankenburg, F., Bestmann, S. et al. Exp Brain Res (2010) 206: 153. doi:10.1007/s00221-010-2205-7
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Cognitive processes, such as spatial attention, are thought to rely on extended networks in the human brain. Both clinical data from lesioned patients and fMRI data acquired when healthy subjects perform particular cognitive tasks typically implicate a wide expanse of potentially contributing areas, rather than just a single brain area. Conversely, evidence from more targeted interventions, such as transcranial magnetic stimulation (TMS) or invasive microstimulation of the brain, or selective study of patients with highly focal brain damage, can sometimes indicate that a single brain area may make a key contribution to a particular cognitive process. But this in turn raises questions about how such a brain area may interface with other interconnected areas within a more extended network to support cognitive processes. Here, we provide a brief overview of new approaches that seek to characterise the causal role of particular brain areas within networks of several interacting areas, by measuring the effects of manipulations for a targeted area on function in remote interconnected areas. In human participants, these approaches include concurrent TMS-fMRI and TMS-EEG, as well as combination of the focal lesion method in selected patients with fMRI and/or EEG measures of the functional impact from the lesion on interconnected intact brain areas. Such approaches shed new light on how frontal cortex and parietal cortex modulate sensory areas in the service of attention and cognition, for the normal and damaged human brain.
KeywordsAttention fMRI Lesion TMS-fMRI TMS Neglect Extinction Parietal FEF
A second line of evidence, in which Pizzamiglio and colleagues have also long been active (e.g., see Vallar et al. 1999; Galati et al. 2000), concerns functional neuroimaging data, typically PET or fMRI data, from neurologically healthy subjects as they carry out specific cognitive tasks. This very different type of evidence has also often suggested that extensive brain networks may underlie spatial cognition (e.g., Vallar et al. 1999) and spatial attention (e.g., Corbetta and Shulman 2002; Driver et al. 2004). Moreover, there has often been considerable overlap between those brain networks found in fMRI studies of spatial cognition and attention in healthy participants, with those implicated by the extensive brain lesions of typical neglect patients (e.g., Husain and Rorden 2003; Driver et al. 2004); see again the schematic in Fig. 1. Taken together, such lines of evidence from lesioned patients or functional neuroimaging in neurologically intact subjects have led to the emerging view that rather than single brain areas being identified with single cognitive functions, cognition may be subserved by extended networks of interconnected brain areas (e.g., see Corbetta and Shulman 2002; Driver et al. 2009; Ruff et al. 2009a).
On the other hand, studies that target specific brain areas more selectively have led to suggestions that a given area may play an essential role in a specific cognitive process. In research with human participants, transcranial magnetic stimulation (TMS) has often been used to target specific brain areas (provided they are near enough to the surface to be approached by TMS) in order to test such hypotheses (e.g., for reviews, see Walsh and Pascual-Leone 2005; Wassermann et al. 2008). In rare cases where invasive electrodes were available for surgical reasons, targeted invasive stimulations have also been possible in a few human patients (e.g., Thiebaut de Schotten et al. 2005), somewhat analogous to microstimulation work in non-human primates (e.g., see Cohen and Newsome 2004). Such interventional approaches have also been supplemented with conventional focal lesion work, either by selecting human patients with unusually focal damage (e.g., Husain et al. 2003), or by experimental (often reversible) lesions in animals (e.g., Lomber and Galuske 2002). These more targeted approaches have led to hypotheses that specific single brain areas may make unique contributions to particular cognitive processes, such as for those aspects of spatial cognition and attention that we consider here. But given the coexisting evidence for more extensive networks of interconnected brain areas (see above and Fig. 1), this then raises the question of how an implicated specific brain area may interact with closely interconnected regions within the same network, as a function of the current task requirements.
In this context, several sophisticated analysis approaches have been developed for application to standard fMRI, EEG or MEG data, which seek to uncover patterns of functional influences or ‘effective connectivity’ between interconnected brain regions. Such patterns of effective connectivity may relate to particular cognitive processes and may even change dynamically in a task-dependent manner (e.g., Friston et al. 2003; Goebel et al. 2003; Schnitzler and Gross 2005; Valdés-Sosa et al. 2005). But here we focus instead on more interventional approaches that target a particular brain area with a causal intervention (e.g., TMS, or microstimulation or even a permanent lesion), while studying the impact on brain function in remote but interconnected areas within a more extended brain network.
Combining TMS with concurrent fMRI to study causal influences in the brain networks subserving attention and spatial cognition
TMS has been combined with PET (e.g., Fox et al. 1997; Paus et al. 1997; Siebner et al. 1999), but this does not allow the same temporal or anatomical resolution as fMRI. Pioneering studies established the feasibility of combining TMS with fMRI about 10 years ago (e.g., see Bohning et al. 1999). The technical challenges for successfully combining TMS with concurrent fMRI are considerable and are reviewed elsewhere (e.g., Bestmann et al. 2008; Bohning et al. 2003; Siebner et al. 2009; Weiskopf et al. 2009). While the BOLD signals revealed by fMRI may not index all forms of neural activity (Logothetis 2008) and may be insensitive to lower intensity TMS (Bohning et al. 1999), concurrent TMS-fMRI offers the advantage of potentially tracking the causal impact on many brain areas of TMS applied to one or other targeted site. Space constraints preclude an exhaustive review of all concurrent TMS-fMRI studies here. Instead we focus on use of concurrent TMS-fMRI to study the brain basis of spatial attention and spatial cognition, initially describing our own work and then expanding the focus to include potentially related studies.
In follow-up studies, Ruff and colleagues went on to show that stimulating human intraparietal cortex, rather than FEF, led to a distinct pattern of influence upon visual cortex (Ruff et al. 2008); see Fig. 2c, d. Moreover, they subsequently found some right-hemisphere predominance for these remote functional effects in humans (Ruff et al. 2009b); compare Fig. 2d, e. Notably, left-intraparietal TMS had no impact on BOLD signals in visual cortex, quite unlike the robust effects due to right-intraparietal TMS. Right FEF TMS also had more substantial effects on visual cortex than left-FEF TMS. Such lateralisation appears broadly consistent with that found for purely behavioural TMS effects in several visual tasks with humans (e.g., see Grosbras and Paus 2002; O’Shea et al. 2004; Silvanto et al. 2006). It also accords with the extensive clinical evidence from neglect patients for some right-hemisphere predominance in the networks subserving spatial cognition and attention (e.g., see Karnath et al. 2001, 2004; Mort et al. 2003; Vallar 2001; Verdon et al. 2009). Thus, Ruff et al.’s findings with concurrent TMS-fMRI are consistent with the emerging view that parietal cortex has undergone particular hemispheric specialisation in humans (e.g., see Milner and Goodale 1996).
Several other groups have also combined TMS with fMRI in potentially related work (see e.g., Baudewig et al. 2001; Bohning et al. 2003; Denslow et al. 2005; Kemna and Gembris 2003; Sack et al. 2007 for other concurrent TMS-fMRI examples; and Hubl et al. 2008; O’Shea et al. 2007 for examples of fMRI utilised before and after an intervening off-line, repetitive TMS intervention that was intended to produce a relatively long-lasting disruption). In one illustrative example of concurrent TMS-fMRI, Sack et al. (2007) applied TMS over left or right parietal cortex, during a spatial cognition task (angle judgements, somewhat reminiscent of some of the ‘clock’ tasks often used with neglect patients) or during a non-spatial control task. Right but not left parietal TMS disrupted spatial performance. Concurrent fMRI revealed effects of right but not left parietal TMS for BOLD signals in right parietal and interconnected right frontal cortex that correlated with the behavioural effects.
Combining TMS with concurrent EEG to study the possible causal impact of a targeted brain region upon others
TMS can also be combined with concurrent EEG, which can provide a much finer temporal resolution than fMRI, at the expense of spatial anatomical resolution. Again there are technical issues to overcome (such as the instantaneous electrical artefact during each TMS pulse, plus the ERPs triggered by the associated click-sound and scalp-sensation, etc). These technical challenges are all surmountable (e.g., see Thut and Pascual-Leone 2010; Ilmoniemi and Kicic 2010). Several recent studies have used concurrent TMS-EEG to study possible attention-related effects of TMS over (or near) human FEF, in the context of visual attention paradigms. Taylor et al. (2007) reported that posterior negativities, within ~200 ms of visual target onset, could be modulated by right FEF TMS, in a Posner-like (Posner et al. 1980) spatial precuing paradigm. This was taken to indicate a remote attention-dependent influence on sources in visual cortex. Morishima et al. (2009) reported that TMS over electrode position FC2 (argued by those authors to fall close to human FEF) altered ERPs at occipital electrodes, when participants were forewarned by an early precue that they would have to attend to a face stimulus or a motion stimulus in a composite visual display. These findings were again interpreted as indicating remote attention-dependent influences on sources in visual cortex. Most recently, Capotosto et al. (2009) applied TMS to right frontal eye fields or right intra-parietal sulcus during presentation of a precue that directed attention to a peripheral spatial location, where a target could be presented some seconds later. Concurrent EEG measurements showed that TMS at either cortical site affected anticipatory alpha desynchronisation as measured at parieto–occipital electrodes. Moreover, these effects correlated with response-time slowing for the subsequently presented target. Based on these findings, Capotosto et al. (2009) suggest that FEF and IPS may exert top–down influences on visual processing via neural (de)synchronisation of brain oscillations.
The functional significance of such fairly rapid oscillatory brain phenomena (e.g., from the delta and alpha bands through to beta, gamma and above) can be directly studied with combinations of TMS and EEG, due to the excellent temporal resolution of both techniques. Thut and Miniussi (2009) recently reviewed the possibility of interfering with, or driving, specific brain oscillatory phenomena by using rhythmic TMS at specific frequencies for targeted sites. This remains an exciting direction for future research. Although fMRI data are acquired at a much slower timescale, BOLD signals can also show some (correspondingly slower) oscillatory phenomena (e.g., Fox and Raichle 2007) that might potentially to relate to states of communication among networks of interconnected brain regions (e.g., see Mantini et al. 2007). In the longer-term, TMS might thus be combined not only with EEG but also with fMRI to study the possible causal role of oscillatory neural phenomena (at faster or slower timescales, for EEG or fMRI, respectively) in supporting specific processes such as spatial attention and spatial cognition.
Applying fMRI and/or EEG in focally lesioned patients, to study the possible causal impact of the lesioned brain region upon others
fMRI and EEG can also be applied to brain-damaged patients exhibiting particular neuropsychological symptoms, as in cases of spatial neglect or unilateral extinction. The intention in doing so is not to seek a response from the dead or absent tissue. Rather the aim is to study the possible impact of the lesion upon function in remote surviving regions that might normally interact with the damaged area(s), but then function abnormally when the lesion removes some of the usual influences upon surviving regions. Thus, although chronic brain lesions differ in many respects from application of TMS in healthy participants (as was reviewed above), there is the abstract similarity of being able to look for the remote functional consequences of local brain disruption. Pizzamiglio et al. were among the first to apply functional neuroimaging to neglect patients (e.g., Pizzamiglio et al. 1998). In London, we have used fMRI to study the response of visual cortex to contralateral visual stimuli, in neglect and/or unilateral extinction patients, during unilateral or bilateral visual stimuli. Rees et al. (2000, 2002) reported residual unconscious activation in early right visual cortex for extinguished and/or neglected visual stimuli in the left visual field, together with enhanced responses in surviving parietal and frontal cortex for the same stimuli when consciously detected, in a single case (see also Vuilleumier et al. 2001, 2002; plus Vuilleumier and Driver 2007, for review). Sarri et al. (in press) recently replicated and extended these results to a series of multiple cases of neglect/extinction after right-parietal damage. Marzi et al. (e.g., Marzi et al. 2000, 2001) have made related observations, by using EEG to study ERPs in response to visual stimuli in neglect and/or extinction patients (see also Spinelli et al. 1994). Knight and colleagues have further shown that frontal lesions impact upon visual responses to task-related stimuli, as assessed with ERPs (e.g., Barceló et al. 2000; Yago et al. 2004).
Other groups have also applied fMRI to neglect and/or extinction patients. For instance, Corbetta et al. (2005) and He et al. (2007) reported in a group of neglect patients that task-evoked BOLD responses (Corbetta et al. 2005), or functional connectivity between regions within attention-related extended brain networks as measured with fMRI (He et al. 2007), showed systematic abnormalities within surviving intact regions remote from the lesion. These related to performance in a spatial precuing attention task, and also to the clinical severity/recovery of individual patients. Hyper-activity within left parietal and frontal cortex, contralateral to the damaged hemisphere, contributed to this pattern. Such contralesional hyper-activity in neglect had long been hypothesised on clinical and theoretical grounds (e.g., Kinsbourne 1977) but had rarely if ever been demonstrated directly hitherto (though see Koch et al. 2008).
Pizzamiglio et al. have expanded considerable effort on possible rehabilitation strategies for neglect over many years (e.g., see Pizzamiglio et al. 1990, 1992; Antonucci et al. 1995). One possible strategy follows up on the possibility of hyper-excitability within the undamaged (usually left) hemisphere, as mentioned above. This can be approached using repetitive TMS protocols over the intact hemisphere that aim to reduce such hyper-excitability. The rationale here is that if such hyper-excitability can be returned to normal levels, some of the neglect and/or extinction symptoms might be alleviated. After some initial positive demonstrations for extinction (e.g., Oliveri et al. 1999), there have been further recent developments in the application of TMS as a potential therapy for neglect. These include a recent (Koch et al. 2008) direct demonstration, with twin-coil TMS, of hyper-excitability within parietal-motor networks for the intact left-hemisphere of neglect patients. Moreover, this same study observed that repetitive TMS applied over that intact hemisphere reduced this hyper-excitability back to the normal range and led in parallel to corresponding improvements in neglect symptom (e.g., see Koch et al. 2008).
TMS can now be combined with fMRI and with EEG, as we have reviewed above, to reveal the impact of interventions targeting a specific brain area for function in remote interconnected areas. These combined approaches are now sufficiently well established that they can also begin to be applied to brain-damaged patients. Moreover, TMS already shows exciting possibilities for remediation of neglect and extinction (e.g., Koch et al. 2008; Oliveri et al. 1999); while the available TMS interventions should increasingly be informed by the emerging literature on how rhythmic TMS may affect ongoing brain oscillations (e.g., see Thut and Miniussi 2009). Taking all of these points together, we anticipate that the various different strands of research that we have briefly summarised above are likely to converge in the future, to allow further advances on the topics that Pizzamiglio has studied and highlighted throughout his career. The new methodological combinations allow a distinct approach to enduring questions, while also raising many new questions about how separate but connected brain areas may interact within the normal and damaged human brain.
JD is supported by the Wellcome Trust, the Medical Research Council UK, by EU FP7 200728 (Brain-Synch) and by a Royal Society Anniversary Professorship; FB by the Federal Ministry of Education and Research (BMBF); SB by the Biotechnology and Biological Sciences Research Council; CCR by the University Research Priority Program “Foundations of Human Social Behaviour” at the University of Zurich and by his collaboration with the Brain-Synch network.
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