Mapping the Dynamic Network Interactions Underpinning Cognition: A cTBS-fMRI Study of the Flexible Adaptive Neural System for Semantics

Cerebral Cortex, August 2016;26: 3580–3590 doi:10.1093/cercor/bhw149 Advance Access Publication Date: 30 May 2016 Original Article ORIGINAL ARTICLE Mapping the Dynamic Network Interactions Underpinning Cognition: A cTBS-fMRI Study of the Flexible Adaptive Neural System for Semantics JeYoung Jung and Matthew A. Lambon Ralph Neuroscience and Aphasia Research Unit (NARU), School of Psychological Sciences, University of Manchester, Manchester, UK Address correspondence to Matthew A. Lambon Ralph, Neuroscience and Aphasia Research Unit (NARU), School of Psychological Sciences (Zochonis Building), University of Manchester, Brunswick Street, Manchester M13 9PL, UK. Email: ; JeYoung Jung, Neuroscience and Aphasia Research Unit (NARU), School of Psychological Sciences (Zochonis Building), University of Manchester, Brunswick Street, Manchester M13 9PL, UK. Email: Abstract Higher cognitive function reflects the interaction of a network of multiple brain regions. Previous investigations have plotted out these networks using functional or structural connectivity approaches. While these map the topography of the regions involved, they do not explore the key aspect of this neuroscience principle—namely that the regions interact in a dynamic fashion. Here, we achieved this aim with respect to semantic memory. Although converging evidence implicates the anterior temporal lobes (ATLs), bilaterally, as a crucial component in semantic representation, the underlying neural interplay between the ATLs remains unclear. By combining continuous theta-burst stimulation (cTBS) with functional magnetic resonance imaging (fMRI), we perturbed the left ventrolateral ATL (vATL) and investigated acute changes in neural activity and effective connectivity of the semantic system. cTBS resulted in decreased activity at the target region and compensatory, increased activity at the contralateral vATL. In addition, there were task-specific increases in effective connectivity between the vATLs, reflecting an increased facilitatory intrinsic connectivity from the right to left vATL. Our results suggest that semantic representation is founded on a flexible, adaptive bilateral neural system and reveals an adaptive plasticity-based mechanism that might support functional recovery after unilateral damage in neurological patients. Key words: anterior temporal lobe, bilateral system, cTBS, fMRI, semantic representation Introduction Human higher cognitive function is not localized to single brain region but, rather, reflects the interaction of a network of multiple brain regions that act in concert to achieve flexible cognitive behaviors. Previous studies have demonstrated these brain networks using functional or structural connectivity approaches (Honey et al. 2009; van den Heuvel et al. 2009). While these studies provide the topology of brain networks, they pretermitted a key aspect of this neuroscience principle: how brain regions interact in a dynamic fashion to achieve cognitive function. Here, we explored this issue targeting a higher cognitive function, semantic memory, by employing a combination of transcranial magnetic stimulation (TMS) and fMRI. Semantic memory refers to our collective knowledge about words, pictures, objects, people, emotions, etc. The neural basis of semantic memory reflects a large-scale network of distributed, interconnected brain regions (Patterson et al. 2007; Binder et al. 2009). Accumulating, convergent evidence indicates that among © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. A Flexible Adaptive Bilateral Neural System For Human Semantics these brain areas, the ATLs act as a transmodal hub (Lambon Ralph et al. 1999; Bozeat et al. 2000; Chan et al. 2001; Coccia et al. 2004; Pobric et al. 2007; Lambon Ralph and Patterson 2008; Pobric et al. 2009, 2010a, 2010b, 2010c; Binney et al. 2010; Peelen and Caramazza 2012) which interacts with distributed modality-specific association regions to generate coherent, generalizable semantic representations (Lambon Ralph and Patterson 2008; Lambon Ralph, Sage, et al. 2010). While the key regions within the semantic network have been localized, we know very little about the functionally related interactions within this network and how these generate a relatively robust system capable of withstanding partial damage (e.g., as observed in patients with partial unilateral ATL damage) (Lambon Ralph, Cipolotti, et al. 2010; Schapiro et al. 2013). Therefore, by using a combination of TMS, fMRI, and connectivity analyses, this study investigated the flexible, adaptive nature of the bilateral neural system for semantic representation. Repetitive transcranial magnetic stimulation (rTMS) over left or right ATL generates slowed rather than interrupted semantic performance in healthy participants (Pobric et al. 2007, 2009, 2010a, 2010b, 2010c). Likewise, patients with unilateral ATL damage (either left or right) exhibit mild semantic impairment on sensitive timed assessments but perform much better overall than those with bilateral temporal damage (Lambon Ralph, Cipolotti, et al. 2010; Bi et al. 2011; Lambon Ralph et al. 2012). These findings mirror seminal investigations of unilateral versus bilateral ATL resections in nonhuman primates and 1 human case (Brown and Schafer 1888; Klüver and Bucy 1939; Terzian and Ore 1955) in which unilateral resection generated only a transient multimodal associative agnosia, whereas bilateral resection led to devastated semantic performance. These findings imply that the bilateral ATL semantic system is configured to be a damage-resistant, robust system. The neural mechanism, by which the ATLs interact with each other and other regions to underpin semantic function in the intact and partially damaged situation, remains unclear. Formal computational explorations of a bilaterally configured ATL semantic system suggest that dual representational hubs lead to an inherently greater robustness to unilateral than bilateral damage (even when total damage is held constant) and that this difference is magnified through long-term plasticity-related changes postdamage (as observed in unilateral patients) (Schapiro et al. 2013). Additional clues come from a study of patients with variable receptive language skills poststroke (Warren et al. 2009); overall, the patients showed a decrease in inter-ATL functional connectivity relative to healthy controls. More importantly, their comprehension performance was predicted by the degree of remaining ATL interconnectivity, such that those with preserved ATL connectivity exhibited the best language performance. In the current study, we investigated the neural interactivity underpinning the semantic system through a combin (...truncated)