Activation likelihood estimation meta-analysis of motor-related neural activity after stroke
Highlights
► Quantitative synthesis of motor-related neural activity after stroke. ► Contralesional M1 and bilateral PMC activity differentiates patients and controls. ► Recruitment of original activation sites indicates better clinical outcome. ► No consistent relationship between contralesional M1 activity and clinical deficit.
Introduction
Stroke-induced lesions often disrupt motor circuits in the brain, leading to motor disability (Dum and Strick, 2002, Stinear et al., 2007, Ward et al., 2006), but also to plastic adaptation of the entire network (Carmichael, 2003, Cramer, 2008). Over the past two decades, functional neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were used to assess neural correlates of motor impairment and recovery thereof at the system level. These imaging experiments frequently reported motor-related neural activity in stroke patients over and above levels found in healthy subjects in motor areas of both, the affected (ipsilesional) and the unaffected (contralesional) hemisphere (Chollet et al., 1991, Grefkes et al., 2008, Weiller et al., 1992). However, conclusions based upon single neuroimaging experiments are generally constrained by small sample sizes, especially in well-defined clinical populations. Furthermore, experimental and clinical factors vary considerably between experiments. Studies showed that activity in bilateral premotor areas and contralesional primary motor cortex (M1) correlates with more severe motor impairment (Loubinoux et al., 2007, Marshall et al., 2009, Ward et al., 2003b, Ward et al., 2004). Besides, this additional activity builds up in the first few days after stroke and subsequently decreases over one year while patients recover (Calautti et al., 2001, Jaillard et al., 2005, Loubinoux et al., 2003, Rehme et al., 2011b, Tombari et al., 2004, Ward et al., 2003a). However, other studies showed that motor-related over-activity persists after almost complete functional recovery (Bütefisch et al., 2005, Gerloff et al., 2006, Weiller et al., 1992). These heterogeneous findings probably result from differences in the degree of impairment, time after stroke, and the imaging task. Moreover, functional neuroimaging techniques are indirect assessments of neural activity and, therefore, influenced by various biological and methodological factors which reduce reliability and further increase the experimental variance across studies (Eickhoff et al., 2009).
Quantitative coordinate-based meta-analyses such as activation likelihood estimation (ALE) allow identification of consistent neural activity across different PET and fMRI studies, and are powerful tools to overcome the limited generalizability of single experiments (Eickhoff et al., 2009, Turkeltaub et al., 2011). Here, we used ALE meta-analyses to investigate (i) which brain areas are consistently activated during movements of the affected upper limb in stroke patients, and (ii) which areas are robustly more active in patients when compared to healthy subjects. As outlined above, neural activity after stroke is strongly related to clinical factors. Therefore, we (iii) examined whether motor impairment or time since stroke correlate with the activation likelihood of motor-related brain activity. Finally, we (iv) tested whether the type (active or passive) or complexity of the task influence the likelihood of observing effects in neuroimaging experiments in stroke patients.
Section snippets
Literature search
We conducted a PubMed search (www.pubmed.org) to identify functional neuroimaging studies investigating upper limb movements in stroke patients with motor deficits (search strings: fMRI, PET, stroke, motor, movement). Further studies were identified through review papers and reference tracing of retrieved articles. Studies were included according to the following criteria: (i) fMRI or PET assessments, (ii) patients with ischemic stroke, (iii) recovered or persisting motor impairment, (iv)
Results
Thirty-six publications (25 fMRI, 11 PET studies) fulfilled the inclusion criteria through January 2011 (Table 1). Epidemiological details are given in Supplementary Table 4 (average sample size ± SD: 11 ± 5 patients; mean age: 60 ± 7 years; gender distribution [male:female]: 2:1; lesion location: 71% subcortical, 7% brain stem, 8% cortical, 14% combined cortical and subcortical; lesion side: 48% right, 52% left).
Discussion
Our meta-analysis provides statistical evidence for consistently activated brain regions during affected upper limb movements in stroke patients across multiple patient groups, clinical characteristics, and task variations. Consistently activated regions include key areas of the sensorimotor system in both hemispheres. Moreover, convergence in contralesional M1, vPMC, and bilateral SMA is greater in patients relative to healthy subjects. Patient samples with better motor performance are more
Conclusions
Our meta-analysis provides a quantitative synthesis of the current literature on motor-related neural activity after stroke. Meta-analytic approaches are well-suited to produce novel findings by integrating results across experiments with different study populations. Functional neuroimaging techniques in particular suffer from low reliability because they are indirect assessments of neural activity and, therefore, influenced by various biological and methodological factors. In addition, a
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