In this study, we examine the functional network organisation in AIS patients, as well as the impact of lesions in rich club areas on functional outcome. Functional connectivity has been previously explored in longitudinal studies of motor recovery after stroke \cite{Park_2011,Golestani_2012}. Significant correlations between interhemispheric resting-state connections and functional performance have been identified \cite{Carter2010,Rehme2013}. Nevertheless, the effect of focal ischemic stroke lesions on global functional organization have not been investigated yet. We assess the impact of ischemic insults on brain regions that constitute the rich club backbone, as well as functional network topology at a global level on brain recovery, in a prospective, hospital-based cohort of AIS patients. We hypothesize that a linear regression model incorporating connectivity information will improve the prediction of a patient's functional outcome. We conclude that the connectivity metrics obtained early in the course of acute ischemic stroke can be used to better understand the mechanisms underlying variability in post-stroke functional outcomes.

Materials and Methods

Patient population

Forty-one AIS patients (age range 45-89, average 70; 25 male) were enrolled in the SALVO (Statins augment small vessel function and improve stroke outcomes) study after admission to the Emergency Department at Massachusetts General Hospital. Of these, 15 (37%) had a left hemispheric stroke, 1 (2%) had bilateral stroke, and 25 subjects (61%) had a right hemispheric stroke. The study was approved by the Institutional Review Board and all participants, or their surrogates, gave written informed consent at the time of enrolment. AIS was defined as: (a) acute onset of focal neurological symptoms consistent with cerebrovascular syndrome, (b) MRI findings consistent with acute cerebral ischemia, and (c) no evidence of other neurological disorders to explain the symptoms. Subjects with moderate to severe white matter hyperintensity (WMH) burden defined as Fazekas grade \(\geq 2\) in any of the three categories (periventricular, deep lesion extent and deep lesion count) \cite{Fazekas_1987} were eligible for enrolment in this study. Participants with medical contraindications to gadolinium-based contrast agents were excluded from this study.

Clinical assessment

Upon admission to the hospital, the National Institutes of Health Stroke Scale (NIHSS) score was recorded for each patient. NIHSS is a well-established and widely used stroke severity assessment score \cite{1995} that includes assessment of orientation, cranial nerve function, motor function, sensation, language, and inattention/visuospatial neglect but not that of other cognitive domains, such as memory or learning \cite{Cumming_2010}. The post-stroke functional outcome was also assessed during two follow-up assessments: (1) within 2-5 days after admission (average 2.6 days, "early" in-hospital follow-up) and (2) at 90 days ("late" follow-up). The 90-day NIHSS score was only available for 28 of the patients, while NIHSS score distribution for both assessments is illustrated in Fig.\ref{860740}. Additionally, the modified Rankin Scale (mRS) score \cite{Rankin_1957} was recorded at "late" follow-up to assess functional status of the SALVO patients \cite{Bloch_1988}. mRS ranges from 0 (no symptoms at all) to 6 (dead) and offers no detailed differentiation of neurological domains affected by stroke. It focuses on the assessment of functional independence (ability to return to independent living, including ambulation without assistance), and is widely used in stroke clinical trials based on its high utility and reliability \cite{Wilson_2005,Banks_2007,Quinn_2009}.
 For the late follow-up assessment, NIHSS score was available for 21 of the patients with functional connectivity information. mRS was available for 32 patients. \(mRS \leq 2\) was considered as 'good' outcome (minor disability but patient is functionally independent), while \(mRS > 2\) was considered 'poor' outcome (significant disability, loss of functional independence, including death).