**Neuroimaging of Single Cases: Benefits and Pitfalls**

James Danckert1 and Seyed M. Mirsattarri2

*1Dept of Psychology, University of Waterloo 2Depts of CNS, Med Biophys, Med Imaging, & Psychology, University of Western Ontario Canada* 

### **1. Introduction**

46 Neuroimaging – Cognitive and Clinical Neuroscience

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> Single case studies of neurological patients has a long and storied history (Zillmer & Spiers, 2001). First used as a teaching tool (Haas, 2001), the method of thoroughly exploring the cognitive and motor functions of a unique individual patient has led to extraordinary advances in our understanding of structure-function relationships in the human brain. Single cases have led to important advances in many fields, including pioneering work on language (Broca, 1861; see also Ryalls & Lecours, 1996) and visual perception (Poppelreuter, 1917/1990; see also Humphreys & Riddoch, 1996) to more recent work on memory systems (Scoville & Milner, 1957; Milner & Penfield, 1955-1956; see Milner, 2005 for a recent review) where one patient (HM) has arguably done more to advance that field than any other single case study in history. Prior to the advent of x-rays and eventually computerised axial tomography (CT scans), the method of studying single cases was the only way to determine the location of a patient's pathology. The advent of CT scans in the 1970's obviated, to some degree, the need for detailed neuropsychological testing, at least as it was needed to determine the *location* of pathology (Banich, 2004; Lezak, et al., 2004; Kolb & Wishaw, 2009). A few decades later and the advent of functional MRI (fMRI) provides an even more powerful tool for examining the nature of structure-function relationships in humans and in non-human primates (Ogawa et al., 1992; Ford et al., 2009). Indeed, the rapid rise of fMRI studies (Fox, 1997; Raichle, 1994) has outstripped the pace of single case studies in the past few decades (Figure 1).

> By 2005 the proportion of neuroimaging abstracts accepted for presentation at the Cognitive Neuroscience Society meeting was around 35% compared to only 15% for patient studies (which included group and single case methods; Chatterjee, 20051).

> There are a range of reasons behind the rise of functional neuroimaging studies including the ease and relatively low cost with which these studies can be carried out (Chatterjee, 2005). Although per hour imaging costs seem high to most, the cost of patient research is undoubtedly far higher both in time committed and real costs related to screening and following patients over longer periods of time (Chatterjee, 2005). In addition, each method

<sup>1</sup> A search of the 2011 CNS program using "fMRI", "neuroimaging" and "patients" separately showed that neuroimaging references were almost double those of references to patients.

Neuroimaging of Single Cases: Benefits and Pitfalls 49

& Price, 2003). On the other hand, case studies of neurological patients, while capable of demonstrating which brain regions are necessary for a given function, encounter a range of distinct problems (Rorden & Karnath, 2004). Human lesions tend to be large and highly variable and in turn lead to heterogeneous behavioural symptoms. Furthermore, it is not possible to determine the effects of disconnection – the consequences not only of damage to a particular brain region but of removing that 'node' from the network of regions it once

Perhaps the best way to compensate for the shortcoming of single case and neuroimaging methods is to combine the two (Friston & Price, 2003; Price et al., 2006, 1999; Chatterjee, 2005). Unfortunately, both methods demonstrate a strong within citation bias (although the bias is stronger in neuroimaging work; Chatterjee, 2005). There have been elegant studies using fMRI in groups of patients to address a wide variety of behaviours from motor control in Parkinson's disease (e.g., Nandhagopal et al., 2008), to strategy selection in social games in psychopathy (Rilling et al., 2007; see also Hoff et al., 2009 for a single case study of psychopathy) and recovery of function in neglect patients – a common disorder typically arising from right hemisphere strokes (Corbetta et al., 2005). Far fewer studies have made use of fMRI to examine single case studies. In this chapter we will first discuss some of the challenges to using fMRI as another tool for exploring single cases before giving some examples of how such an approach could be used to advance our understanding of

Several technical aspects related to collecting the Blood Oxygenated Level Dependent (BOLD) response that forms the basis of fMRI data pose problems for single case studies. First, the shape of the haemodynamic response function (HRF) may vary from one experimental session to another (Aguirre et al., 1998). Within a given subject the shape of the HRF tends to be robust particularly within a single scanning session (Aguirre et al., 1998). More variability is evident within individuals when scanning runs span multiple sessions. This may be related to hardware issues in the scanner itself with some variability in measures of magnetic susceptibility from one session or day to the next (Huettel et al., 2004). Noise may also be introduced from the subject themselves with differing levels of alertness being an important factor in testing neurological patients (Lerdal et al., 2009; see also Tyvaert et al., 2008 for a study of the effects of alertness on BOLD signals). Even factors such as levels of caffeine influence the BOLD signal (Chen & Parrish, 2009). The variability of the HRF and subsequent BOLD measures when testing over multiple sessions is particularly problematic for single case designs as it constrains the number of tasks, and repetition of those tasks, one can expect to complete in a given session. Commonly, fMRI designs require multiple repetitions of the same task within a single session to achieve the appropriate statistical power to demonstrate a robust change in the BOLD signal (Huettel et al., 2004; Monti, 2011). While the same can be said of behavioural studies of single cases, such studies can often extend over days or weeks with an opportunity to replicate findings within the patient and to examine an extensive range of behaviours (e.g., Danckert et al., 2002; Branch-Coslett & Lie, 2008). Issues of fatigue in this instance can be addressed by testing the patient at the same time of day in each instance or collecting a control task as an index of fluctuations in alertness (e.g., a basic information processing task such as the Trails A test

participated in (e.g., Bartolomeo, et al., 2007).

structure-function relationships in humans.

**2. Design issues relevant to single case studies in fMRI** 

Fig. 1. Proportion of single case and fMRI studies in the past few decades. Upper panel shows the results of two Pubmed searches, the first using the term 'memory' (open bars) and the second using the conjunction search terms 'memory AND fMRI'. The first search included the following constraints: case studies published in English, dating from 1970 onwards (under the 'limits' tab of Pubmed the following criteria were selected: 'English', 'Humans', 'Case Studies', 'dates from 1970.01.01 to 2010.01.01'). The resulting abstracts were inspected to ensure that only single case studies of neurological patients were included. The second search term included the same constraints with the exception that the constraint 'case studies' was removed from the search term. Again, all abstracts were inspected to ensure that only fMRI studies examining memory processes were included.

provides distinct information. By design, human functional neuroimaging studies are necessarily correlational and as such can not address which brain regions are *necessary* for a given function but highlight only those regions or networks that are *sufficient* (Chatterjee, 2005; Friston & Price, 2003). In fact, given that the vast majority of fMRI studies present only group averaged data, it is feasible that much of what we see represents 'cognitively degenerate' neural systems - that is, typical imaging findings may highlight only one of several regions or networks each capable of subserving the same cognitive function (Friston

Fig. 1. Proportion of single case and fMRI studies in the past few decades. Upper panel shows the results of two Pubmed searches, the first using the term 'memory' (open bars) and

provides distinct information. By design, human functional neuroimaging studies are necessarily correlational and as such can not address which brain regions are *necessary* for a given function but highlight only those regions or networks that are *sufficient* (Chatterjee, 2005; Friston & Price, 2003). In fact, given that the vast majority of fMRI studies present only group averaged data, it is feasible that much of what we see represents 'cognitively degenerate' neural systems - that is, typical imaging findings may highlight only one of several regions or networks each capable of subserving the same cognitive function (Friston

the second using the conjunction search terms 'memory AND fMRI'. The first search included the following constraints: case studies published in English, dating from 1970 onwards (under the 'limits' tab of Pubmed the following criteria were selected: 'English', 'Humans', 'Case Studies', 'dates from 1970.01.01 to 2010.01.01'). The resulting abstracts were inspected to ensure that only single case studies of neurological patients were included. The second search term included the same constraints with the exception that the constraint 'case studies' was removed from the search term. Again, all abstracts were inspected to ensure

that only fMRI studies examining memory processes were included.

& Price, 2003). On the other hand, case studies of neurological patients, while capable of demonstrating which brain regions are necessary for a given function, encounter a range of distinct problems (Rorden & Karnath, 2004). Human lesions tend to be large and highly variable and in turn lead to heterogeneous behavioural symptoms. Furthermore, it is not possible to determine the effects of disconnection – the consequences not only of damage to a particular brain region but of removing that 'node' from the network of regions it once participated in (e.g., Bartolomeo, et al., 2007).

Perhaps the best way to compensate for the shortcoming of single case and neuroimaging methods is to combine the two (Friston & Price, 2003; Price et al., 2006, 1999; Chatterjee, 2005). Unfortunately, both methods demonstrate a strong within citation bias (although the bias is stronger in neuroimaging work; Chatterjee, 2005). There have been elegant studies using fMRI in groups of patients to address a wide variety of behaviours from motor control in Parkinson's disease (e.g., Nandhagopal et al., 2008), to strategy selection in social games in psychopathy (Rilling et al., 2007; see also Hoff et al., 2009 for a single case study of psychopathy) and recovery of function in neglect patients – a common disorder typically arising from right hemisphere strokes (Corbetta et al., 2005). Far fewer studies have made use of fMRI to examine single case studies. In this chapter we will first discuss some of the challenges to using fMRI as another tool for exploring single cases before giving some examples of how such an approach could be used to advance our understanding of structure-function relationships in humans.

#### **2. Design issues relevant to single case studies in fMRI**

Several technical aspects related to collecting the Blood Oxygenated Level Dependent (BOLD) response that forms the basis of fMRI data pose problems for single case studies. First, the shape of the haemodynamic response function (HRF) may vary from one experimental session to another (Aguirre et al., 1998). Within a given subject the shape of the HRF tends to be robust particularly within a single scanning session (Aguirre et al., 1998). More variability is evident within individuals when scanning runs span multiple sessions. This may be related to hardware issues in the scanner itself with some variability in measures of magnetic susceptibility from one session or day to the next (Huettel et al., 2004). Noise may also be introduced from the subject themselves with differing levels of alertness being an important factor in testing neurological patients (Lerdal et al., 2009; see also Tyvaert et al., 2008 for a study of the effects of alertness on BOLD signals). Even factors such as levels of caffeine influence the BOLD signal (Chen & Parrish, 2009). The variability of the HRF and subsequent BOLD measures when testing over multiple sessions is particularly problematic for single case designs as it constrains the number of tasks, and repetition of those tasks, one can expect to complete in a given session. Commonly, fMRI designs require multiple repetitions of the same task within a single session to achieve the appropriate statistical power to demonstrate a robust change in the BOLD signal (Huettel et al., 2004; Monti, 2011). While the same can be said of behavioural studies of single cases, such studies can often extend over days or weeks with an opportunity to replicate findings within the patient and to examine an extensive range of behaviours (e.g., Danckert et al., 2002; Branch-Coslett & Lie, 2008). Issues of fatigue in this instance can be addressed by testing the patient at the same time of day in each instance or collecting a control task as an index of fluctuations in alertness (e.g., a basic information processing task such as the Trails A test

Neuroimaging of Single Cases: Benefits and Pitfalls 51

some level of activity even in abnormal tissue) and comparisons with similar patients and healthy controls can also partly address these concerns (e.g., Danckert et al., 2007; Danckert & Culham, 2010). These approaches however, never fully remove the concerns surrounding null results and can be seen only as increasing the degree of confidence regarding alternate reasons for an absence of activation. This issue will be revisited with the examples to be discussed in

One final vital issue when utilising neuroimaging techniques with neurological patients concerns task design. As already suggested, it is often best to make use of tasks that lead to well documented, robust activation patterns (e.g., tasks known to activate primary sensory and motor cortices). Given that each patient presents with a unique behavioural deficit, however, it is not always possible to stick with the robust, simple tasks. In that sense, task choice and design necessarily feeds off neuropsychological testing – in other words single case methodology. While the temptation may be to choose tasks that fully highlight the patient's particular deficits, this may not be the ideal approach (Price & Friston, 1999). If the patient is completely incapable of performing a given task, interpretation of any neural activity (should any even exist) is limited. Instead, those tasks that the patient can perform either to the same level as healthy controls or to some suboptimal level, should be preferred. In the first instance, when a patient performs to an equivalent level of controls, it is possible to explore the extent to which the same networks are invoked (e.g.,. Yucel et al., 2002). In many instances, patients will utilise alternate neural networks to achieve the same level of behavioural performance as controls (this may be especially important when investigating disorders such as schizophrenia). The difficulty with this kind of finding comes from interpreting the abnormal neural responses as either *causing* the behavioural syndrome or deficit in question or arising as a *consequence* of the syndrome/deficit (note: in this case the task used may show no deficit per se but tap into a component process known to be impaired in the patient; Price & Friston, 2006). Essentially this arises from the fact that neuroimaging data are correlational in nature and do not allow for conclusions related to the cause of changed patterns of activation. In the second instance, in which the patient performs a task at suboptimal levels, it is possible to correlate performance with the BOLD signal directly (i.e., activations related to correct vs. error trials; Price & Friston, 2006) or to address which parts of the normal neural network are necessary for the task at hand (e.g., Steeves et al., 2004). For example, Steeves and colleagues (2004) examined object processing in a visual form agnosic patient who performed at above chance levels, but well below that of healthy individuals, when asked to recognise visual representations of objects. In their study they were able to examine more precisely which components of object recognition, including colour diagnostics, form outlines and greyscaled images, were most impaired in their patient thereby enabling a more detailed exploration of the variety of processes involved in object perception (Steeves et al., 2004). In instances such as these, however, there remains the possibility that abnormal neural activation patterns arise due to either a loss of function from the damaged region or as a consequence of the fact that the damaged region is disconnected from a broader network (see Price & Friston, 2006 for a detailed review of

more detail below.

these and related issues in single case neuroimaging).

Task choice and design are ultimately dictated by the nature of the question being asked. In many instances (including the first two patients to be discussed below) the questions asked are primarily patient focused - that is, the studies represent an attempt to determine the degree of recovery or reorganisation of function in a given patient. In this instance tasks with well-described patterns of activation in the healthy population are essential. In other

would suffice for this purpose; e.g., Gaudino et al., 1995). In contrast, collecting fMRI data across a range of cognitive functions within one scanning session can be time prohibitive, especially in instances where repetition of each domain specific task is ideal to achieve the appropriate statistical power (Huettel et al., 2004). These limitations can in part be overcome through the choice of tasks to be implemented and the design chosen (i.e., block design vs. the various forms of event-related designs). In general, block designs lead to larger percent signal changes than do event-related designs (Bandettini & Cox, 2000) due to a loss of signal-to-noise ratio for the latter. Tasks exploring basic sensory or motor functions also tend to lead to larger BOLD signal changes than do tasks exploring more complex cognitive functions (Huettel et al., 2004).

A second issue in fMRI scanning impacting upon single case studies using this methodology relates to susceptibility artefacts (Huettel et al., 2004). Susceptibility artefacts can be readily distinguished from true BOLD signal and other artefacts such as motion, using a range of statistical techniques including independent components analysis (e.g., DeMartino et al., 2008). With abnormally developed or injured brains, however, these issues could be compounded. In particular, if one is interested in examining hemispheric differences in activation, it is important to determine that susceptibility artefacts do not impact the damaged and undamaged hemispheres differentially (e.g., Danckert et al., 2007). This can be overcome statistically by contrasting activation for similar regions across each hemisphere (Adcock et al., 2003; Danckert et al., 2007; Shulman et al., 2010). In this instance, however, it is crucial to first determine what one might expect in the healthy brain. For example, basic sensory processes may be expected to lead to symmetrical activations across the two hemispheres (e.g., motion processing and object perception; Dukelow et al., 2001; Kourtzi & Kanwisher, 2000), whereas more complex cognitive processes may be expected to lead to asymmetric activations (e.g., language processing; Price, 2000, 2010). Language functions represent a pertinent case as many individuals may be expected to have bilateral activations during language tasks (Fernandes et al., 2006; Fernandes & Smith, 2000) or even shifted language dominance to the right hemisphere (e.g., Peng & Wang, 2011; Wong et al., 2009). In this instance, fMRI with a single case suffers from the same methodological issues that behavioural studies do – without a baseline measure of performance in some cognitive domains it is difficult if not impossible to determine what has *changed* for the patient. This is particularly problematic for patients suffering from traumatic brain injury (TBI), especially at the mild end of the spectrum, in which subtle changes to executive functions, social functioning and personality are difficult to quantify (e.g., Vaishnavi et al., 2009).

Another issue to consider concerns the nature of damaged or abnormal tissue in neurological patients. More to the point, given that BOLD fMRI depends on changes in oxygenation at the level of capillaries (Huettel et al., 2004; Price et al., 1999), it is possible that damaged or abnormal tissue will also demonstrate abnormal, or at the very least altered, vascularization (Beck & Plate, 2009). Cerebral angiograms are not useful in this circumstance as only gross vascular morphology can be imaged (e.g., obvious abnormalities such as arterioveinous malformations can be detected but the consequences of such malformations for the capillary bed are more complex). This is particularly problematic when faced with null results, an issue we will explore in more detail below. Briefly, any absence of activation could, among other things, be explained due to abnormal vascularization related to the pathology in question. This could be related to abnormally developed tissue (e.g., heterotopias; Guerrini & Barba, 2010) or changes to vascularization due to insults such as stroke (Beck & Plate, 2009). Statistical approaches can in part address this issue (i.e., lowering statistical thresholds should show

would suffice for this purpose; e.g., Gaudino et al., 1995). In contrast, collecting fMRI data across a range of cognitive functions within one scanning session can be time prohibitive, especially in instances where repetition of each domain specific task is ideal to achieve the appropriate statistical power (Huettel et al., 2004). These limitations can in part be overcome through the choice of tasks to be implemented and the design chosen (i.e., block design vs. the various forms of event-related designs). In general, block designs lead to larger percent signal changes than do event-related designs (Bandettini & Cox, 2000) due to a loss of signal-to-noise ratio for the latter. Tasks exploring basic sensory or motor functions also tend to lead to larger BOLD signal changes than do tasks exploring more complex cognitive

A second issue in fMRI scanning impacting upon single case studies using this methodology relates to susceptibility artefacts (Huettel et al., 2004). Susceptibility artefacts can be readily distinguished from true BOLD signal and other artefacts such as motion, using a range of statistical techniques including independent components analysis (e.g., DeMartino et al., 2008). With abnormally developed or injured brains, however, these issues could be compounded. In particular, if one is interested in examining hemispheric differences in activation, it is important to determine that susceptibility artefacts do not impact the damaged and undamaged hemispheres differentially (e.g., Danckert et al., 2007). This can be overcome statistically by contrasting activation for similar regions across each hemisphere (Adcock et al., 2003; Danckert et al., 2007; Shulman et al., 2010). In this instance, however, it is crucial to first determine what one might expect in the healthy brain. For example, basic sensory processes may be expected to lead to symmetrical activations across the two hemispheres (e.g., motion processing and object perception; Dukelow et al., 2001; Kourtzi & Kanwisher, 2000), whereas more complex cognitive processes may be expected to lead to asymmetric activations (e.g., language processing; Price, 2000, 2010). Language functions represent a pertinent case as many individuals may be expected to have bilateral activations during language tasks (Fernandes et al., 2006; Fernandes & Smith, 2000) or even shifted language dominance to the right hemisphere (e.g., Peng & Wang, 2011; Wong et al., 2009). In this instance, fMRI with a single case suffers from the same methodological issues that behavioural studies do – without a baseline measure of performance in some cognitive domains it is difficult if not impossible to determine what has *changed* for the patient. This is particularly problematic for patients suffering from traumatic brain injury (TBI), especially at the mild end of the spectrum, in which subtle changes to executive functions, social

functioning and personality are difficult to quantify (e.g., Vaishnavi et al., 2009).

Another issue to consider concerns the nature of damaged or abnormal tissue in neurological patients. More to the point, given that BOLD fMRI depends on changes in oxygenation at the level of capillaries (Huettel et al., 2004; Price et al., 1999), it is possible that damaged or abnormal tissue will also demonstrate abnormal, or at the very least altered, vascularization (Beck & Plate, 2009). Cerebral angiograms are not useful in this circumstance as only gross vascular morphology can be imaged (e.g., obvious abnormalities such as arterioveinous malformations can be detected but the consequences of such malformations for the capillary bed are more complex). This is particularly problematic when faced with null results, an issue we will explore in more detail below. Briefly, any absence of activation could, among other things, be explained due to abnormal vascularization related to the pathology in question. This could be related to abnormally developed tissue (e.g., heterotopias; Guerrini & Barba, 2010) or changes to vascularization due to insults such as stroke (Beck & Plate, 2009). Statistical approaches can in part address this issue (i.e., lowering statistical thresholds should show

functions (Huettel et al., 2004).

some level of activity even in abnormal tissue) and comparisons with similar patients and healthy controls can also partly address these concerns (e.g., Danckert et al., 2007; Danckert & Culham, 2010). These approaches however, never fully remove the concerns surrounding null results and can be seen only as increasing the degree of confidence regarding alternate reasons for an absence of activation. This issue will be revisited with the examples to be discussed in more detail below.

One final vital issue when utilising neuroimaging techniques with neurological patients concerns task design. As already suggested, it is often best to make use of tasks that lead to well documented, robust activation patterns (e.g., tasks known to activate primary sensory and motor cortices). Given that each patient presents with a unique behavioural deficit, however, it is not always possible to stick with the robust, simple tasks. In that sense, task choice and design necessarily feeds off neuropsychological testing – in other words single case methodology. While the temptation may be to choose tasks that fully highlight the patient's particular deficits, this may not be the ideal approach (Price & Friston, 1999). If the patient is completely incapable of performing a given task, interpretation of any neural activity (should any even exist) is limited. Instead, those tasks that the patient can perform either to the same level as healthy controls or to some suboptimal level, should be preferred. In the first instance, when a patient performs to an equivalent level of controls, it is possible to explore the extent to which the same networks are invoked (e.g.,. Yucel et al., 2002). In many instances, patients will utilise alternate neural networks to achieve the same level of behavioural performance as controls (this may be especially important when investigating disorders such as schizophrenia). The difficulty with this kind of finding comes from interpreting the abnormal neural responses as either *causing* the behavioural syndrome or deficit in question or arising as a *consequence* of the syndrome/deficit (note: in this case the task used may show no deficit per se but tap into a component process known to be impaired in the patient; Price & Friston, 2006). Essentially this arises from the fact that neuroimaging data are correlational in nature and do not allow for conclusions related to the cause of changed patterns of activation. In the second instance, in which the patient performs a task at suboptimal levels, it is possible to correlate performance with the BOLD signal directly (i.e., activations related to correct vs. error trials; Price & Friston, 2006) or to address which parts of the normal neural network are necessary for the task at hand (e.g., Steeves et al., 2004). For example, Steeves and colleagues (2004) examined object processing in a visual form agnosic patient who performed at above chance levels, but well below that of healthy individuals, when asked to recognise visual representations of objects. In their study they were able to examine more precisely which components of object recognition, including colour diagnostics, form outlines and greyscaled images, were most impaired in their patient thereby enabling a more detailed exploration of the variety of processes involved in object perception (Steeves et al., 2004). In instances such as these, however, there remains the possibility that abnormal neural activation patterns arise due to either a loss of function from the damaged region or as a consequence of the fact that the damaged region is disconnected from a broader network (see Price & Friston, 2006 for a detailed review of these and related issues in single case neuroimaging).

Task choice and design are ultimately dictated by the nature of the question being asked. In many instances (including the first two patients to be discussed below) the questions asked are primarily patient focused - that is, the studies represent an attempt to determine the degree of recovery or reorganisation of function in a given patient. In this instance tasks with well-described patterns of activation in the healthy population are essential. In other

Neuroimaging of Single Cases: Benefits and Pitfalls 53

Fig. 2. Selected results from the first case study discussed. Panel A shows anatomical images showing that the patient's skull had been deformed by his porencephalic cyst making it difficult to align the patient's images to a standardised space (indicated in the Panel B using the Talairach template from BrainVoyager software). Panel C shows two data points from this patient. To the left is activity during a silent word naming task in which a left frontal region was activated. Given the distortions evident in the patient's brain and skull it is impossible to know whether this region represents Broca's area. Similarly, the data to the right shows activity in a remaining portion of occipital cortex during silent word naming. This region would not normally be activated in this task (and the undamaged hemisphere showed no occipital activity) and the patient was hemianopic suggesting that the remaining occipital cortex was unlikely to support visual functioning. Nevertheless, caution should be employed when interpreting data of this sort in terms of functional reorganisation. Data

adapted from Danckert et al., 2004.

instances, the patient serves as a means to understanding normal cognitive processes by virtue of either the demonstrated behavioural deficits or alterations in neural functioning needed attain normal performance (Price & Friston, 2006). Here one can utilise behavioural performance in conjunction with imaging data (e.g., correlate BOLD with correct vs. incorrect trials) to examine changes in neural function.

In summary, single cases of unique neurological patients provides an opportunity to examine structure-function relationships, with a particular focus on which brain regions may be necessary for a given behaviour. Functional MRI provides another tool that can be used with single cases to examine a broad range of issues. In utilising fMRI with single cases it is important to consider the nature of the pathology for the particular patient, expectations regarding activation in the healthy brain (i.e., is there a demonstrated pattern of activity in healthy individuals related to the task at hand?) and the limitations of the paradigms to be employed (e.g., block designs focussing on well-documented structure-function relationships vs. event-related designs focussing on more complex behaviours). Some of these issues will be explored further below relative to particular examples of fMRI used with single cases.
