Cognition and Functional Connectivity after Elective Treatment of Brain Aneurysms

The aim of this proposal is to investigate the effects of uneventful microsurgical and endovascular treatment of unruptured saccular non-giant anterior communicating artery [ACoA] aneurysms on resting state functional connectivity levels of higher order cognitive networks and to correlate the connectivity levels of these networks with neuropsychological performance and functional outcome. Our hypothesis is that the functional connectivity of various cognition networks, i.e. cognitive control network, emotion control of cognitive networks, and working memory networks, as assessed by resting state functional magnetic resonance imaging [rsfMRI], can be impaired after uneventful microsurgical and endovascular treatment of unruptured ACoA aneurysms and can be correlated with neuropsychological performance. We propose to investigate 38 patients harboring unruptured ACoA aneurysms and 19 healthy controls over a 36 (until 48) months period. Patients and healthy controls will undergo baseline structural MRI, task fMRI, rsfMRI, and baseline neuropsychological examinations prior as well as 2 months after either microsurgical or endovascular aneurysm treatment or baseline examinations, respectively. Furthermore all subjects will undergo additional neuropsychological examinations 12 months after baseline examination or long-term recovery from microsurgical and endovascular treatment, respectively. The research question is of substantial importance for this patient population, since it is currently incompletely understood how the minor structural brain tissue damages seen after both treatment methods of unruptured ACoA aneurysms translate into the observed neuropsychological deficits which are often subtle and transient in nature but still insufficiently explained on grounds of morphology and structural connectivity alone. The sensitivity of rsfMRI to depict the functional communication of spatially remote brain regions presents a novel opportunity to investigate these deficits on a whole brain scale by mapping resting state functional connectivity in higher order cognition networks that are thought to be endangered by events related to both microsurgery and embolization. Correlating these data seems promising for several reasons. First, functional connectivity analysis could be correlated with the neuropsychological impairment in various neuropsychiatric disorders and in ischemic stroke. Ischemic damage to the territories supplied by ACoA perforating arteries is involved in many cases of postoperative neuropsychological impairment after ACoA aneurysm treatment. Second, neuropsychological evaluations have become increasingly incorporated into the standard of care in the postoperative follow-up of cerebral aneurysm patients. RsfMRI could serve as a novel adjunct to neuropsychological outcome assessment. Third, the results could add relevant information to our perception of the role of frontal lobe and forebrain damage in the pathophysiology of neurocognitive impairment. This could have an impact on neurorehabilitation programs to improve neurocognitive outcome and quality of life in this patient population. Forth, the correlation of validated neuropsychological tests with the functional connectivity rsfMRI data would further enhance the role of rsfMRI in neuroscience and its clinical use. Word count: 487

Long term outcome studies of aneurysmal subarachnoid hemorrhage survivors have demonstrated a variety of persistent neuropsychological deficits ranging from impairments of verbal memory, executive and motor function as well as in language and visual perception. In contrast, patients harboring unruptured intracranial aneurysms are usually without neurologic or behavioral impairment prior to surgery. However, neuropsychological deficits have been reported to occur in this patient group as a result of neurosurgical interventions, which comprise both, endovascular and surgical procedures. In summary, clinical studies describing the management of unruptured cerebral aneurysms emphasize that neurologic and behavioral impairment may occur and that patients harboring aneurysms of the anterior communicating artery (ACoA) have a higher risk to suffer such complications. Since the ACoA is the most frequent location for intracranial aneurysm formation (around 40%) these findings are of major concern. Therefore, we proposed a study that intended to investigate the neural consequences of uneventful microsurgical treatment of unruptured saccular non-giant ACoA aneurysms with structural and functional magnetic resonance imaging (MRI). In this study we were able to demonstrate for the first time the feasibility of functional MRi in patients after aneurysm clipping and coiling of an ACoA aneurysm. In detail, we found no signal drop-outs in preoperative and a low rate of signal drop outs in postoperative structural and functional MRI scanning (area around the aneurysm clip). Analysis of functional MRi showed activation as well as integration information of the region of interest (ventromedial prefrontal cortex) in all of the three paradigms (resting state with opened and closed eyes, memory experiments). In detail, patient data indicated that connectivity of distinct brain regions related to stimulus-value association and action consideration markedly decreased after surgery. The observed disconnection is remarkable and highly sensitive since it has been observed in each patient on an individual level. It is noteworthy that our imaging results are in accordance with behavioral measures since we found a significant alteration in neuropsychological testing based on increasing affect and emotion. However, our data do not support the idea of long-lasting neuronal alterations given the observed normalization of behavioral data within a year, a finding, which is limited by the rather small sample size. Based on the proven technical feasibility and patients' safety in this study our results will form the basis for future large studies in the field of functional MRi and the analysis of patients after elective microsurgical treatment of intracranial aneurysms.