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Neural Plasticity After Acquired Brain Injury: Evidence from Functional Neuroimaging
Future Issues and Controversies
Neural Plasticity After Acquired Brain Injury: Evidence from Functional Neuroimaging Haiwen Chen, BA, Jane Epstein, MD, Emily Stern, MD Abstract: The reorganization of the adult central nervous system after damage is a relatively new area of investigation. Neuroimaging methods, such as functional magnetic resonance imaging, diffusion tensor imaging, and positron emission tomography, have the ability to identify, in vivo, some of the processes involved in these neuroplastic changes and can help with diagnosis, prognosis, and potentially treatment approaches. In this article, traumatic brain injury and stroke are used as examples in which neural plasticity plays an important role in recovery. Basic concepts related to brain remodeling, including spontaneous reorganization and training-induced recovery, as well as characteristics of reorganization in successful recovery, are reviewed. The microscopic and molecular mechanisms that underlie neural plasticity and neurogenesis are briefly described. Finally, exciting future directions for the evaluation, diagnosis, and treatment of severe brain injury are explored, with an emphasis on how neuroimaging can help to inform these new approaches. PM R 2010;2:S306-S312
INTRODUCTION Until relatively recently, neuroscience viewed the mature central nervous system as having little capacity to repair or reorganize. Now, evidence clearly suggests that the human brain is plastic, maintaining the ability to change in neural structure, connectivity, and function throughout life. In development, natural plasticity occurs with (1) the proliferation of dendrites and axons during cytogenesis and histogenesis, (2) the formation of synapses and cellular differentiation during migration, and (3) apoptotic phenomena [1]. In adulthood, structural magnetic resonance imaging (MRI) has shown activity-dependent responses in brain structure; for instance, in London taxi drivers, increased hippocampal volume, thought to be related to spatial navigation, correlated with the amount of time that the drivers spent in navigating the streets of London [2]. Draganski et al [3] found that individuals who learned to juggle for a limited period of time showed transient and selective structural expansion in gray matter in the mid-temporal area and left posterior intraparietal sulcus, areas associated with processing and storage of complex visual motion. Changes in brain structure also have been correlated with changes in physiological states. In women, hippocampal volume has been shown to vary across the normal menstrual cycle, with volume alterations correlating with changes in cognitive function (Figure 1) [4]. Likewise, functional magnetic resonance imaging (fMRI) studies suggest that subjects learning sequential finger movements demonstrate changes in the motor cortex, cerebellum, and basal ganglia [5]. Even after brain injury, such as stroke or traumatic brain injury (TBI), neural plasticity is possible because of the existence of significant diffuse and redundant connectivity within the central nervous system, as well as the ability of new circuits to form through remapping [6]. Given the morbidity and mortality of these conditions, it is imperative to understand possible mechanisms of plasticity after stroke and TBI to foster new approaches to promote recovery. In recent decades, the development of functional imaging techniques such as positron emission tomography (PET) and fMRI have provided more information regarding this ability to remodel by identifying neural systems or components that continue to function after an insult (in addition to those that are impaired), as well as specific sites and patterns PM&R
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H.C. Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Chestnut Hill, MA; and University of Maryland School of Medicine, Baltimore, MD Disclosure: nothing to disclose J.E. Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Chestnut Hill, MA Disclosure: nothing to disclose E.S. Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, 824 Boylston Street, Harvard Medical School, Chestnut Hill, MA 02467. Address correspondence to E.S.; e-mail: [email protected] Disclosure: nothing to disclose Submitted for publication October 5, 2010; accepted October 7, 2010.
© 2010 by the American Academy of Physical Medicine and Rehabilitation Suppl. 2, S306-S312, December 2010 DOI: 10.1016/j.pmrj.2010.10.006
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Figure 1. Sagittal, coronal, and axial images demonstrating statistically significant increased right anterior hippocampal (yellow/orange) and decreased right dorsal basal ganglia (purple/blue) gray matter in the postmenstrual compared to the premenstrual phase (n ⫽ 21; P ⬍ .005). Verbal declarative memory was also increased in the post- versus premenstrual phase [4].
associated with recovery [7]. Functional neuroimaging also complements behavioral assessments by pointing to underlying mechanisms and molecular and cellular techniques and allowing in vivo observation of networks not obvious at a microscopic level. Here we review neuroimaging with adjunct clinical, behavioral, and molecular and cellular research on neuroplastic change after brain injury, specifically stroke and TBI, to understand plasticity related to different forms of recovery and its underlying mechanisms. Because lateralized focal traumatic brain lesions parallel focal vascular lesions in most respects [8], we will consider research performed in both areas together.
NEUROIMAGING METHODS Functional neuroimaging techniques provide powerful tools for the in vivo examination of brain function. In addition to localizing the neural circuitry responsible for normal perception, cognition, emotion, and behavior, these methods allow one to probe dysfunction that occurs in the setting of disease and injury [9]. Symptoms can be imaged directly as they occur, either spontaneously or via experimental paradigms involving symptom provocation. Alternatively, neuropsychological functions that are hypothesized to be affected in specific disorders can be probed with the use of “activation” tasks, in which the subject is asked to perform specific mental activities. fMRI has become a widely used method for map-
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ping brain function. Its strengths, compared with techniques such as PET, include improved spatial and temporal resolution, absence of ionizing radiation, and wide availability. Limitations of fMRI include the confining scanner environment, acoustic noise (resulting from the rapid alteration of currents in the gradient coils), and signal artifacts in orbitofrontal and mesotemporal brain regions, particularly at greater field strength. The most commonly used fMRI method is blood oxygen level– dependent imaging [10,11], in which changes in the amount of deoxyhemoglobin that occur in association with increases or decreases in neuronal activity are detected. Other techniques, such as arterial spin labeling, utilize a more direct measure of blood flow changes associated with neuronal activity [12]. PET methods can be used to assess either blood flow or metabolic changes that occur with neuronal activation. In addition, by radiolabeling organic molecules, PET can be used to provide information related to many pre- and postsynaptic neurochemical and neurophysiological processes [9]. Compared with PET, magnetic resonance spectroscopy is a less sensitive but noninvasive method that can be used to examine compounds involved in brain chemistry and metabolism [13]. Compounds that are of neuroscientific interest that can be measured include lactate, N-acetyl aspartate (a neuronal cell marker), creatine, choline, glutamate, and ␥-aminobutyric acid. Of importance, functional imaging techniques also can be combined with clinical and/or physiological data to provide more comprehensive, integrated information about brain– body function (Figure 2) [14]. Advances in evaluating detailed brain structure are also critical to the study of the postinjury brain. Diffusion tensor imaging (DTI) allows one to visualize and measure the diffusion of water in brain tissue [15]. This is particularly applicable to the study of white matter tracts, thereby providing important information on structural connectivity. This technique has been used to study normal connectivity over the lifespan, as well as abnormalities that occur in a wide variety of disorders [16]. It is of particular relevance to TBI and stroke, as compromise of white matter integrity caused by shearing injury and/or ischemia is present, and DTI may be used for early evaluation, diagnosis, and as a predictor of outcome.
FORMS OF RECOVERY Recovery after brain injury can generally be categorized into 2 main stages: (1) spontaneous reorganization and (2) training-induced recovery. Spontaneous reorganization occurs during a period proximal to injury and likely reflects the recovery of neurotransmission in spared tissue near and remote from the site of injury [7,17,18]. Spontaneous recovery after stroke typically plateaus approximately 3 months after insult [7,19], whereas spontaneous recovery after TBI is
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Figure 2. Axial brain images showing differences in blood oxygen level– dependent signal when viewing fearful pictures (related to the World Trade Center disaster) compared with scrambled control images, correlated with cortisol change prescan to postscan. Cortisol change is positively correlated with activity in the right amygdala (A), and the anterior and posterior regions of the left and right hippocampi (C and D); negative correlations are present in the ventromedial prefrontal cortex (B). These regions are important in modulating fear-related responses, and this study demonstrates how they are associated with stress-induced reactivity of the hypothalamic–pituitary–adrenal axis [14].
found to plateau about 6 months after injury [20]. Traininginduced recovery is not limited by time and has been observed long after injury; however, it is dependent on individual experience and adaptation and/or specific rehabilitation, likely by means of processes involved in ordinary learning.
Spontaneous Reorganization Initial acute recovery results primarily from resolution of reversible factors. In stroke, reperfusion of the ischemic penumbra corresponds with early rapid recovery [7,21]. In both stroke and TBI, resolution of reversible factors, such as regression of edema, clearing of inflammatory infiltration, or mass effect, can also induce recovery [22,23]. In addition, because a lesion may impair processes remote from the site of injury and cause dysfunction in additional nodes within a functional network, subacute and chronic recovery involve the renewal and stabilization of functional brain networks. Studies in a variety of areas such as motor, language, cognitive, sensory, and resting-network function reflect this process. The literature suggests that, after stroke, a temporal series of activation shifts take place that involve an early recruitment of contralesional homologous brain regions, activation of learning structures, and finally a settling toward an ipsilesional or distributed recruitment pattern [24], where greater shift to a more “normal” pattern corresponds to better recovery [25-27]. In a longitudinal fMRI study of locomotor recovery after stroke, Kim et al [28] found that paretic leg movement was associated with contralateral (ipsilesional) and ipsilateral (contralesional) activity in the primary sensorimotor cortex and supplementary motor area (SMA) during the subacute stage but shifted in laterality in the chronic stage with increased contralateral and reduced ipsilateral activity. Similarly, functional imaging of stroke-induced aphasia suggests increased activation in the bilateral language network, particularly in the right Broca-homologue, during the subacute stage, followed by reshift of main activation to left-hemisphere language areas, which were correlated with
improved language function [29]. Similar patterns have been found for recovery from hemispatial neglect as well in frontoparietal attention networks [30]. Somatosensory recovery has been relatively understudied, perhaps complicated by high individual variability [31], although Carey and Seitz [7] propose an interhemispheric, multimodal model. Nakamura et al [20] examined resting networks 3 and 6 months after severe TBI and found a decreased number of highly significant connections, reduced overall strength in connectivity, and increased “small-worldness” (a measurement in mathematical graph theory in which most nodes are not neighbors of one another, but can be reached from every other node by a small number of steps). This finding suggests a shift from greater neural dynamics and flexibility during early stages of recovery to increasing efficiency and decreasing malleability during later stages of recovery to reduce the cost of and formalize the network. Activation studies on cognitive function after TBI complement these findings in showing more widespread cerebral activation patterns during the period shortly after injury [32].
Training-Induced Recovery Experience and specific rehabilitation can interact with spontaneous factors. During the spontaneous recovery period, activation of learning networks facilitates plastic changes. For instance, motor control and task learning networks, including the primary motor cortex, parietal lobes, SMA, and cerebellum, which are usually active only during development, re-emerge in recovering patients to facilitate relearning [24]. Training can also induce plastic changes in the brain to promote longer-term improvement. Training-facilitated neural changes, on the whole, appear to parallel those observed during spontaneous recovery but are not limited by time after stroke [7]. Functional imaging studies on the effects of constraint-induced movement therapy show treatment-associated activation increases in the ipsilesional primary motor cortex, dorsal premotor cortex, and SMA during affected hand
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movement months to years after stroke [33]. A comparable study on subjects with TBI produced similar results [34]. Extension of the constraint-induced movement therapy approach to aphasia in constraint-induced aphasia therapy has been linked to language improvement and shifting of right-hemisphere activation to left-hemisphere activation in patients more than 12 months after stroke [35,36]. In addition, repetitive training of stereotyped movement [37] and robot-based motor therapy [38] have been show to improve motor functionality and to facilitate motor cortical activity and reorganization.
REORGANIZATION IN SUCCESSFUL RECOVERY Successful functional recovery is generally accompanied by novel patterns of activation. Overall, this may take the form of the following: (1) plasticity in regions surrounding the damaged area, (2) reorganization or reweighting of interactions within an existing network, or (3) recruitment of new areas or use of alternative networks [39]. For example, studies in which the authors examined recovery from injury-induced aphasia and agnosia have found associations with all 3 forms. More specifically, Leger et al [40] related recovery from aphasia after a left-sided ischemic lesion to activation of language areas surrounding the lesion. Another study, by Zahn et al [41], associated recovery from aphasia after left middle cerebral artery infarction with takeover of related functional areas, including the left extrasylvian temporal and right posterior parietal cortices. Yet others, as previously mentioned, have associated recovery of aphasia with recruitment of homologous contralesional areas. Recovery from auditory agnosia in a patient with bilateral perisylvian strokes, who partially regained the ability to recognize environmental sounds, showed activation of a bilateral network (with recruitment of regions homologous to those responsible for normal function), involvement of peri-infarct areas, and the engagement of a more widespread neocortical network [42]. Similar findings can be seen in motor recovery as well. A number of studies have shown the activation of ipsilateral, perilesional areas related to sensorimotor activity [43]. In addition, studies have also shown regional reorganizations such as posterior shifts in primary sensorimotor cortex [44]. Interestingly, poststroke recovery from impaired sensorimotor integration was shown to be associated with cross-modal recruitment of visual networks [45]. Structural changes have also been associated with recovery from severe injury. In a case of a patient with late recovery from the minimally conscious state [46], the use of DTI showed changes in anisotropy in the posterior white matter and the midline cerebellar white matter that correlated with clinical improvements in motor function. The cerebellar
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finding also correlated with an increase in resting metabolism as measured by PET. In part, the form of reorganization may be time sensitive, as discussed earlier. The form and degree of reorganization may also be related to the extent of injury and the extent of surviving ischemic penumbra, areas that show reduced blood flow but preserved structural integrity. Reorganization tends to be more peri-infarct for smaller lesions and to involve more remodeling for extensive damage [39]. The results of research in animals also suggest a strong distinction between peripheral injuries and central injuries [1]. Peripheral lesions are usually followed by acute reorganization, probably through unmasking of latent connections, and subsequently may be reversed, stabilized, or strengthened [6]. Central, that is, cortical, lesions can be followed by new cortical representations with subsequent experience-dependent enlargement of these representations. Abnormal functional imaging may reveal specific information regarding injury. Underactivation may suggest damage to local or distant tissue and/or cognitive reorganization [47]. Overactivation, however, may suggest learning-related plasticity, disinhibition of duplicate networks, and/or cognitive reorganization.
MECHANISMS OF PLASTICITY These macroscopic plastic changes, described previously, arise from microscopic changes in synapses, cytoarchitecture, and neurogenesis. At the synaptic level, initial recovery involves hyperexcitability secondary to transient loss of inhibition [1,6]. Inhibitory ␥-aminobutyric acid interneurons that typically block horizontal connections to stabilize cortical representations may be suppressed [1]. Homeostatic plasticity may also reduce synaptic activity by up-regulating presynatic release and postsynaptic response to neurotransmitters to reset activity to a set point [6]. This environment thus triggers the unmasking of latent connections and the formation of new synapses and new adaptive functional connections. Next, neural circuits are refined, perhaps by mechanisms of Hebbian plasticity, whereby synapses that are coincidently active are strengthened, producing activity-dependent changes. Glia, which have been shown to affect excitability and synaptic transmission and to coordinate activity across networks, may also play a role in modulating neuronal activity [48]. Brain injury also induces an axonal sprouting response in temporally and spatially permissive zones in peri-infarct or pericontused cortical regions arising from both extrinsic and intrinsic control [49,50]. Extrinsically, the extracellular environment promotes sprouting through increased growthpromoting factors and decreased growth-inhibiting factors. Intrinsically, a switch to growth-promoting mode promotes sprouting with regulated induction of sequential waves of neuronal growth-promoting genes and expression of proteins that regulate the maturation process.
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Furthermore, brain injury may stimulate neurogenesis and neuroblast migration [51]. In general, persistent neurogenesis has been found in the subventricular zone (SVZ)– olfactory bulb region, and the subgranular zone of the dentate gyrus of the hippocampus. Stroke may stimulate SVZ neurogenesis and induce SVZ neuroblasts to migrate to the injured region, whereas TBI may stimulate similar processes in the subgranular zone. However, the extent and relevance of injury-induced neurogenesis and neuroblast migration are still not well understood.
FUTURE DIRECTIONS Novel interventional approaches hold potential promise to improve functional outcomes after brain injury from stroke or trauma by inducing neural plasticity. Although the current best approach for motor recovery appears to be intensive physical therapy, auxiliary interventions that can augment the response of the motor system are needed. Noninvasive brain stimulation is one such approach. Both transcranial magnetic stimulation and transcranial direct current stimulation are methods of noninvasive brain stimulation that can prime cortical excitability before motor rehabilitation [52]. Both can induce long-term effects on cortical excitability thought to involve neural plasticity [53,54]. This is believed to compensate for poststroke decreased cortical excitability in the affected primary motor areas, and can help to restore activity across bihemispheric neural networks and lead to more adaptive plasticity [55,56] New, more invasive technologies such as deep brain stimulation may also play a role in future approaches to severe brain injury because they have been shown to promote late functional recovery in preliminary studies [57]. Pharmacologically, neuroprotective agents may help to reduce damage and apoptosis [58]. Other novel agents, such as glibencamide (a selective sulfonylurea receptor 1 inhibitor), can specifically target damage from secondary neuroinflammation. After injury, D-cycloserine, a partial agonist of the N-methyl-D-aspartate (NMDA) receptor for glutamate, can potentiate cognitive– behavioral interventions [59] that may include cognitive rehabilitation. Neural repair with stem cells, growth factors, and gene therapy may also add to the therapeutic armamentarium in the future [60,61]. Functional neuroimaging will be an important tool to measure changes in structure and activity that occur with these interventions. Other novel imaging techniques will be able increasingly to shed light on the pathophysiology underlying damage and repair that occur both spontaneously and with therapy. For example, PET scanning with [11C]-PK11195, a novel peripheral benzodiazepine receptor ligand that binds to activated microglia in the brain, is a marker of neuroinflammation. This radioligand has already provided information regarding the evolution of neuroinflammatory change after carotid stroke in human beings [62]. Magnetic resonance
Figure 3. Axial brain images showing significant decreases in activation to positive stimuli in depressed patients (n ⫽ 10) compared with healthy subjects (n ⫽ 12) in the ventral striatum bilaterally. This region is associated with the processing of reward and positive stimuli, and suggests a contributing neural substrate of the inability to experience pleasure in these patients [67].
spectroscopy, which can noninvasively measure brain metabolites, can assess, for example, neuronal integrity. Early studies suggest that this information may have the potential to aid in the assessment of clinical severity and to predict disease outcome in TBI [63]. Functional neuroimaging will also likely be used to evaluate brain function in increasingly severe forms of brain injury. The degree of functional awareness in disorders of consciousness, including the vegetative state and the minimally conscious state, remains very difficult to evaluate accurately. By identifying the presence of cognitive ability, these techniques have the potential to assist with differential diagnosis, identification of pathophysiological processes, and determination of prognosis [64,65]. In addition to assessing the presence of cognitive function, fMRI tasks can be used to assign “yes” and “no” labels to particular tasks, thus enabling communication by the patients in response to questions [66]. Another frontier for the study of neural plasticity lies in the use of imaging techniques to investigate the functional neuraoanatomy of psychiatric diseases [67] (Figure 3), and their treatment. In addition to shedding light on the specific disorders under investigation, these studies can serve as a model to examine neural plasticity in response to pharmacotherapy and cognitive therapeutic approaches. Early studies suggest meaningful functional changes, identified with functional neuroimaging techniques, following therapy for depression, obsessive-compulsive disorder, social anxiety disorder, and posttraumatic stress disorder [68].
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CAVEATS AND CONCLUSIONS A few caveats should be noted. First, cortical plasticity appears to be possible only if subcortical connectivity is preserved. Studies in both stroke and TBI suggest that extensive white matter damage may result in severe permanent deficits, perhaps because disruption of connectivity may constrain reorganization of networks [1,8]. Second, plasticity may have negative consequences resulting from maladaptive changes [7]. Learned nonuse may result from association of motor attempts with failure during acute and subacute states, and may create a condition of maladaptive plasticity wherein the reorganization of circuitry interferes with regaining of function [6,69]. There is also potential for maladaptive changes resulting from sensory competition. For instance, chronic stroke patients with somatosensory impairments have been reported to have abnormalities of spatial discrimination linked to reduced spatial specificity in somatosensory cortex [7]. Moreover, early contralateral homologous region recruitment may be a compensatory adaptation early on but may become maladaptive over time. In general, however, increases in neural plasticity after brain injury allow functional recovery that can be seen from microscopic to macroscopic levels. These processes may be spontaneous or induced by training, although the former occurs only within a critical period after injury. They result in reorganization, the extent of which depends on factors such as degree and type of injury. Synaptic, cytoarchitectural, and neurogenesis changes constitute the mechanisms of reorganization. Although much work remains to be done, continued progress in the investigation of neural plasticity should enhance our ability to understand, prevent, and treat debilitating brain injuries such as stroke and TBI. In particular, functional neuroimaging shows great promise in elucidating the pathophysiology of plastic changes, aiding in the determination of diagnosis and prognosis after insults to the brain, and helping to guide therapeutic approaches.
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50. Harris N, Mironova Y, Hovda D, Sutton R. Pericontusion axon sprouting is spatially and temporally consistent with a growth-permissive environment after traumatic brain injury. J Neuropathol Exp Neurol 2011;69:139. 51. Kernie S, Parent J. Forebrain neurogenesis after focal Ischemic and traumatic brain injury [review]. Neurobiol Dis 2010;37:267-274. 52. Bolognini N, Pascual-Leone A, Fregni F. Using non-invasive brain stimulation to augment motor training-induced plasticity. J Neuroeng Rehabil 2001;6:8. 53. Fregni F, Boggio PS, Valle AC, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2001;37:2115-2122. 54. Triggs WJ, McCoy KJ, Greer R, et al. Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold. Biol Psychiatry 1991;45:1440-1446. 55. Fregni F, Pascual-Leone A. Technology insight: Noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat Clin Pract Neurol 2001;3:383-393. 56. Hummel FC, Cohen LG. Non-invasive brain stimulation: A new strategy to improve neurorehabilitation after stroke? Lancet Neurol 2001; 5:708-712. 57. Schiff ND, Giacino JT, Kalmar K, et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 2001; 448:600-603. 58. Lauterbach EC, Victoroff J, Coburn KL, et al. Psychopharmacological neuroprotection in neurodegenerative disease: Assessing the preclinical data. J Neuropsychiatry Clin Neurosci 2011;22:8-18. 59. Ganasen KA, Ipser JC, Stein DJ. Augmentation of cognitive behavioral therapy with pharmacotherapy. Psychiatr Clin North Am 2011;33: 687-699. 60. Marr RA, Thomas RM, Peterson DA. Insights into neurogenesis and aging: Potential therapy for degenerative disease? Future Neurol 2011; 5:527-541. 61. Ji Y, Lu Y, Yang F, et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2011;13:302-309. 62. Price CJ, Wang D, Menon DK, et al. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke 2001;37:1749-1753. 63. Marino S, Ciurleo R, Bramanti P, Federico A, De Stefano N. (1)H-MR spectroscopy in traumatic brain injury. Neurocrit Care 2011;2010:25. 64. Coleman MR, Davis MH, Rodd JM, et al. Towards the routine use of brain imaging to aid the clinical diagnosis of disorders of consciousness. Brain 2001;132:2541-2552. 65. Giacino JT, Hirsch J, Schiff N, Laureys S. Functional neuroimaging applications for assessment and rehabilitation planning in patients with disorders of consciousness. Arch Phys Med Rehabil 2001;87:S67-S76. 66. Monti MM, Vanhaudenhuyse A, Coleman MR, et al. Willful modulation of brain activity in disorders of consciousness. N Engl J Med 2011;362: 579-589. 67. Epstein J, Pan H, Kocsis JH, et al. Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. Am J Psychiatry 2001;163:1784-1790. 68. Frewen P, Dozois D, Lanius R. Neuroimaging studies of psychological interventions for mood and anxiety disorders: Empirical and methodological review. Clin Psychol Rev 2001;28:228-246. 69. Taub E, Uswatte G, Elbert T. New treatments in neurorehabiliation founded on basic research. Nat Rev Neurosci 2001;3:228-236.
Neural Plasticity After Acquired Brain Injury: Evidence from Functional Neuroimaging Haiwen Chen, BA, Jane Epstein, MD, Emily Stern, MD Abstract: The reorganization of the adult central nervous system after damage is a relatively new area of investigation. Neuroimaging methods, such as functional magnetic resonance imaging, diffusion tensor imaging, and positron emission tomography, have the ability to identify, in vivo, some of the processes involved in these neuroplastic changes and can help with diagnosis, prognosis, and potentially treatment approaches. In this article, traumatic brain injury and stroke are used as examples in which neural plasticity plays an important role in recovery. Basic concepts related to brain remodeling, including spontaneous reorganization and training-induced recovery, as well as characteristics of reorganization in successful recovery, are reviewed. The microscopic and molecular mechanisms that underlie neural plasticity and neurogenesis are briefly described. Finally, exciting future directions for the evaluation, diagnosis, and treatment of severe brain injury are explored, with an emphasis on how neuroimaging can help to inform these new approaches. PM R 2010;2:S306-S312
INTRODUCTION Until relatively recently, neuroscience viewed the mature central nervous system as having little capacity to repair or reorganize. Now, evidence clearly suggests that the human brain is plastic, maintaining the ability to change in neural structure, connectivity, and function throughout life. In development, natural plasticity occurs with (1) the proliferation of dendrites and axons during cytogenesis and histogenesis, (2) the formation of synapses and cellular differentiation during migration, and (3) apoptotic phenomena [1]. In adulthood, structural magnetic resonance imaging (MRI) has shown activity-dependent responses in brain structure; for instance, in London taxi drivers, increased hippocampal volume, thought to be related to spatial navigation, correlated with the amount of time that the drivers spent in navigating the streets of London [2]. Draganski et al [3] found that individuals who learned to juggle for a limited period of time showed transient and selective structural expansion in gray matter in the mid-temporal area and left posterior intraparietal sulcus, areas associated with processing and storage of complex visual motion. Changes in brain structure also have been correlated with changes in physiological states. In women, hippocampal volume has been shown to vary across the normal menstrual cycle, with volume alterations correlating with changes in cognitive function (Figure 1) [4]. Likewise, functional magnetic resonance imaging (fMRI) studies suggest that subjects learning sequential finger movements demonstrate changes in the motor cortex, cerebellum, and basal ganglia [5]. Even after brain injury, such as stroke or traumatic brain injury (TBI), neural plasticity is possible because of the existence of significant diffuse and redundant connectivity within the central nervous system, as well as the ability of new circuits to form through remapping [6]. Given the morbidity and mortality of these conditions, it is imperative to understand possible mechanisms of plasticity after stroke and TBI to foster new approaches to promote recovery. In recent decades, the development of functional imaging techniques such as positron emission tomography (PET) and fMRI have provided more information regarding this ability to remodel by identifying neural systems or components that continue to function after an insult (in addition to those that are impaired), as well as specific sites and patterns PM&R
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H.C. Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Chestnut Hill, MA; and University of Maryland School of Medicine, Baltimore, MD Disclosure: nothing to disclose J.E. Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Chestnut Hill, MA Disclosure: nothing to disclose E.S. Functional Neuroimaging Laboratory, Brigham and Women’s Hospital, 824 Boylston Street, Harvard Medical School, Chestnut Hill, MA 02467. Address correspondence to E.S.; e-mail: [email protected] Disclosure: nothing to disclose Submitted for publication October 5, 2010; accepted October 7, 2010.
© 2010 by the American Academy of Physical Medicine and Rehabilitation Suppl. 2, S306-S312, December 2010 DOI: 10.1016/j.pmrj.2010.10.006
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Figure 1. Sagittal, coronal, and axial images demonstrating statistically significant increased right anterior hippocampal (yellow/orange) and decreased right dorsal basal ganglia (purple/blue) gray matter in the postmenstrual compared to the premenstrual phase (n ⫽ 21; P ⬍ .005). Verbal declarative memory was also increased in the post- versus premenstrual phase [4].
associated with recovery [7]. Functional neuroimaging also complements behavioral assessments by pointing to underlying mechanisms and molecular and cellular techniques and allowing in vivo observation of networks not obvious at a microscopic level. Here we review neuroimaging with adjunct clinical, behavioral, and molecular and cellular research on neuroplastic change after brain injury, specifically stroke and TBI, to understand plasticity related to different forms of recovery and its underlying mechanisms. Because lateralized focal traumatic brain lesions parallel focal vascular lesions in most respects [8], we will consider research performed in both areas together.
NEUROIMAGING METHODS Functional neuroimaging techniques provide powerful tools for the in vivo examination of brain function. In addition to localizing the neural circuitry responsible for normal perception, cognition, emotion, and behavior, these methods allow one to probe dysfunction that occurs in the setting of disease and injury [9]. Symptoms can be imaged directly as they occur, either spontaneously or via experimental paradigms involving symptom provocation. Alternatively, neuropsychological functions that are hypothesized to be affected in specific disorders can be probed with the use of “activation” tasks, in which the subject is asked to perform specific mental activities. fMRI has become a widely used method for map-
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ping brain function. Its strengths, compared with techniques such as PET, include improved spatial and temporal resolution, absence of ionizing radiation, and wide availability. Limitations of fMRI include the confining scanner environment, acoustic noise (resulting from the rapid alteration of currents in the gradient coils), and signal artifacts in orbitofrontal and mesotemporal brain regions, particularly at greater field strength. The most commonly used fMRI method is blood oxygen level– dependent imaging [10,11], in which changes in the amount of deoxyhemoglobin that occur in association with increases or decreases in neuronal activity are detected. Other techniques, such as arterial spin labeling, utilize a more direct measure of blood flow changes associated with neuronal activity [12]. PET methods can be used to assess either blood flow or metabolic changes that occur with neuronal activation. In addition, by radiolabeling organic molecules, PET can be used to provide information related to many pre- and postsynaptic neurochemical and neurophysiological processes [9]. Compared with PET, magnetic resonance spectroscopy is a less sensitive but noninvasive method that can be used to examine compounds involved in brain chemistry and metabolism [13]. Compounds that are of neuroscientific interest that can be measured include lactate, N-acetyl aspartate (a neuronal cell marker), creatine, choline, glutamate, and ␥-aminobutyric acid. Of importance, functional imaging techniques also can be combined with clinical and/or physiological data to provide more comprehensive, integrated information about brain– body function (Figure 2) [14]. Advances in evaluating detailed brain structure are also critical to the study of the postinjury brain. Diffusion tensor imaging (DTI) allows one to visualize and measure the diffusion of water in brain tissue [15]. This is particularly applicable to the study of white matter tracts, thereby providing important information on structural connectivity. This technique has been used to study normal connectivity over the lifespan, as well as abnormalities that occur in a wide variety of disorders [16]. It is of particular relevance to TBI and stroke, as compromise of white matter integrity caused by shearing injury and/or ischemia is present, and DTI may be used for early evaluation, diagnosis, and as a predictor of outcome.
FORMS OF RECOVERY Recovery after brain injury can generally be categorized into 2 main stages: (1) spontaneous reorganization and (2) training-induced recovery. Spontaneous reorganization occurs during a period proximal to injury and likely reflects the recovery of neurotransmission in spared tissue near and remote from the site of injury [7,17,18]. Spontaneous recovery after stroke typically plateaus approximately 3 months after insult [7,19], whereas spontaneous recovery after TBI is
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Figure 2. Axial brain images showing differences in blood oxygen level– dependent signal when viewing fearful pictures (related to the World Trade Center disaster) compared with scrambled control images, correlated with cortisol change prescan to postscan. Cortisol change is positively correlated with activity in the right amygdala (A), and the anterior and posterior regions of the left and right hippocampi (C and D); negative correlations are present in the ventromedial prefrontal cortex (B). These regions are important in modulating fear-related responses, and this study demonstrates how they are associated with stress-induced reactivity of the hypothalamic–pituitary–adrenal axis [14].
found to plateau about 6 months after injury [20]. Traininginduced recovery is not limited by time and has been observed long after injury; however, it is dependent on individual experience and adaptation and/or specific rehabilitation, likely by means of processes involved in ordinary learning.
Spontaneous Reorganization Initial acute recovery results primarily from resolution of reversible factors. In stroke, reperfusion of the ischemic penumbra corresponds with early rapid recovery [7,21]. In both stroke and TBI, resolution of reversible factors, such as regression of edema, clearing of inflammatory infiltration, or mass effect, can also induce recovery [22,23]. In addition, because a lesion may impair processes remote from the site of injury and cause dysfunction in additional nodes within a functional network, subacute and chronic recovery involve the renewal and stabilization of functional brain networks. Studies in a variety of areas such as motor, language, cognitive, sensory, and resting-network function reflect this process. The literature suggests that, after stroke, a temporal series of activation shifts take place that involve an early recruitment of contralesional homologous brain regions, activation of learning structures, and finally a settling toward an ipsilesional or distributed recruitment pattern [24], where greater shift to a more “normal” pattern corresponds to better recovery [25-27]. In a longitudinal fMRI study of locomotor recovery after stroke, Kim et al [28] found that paretic leg movement was associated with contralateral (ipsilesional) and ipsilateral (contralesional) activity in the primary sensorimotor cortex and supplementary motor area (SMA) during the subacute stage but shifted in laterality in the chronic stage with increased contralateral and reduced ipsilateral activity. Similarly, functional imaging of stroke-induced aphasia suggests increased activation in the bilateral language network, particularly in the right Broca-homologue, during the subacute stage, followed by reshift of main activation to left-hemisphere language areas, which were correlated with
improved language function [29]. Similar patterns have been found for recovery from hemispatial neglect as well in frontoparietal attention networks [30]. Somatosensory recovery has been relatively understudied, perhaps complicated by high individual variability [31], although Carey and Seitz [7] propose an interhemispheric, multimodal model. Nakamura et al [20] examined resting networks 3 and 6 months after severe TBI and found a decreased number of highly significant connections, reduced overall strength in connectivity, and increased “small-worldness” (a measurement in mathematical graph theory in which most nodes are not neighbors of one another, but can be reached from every other node by a small number of steps). This finding suggests a shift from greater neural dynamics and flexibility during early stages of recovery to increasing efficiency and decreasing malleability during later stages of recovery to reduce the cost of and formalize the network. Activation studies on cognitive function after TBI complement these findings in showing more widespread cerebral activation patterns during the period shortly after injury [32].
Training-Induced Recovery Experience and specific rehabilitation can interact with spontaneous factors. During the spontaneous recovery period, activation of learning networks facilitates plastic changes. For instance, motor control and task learning networks, including the primary motor cortex, parietal lobes, SMA, and cerebellum, which are usually active only during development, re-emerge in recovering patients to facilitate relearning [24]. Training can also induce plastic changes in the brain to promote longer-term improvement. Training-facilitated neural changes, on the whole, appear to parallel those observed during spontaneous recovery but are not limited by time after stroke [7]. Functional imaging studies on the effects of constraint-induced movement therapy show treatment-associated activation increases in the ipsilesional primary motor cortex, dorsal premotor cortex, and SMA during affected hand
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movement months to years after stroke [33]. A comparable study on subjects with TBI produced similar results [34]. Extension of the constraint-induced movement therapy approach to aphasia in constraint-induced aphasia therapy has been linked to language improvement and shifting of right-hemisphere activation to left-hemisphere activation in patients more than 12 months after stroke [35,36]. In addition, repetitive training of stereotyped movement [37] and robot-based motor therapy [38] have been show to improve motor functionality and to facilitate motor cortical activity and reorganization.
REORGANIZATION IN SUCCESSFUL RECOVERY Successful functional recovery is generally accompanied by novel patterns of activation. Overall, this may take the form of the following: (1) plasticity in regions surrounding the damaged area, (2) reorganization or reweighting of interactions within an existing network, or (3) recruitment of new areas or use of alternative networks [39]. For example, studies in which the authors examined recovery from injury-induced aphasia and agnosia have found associations with all 3 forms. More specifically, Leger et al [40] related recovery from aphasia after a left-sided ischemic lesion to activation of language areas surrounding the lesion. Another study, by Zahn et al [41], associated recovery from aphasia after left middle cerebral artery infarction with takeover of related functional areas, including the left extrasylvian temporal and right posterior parietal cortices. Yet others, as previously mentioned, have associated recovery of aphasia with recruitment of homologous contralesional areas. Recovery from auditory agnosia in a patient with bilateral perisylvian strokes, who partially regained the ability to recognize environmental sounds, showed activation of a bilateral network (with recruitment of regions homologous to those responsible for normal function), involvement of peri-infarct areas, and the engagement of a more widespread neocortical network [42]. Similar findings can be seen in motor recovery as well. A number of studies have shown the activation of ipsilateral, perilesional areas related to sensorimotor activity [43]. In addition, studies have also shown regional reorganizations such as posterior shifts in primary sensorimotor cortex [44]. Interestingly, poststroke recovery from impaired sensorimotor integration was shown to be associated with cross-modal recruitment of visual networks [45]. Structural changes have also been associated with recovery from severe injury. In a case of a patient with late recovery from the minimally conscious state [46], the use of DTI showed changes in anisotropy in the posterior white matter and the midline cerebellar white matter that correlated with clinical improvements in motor function. The cerebellar
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finding also correlated with an increase in resting metabolism as measured by PET. In part, the form of reorganization may be time sensitive, as discussed earlier. The form and degree of reorganization may also be related to the extent of injury and the extent of surviving ischemic penumbra, areas that show reduced blood flow but preserved structural integrity. Reorganization tends to be more peri-infarct for smaller lesions and to involve more remodeling for extensive damage [39]. The results of research in animals also suggest a strong distinction between peripheral injuries and central injuries [1]. Peripheral lesions are usually followed by acute reorganization, probably through unmasking of latent connections, and subsequently may be reversed, stabilized, or strengthened [6]. Central, that is, cortical, lesions can be followed by new cortical representations with subsequent experience-dependent enlargement of these representations. Abnormal functional imaging may reveal specific information regarding injury. Underactivation may suggest damage to local or distant tissue and/or cognitive reorganization [47]. Overactivation, however, may suggest learning-related plasticity, disinhibition of duplicate networks, and/or cognitive reorganization.
MECHANISMS OF PLASTICITY These macroscopic plastic changes, described previously, arise from microscopic changes in synapses, cytoarchitecture, and neurogenesis. At the synaptic level, initial recovery involves hyperexcitability secondary to transient loss of inhibition [1,6]. Inhibitory ␥-aminobutyric acid interneurons that typically block horizontal connections to stabilize cortical representations may be suppressed [1]. Homeostatic plasticity may also reduce synaptic activity by up-regulating presynatic release and postsynaptic response to neurotransmitters to reset activity to a set point [6]. This environment thus triggers the unmasking of latent connections and the formation of new synapses and new adaptive functional connections. Next, neural circuits are refined, perhaps by mechanisms of Hebbian plasticity, whereby synapses that are coincidently active are strengthened, producing activity-dependent changes. Glia, which have been shown to affect excitability and synaptic transmission and to coordinate activity across networks, may also play a role in modulating neuronal activity [48]. Brain injury also induces an axonal sprouting response in temporally and spatially permissive zones in peri-infarct or pericontused cortical regions arising from both extrinsic and intrinsic control [49,50]. Extrinsically, the extracellular environment promotes sprouting through increased growthpromoting factors and decreased growth-inhibiting factors. Intrinsically, a switch to growth-promoting mode promotes sprouting with regulated induction of sequential waves of neuronal growth-promoting genes and expression of proteins that regulate the maturation process.
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Furthermore, brain injury may stimulate neurogenesis and neuroblast migration [51]. In general, persistent neurogenesis has been found in the subventricular zone (SVZ)– olfactory bulb region, and the subgranular zone of the dentate gyrus of the hippocampus. Stroke may stimulate SVZ neurogenesis and induce SVZ neuroblasts to migrate to the injured region, whereas TBI may stimulate similar processes in the subgranular zone. However, the extent and relevance of injury-induced neurogenesis and neuroblast migration are still not well understood.
FUTURE DIRECTIONS Novel interventional approaches hold potential promise to improve functional outcomes after brain injury from stroke or trauma by inducing neural plasticity. Although the current best approach for motor recovery appears to be intensive physical therapy, auxiliary interventions that can augment the response of the motor system are needed. Noninvasive brain stimulation is one such approach. Both transcranial magnetic stimulation and transcranial direct current stimulation are methods of noninvasive brain stimulation that can prime cortical excitability before motor rehabilitation [52]. Both can induce long-term effects on cortical excitability thought to involve neural plasticity [53,54]. This is believed to compensate for poststroke decreased cortical excitability in the affected primary motor areas, and can help to restore activity across bihemispheric neural networks and lead to more adaptive plasticity [55,56] New, more invasive technologies such as deep brain stimulation may also play a role in future approaches to severe brain injury because they have been shown to promote late functional recovery in preliminary studies [57]. Pharmacologically, neuroprotective agents may help to reduce damage and apoptosis [58]. Other novel agents, such as glibencamide (a selective sulfonylurea receptor 1 inhibitor), can specifically target damage from secondary neuroinflammation. After injury, D-cycloserine, a partial agonist of the N-methyl-D-aspartate (NMDA) receptor for glutamate, can potentiate cognitive– behavioral interventions [59] that may include cognitive rehabilitation. Neural repair with stem cells, growth factors, and gene therapy may also add to the therapeutic armamentarium in the future [60,61]. Functional neuroimaging will be an important tool to measure changes in structure and activity that occur with these interventions. Other novel imaging techniques will be able increasingly to shed light on the pathophysiology underlying damage and repair that occur both spontaneously and with therapy. For example, PET scanning with [11C]-PK11195, a novel peripheral benzodiazepine receptor ligand that binds to activated microglia in the brain, is a marker of neuroinflammation. This radioligand has already provided information regarding the evolution of neuroinflammatory change after carotid stroke in human beings [62]. Magnetic resonance
Figure 3. Axial brain images showing significant decreases in activation to positive stimuli in depressed patients (n ⫽ 10) compared with healthy subjects (n ⫽ 12) in the ventral striatum bilaterally. This region is associated with the processing of reward and positive stimuli, and suggests a contributing neural substrate of the inability to experience pleasure in these patients [67].
spectroscopy, which can noninvasively measure brain metabolites, can assess, for example, neuronal integrity. Early studies suggest that this information may have the potential to aid in the assessment of clinical severity and to predict disease outcome in TBI [63]. Functional neuroimaging will also likely be used to evaluate brain function in increasingly severe forms of brain injury. The degree of functional awareness in disorders of consciousness, including the vegetative state and the minimally conscious state, remains very difficult to evaluate accurately. By identifying the presence of cognitive ability, these techniques have the potential to assist with differential diagnosis, identification of pathophysiological processes, and determination of prognosis [64,65]. In addition to assessing the presence of cognitive function, fMRI tasks can be used to assign “yes” and “no” labels to particular tasks, thus enabling communication by the patients in response to questions [66]. Another frontier for the study of neural plasticity lies in the use of imaging techniques to investigate the functional neuraoanatomy of psychiatric diseases [67] (Figure 3), and their treatment. In addition to shedding light on the specific disorders under investigation, these studies can serve as a model to examine neural plasticity in response to pharmacotherapy and cognitive therapeutic approaches. Early studies suggest meaningful functional changes, identified with functional neuroimaging techniques, following therapy for depression, obsessive-compulsive disorder, social anxiety disorder, and posttraumatic stress disorder [68].
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CAVEATS AND CONCLUSIONS A few caveats should be noted. First, cortical plasticity appears to be possible only if subcortical connectivity is preserved. Studies in both stroke and TBI suggest that extensive white matter damage may result in severe permanent deficits, perhaps because disruption of connectivity may constrain reorganization of networks [1,8]. Second, plasticity may have negative consequences resulting from maladaptive changes [7]. Learned nonuse may result from association of motor attempts with failure during acute and subacute states, and may create a condition of maladaptive plasticity wherein the reorganization of circuitry interferes with regaining of function [6,69]. There is also potential for maladaptive changes resulting from sensory competition. For instance, chronic stroke patients with somatosensory impairments have been reported to have abnormalities of spatial discrimination linked to reduced spatial specificity in somatosensory cortex [7]. Moreover, early contralateral homologous region recruitment may be a compensatory adaptation early on but may become maladaptive over time. In general, however, increases in neural plasticity after brain injury allow functional recovery that can be seen from microscopic to macroscopic levels. These processes may be spontaneous or induced by training, although the former occurs only within a critical period after injury. They result in reorganization, the extent of which depends on factors such as degree and type of injury. Synaptic, cytoarchitectural, and neurogenesis changes constitute the mechanisms of reorganization. Although much work remains to be done, continued progress in the investigation of neural plasticity should enhance our ability to understand, prevent, and treat debilitating brain injuries such as stroke and TBI. In particular, functional neuroimaging shows great promise in elucidating the pathophysiology of plastic changes, aiding in the determination of diagnosis and prognosis after insults to the brain, and helping to guide therapeutic approaches.
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