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Does stroke imaging provide insights into the neural basis of cognition?
Paresh A. Malhotra1 and Charlotte Russell2
1 Centre for Restorative Neuroscience, Division of Brain Sciences, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, United Kingdom.
2 Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London.
Corresponding author: [email protected]
Keywords: Stroke, Neuropsychology, Lesion-mapping, Neglect, AttentionWord Count: 3915
Abstract
Since the advent of in vivo imaging, first with CT, and then MRI, structural
neuroimaging in patients has been widely used as a tool to explore the neural
correlates of a wide variety of cognitive functions. Findings from studies using
this methodology have formed a core component of current accounts of
cognition, but there are a number of problematic issues related to inferring
cognitive functions from structural imaging data in stroke and more generally,
lesion-based neuropsychology as a whole. This review addresses these concerns
in the context of spatial neglect, a common disorder most frequently
encountered following right hemisphere stroke. Recent literature, including
attempts to address some of these questions, is discussed. Novel approaches and
findings from related fields that may help to put stroke-based lesion-mapping
studies into perspective are reviewed, allowing critical but constructive
evaluation of previous work in the field.
Introduction
The birth of Neuropsychology and the lesion-method for exploring the
underpinnings of cognition is widely accepted to have occurred with Paul
Broca’s descriptions of two aphasic patients, Louis Victor Leborgne and Lazare
Lelong, in 1861 [1]. Since that time and particularly following the advent of in
vivo imaging, first with Computed Tomography (CT) and then Magnetic
Resonance Imaging (MRI), there has been a vast number of further studies using
lesion anatomy in order to attempt to determine which brain regions are
responsible for particular aspects of behavior. Crucially, these studies have
formed a major component of current accounts of human cognition. For example,
at the time of writing, one such paper examining the neural underpinnings of
sarcasm recognition has received a great deal of media attention [2]. The
majority of these studies have involved adult patients who have suffered from
hemispheric stroke, most often ischaemic and embolic rather than lacunar or
haemorrhagic, and have ranged from single case descriptions to group studies
involving hundreds of patients [3 4]. However, over the last thirty years or so,
researchers have had access to newer methodologies to investigate human
cognition in healthy individuals. In particular, functional imaging, first with
SPECT and PET, then with fMRI, has produced a huge and rapidly increasing
number of cerebral localization studies. In addition, cognitive neuroscience has
exploited ever-improving ERP and EEG recording and analysis, as well as brain
stimulation techniques which augment specific brain functions or induce ‘virtual
lesions’. However, lesion-based studies, most frequently involving stroke
patients, are still used by a large number of researchers to explore the
underpinnings of cognitive processes and remain vitally important. Increasingly
sophisticated imaging techniques, analysis tools and psychophysical measures
have allowed ever more complex examination of the brain-behaviour
relationship in patient studies. However, modern scanning and analysis tools do
not necessarily overcome problematic issues with the lesion-behaviour mapping
approach and in this review we will discuss these concerns, with a focus on the
spatial neglect syndrome, a disorder that is most commonly caused by strokes
affecting the right cerebral hemisphere. The issue of the anatomy of neglect is
one that has been controversial and widely discussed over the last 15 years [4-
12]. This is not an exhaustive review of the subject - instead, the aim is to use
this field to illustrate some of the more general issues pertaining to the lesion-
behaviour method in stroke.
Stroke Imaging and Lesion Mapping
With the introduction of CT scanning in the 1970s, it became possible to map
stroke patients’ lesions in vivo, and correlate lesion anatomy with behavioural
deficits [13 14]. The development of MRI in the 1980s allowed even more refined
lesion mapping [15]. Since that time investigators have tended to use a
combination of both CT and MR images [5 9 16]. On a single case basis, it is
possible to determine specifically which regions are affected in that patient. , and
where many patients manifest the same disorder, lesions can be overlapped onto
a single template to look for a shared neuroanatomical locus for a disorder. More
recently, it has been possible not only to use analysis software to overlap lesions
of patients with a particular disorder, but also to subtract the lesions of
individuals without that disorder, allowing visualization of both the set of
regions involved when a patient suffers from a particular deficit, and
simultaneously those regions affected in those patients without it. By
incorporating such a behavioural control group into analysis, it is possible to
avoid some of the confounds associated with simply overlapping all the patients
who have a specific deficit or behavioural impairment [17].
In parallel with the development of functional imaging analysis, researchers have
refined statistical methods for examining lesion-behaviour relationships. These
techniques interrogate imaging data at a voxel level and produce statistical data
that relate the presence of damage to particular voxels with specific behavioural
deficits [18]. Such voxel-based lesion symptom mapping has been viewed as
overcoming a large number of problems associated with previous
methodologies, especially in studies with larger patient numbers.
In addition to examining lesion data in this way, investigators have also begun to
directly address the importance of white matter damage in cognitive deficits
[19]. Through probabilistic analysis of group data as well as in vivo dissection on
a smaller scale, it has been possible to determine which white matter tracts are
damaged in stroke patients with a particular impairment or syndrome [20 21].
However, it has been argued by some investigators that these approaches remain
fundamentally flawed, and that lesion mapping in patients who have suffered
from ischaemic stroke is intrinsically biased because of the relationship between
lesion anatomy and the architecture of the vascular tree [22]. These authors have
suggested that a more complex approach using machine learning and much
larger patient datasets is the only solution able to rectify this bias. As discussed
below such anatomical considerations are not the only concern when evaluating
neuroimaging studies of cognition following stroke, and we suggest that an
inclusive approach may prove to be most helpful.
Advantages of the Lesion-Behaviour Approach
In contrast to functional imaging methods in the healthy brain, examining lesion-
behaviour relationships allows researchers to identify which brain regions are
absolutely necessary for a particular cognitive process [17]. Functional imaging
in healthy participants, by demonstrating which regions are activated during a
specific task, is essentially correlational and, as such, cannot provide direct
information about which brain regions are essential for the task being carried
out. Experimental methods which disrupt human brain function also have
significant limitations, including a lack of knowledge about precisely which brain
regions are being affected and to what degree any behavioural effects are caused
by inhibition, excitation, or a combination of the two [23]. Moreover, at present
these techniques are limited with respect to the accessibility of brain regions, in
that the only areas that can be reliably and systematically influenced are
relatively close to the scalp. One further method that provides extremely high
quality data is intraoperative stimulation/ recording but this can only be used in
very specific situations in a highly selective group of patients [24].
Spatial Neglect-A Clinical Syndrome
Neglect is defined as an inability to perceive, report and orient to sensory events
occuring contralateral to the lesion and, although it often coexists with a primary
sensory deficit, it need not do so [25]. Patients with neglect appear to ignore
objects, events and individuals on their neglected side and, when asked to draw
or copy a picture, they often produce remarkable images suggesting a lack of
awareness for one side of a scene or object. There are no directly comparable
animal models, and the syndrome has not only attracted the interest of
neurologists and neuropsychologists, but also philosophers and even novelists
[26 27]. It is widely accepted to be primarily a disorder of spatial attention [28-
30] but, as discussed below, it is a heterogeneous entity rather than a unitary
disorder [31]. Some researchers have described anatomical studies of neglect
patients claiming they demonstrate the neural correlates of spatial awareness,
but these claims must be carefully evaluated and put into context [16].
Neglect is a clinical syndrome which can be diagnosed and evaluated with a wide
variety of tasks (See Figure) [31]. Although investigators have suggested a ‘core
deficit’ that consists of an egocentric attentional bias in space, diagnosis and
classification for the purposes of lesion studies is almost always on the basis of
more than one feature as well as general clinical observation[32]. Furthermore,
it should be noted that neglect can be modulated, or even elicited, through the
use of more demanding or complex paradigms such that it may be present on
one version of a task and absent on another version [33 34] For example, if
patients are tested with one type of cancellation task where they have to find
targets on a sheet of paper, they may show normal performance. However a
similar, more challenging, task with targets embedded amongst distractors is
more likely to elicit neglect behavior [35]. Moreover, neglect can vary on a day-
to-day basis and has been observed to vary within individuals on the same day
[36] [37]. Hence, neglect is a complex construct and more than one cognitive
deficit appears to be involved [28 38]. Neglect is worsened by non-spatial deficits
in attention and related processes and it has been shown that even motivational
influences can affect patients’ performance on diagnostic tests [39 40]. Thus,
equating the anatomy of neglect with the anatomy of a single cognitive process is
problematic and it might be more worthwhile to consider the anatomy of
impaired performance on individual neuropsychological tests, as these are
known to dissociate. For example, individuals may continue to manifest neglect
on a line bisection task while performing normally on cancellation tasks and vice
versa [41 42].
However, even single tasks may require multiple cognitive processes and it is,
therefore, necessary to carefully consider the requirements of any individual
test. For example, it has been shown that a non-lateralised deficit in spatial
working memory appears to contribute to impaired performance on cancellation
tasks [43]. Thus, where possible, the use a targeted experimental paradigm is
preferable, as this is likely to probe fewer cognitive domains than standardized
pen-and-paper tests.
The Anatomy of Neglect
Neglect is most frequently observed in patients with moderate to large strokes
affecting the right middle cerebral artery territory. Until the beginning of this
century it was widely accepted that it tended to be a particular consequence of
parietal damage, particularly the inferior parietal lobule (IPL), although there
were reports of neglect occurring following damage to other regions, including
the frontal lobes and subcortical areas [14 44-46]. In 2001, Karnath and
colleagues published a paper, which controversially stated that neglect localized
to the superior temporal gyrus [16]. The result was based on twenty-five
patients who had suffered from ischaemic and hameorrhagic stroke from 1 to
140 days previously and the main analysis excluded all patients with visual field
deficits, as well as those individuals who suffered from subcortical lesions and
those with subcortical damage in regions known to be associated with neglect.
The remaining patients with neglect were compared with control subjects who
had suffered from right hemisphere stroke, but did not manifest neglect (or have
visual deficits or involvement of the subcortical regions previously linked to
neglect). Although the patients were described as having ‘pure’ neglect because
of the exclusion of patients with hemianopia, it should be noted that diagnosis
was made on the basis of clinical observation and the presence of neglect on at
least two out of four diagnostic tests. The finding of a superior temporal locus
associated with neglect was controversial, and since then there has been a great
deal of further work in the field, including by the authors of that paper,
addressing some of the concerns raised with this study as well as more general
issues relating to lesion-mapping in stroke. These issues include the nature of the
behavioural assessments being used, recruitment of appropriate control groups,
chronicity of patient assessment, the utilisation of MRI versus CT (and the use of
different MRI modalities), the importance of white matter damage, and the need
to take a network-based rather than region-based approach to the problem [4 5
7 47-49].
Behavioural Tasks in Neglect
Although neglect can often be diagnosed by observation, this is clearly
dependent to an extent on the clinician and does not allow easy quantification of
neglect severity. It has long been known that impaired performance on the two
main neuropsychological tests used to diagnose and quantify neglect, line
bisection and cancellation tasks, appears to localise to different brain regions
[50]. A number of investigators have carried out further studies in order to
characterize different types of neglect behavior and localize them to specific
brain regions [6 51 52]. In a recent paper, Verdon et al used principal
components analysis to demonstrate that tests examining allocentric, or object-
based neglect (where patients show reduced awareness for the contralesional
side of individual objects, regardless of their location) localized more to deep
temporal regions, whereas more visuo-perceptive impairment related to the IPL
and visuo-motor components to the dorsolateral prefrontal cortex [9]. Meta-
analyses of multiple lesion–mapping studies have also suggested such a
dissociation between egocentric and allocentric neglect [53 54]. Thus, the use of
test batteries to characterize patients with a clinical syndrome may be
particularly unhelpful when considering lesion anatomy. Investigating the neural
correlates of a single task or carrying out a principal components analysis to
determine the underlying factors linking impaired task performance with lesion
location is likely to constitute a more fruitful approach [54].
Chronicity
Up to 82% of right hemisphere stroke patients manifest some degree of neglect
in the acute stage and one third of patients may manifest neglect when tested a
year later [47 55], although it should be noted that this proportion increases if
more sophisticated psychophysical tests are used [56]. One issue that has
confronted researchers is how to address this and whether the neuroanatomy of
chronic neglect is somehow more indicative of the neural correlates of
visuospatial attention [5]. In the acute stage, cognitive deficits may not only be
directly due to the lesion, but there may be related impaired function of nearby,
or distant but functionally connected, brain regions (See below for further
discussion). In addition, there is often acute oedema, such that the effective
lesion size is greater than that visualized by standard MRI. Thus, some authors
have looked only at chronic neglect and others have compared lesion anatomy
between patients who had neglect acutely and then recovered, and patients who
have longstanding chronic neglect [5 47]. However, it should be noted that
plastic changes in those individuals who have recovered can make it difficult to
interpret their lesion anatomy [32].
Scanning Methodology
Although a number of major studies have used CT images to explore the anatomy
of neglect, MRI is the modality of choice [7 14]. Lesion mapping methods using
CT have improved, but it is still the case that CT scans obtained for clinical
purposes tend to be of far lower resolution than MRI, and may be less likely to
demonstrate ischaemic strokes, particularly in the hyperacute stage but also 2 to
4 weeks after the ischaemic event [57]. Therefore, carrying out a voxel level
interrogation of lesion maps derived from such low quality imaging data is not
appropriate. With respect to structural MRI, DWI scans are particularly helpful in
the hyperacute stage and are predictive of eventual lesion size [58]. Again, scans
obtained for clinical purposes may well be of lower resolution, and specific high-
resolution protocols can provide more detailed anatomical information [7].
One further MR modality that has been employed to investigate neglect is
perfusion weighted imaging (PWI). Subcortical regions have long been known to
be associated with neglect, and Hillis and colleagues explored the mechanism
using PWI/DWI mismatch [59]. By examining which areas were hypoperfused,
they were able to show that subcortical strokes caused neglect via the
hypoperfusion of neighbouring cortical areas that were structurally intact, rather
than via direct subcortical damage per se. Thus, without the added use of
perfusion imaging (or other dynamic/functional modalities), interpretation of
structural imaging alone in the acute stage is problematic.
The Importance of White Matter
Although earlier studies had demonstrated that focal white matter damage was
relevant in patients with neglect [46 60], its importance has been increasingly
noted over the last decade following a key study in patients undergoing
intraoperative brain stimulation during surgery and the evolution of methods for
white matter tract delineation [19 24]. It has been now been shown that damage
to the superior longitudinal fasciculus, a structure connecting the frontal and
parietal lobes, is extremely common in neglect patients [20]. In addition, the
importance of the SLF has been highlighted by the occurrence of neglect in two
individuals with iatrogenic SLF damage during neurosurgery [61]. Furthermore,
when other studies that did not include dedicated white matter analysis have
been closely re-examined, similar findings have been demonstrated [10]. A
recent study confirmed the importance of the SLF in acute and chronic neglect
patients, but also highlighted the potential role of damage to the forceps major of
the corpus callosum, a tract that connects the two occipital lobes [11]. Umarova
and colleagues have examined white matter integrity in the unaffected left
hemisphere of neglect cases and found that changes in the superior parietal lobe,
optic radiation and corpus callosum were related to delayed recovery [62]. The
authors of the study suggested that these left hemisphere changes induced white
matter re-modelling, but further work will be needed to determine exactly how
such changes relate to the primary stroke, or whether they in fact pre-date it.
A Network-based approach
The importance of white matter damage as described above highlights the need
to understand cognitive deficits at the level of brain networks rather than single
cortical regions. With respect to spatial neglect, this improved understanding has
come from close interrogation of structural imaging as discussed above and also
from task-related and ‘resting-state’ functional imaging studies in patient groups
[42 [63] [64] [49]. Although authors have consistently attempted to find a critical
lesion site for neglect (see above), it has long been appreciated that it is caused
by damage to brain networks that are responsible for spatial attention and
related processes [45 65]. Evidence from neglect patients, when examined in
tandem with data from functional imaging studies in healthy volunteers,
suggests that neglect arises from the combination of a critical deficit in a spatial
attention network, resulting in an ipsilesional bias, along with damage to other
right-dominant frontoparietal networks responsible for processes including
arousal, salience and spatial working memory [28 38]. By using functional
imaging in neglect patients over the last ten years, investigators have been able
to directly examine whether these networks are affected in neglect and what
changes take place during recovery [49 63]. For example, by using functional
connectivity analysis, researchers have shown that there appears to be an acute
disruption of interparietal connectivity in neglect patients [63] although other
work has suggested that interparietal imbalance is not critical [64]. The most
prevalent current account of neglect stems from this work, utilising results from
both patient studies and functional imaging findings in healthy volunteers. This
suggests that neglect involves structural damage to a ventral right-lateralized
network involved in arousal and directing attention to salient and novel events,
as well as functional disruption of a dorsal attention network responsible for the
deployment of spatial attention [28]. Evidence from stimulation work may be
critical here, as it has shown that the spatial bias in neglect can be improved by
systematically influencing interparietal balance with transcranial direct current
stimulation (tDCS), even to the unlesioned hemisphere [66].
Future Methodologies
As mentioned in the introduction, it has recently been suggested that previous
methods of lesion-mapping are inherently biased due to the propensity of
ischaemic strokes to damage certain sets of voxels because of their location with
respect to the arterial tree [22]. The authors of this study have stated that
correcting this systematic error requires more sophisticated analysis using novel
machine learning techniques in much larger patient numbers than have been
previously been recruited. Two recent studies have employed multivariate
analysis using machine-learning in order to address this issue [67] [48]. The first
of these, by Smith and colleagues, demonstrated that multi-region patterns of
damage were more predictive of neglect than any single voxel, but that damage
to the superior temporal gyrus seemed particularly predictive. However, it
should be noted that this study utilized data from a previous paper, which again
used a combination of neuropsychological tests and clinical observation to
classify patients into neglect and non-neglect groups [4 48]. Moreover, it has
been suggested that the large region-of-interest method that was used does not
overcome the previously described confounds associated with vascular anatomy
[68].
In a second study, Corbetta and colleagues did not just address neglect but
looked at multiple cognitive domains across a relatively large group of patients
presenting with a first stroke. They found that the majority of lesions were
subcortical, affecting white matter [67]. As per the multivariate study by Karnath
et al, each deficit was associated with damage to multiple regions but - consistent
with the concept of neglect as a multi-component syndrome - three component
factors were recognised (deficits in lateralised spatial attention, sustained
attention and attentional re-orienting). Regions involved included the white
matter relating to the superior longitudinal fasciculus, the inferior frontal gyrus,
insula, thalamus, and parahippocampal gyrus but not the temporo-parietal
junction, although it should be noted that this was not well sampled.
Conclusions
A clear conclusion from the number and diversity of the studies reviewed here is
that stroke imaging is indeed a viable and valuable method for exploring the
anatomy of cognitive processes. We have focused on the neglect syndrome but
the issues that have been raised are pertinent to other cognitive domains. The
majority of these studies have employed a lesion-mapping approach with stroke
patients, but it should be noted that this appears to be most effective when
supported by data from other methodologies including functional imaging and
non-invasive brain stimulation. Moreover, thorough neuropsychological testing
and targeted behavioural tasks are critical to a deeper understanding of how
anatomical damage might actually relate to cognitive deficits. Advanced imaging
and analysis methodology can only be helpful if combined with considered
behavioural paradigms and appropriate control groups.
Although the lesion method of stroke neuroimaging can be improved to some
extent by more sophisticated analysis, there remain a number of concerns that
cannot easily be overcome. These include the presence of concurrent small
vessel disease and atrophy, both of which have been shown to influence
performance [69 70]. Genotype is a factor that has been shown to influence
attentional asymmetry in healthy populations, but has not been systematically
explored in the context of cognitive disorders following stroke [71]. In addition,
it should be noted that strokes are not the only cause of focal pathology in the
brain. For a comprehensive understanding of the neural basis of cognition, a
more inclusive position may be the most fruitful approach [72]. As well as using
multiple imaging modalities and methodologies, and incorporating data from
techniques such as brain stimulation, it is essential to consider relevant findings
from other patient groups, including individuals with focal dementias as well as
patients with brain tumours [73-75]. Although neuroimaging in these
populations is also associated with a number of confounds, these are largely
different to those associated with focal stroke lesion-mapping. In fact, a recent
study looking at frontal damage across a number of pathologies suggested that
there was no major difference in the cognitive performance of patients with
damage caused by different aetiologies, after accounting for the effects of age and
premorbid IQ [76]. Thus, an inclusive approach to the problems associated with
stroke neuroimaging and cognition might allow us to consolidate previous
findings in the light of current concerns, without ‘throwing out the baby with the
bathwater’.
Figure Legend
Tests used to examine for the presence of neglect.
Panel A shows a standard cancellation task (Behavioural Inattention Test). These
tasks require subjects to search for targets (here the small stars), often amongst
distractors) on a piece of paper. Patients with neglect tend to find the most
ipsilesional targets and omit the more contralesional targets, and often begin by
marking target items on the ipsilesional side of the array. Panel B shows a
neglect patient’s line bisection. Although the patient has been asked to find and
mark the true centre of the line, they have clearly erred to the right. As well as
these pen-and-paper tests for neglect, patients are often diagnosed by clinical
observation of their general behaviour. Panel C shows how a patient responded
when asked to name objects around him in the room. All the objects are well to
the right of the midline.
Patients with neglect can show deficits on all three of these tasks or can be
diagnosed on the basis of impaired performance on one or two of them. This
behavioural heterogeneity is likely to underlie many of the conflicting findings in
the related neuroimaging research.
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