CAUSAL MECHANISMS OF DISTRIBUTED BRAIN NETWORK FUNCTION DURING EPISODIC MEMORY RETRIEVAL

Research Statement SIGNIFICANCE Memory impairments are common to several neurological and psychiatric disorders, including Alzheimer's disease and depression, and these impose a heavy burden on patients, families and society (Dickerson and Eichenbaum, 2007). Novel treatment and diagnostic strategies are needed, and these may arise from a deeper understanding of the brain basis of episodic memory (Tulving, 1983).

Group-averaged neuroimaging studies have revealed that a distributed network, known as the 'default network' (DN), increases activity during the recollection of past events (Buckner et al. 2008). This network occupies regions including posteromedial cortex (PMC), posterior parietal cortex (PPC), and the medial temporal lobe (MTL), as well as lateral temporal and lateral and medial prefrontal cortices. Building on recent advances in functional magnetic resonance imaging (fMRI; Poldrack et al., 2015; Laumann et al., 2015), recent evidence has shown that when functional anatomy is defined in individuals, the DN comprises at least two juxtaposed networks, named DN-A and DN-B for convenience (Figure 1). This finding forces us to reconsider the role of the DN in episodic processes (see also: Dastjerdi et al., 2011; Andrews-Hanna et al., 2010). Here we propose experiments to deepen our understanding of these networks using a multimodal approach that provides high spatiotemporal resolution and whole-brain network definition. We will combine within-individual fMRI mapping with intracranial electroencephalography (iEEG) and electrical brain stimulation (EBS). We will directly record local field potentials from precisely mapped network regions, and apply electrical stimulation with millimeter precision. This will provide novel information regarding episodic memory in two domains that cannot be gathered by fMRI alone: i) characterizing fast temporal dynamics of network recruitment during episodic recollection, and ii) establishing causal interactions between brain regions during recollection.

INNOVATION Methodologically, this project will provide proof of principle that precision fMRI mapping can be performed in a clinical population and successfully combined with invasive recordings and stimulation. Theoretical innovation will be obtained through a deeper understanding of the task-response dynamics, coupling, and causal relationships between regions of distributed networks, including how neural engagement changes during memory recollection. Finally, this proposal provides translational innovation by directly testing whether precision-fMRI guided intracranial stimulation can be used modulate memory performance.

APPROACH General methods: Participants in the proposed experiments will be neurosurgical patients with presumed focal epilepsy that are to undergo implantation with intracranial electrodes for localizing seizure foci. The proposal will be carried out at the Northwestern University Feinberg School of Medicine. Patients scheduled for intracranial seizure monitoring will be invited to enroll in the study and will undergo 1 to 4 sessions of fMRI prior to surgical implantation of electrodes. After surgery, patients are typically monitored for ~7 days in the Northwestern Memorial Hospital Comprehensive Epilepsy Centre (CEC), during which they will be invited to participate in the proposed experiments. All subjects must provide informed consent before participating.

Enrollment: A minimum of 40-50 patients are expected to be monitored at the CEC over the next 3 years. Electrode locations are determined by the clinical needs of the patient. 60-70% of patients are typically implanted with dense coverage of the medial temporal lobes achieved through depth electrodes with trajectories that allow sampling of lateral temporal cortices. A small number of electrodes are also typically implanted in posterior cingulate, lateral inferior parietal and ventromedial prefrontal cortex. Due to the distributed nature of the networks under investigation, which contain regions in multiple cortical zones, it is likely that we will have coverage over relevant brain regions in many cases. Some patients are also likely to be implanted with broader cortical coverage using subdural grids. Preliminary results have shown that even when a patient is implanted only with depth electrodes, which are not placed on the cortical surface but penetrate into the brain, coverage of different candidate network regions was often achieved along the electrode trajectory. With conservative estimates, 20-30 subjects will be good candidates for the project aims outlined below. Given the high signal-to-noise ratio of iEEG (usually a 200-300% task-evoked increase in signal from baseline; Parvizi and Kastner, 2017), reliable effects can typically be found within individuals. All proposed analyses will be carried out within individuals, hence multiple subjects are required to generalize the findings, not increase statistical power. Therefore, a small number of subjects (as low as n = 12) would be sufficient (e.g. Braga and Buckner, 2017; Foster et al., 2013).