C 2005) Neuropsychology Review, Vol. 15, No. 4, December 2005 ( DOI: 10.1007/s11065-005-9178-5
Functional Neuroimaging Studies of Cognitive Recovery After Acquired Brain Damage in Adults 1,2,3 Marcos Rios-Lago,1,4,6 Nuria Paul,1 ˜ Juan M. Munoz-Cespedes, 3,5 and Fernando Maestu
The first two decades of cognitive neuroimaging research have provided a constant increase of the knowledge about the neural organization of cognitive processes. Many cognitive functions (e.g. working memory) can now be associated with particular neural structures, and ongoing research promises to clarify this picture further, providing a new mapping between cognitive and neural function. The main goal of this paper is to outline conceptual issues that are particularly important in the context of imaging changes in neural function through recovery process. This review focuses primarily on studies made in stroke and traumatic brain injury patients, but most of the issues raised here are also relevant to studies using other acquired brain damages. Finally, we summarize a set of methodological issues related to functional neuroimaging that are relevant for the study of neural plasticity and recovery after rehabilitation. KEY WORDS: neuropsychological rehabilitation; functional neuroimaging; outcome; neuronal plasticity.
Functional neuroimagmg has revolutionized the. neuropsychological study of brain–mind function and dysfunction. Researchers are now able to localize brain regions and circuits associated with human perceptual, cognitive, emotional, and behavioral functions noninvasively, in vivo. These techniques are most powerful when used in the context of developments in the allied fields of clinical neuropsychology, cognitive psychology, and basic neuroscience. The traditional view in neuroscience during the first three quarters of the last century was that the mature Central Nervous System (CNS) has little capacity to repair and reorganize itself in response to injury. Nevertheless, since the studies by Kennard (1942) and Twitchell (1951),
several authors have carried out experiments trying to clarify how the brain sustains a reorganization of function to compensate for damaged areas. More recently, it is known that the CNS does have some capacity to reorganize itself functionally after pathological conditions, including injury to the peripheral nervous system and brain injury. Reorganization is now recognized to be the principal process responsible for spontaneous recovery of function after acquired brain damage (Hallett, 2000). It is generally accepted that there are two different types of mechanism underlying the process of recovery from brain damage (Bond, 1986; Kolb, 1995; Richardson, 2000). First, there are a number of mechanisms of primary recovery that operate at a neuronal level from the instant that the injury occurs. The effects are manifest in the neurological outcome and especially in the recovery of motor function. Clinical findings suggest that in these terms recovery is complete or else reaches a plateau within 6 months of a closed head injury (Livingston and Livingston, 1985). However, recent physiological evidence indicates that the regenerative process may continue over a much longer period (Stein, 1998; Stein and Hoffman, 2003a,b). Second, the possibility of improvement beyond this 6-month period depends upon the patient’s adaptation to
1 Brain
Damage Unit, Hospital Beata Mar´ıa Ana (HHSCJ), Madrid, Spain. 2 Department of Basic Psychology II, Universidad Complutense, Madrid, Spain. 3 Deceased. 4 Department of Basic Psychology II, UNED, Madrid, Spain. 5 Centro de Magnetoencefalografia Dr. Perez Modrego, Universidad Complutense, Madrid, Spain. 6 To whom correspondence should be addressed at Unidad de Da˜ no Cerebral, Hospital Beata Mar´ıa Ana, C/Vaquerias, 7, 28007 Madrid, Spain; e-mail:
[email protected]
169 C 2005 Springer Science+Business Media, Inc. 1040-7308/05/1200-0169/0
˜ Munoz-Cespedes, Rios-Lago, Paul, and Maestu
170 residual deficits and the development of compensatory strategies (Bach-Y-Rita, 2000; Jennett and Bond, 1975). These in turn demand the patient’s awareness of the nature and extent of his or her disability, and hence they begin with the restitution of full consciousness at the end of the period of PTA. The literature suggests that the processes of spontaneous recovery of higher cognitive functions and the establishment of changes in personality and in social behavior also occur predominantly within the first 6 months following a closed head injury (Bond, 1979), but the key to rehabilitative endeavors is that such processes may persist for much longer. From the perspective of functional imaging techniques, we might define neuroplasticity as the reorganization of distributed patterns of normal task-associated brain activity that accompany action, perception, and cognition and that compensate impaired function resulting from disease or brain injury. There are few studies in the literature that correlate behavioral and imaging data in the field of recovery. Up to now these have had less spectacular impact on clinical diagnostics than anatomical imaging methods such as CT scanning and MRI. However, according to Mazziotta et al. (2000), these studies focus on: (a) the understanding of pathophysiological mechanisms (e.g., in cerebrovascular disease), (b) the detection of preclinical disease (e.g., in degenerative disease), (c) the assessment and control of therapy and plastic change (e.g., the monitoring of fetal mesencephalic graft survival in the brain of parkinsonian patients). A controversy remains about the effectiveness of rehabilitation. Even if it seems from many series that rehabilitation may be effective, there is ignorance about the best and most valid rehabilitation procedures and their neural substrates (Carney et al., 1999; Cicerone et al., 2000; Zabala Rabad´an et al., 2003). Most of our knowledge about recovery after acquired brain damage has been acquired by indirect observation. Only recently after the introduction of sophisticated imaging techniques direct studies of brain functions in humans have become possible. Nowadays, functional neuroimaging may bridge the gap between clinical practice and an understanding of recovery mechanism. These techniques may allow us to learn not just whether an intervention restores function but also gain insight to why and how this happens. This knowledge is expected to facilitate the further development of therapies, thus, they can be targeted even closer to the underlying mechanisms of disability, select patients for treatment (pharmacological, neuropsychological
rehabilitation. . .), and identify and monitor its cerebral effects. In the last years neuroscientists have shown increasing interest in the rehabilitation of physical (e.g., Calautti and Baron, 2003; Nudo, 1999) and cognitive deficits (e.g., Carlomagno et al., 1997; Laatsch et al., 2004; Pizzamiglio et al., 2001; Robertson and Murre, 1999; Wykes et al., 2002) in brain-damaged patients. Neuropsychology is also interested in how rehabilitation may be influenced by findings from functional neuroimaging. The characterization of various brain imaging activation patterns may have clinical value, as they can help to predict which patients can benefit from specific rehabilitative strategies. Therefore, the aim and scope of this article is to outline clinical findings, conceptual and methodological issues that are particularly important in the context of imaging changes in neural function during recovery process.
CEREBRAL REORGANIZATION OF FUNCTION AFTER BRAIN DAMAGE A CNS lesion results in two forms of damage: neuronal cell death and deafferentation resulting from the interruption of activity in neural networks. The latter process causes a much greater initial loss of function than the one accounted by the loss of neurons. However, the brain has substantial potential for physiological and even anatomical plasticity, which may underlie the recovery of patients following traumatic or ischemic injury (for an example see Fig. 1). According to Grady and Kapur (1999), recovery of functions could take several forms: (a) Reorganization or reweighting of functional interactions within an existing network of brain regions. (b) Recruitment of new areas into the network or use of an alternate network not normally used for task performance. (c) Plasticity in regions of cortex surrounding the damaged area. One possibility would be a reorganization or reweighting of functional interactions within an existing network of brain regions. An example of this might be increased utilization of the supplementary motor area or some other motor-related brain regions after damage to primary motor cortex (Kollias et al., 2001; Newton et al., 2002; Weiller et al., 1993). A second possibility would be the recruitment of new areas into the network or use of an alternate network not normally used for that task performance. This type
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Fig. 1. Several processes can restore the functioning of the network and lead to recovery: remaining connections within damaged cell assemblies can be strengthened, silent pathways can be unmasked, and axonal sprouting can bridge disruptions that result from the damage. In the future, it might also be possible to reduce the consequences of CNS damage through transplantation (reproduced with permission: Taub et al., 2002).
of alteration in brain function would imply that the same task is carried out in a different way compared to prior to the injury, perhaps through the use of new strategies. An example of this recruitment of new areas is episodic memory. Different results with PET suggest that older subjects do not use the encoding network as effectively as younger individuals. However, if they are able to engage other areas during both encoding and retrieval, their performance will not change. This reorganization may thus serve as a compensatory mechanism in the same way as it does in patients with recovery after stroke (Cabeza et al., 1997; Maestu et al., 2004a). Another form of functional plasticity is sensory substitution. Here, a cortical region previously devoted to receiving the sensory input of one modality is now capable of processing a new kind of sensory input. Rauschecker (1995) has shown that if the visual (occipital) cortex is deprived of its inputs from the optic nerves, the same cortex can be stimulated by auditory input. This form of sensory substitution has also been documented in subjects who were blind from birth and whose visual cortices (area VI) now serve as a relay station for tactile information used in Braille reading (Stiles, 2000). The visual cells were taken over by the auditory and somatosensory nerve fibers, thus both the auditory and somatosensory cortex expand into the territory previously controlled and occupied by visual inputs. These three possibilities could be indistinguishable in some cases for an external observer only seeing a pa-
tient performing different tasks. But the information about the pattern of activity found with functional neuroimaging is giving a clue of the underlying mechanism of recovery. This information could help guide the treatment into restitution, substitution, or compensation strategies in order to reduce the patient difficulties. Knowledge of such underlying neurophysiology might somehow prove useful to guide rehabilitation programs (Strangman et al., 2005). Until the recent development of highly sophisticated imaging and electrophysiological techniques it was not possible to determine whether, in fact, such equipotential, vicarious, or pluripotent systems did or did not exist. Broadly speaking, there are two fundamental strategies for examining plasticity after recovery of brain injury (Poldrack, 2000). In the longitudinal approach, individuals are examined multiple times over the course of rehabilitation. Data analysis techniques are then used to determine whether brain activity has changed in association with training on the tasks. This approach and imaging from neurological conditions are particularly useful when recovery occurs over a relatively short period of time (e.g., Leger et al., 2002). The other strategy is known as crosssectional approach. In this strategy the objective is to compare individuals with varying levels of a given skill and identify differences in neural function or structure related to their skill level. The cross-sectional approach is useful in examining plasticity following brain injury such as stroke or TBI, where a longitudinal study would require months or even years of follow-up (Cabeza et al., 2001).
172 Each of these approaches has different advantages and disadvantages. The advantage of the longitudinal strategy is that it provides optimal power to identify changes because of its within-subject nature, given that variability between subjects is much greater than the variability between imaging sessions for a given subject. However, longitudinal designs can suffer from experimental or practice effects, since subjects are examined on multiple occasions and they may acquire particular knowledge or skills related to participation in the study.
NEUROIMAGING TECHNIQUES AND NEUROPSYCHOLOGICAL PARADIGMS Functional neuroimaging allows the study of brain activity in normal and brain-damaged subjects, and compensate for the incompleteness of the lesion deficit model. Functional imaging offers several advantages over the lesion deficit model. The most obvious is that brain activity can be observed noninvasively in subjects who have normal physiological and psychological responses. The other major advantage is that, unlike the lesion deficit model, functional imaging is not limited to a particular region of the brain that has been damaged, allowing the identification of the system of distributed cortical areas that sustain sensory, motor, or cognitive tasks. Each technique has strengths and limitations, and can be best employed when these are understood. SPECT, PET, and fMRI depend on changes in rCBF (regional cerebral blood flow) to demarcate a functional area. They are indirect measures of neural activity, depending on wellbehaved blood flow responses to metabolic needs (Maestu et al., 2003). Generally, they have good spatial resolution and poor temporal resolution. One problem with PET is that the magnitude of the blood flow change in a region is confounded by the size of the responsive region. For example, an apparent enlargement of a region may just be an increase in metabolic activity. This is less of a problem with fMRI (Hallett, 2000). fMRI has several advantages over PET studies, not only about the lower invasiveness and resolution, but also about the experimental design possibilities. fMRI does not involve exposure to ionizing radiation as does PET, enabling extended or detailed longitudinal studies, so important in the rehabilitation context. In addition, the higher temporal resolution and the introduction of new paradigm designs (event-related and mixed designs) rises the possibility of separate transient, trial-related activity from sustained activity in fMRI experiments. EEG and MEG are also measures of neural activity, but they are direct measures in real time (Maestu
˜ Munoz-Cespedes, Rios-Lago, Paul, and Maestu et al., 2003). Other methods such as Transcranial Magnetic Stimulation (TMS) have been a valuable tool for studying plasticity. This method can map muscle or movement representations of the primary motor cortex (Ml) with a high degree of precision (Theoret et al., 2004). Various measures can evaluate different aspects of cortical excitability: including threshold, recruitment curve, intracortical inhibition, intracortical facilitation (Calvo Merino and Haggard, 2004). In the future, the combination of EEG/MEG with PET/fMRI and the use of some other combinations will be stronger than either type of method alone (Horowitz and Poeppel, 2002; Mu˜noz-C´espedes et al., 2004)[Fig. 2] The introduction of functional neuroimaging techniques has contributed to understanding of the neural correlates of recovery of motor, sensory, and cognitive functions after brain injury. But the most frequently used experimental designs do not permit directly relating changes in brain activity to functional recovery. Thereby, the importance of accurate behavioral measures is emphasized and new alternative experimental designs based on correlation between behavioral performance and brain activations are outlined (Pizzamiglio et al., 2001; Wilkinson and Halligan, 2004). The joint and complementary use of neuroimaging and neuropsychology offers a fundamental advantage over either technique in isolation. By the study of normal subjects and patients, one can define sufficiency and necessity of different structures involved in task performance (Price et al., 1999). Neuropsychological and lesion studies are required to identify the necessary regions, and functional imaging studies on normals and patients are required to identify the sufficient sets of regions for the correct performance of a task. A sufficient set of regions comprises all regions activated by normal subjects minus the notnecessary areas in each patient. Neuropsychology establishes the necessity of component brain areas in one of two ways. The first, most conventional, approach involves identifying the lesion site associated with a functional deficit. The second approach involves inferences from patients who are not functionally impaired on a specified neuropsychological test but nevertheless have damage to parts of the system defined by neuroimaging. In this latter case, some patients may be able to perform the task by activating perilesional tissue that appears to be damaged in routine structural imaging. Another possibility is that functionality is preserved due to neuronal reorganization, involving the homologue region in the contralateral hemisphere or cognitive reorganization. To discount these possibilities, functional imaging of the patient is prerequisite. But it is worth noting that only the application of both approaches (Neuroimaging and Neuropsychology)
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Fig. 2. Comparison among techniques. The temporal and spatial resolution of methods for studying brain functions. Abbreviations: MEG – Magnetoencephalography; ERP – Event-related potentials; fMRI – Functional magnetic resonance imaging; PET – Positron emission tomography (redrawn from Cohen and Bookheimer, 1994).
would give us the two parameters (Price and Friston, 2002; Wilkinson and Halligan, 2004). According to Price and Friston (2001) the interpretation of neuroimaging studies of psychologically impaired patients depends on intact task performance and a detailed task analysis. From this they conclude that abnormal activation shown by a patient requires the comprehension of two basic concepts: (a) Functional segregation/integration (b) Cognitive/neuronal reorganization Functional segregation/integration. Most neuroimaging studies assume that different tasks will be associated with a different set of cortical areas, and investigations aim to identify the areas where there are changes in regional activity in response to changes in task or to pathology. The concept of functional segregation refers to the specialization evident when different cognitive processes or tasks are associated with activity in different brain regions. Functional integration refers to the integration of activity in different brain regions where the interactions among areas may be profoundly task dependent. This distinction between studies of functional segregation and functional integration is crucial for imaging patients because some subjects suffer from abnormal
functional segregation (e.g., Broca’s area), and some patients suffer from abnormal functional integration (e.g., prefrontal cortex lesion). Cognitive/neuronal reorganization. Once performance is matched, two types of patients can be distinguished: those who perform the task using the same cognitive and neuronal architectures as normal and those who show an abnormal cognitive or neuronal reorganization. Cognitive reorganization occurs when a patient uses a different set of cognitive processes to perform the same task either because a new cognitive procedure has been learned or because of increased demands on normal cognitive processes, particularly attention. Neuronal reorganization (or plasticity) refers to the changes in a task-specific neuronal architecture that take place during learning or relearning in the normal or damaged brain. The more difficult issue is to distinguish whether the functional reorganization is cognitive or neuronal. In nature, although neuropsychological and behavioral assessment may reveal explicit signs that an abnormal cognitive strategy is being used. For example, some patients may retain the ability to read words but by naming the letters of the word before producing a response, a so-called letter by letter reading strategy. If we know a priori that the patient is using an abnormal set of cognitive processes to perform a task, the functional imaging can specify the
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Table 1. How Abnormal Brain Activation Can Inform about Models Normal/Abnormal Cognitive Processing? (From Price and Friston, 2001) Abnormal brain activation Models of normal cognitive processing
Models of abnormal cognitive processing
Underactivation • Redundant areas (not necessary for task performance) • Connections between damage and underactive area
Underactivation • Damage to local tissue • Damage to distant tissue (e.g., a diaschisis)
Overactivation • Duplicated neuronal system • Alternative cognitive strategies
• Cognitive reorganization Overactivation • Learning-related plasticity • Disinhibition of duplicated neuronal system • Cognitive reorganization
corresponding neuronal systems. Knowing which areas of the brain are important for alternative cognitive strategies may be useful to adopt these strategies and design cognitive rehabilitation programs (Price and Friston, 1999). In patients, abnormal activation falls into two categories: underactivity and overactivity. Areas of underactivity in the patients could indicate damage to the tissue itself, damage to the inputs into the underresponsive region (diaschisis), or changes in cognitive strategy (cognitive reorganization). In contrast, areas of overactivity in patients can reflect a disinhibition of a duplicate neuronal system that can implement the same task, learning-related plasticity, or cognitive reorganization (Price and Friston, 2001). Table 1 summarizes how abnormal activation in the context of normal performance might inform normal and abnormal models of cognitive processing. The relevance of neuropsychological paradigms development must be noted. Neuropsychological paradigms can be utilized in the scanning session to probe particular cognitive functions or neuroanatomical regions. For the former, a cognitive subtraction design is commonly used in which the subject is scanned in two conditions, an activation and a control condition. In a typical experiment, these conditions share the same mental operations except for the one of particular interest (Posner et al., 1988). The validity of using the so-called “resting state” as a control condition is not universally agreed upon (Binder et al., 1999; Gusnard and Raichle, 2001). The concern is that the variability in the mental state during such a condition is such that it may not serve a useful purpose. A continuous performance task is sometimes used to maintain a more controlled, constant mental state. This can be useful, but does not provide a true baseline state. In addition, at “rest” people will tend to think about topics in a manner that is relevant to the underlying mental state, e.g., patients with obsessive-compulsive disorder will tend to have obsessive thoughts and normal participants will tend to think
about topics in a nonpathological manner (Lowe et al., 1998). To solve partially this problem Price and Friston (1997) described another method called cognitive conjunction, in which there is more than one set of task pairs. For all pairs, the only common factor is the cognitive process of interest. The brain areas responsible for this cognitive process are therefore represented by activations that are common to the subtractions of all task pairs. One of the advantages of cognitive conjunction designs are that the baseline control condition does not need to be as strictly matched to the activation condition, allowing more flexibility. Also, it is not necessary to make the assumption that the cognitive process of interest has no effect on the other mental operations that are represented in the activation and control condition. A disadvantage is that, since there are more tasks, more scans must be performed to achieve the same statistical power.
APPLICABILITY OF FUNCTIONAL NEUROIMAGING FOR THE STUDY OF FUNCTIONAL RECOVERY With the application of functional neuroimaging techniques to brain-injured patients, we can measure in vivo the re-emergence of previously lost abilities, at least at a macroscopic level. In the field of brain damage rehabilitation, functional magnetic resonance imaging provides researchers with an alternative method to examine brain changes, evaluate patient outcomes, and validate treatment interventions (Grady and Kapur, 1999; Ricker et al., 2001a; R´ıos et al., 2004): • Provides insight into alternate ways a particular cognitive or motor task can be accomplished. Then, one could design a training program that
Functional Neuroimaging and Neuropsychological Rehabilitation makes use of strategies or processes “allocated” in intact areas. This could aid in the development of specific strategies for cognitive rehabilitation, • Imaging studies that determine which brain areas are necessary for recovery to occur could aid in identifying those patients most likely to benefit from rehabilitation, • Monitor the effectiveness of rehabilitation procedures as training progresses or after training is complete. The degree to which the new network or modified network is engaged during task performance could be determined as well as whether any unexpected changes have occurred. Correlation of specific brain patterns with recovered or nonrecovered behaviors would be a very powerful way of determining whether the goals of the rehabilitation effort have been achieved, and how the recovered function has been implemented via altered brain responses. Most studies have been devoted to motor and language systems, which have a well-understood brain topography, and probably because hemiparesis and aphasia are the deficits most commonly encountered after stroke. Less attention has been given to the recovery of spatial, memory, or executive processes. RECOVERY OF MOTOR FUNCTIONS Multiplexing in the brain consists of multiple uses of neurons and fibers so that they participate in various functions. A number of studies have demonstrated multiple sensory and motor representations of a single brain region and overlap of representation. This may provide the
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neural substrates for some plastic change with training: examples include the greatly increased cortical representation of a fingertip area in monkeys following training in haptic exploration (Jenkins et al., 1990), and the expanded finger motor cortex representation in piano players as well in the sensorimotor cortex in Braille readers, reported by Pascual-Leone and Torres (1993) and Cohen et al. (1997). Human fMRI studies (Anton et al., 1996) have strongly suggested that in the primary hand region around the central sulcus, the same neuronal population is active in the three tasks studied (active finger apposition, texture on fingers, and haptic exploration). Investigators have also shown that reorganization and expansion of functional cortical maps can be made to occur simply by providing intensive training experience in brain-injured patients. Changes in reorganization may be very longlasting and depend upon postinjury experience (see Fig. 3 for an example). Human studies of recovered motor functions in patients having suffered a stroke, suggest that a considerable plasticity of cortical function underpins recovered motor responses, with recovery being mediated by extension of specialized areas adjacent to the lesioned site (Chollet and Weiller, 1994). Nevertheless, few studies have suggested the exclusive role of the ipsilesional structures. A study with fMRI (Cramer et al., 2001) observed an increased activation of ipsilateral motor regions that was interpreted as a compensatory role of preexisting uncrossed motor neural pathways. In another single subject study by Rossini et al. (1998) with fMRI, MEG and TMS maps found an enlargement and a posterior shift of the sensoriomotor areas in the affected hemisphere after excellent motor recovery. Recovery may be related in this case with the volume of the surviving “ischemic
Fig. 3. Motor recovery after stroke (fMRI). Longitudinal fMRI studies showing the recovery after stroke during a right finger tapping task. As is shown, the contralateral cortex is progressively representing the right hand (R´ıos et al., in preparation).
176 penumbra” exhibiting initially reduced blood flow but preserved structural integrity. Most studies have examined the role of the healthy contralesional hemisphere or both hemispheres in recovery. One of the first studies comes from Di Piero et al. (1992). They have found no correlation between recovery and the mean relative increased metabolism in cerebral regions involved in motor functions, particularly in the ipsilateral primary motor cortex. Good recovery has been associated with increased metabolism of contralesional areas, but the best motor improvement was observed when metabolic activity increased bilaterally. Several human studies have attempted to force usage of the hemiparetic (paralyzed) limb following stroke and, in general, improvements in function have been obtained long after the hemiparesis has plateaued. One controlled study found improvements lasting up to 2 years in everyday usage of the hemiparetic upper limb after a 2-week period of inmobilization of the nonaffected upper limb (Taub et al., 1993), along with encouragement to use the affected limb. Liepert et al. (1998) showed that with constraint-induced movement therapy for persons with chronic upper extremity dysfunction following stroke, functional recovery was accompanied by an increase in both the size of the motor, output area, and the amplitudes of the motor-evoked potentials (MEPs), which they believed to be evidence of enhanced neuronal excitability in the damaged hemisphere for the target muscles studied. There was also evidence of recruitment of motor areas adjacent to the original location. The third group of studies has focused on factors (age, cerebral structures, time elapsed since brain injury) predicting the motor outcome. Age of onset of brain injury is a key factor with respect to activation, which plays a major role in recovery after childhood-onset damage (Eyre et al., 2001). Related to cerebral structures, Binkofski et al. (1996) studied a large population of stroke patients and found no correlation in the whole group between motor recovery, size of the lesion, or the remote depression of glucose metabolism. The subgroup of patients showing poor recovery presented in a PET study a strong depression of glucose metabolism in the ipsilateral thalamus. These subjects also presented more severe damage of the pyramidal tract, according to the structural MRI, and a greater reduction in the amplitude of the magnetic-evoked motor potentials. The role of the thalamus had been already emphasized by Fries et al. (1993) in a structural neuroimaging study, particularly when capsular lesions were associated with thalamic lesions. In addition, motor constraint-induced therapy and training-induced brain plasticity are possible not only in subacute but also in chronic brain damaged patients, e.g., the time elapsed
˜ Munoz-Cespedes, Rios-Lago, Paul, and Maestu since stroke onset does not appear to be a limiting factor for this effect (Carey et al., 2002). Finally, several researchers have used functional neuroimaging to determine the influence of different drugs in motor rehabilitation. Pariente et al. (2001) conducted a prospective, double blind, placebo-controlled study on eight patients with pure motor hemiparesia. Each patient underwent two fMRI examinations: one under fluoxetine and one under placebo. Motor performance was evaluated immediately before the examinations to investigate the effect of fluoxetine on motor function. Under fluoxetine, during the active motor tasks, hyperactivation in the ipsilesional primary motor cortex was found. This redistribution of activation toward the motor cortex output was associated with an enhancement of motor performance. Nevertheless, further studies are required to analyze the effect of chronic administration of fluoxetine on motor function. Other investigations have focused on cortical responsiveness to levodopa in hemiparkinsonian patients. Buhmann et al. (2003) used fMRI and a simple finger opposition task to correlate blood oxygenation level-dependent (BOLD) signal changes with motor performance in eight drug-naive patients with an akinetic idiophatic hemiparkinsonian syndrome and 10 healthy controls. Patients performed the task every 3 s before and repeatedly every 20 min after intake of 300 mg of fast-release L-dopa. Contralateral primary motor cortex to the affected hand and supplementary motor area, predominantly of the contralateral side, showed a BOLD signal increase after L-dopa intake. These data are in accordance with the hypothesis that motor cortex hypoactivation in contralateral primary motor cortex and bilateral supplementary area is caused by a decreased input from the subcortical motor loop, which is reversible by L-dopa.
RECOVERY FROM APHASIA The neural mechanisms underlying recovery of aphasic patients are incompletely understood. Studies of reorganization of language in the process of recovery froma aphasia in adults have used SPECT, PET, fMRI, and MEG (Cappa et al., 1997; Levin, 2003; Papanicolaou et al., 1988; Thompson, 2000; Thulborn et al., 1999). However, the neural mechanisms underlying recovery of aphasic patients are incompletely understood. Since the work of Wernicke in the nineteenth century, a debate has been ongoing regarding whether recovery is mediated by remaining left hemisphere language regions or by contralateral homologous regions. Some researchers have provided evidence for recruitment of homotopic areas of the right hemisphere in
Functional Neuroimaging and Neuropsychological Rehabilitation recovery of language in at least a subgroup of adult aphasics (Maestu et al., 2004b). Consistent with this evidence, Weiller et al. (1995) in a PET study found that repetition of pseudowords and verb generation tasks produced activation of the right middle and superior temporal gyri and the right inferior frontal area, areas that were homotopic to the regions activated in neurologically intact adults performing these tasks. Buckner et al. (1996) also found right inferior frontal activation on a word stem completion task in a patient who had sustained an inferior left frontal stroke. Converging evidence for recruitment of right hemisphere structures in recovery from fluent aphasia is also provided by two recent studies. In one, Rosen et al. (1998), a group of patients (n = 3) and age-matched control subjects (n = 6) were examined. The patients had all suffered strokes that included the left frontal operculum and, on initial presentation, exhibited nonfluent aphasia. These patients were scanned (fMRI) in their chronic phase 6 months to 1 year after the onset of aphasia. The three patients showed significant activation in the right frontal operculum in a region nearly homologus to the region activated by the control subjects of the left side. Both the patients and the control subjects performed the word-stem completion task at moderate to good levels (67% correct for patients, 84% correct for controls). In another study, Musso et al. (1999) performed PET scans with activation by a language comprehension task (an adaptation of the Token Test) in four adults with fluent aphasia associated with left hemisphere lesions. The patients underwent intensive auditory language comprehension training sessions scheduled during the intervals between PET scans. These authors found that improved language comprehension was correlated with increased right regional blood flow. Apart from various sites in the individuals, the group analysis revealed two areas that fitted best the response curve of language improvement: posterior part of the right superior temporal gyrus and the left precuneus. Although the findings reported by Musso et al. support the role of right hemisphere participation in training-induced recovery from aphasia, it is questionable whether there is interhemispheric evidence of laterality shift of word retrieval to the right temporal region (Warburton et al., 1999). In contrast, some activation studies have shown that spared perilesional regions of the left hemisphere were the main substrate of recovery mechanisms. In the aforementioned research by Warburton et al. (1999) six patients with large left temporoparietal lesions who had lost, and then recovered, the ability to generate words were scanned during a word generation task and during rest. Data from each patient were analyzed independently and compared to a group of nine control subjects. In normal subjects, the word generation task consistently activated a widely dis-
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tributed system of language regions in the left hemisphere (in particular, the left prefrontal and posterior temporal cortices). All six recovered aphasics also had activation in the left prefrontal region, all but one activated the damaged left temporal lobe. The conclusions of this study were that activations associated with cued word retrieval in the recovered aphasics were indistinguishable from those of the normal controls, except in the presence of a lesion the activations were perilesional. Similar results had been obtained in a single case study (Heiss et al., 1997) showing that the recovery from aphasia was related to the reactivation of left hemispheric speech areas surrounding the area of infarction . More recently a fMRI experiment was performed before and after a specific and intensive speech therapy in a patient with long-lasting speech output deficit following a left-sided ischemic lesion (Leger et al., 2002). Overt picture naming and picture/word rhyming were used as activation tasks in the patient and six control subjects. The speech therapy program improved naming performance inducing a pattern of activation close to that observed in control subjects, involving left-sided language areas surrounding the lesion. In another study using fMRI there were analyzed two consecutives cases with left middle cerebral artery infarction and transcortical sensory aphasia (Zahn et al., 2002). Their recovery of language comprehension was associated with functional takeover occurring in areas with related functions as prefrontal regions, left Wemicke area, or the left posterior middle and inferior temporal cortex (“redundancy recovery”) rather than in previously unrelated areas (“vicarious functioning”). The research on this topic is more complex because the nature of the different hemispheric activation could be task-specific. For instance, left-sided activations were reported by Belin et al. (1996) and Small et al. (1998) in patients who benefited from melodic Intonation Therapy or a phonological training of reading aloud, respectively. On the other hand, as we have commented, Musso et al. (1999) showed a correlation between increased activity in the right temporal cortex and comprehension scores, in Wernicke-type patients undergoing an intensive training of comprehension between scanning sessions. Similarly, a therapy program devoted to sentence processing was associated with changes in the right hemisphere during a sentence–picture matching task, in a patient described by Thompson (2000). After treatment Calvert et al. (2000) have also remarked that the patients, in contrast to controls, activated during performance of a verbal semantic decision task a network of brain areas that excluded the inferior frontal gyrus (in either hemisphere). During a second task involving rhyme judgement, the most prominent activation in the patients occurred in the right homologue
178 of Broca’s area. The recent study of Perani et al. (2003) suggest that the pattern of brain activation was highly influenced by task requirements showing intra and interhemispheric differences between word retrieval to letter cues and semantic fluency tasks after recovery. In summary, these results suggest that remediation may elicit activation in the right hemisphere whereas the left hemisphere would be recruited when speech output is required.
MEMORY IMPAIRMENT AND FUNCTIONAL NEUROIMAGING The neural correlates of memory Impairment in acquired brain-damaged patients can be studied with functional neuroimaging techniques. These findings have in turn been related to neuropsychological test performance (Fontaine et al., 1999; Ichise et al., 1994). Most functional neuroimaging research in TBI has been applied to assess changes in neural circuitry in response to specific tasks with well-described functional neuroanatomical characteristics. For example, McAllister et al. (1999) used fMRI to compare patterns of brain activation during performance of an auditory n-back working memory task in neurologically intact adults and adults who had sustained a mild TBI uncomplicated by structural lesions 1 month earlier. Both groups exhibited increased activation as a function of memory load. The group difference in brain activation was especially marked in the right dorsolateral frontal and right lateral parietal regions, which are thought to be engaged in the manipulation and storage of information, respectively. These authors replicated and extended these findings by increasing the task difficulty (McAllister et al., 2001). Although mild TBI patients disproportionately increased their activation under a moderate processing load, they showed less incremental activation than the control group when asked to respond in more difficult tasks. These results suggest that mild TBI may result in difficulty in modulating processing resources in response to gradations of processing load and might be ameliorated with specific neuropsychological interventions. Using also a modified paced auditory serial addition task in a group of moderate and severe TBI patients, Christodoulou et al. (2001) found that the pattern of activation was regionally more dispersed around the middle frontal and middle temporal gyri in the TBI patients and more lateralized to the right hemisphere as compared with the control subjects. To study the effects of moderate to severe TBI on the functional neuroanatomy supporting memory retrieval and recovery Ricker et al. (2001b), using PET with a sample of five severe TBI noted to have reduced frontal activation relative to four healthy adults during free recall,
˜ Munoz-Cespedes, Rios-Lago, Paul, and Maestu but increased frontal activation during recognition. Recently, Levine et al. (2002) analyzed the effects of six TBI patients who had made a good recovery related to controls on brain activation in response to memory retrieval demands during a PET scan. The TBI patients performed memory tasks using altered functional neuroanatomical networks. These changes have been associated with diffuse axonal injury and may reflect compensation for mnemonic inefficiency, increased effort, and increased internal monitoring. Further research is necessary to determine the adaptiveness of these changes. As in the case of brain dysfunction due to accident or stroke, normal aging is accompanied by a variety of cognitive deficits in memory. Although cognitive aging and neural aging have been thoroughly studied in isolation, the relations between the two phenomena are still largely unexplored. One way of relating neural and cognitive aspects of aging is to correlate measures of brain activity to measures of cognitive ability, such as memory performance. Recently, functional neuroimaging techniques, such as PET (Anderson et al., 2000), fMRI (Daselaar et al., 2003), and MEG (Maestu et al., 2001, 2004a), have provided a more direct link between cerebral and cognitive aging. These studies can now reveal which brain regions are activated during a certain cognitive task, how this activity is affected by aging, and if is possible to ameliorate the memory performance by cognitive or pharmacological stimulation.
METHODOLOGICAL CONSIDERATIONS In this section we will critically examine the main methodological limits of the experimental designs most frequently used in neuroimaging studies, and will emphasize the requirements that must be realized if changes in brain activity are to be related to functional recovery (for a review of the difficulties, solutions, and guidelines for conducting a fMRI research in TBI patients see also Hillary et al., 2002). An understanding of methodological and conceptual issues is a necessary prerequisite for the development of new imaging methods with improved capabilities, for the careful application of existing methods to neuropsychological problems, and for the interpretation of published studies. Many cognitive functions can now be associated with particular neural structures, and ongoing research promises to clarify this picture further, providing a fine-grained mapping between cognitive function and neural function (Poldrack, 2000). Although the resultant images are alluring, it is important to understand that they cannot be simple phrenological pictures (Brett et al., 2002; Maestu et al., 2003; Silbersweig and
Functional Neuroimaging and Neuropsychological Rehabilitation Stern, 1997; Uttal, 2001). They are a visualization of more important mathematical and statistical analyses performed on large numbers of images, sampling contrasting brain/mental states, with appropriate control conditions and subjects. Now, there are studies not trying to “simply” localize a function, but trying to explain a cognitive component or a network functioning (e.g., Donaldson, 2004; Gauthier et al., 1999; Kanwisher et al., 1997; Perianez et al., 2004). This new approach centred on the context of brain networks (and not on a localizationist approach) allows researchers to examine the interactions among brain areas, and how these interactions change as behavior changes. Application of functional imaging to brain injury patients presents some difficulties. The most severe challenge is motion. Brain motion on the order of mm disrupts the ability to interpret fMRJ data—even motion associated with the respiratory and cardiac cycles can affect functional imaging of the brain. In particular, it is difficult to image overt speech production during fMRI studies because of the head motion and the changes in air volume associated with overt speech (Birn et al., 1999). Actually, researchers are working to develop new paradigms that allow for performance measurement of verbal fluency and confrontation naming and overcome the potential artifacts resulting from overt speech during image acquisition, providing useful neuropsychological tools to investigate cognitive deficits in clinical populations (Abrahams et al., 2003). Global cognitive impairment, aphasia, neglect, substantial sensory disturbances, and severe depression often constitute exclusion criteria. Claustrophobia is an additional exclusion criterion, especially for fMRI. There are also other methodological difficulties such as metal implants or metal shaving, typically related to this kind of patients due to surgery interventions, and specially important for both fMRI and MEG. One consequence of all these constraints is that primarily very small patient samples have been studied, which furthermore may not represent the entire spectrum of deficit and recovery, and therefore replicability of results and generalization of findings are important issues. As Hillary et al. (2002) emphasized, it is important to remark that there have been no systematic examination of the effects of collecting of loose blood, such as subarachnoid haemorrhage or subdural haematoma, or increased intracranial pressures among factors that may alter hemodynamic response measured by fMRI. The interpretation of BOLD contrast is limited to regions of normal diffusion and perfusion and adequate reserved perfusion capacity. No method currently exists for the interpretation of BOLD contrast in areas of abnormal perfusion in the clinical setting (Strangman et al., 2005). This is an important question still waiting for a definite answer.
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Another difficulty relies on the effects of brain lesions after TBI on the preprocessing of fMRI data. There are studies that have investigated this aspect on patients with focal brain lesions providing an effective method to preprocess a damaged brain (Brett et al., 2001; Ward et al., 2003). Nevertheless, in addition to the typical damage produced within the frontal poles and the anterior areas of the temporal lobes, it is highly relevant to the diffuse axonal injury in TBI patients. These patients suffer not only from localized damage in a restricted area, but also of white matter injury in the cerebral hemispheres, corpus callosum, and frequently in the brainstem. The result is a highly distributed area difficult to delineate, and even not visible using conventional neuroimaging techniques (Bigler, 2001; Povlishock, 1993). Thus, the relationship between the location of the injury and the nature of the pathophysiology, such as diffuse axonal injury, and observable changes in the brain activation remain unknown (Hillary et al., 2002). From the standpoint of analysis approaches, there are a number of possible confounds related to the interpretation of neuroimaging data in the recovery process. Functional imaging studies have usually been able to make inferences by pooling data from different patients into one group and then comparing the patient group to a group of normal subjects (e.g., Weiller et al., 1995). Since perilesional activity inevitably varies from patient to patient depending on the size and location of the lesion, it will not be detected in group-to-group comparisons. The demonstration of perilesional activity therefore relies on studies where each subject is analyzed individually, given that variability between subjects may be much greater than the variability between groups or imaging sessions for a given subject. Another example comes from the studies of motor, language, and cognitive recovery, which report only one neuroimaging session after a short or long interval from the stroke or TBI. The conclusions drawn in these studies are only tentative, since they are based on the speculation that all the clinical improvement in a particular function is related to the activation found at a given moment. A more appropriate design would require measuring the physiological indices of brain activity during the activation and the baseline tasks, both before and after functional recovery. This is a factorial design, in which the task (activation vs. baseline) × time (before vs. after recovery) interaction is the factor of interest (Pizzamiglio et al., 2001). It must be emphasized that not all of the reorganization is necessarily adaptive or beneficial to the organism— e.g., phantom limb phenomena in response to amputation (Ramachandran et al., 1995). The recovery-related activation of regions not normally engaged in a given task may reflect a maladaptive process and be responsible for the
180 persistence of residual deficits and not for the degree of recovery achieved. One way to control for this variable would be to contrast the activation related to folly recovered behavior with that related to forms of behavior that are still dysfunctional. In addition, the reorganization and recovery of function do not cease at any arbitrary time, such as 6 months: the potential could exist for many years after injury (Bach-Y-Rita, 2003), and late changes—over a period of 33 months—in functional representation have been noted by Wassermann et al. (1996). This is becoming an important area in the field of neurorehabilitation, since it appears that, in humans, specific late neuropsychological rehabilitation programs are necessary to exploit that potential. Finally, recovery of function may imply the reconnection or the recoordination of a network of areas, each of which may be specialized in one or more aspects of the lost function, but which requires the coherent and timely support from others to reach a high level of proficiency. It must be also noted that the functional recovery noted in some cases of recovery from brain damage with neuropsychological rehabilitation programs may be related not only to neuroplasticity factors, but also to psychosocial factors (e.g., social support, motivation, supportive and optimistic rehabilitation therapist. . .), environmental considerations, and the functionality of the rehabilitation program.
CONCLUDING REMARKS The literature reviewed shows evidence to support the view that behavioral and environmental manipulations can modify function of the brain following acquired brain damage in adults, and that these changes can be quantified with imaging. More specifically, as Taub et al. (2002) remarked, we would like to know whether the relationship between spontaneous recovery and cortical plasticity could be manipulated to improve the potential for recovering function, so that it would be advantageous to a patient with neurological injury. However, the application of the new neuroimaging techniques (both structural and functional) to recovery processes remains in its infancy and is still wide open for investigation. These techniques hold the promise of greater integration of what is known about behavioral and brain changes such as plasticity after brain damage (Hillary et al., 2002). The combination of different methods (EEG/MEG with PET/fMRI) to reveal plastic changes is becoming more widespread. New techniques such as diffusion tensor imaging are being added to the range of neuroimaging methods, providing the opportunity of getting noninvasive maps of microscopic structural information like the course and integrity of white matter projections (Klinberg et al., 2000; Moseley et al., 2002).
˜ Munoz-Cespedes, Rios-Lago, Paul, and Maestu The combination of both functional neuroimaging for cortical activation and diffusion tensor imaging for structural connectivity offers a promising vehicle to further extend our current understanding of cortical reorganization. Such combinations will be useful for cross validating methods, for achieving complementary information on mechanisms of reorganization, and constitutes the basis for more systematic and valid therapeutic interventions. This work has been done most extensively for motor and language systems, which have a well-understood brain topography. Then, there are some studies that have focused their interest on aspects of memory function (working memory), attentional performance (neglect), and sensory systems. Nevertheless, technical and methodological difficulties have complicated the study of basic components in neuropsychological rehabilitation programs using these neuroimaging methods. Processes such as selective attention, memory, and executive functions are main aspects for the outcome of brain-damaged patients. All these systems are cornerstones for a good vocational, social, and personal readaptation after brain injury. In the future, we should focus on these processes given that neuroimaging could be useful both in designing rehabilitation programs and in monitoring the effectiveness of such programs, assessing outcomes and the success of rehabilitation treatments. Moreover, these methods could help to point out the ties between cognitive models of therapeutic practice, the nature of functional recovery, and its neurobiological substrate, at a macroscopic level and even at a purely physiological level. Few neuropsychologists are formally trained in technological development. What has emerged thus far is a collection of individual efforts that remain to be integrated into more comprehensive tools for the rehabilitation professions. The new technologies presented here are meant to illustrate past difficulties in the emergence of this subspeciality and point to new applications and technological integration that may prove fruitful. The convergence of neuroengineering, functional neuroimaging, basic neuroscience, and cognitive and adaptive assessment presage future developments in neuropsychological rehabilitation. ACKNOWLEDGMENT Work was partially supported by Obra Social de Caja de Madrid. REFERENCES Abrahams, S., Goldstein, L. H., Simmons, A., Brammer, M. J., Williams, S. C., Giampietro, V., et al. (2003). Functional magnetic resonance imaging of verbal fluency and confrontation naming using
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