CHAPTER 1 INTRODUCTION
3. Neuroplasticity
3.1. fMRI studies
Task-based functional neuroimaging contributed greatly to current knowledge on brain plasticity in stroke patients. Ischemic stroke is often associated with loss of cognitive and/or motor function. In some patients, these deficits recover spontaneously within three months following the stroke‟s onset.
(Ward et al., 2003b; Corbetta et al., 2005). This makes stroke convenient for studying mechanisms and patterns of functional reorganization in several functional domains such as motor function (Loubinoux et al., 2003; Ward & Cohen, 2004), language (Buckner et al., 1996; Saur et al., 2006; Saur et al., 2010; Meinzer et al., 2011), and attention (Corbetta et al., 1998; Corbetta et al., 2005).
Three main mechanisms of neuroplasticity were highlighted (Cramer, 2008):
(1) somatotopic shifts within intact cortical regions;
(2) increased activity in brain regions distant from, but connected to the stroke zone;
(3) increased activity in the contralesional hemisphere.
Unaffected brain tissue surrounding the lesion in some cases seems to be able to adapt to the loss of function. Such somatotopic shifts in representational maps surrounding the infarcted zone were observed both in animal and in human studies. Specifically, motor and somatosensory cortices were found to display structural and functional reorganization as a result of training and recovery. Neural growth and restructuring or remapping (meaning accommodation of the lost function by adjacent survived neural cells) seem to be important biological mechanisms of this compensational mechanism (Frost et al., 2003; Ward, 2005; Nudo, 2006; Schaechter et al., 2006).
The activation of more extensive cortical areas involving peri-lesional regions was consistently reported in stroke patients (Feydy et al., 2002; Ward et al., 2003b; Saur et al., 2006). This widespread activation was initially thought to reflect the recruitment of adjacent cortical regions to compensate for the deficit. However, several studies have reported that persistent over-activation is negatively associated with function and recovery (O'Shea et al., 2007; Bestmann et al., 2010; Riecker et al., 2010). Conversely, the best recovery of affected behavior was associated with a normalization of activity in the affected areas (Pizzamiglio et al., 1998; Warburton et al., 1999; Ward et al., 2003a;
Zemke et al., 2003). Such plastic changes seem therefore to evolve over time. Within a few weeks following brain damage, functions of the lesioned tissue are reduced and adjacent areas are extensively recruited during task performance, which is expressed by the increased activation. Over the course of recovery (up to three months after stroke), the affected regions resume their functioning and recover a normal activation pattern (Feydy et al., 2002; Dong et al., 2007; Marshall et al., 2009).
This mechanism has been observed in motor (Feydy et al., 2002), language function (Cao et al., 1999;
Warburton et al., 1999) and in spatial attention (Corbetta et al., 2005).
Another type of brain responses that might contribute to brain recovery includes a shift of activation toward the contralesional hemisphere (Raboyeau et al., 2008). Similarly to increased activations in
23
regions surrounding lesion, the best behavioral outcomes several months after stroke have been associated with the greatest return of brain function toward the normal state of activation (Warburton et al., 1999; Zemke et al., 2003; Corbetta et al., 2005; Dong et al., 2007).The introduction of the network approach generated a wealth of clinical research that revealed new aspects of neuroplasticity. In light of the network approach, the lesion impairs behavioral functions because it disrupts communication in brain networks that are relatively specific to particular behavioral domains, yet spatially distributed in the brain. The degree of initial disorganization and the dynamics of reorganization of these functional brain networks may determine the amount of acute impairment and then the level of recovery, respectively (Carter et al., 2012). Evidence of such network dysfunctions and reorganizations come, once again, from studies in patients with focal lesions such as stroke. For instance, preserved connectivity between regions of the language network was found to be indicative of better performance amongst aphasic stroke patients in language tasks (Warren et al., 2009).
Recovery from visuo-spatial neglect was shown to be correlated with a restitution of inter-hemispheric FC between the left and right dorsal parietal cortices (He et al., 2007). Hence, functional MRI data across different functional systems suggest that functional outcome after a stroke depends on the connectivity within the corresponding functional network.
Lesions of neural tissue cause disturbances in distributed spontaneous brain activity. This disturbance has an impact on the way in which the networks are being recruited during active behavior and can explain why the reorganization of networks can be observed not only during cognitive activity, but also at rest (Carter et al., 2012). Indeed, Carter et al. 2010 could predict the motor performance of paretic stroke patients from the coherence of spontaneous BOLD fluctuations between left and right motor cortices (Carter et al., 2010). Resting state connectivity analyses were also actively used to assess behavioral deficits in other disorders. Alzheimer disease patients were found to have disrupted connectivity between several frontal and parietal areas and the hippocampus, which is known to be implicated in memory (Gusnard et al., 2001; Greicius et al., 2004; Zhang & Raichle, 2010). The severity of disconnection was associated with the disease progression, meaning that the more the hippocampus was disconnected, the worse patients performed in memory tests (Zhang & Raichle, 2010). Thus, resting state brain connectivity contains important information on individual functional state. This makes it a useful tool for assessment of behavior that can be applied even in severely affected patients. There is hope that the identification of disease-specific group differences will allow us to gain a better understanding of the functional abnormalities underlying different diseases (Fox &
Greicius, 2010).
All in all, fMRI activation and connectivity studies revealed several important mechanisms of neuroplasticity related to brain dysfunctions and to recovery processes. The resting state approach has several advantages in clinical research as compared to traditional activation studies, as it can provide access to whole brain analysis even in patients with severe deficits. Connectivity analysis is a promising tool that might allow understanding on whether the regional interaction is disrupted, and