Network-targeted cerebellar transcranial magnetic stimulation improves attentional control
Introduction
Attentional control, the ability to select and maintain task-relevant information processing, is critically important for many essential activities of daily life, from effectively accomplishing work/school activities (Kalechstein et al., 2003, Lam and Beale, 1991) to driver safety (Ball et al., 1991, Edkins and Pollock, 1997, Schmidt et al., 2009), and is impaired in a wide range of neurological and psychiatric populations. As attention underlies many other higher-level cognitive functions, attentional impairments can result in deficits of diverse cognitive functions (Fortenbaugh et al., in press). Thus, improvement of attentional control has widespread clinical appeal.
Converging evidence directly implicates a set of frontal and parietal regions, termed the dorsal attention network (DAN), in attentional control (i.e., preparing, initiating, and maintaining goal-directed attention; e.g., Corbetta et al., 2000; Kastner et al., 1999; Langner and Eickhoff, 2013; Fortenbaugh et al., in press). Recently, the DAN has been shown to include both cortical and cerebellar nodes (Brissenden et al., 2016). In contrast, during active engagement of the DAN, the medial prefrontal cortex, the precuneus and lateral inferior parietal regions, known as the default mode network (DMN), are commonly found to be deactivated (Buckner et al., 2008, Raichle et al., 2001; Raichle and Snyder, 2007). Thus, there is evidence that successful completion of attentional tasks requires some form of upregulation of the DAN and concomitant decreased response within the DMN.
Functional connectivity (FC) in the DAN is also related to attentional control. Specifically, increased FC within the DAN at rest corresponds with improved task performance (Hampson et al., 2006). Further, when attention is engaged, it dynamically modifies FC in the DAN. For example, studies have found greater within-DAN FC during the performance of a sustained attention task compared to rest (Bray et al., 2015). Critically, increased connectivity within the DAN, especially between cerebellar and cortical network nodes, corresponds to increased activation during multiple attentional tasks, suggesting a clear link between connectivity and cognitive performance (Brissenden, et al. 2016). In addition, greater resting connectivity between DAN and DMN is associated with poor attentional control and greater distractibility (e.g., Poole et al., 2016). In contrast, within-DMN FC has been less consistently linked with attention (Barber et al., 2015, Bonnelle et al., 2011). Together, FC data suggests that internal communication within the DAN, as well as distinctiveness from task-negative DMN, are reliable markers associated with better performance during tasks requiring voluntary attentional control.
Transcranial magnetic stimulation (TMS), a non-invasive intervention, might have the potential to enhance attention or ameliorate attention deficits due to its unique ability to modulate both brain activity and connectivity (Walsh and Pascual-Leone, 2003, Eldaief et al., 2011, Halko et al., 2014, Wang et al., 2014, Wang and Voss, 2015). Specifically, a key feature of TMS is that the effects are not limited to the stimulated region, but are further distributed to anatomically-connected sites (Ilmoniemi et al., 1997; Bohning et al., 1999; Morishima et al., 2008). These distributed effects of TMS, achieved through trans-synaptic activation (Amassian et al., 1990; Paus et al., 1997), can induce changes in functional connectivity (FC) between regions that include both the stimulated region (Eldaief et al., 2011, Halko et al., 2010, Wang et al., 2014, Wang and Voss, 2015), and its connected networks (Grosbras and Paus, 2002, Taylor et al., 2006, Silvanto et al., 2006, Ruff et al., 2006, Halko et al., 2014). Thus, effective therapeutic TMS interventions must rely upon an understanding of the targeted network, distributed effects (Dubin et al., 2017; Drysdale et al., 2017), as well as the state of the stimulated neuronal population (Silvanto et al., 2008; Miniussi et al., 2010).
TMS applied to regions of the DAN, such as the frontal eye field (FEF) and other frontal-parietal regions, has shown to decrease performance of orienting, distractor suppression, visual detection, and sustained attention (Chambers and Mattingley, 2005, Capotosto et al., 2012, Esterman et al., 2015). Stimulation of the FEF has also been found to increase BOLD responses in distal, but connected visual cortex, improving visual detection and enhancing excitability of visual areas (Grosbras and Paus, 2002, Taylor et al., 2006, Silvanto et al., 2006, Ruff et al., 2006). In contrast to the DAN, no work to our knowledge has considered the effects of DMN stimulation on attentional performance; this may partially be due to the inaccessibility of the core cortical regions of this network. Notably, an increase in the resting FC within the DAN and the DMN occurred after stimulation of distinctly localizable regions of the cerebellum (Halko et al., 2014), although this study did not measure cognition. Specifically, intermittent theta burst TMS (iTBS) increased resting FC within the DAN or within the DMN (Halko et al., 2014) after stimulation that targeted midline and lateral regions of the cerebellum respectively, regions exhibiting functional connectivity with cortical DAN and DMN regions. This stimulation of the cerebellum could induce these network-specific modulations by virtue of an indirect connection to brain networks via the thalamus (Schmahmann and Pandya, 1997, Strick et al., 2009) which can be observed with resting state FC (Buckner et al., 2011).
As attentional performance has been associated with FC within the DAN (Hampson et al., 2006, Bray et al., 2015, Brissenden et al., 2016), we examined whether TMS applied to the cerebellar node of the DAN could enhance attention. Since attentional performance is less associated with FC within the DMN, we contrasted cerebellar DAN stimulation to cerebellar DMN stimulation (as an active control). Specifically, we compared performance on a sustained attention task, the gradual onset continuous performance task (gradCPT), and a transient attention task, the attentional blink task pre/post iTBS. ITBS was applied at the midline cerebellar node of the DAN and the right cerebellar node of the DMN. We accessed the DAN/DMN via a network-based localization method (see localization approach in method section). Behavioral blocks preceding cerebellar-iTBS served as baseline performance measures. Given the importance of DAN activity and FC for sustained and selective aspects of attention, we hypothesized that stimulation of the DAN cerebellar node would improve attentional performance. Specifically, following cerebellar DAN stimulation, we predicted 1) reduced commission errors on the gradCPT, particularly while in the zone (Esterman et al., 2015), 2) enhanced ability to overcome the attentional blink as measured by fewer errors in reporting the second target, and 3) absence of attentional modulation following DMN cerebellar stimulation.
Section snippets
Participants
Fifteen healthy participants (11 males, mean age = 22.27, SD = 3.69) were recruited from Northeastern University and Boston University. All participants met the screening criteria for TMS (Rossi et al., 2009) and reported to be free of neurologic and psychiatric conditions. Subjects gave informed consent and the study was approved by the VA Boston Healthcare System IRB.
Overall experimental procedure
Using a within-subjects cross-over design, participants completed two 1–2 h TMS sessions separated by a washout period of 48
Participants
Our final sample consisted of 14 subjects (10 males, mean age = 22.29, SD = 3.83) after excluding one outlier (22-year-old male) based on Chauvenet's criterion (see Methods for a description). The outlier's pre/post change in gradCPT commission error rate (averaged across both stimulation sessions) was 2.8 SD from the mean.
Accuracy
We first sought to test whether there was an effect of cerebellar DAN vs. cerebellar DMN stimulation on commission error (CE) rate, with a three-way ANOVA with site (DAN/DMN),
Discussion
We applied iTBS to DAN and DMN hubs in the cerebellum in an attempt to enhance sustained and transient attentional control using a network-based localization method. Our results show that cerebellar DAN-targeted stimulation significantly reduced commission error rate during the gradCPT task post-iTBS compared to baseline pre-iTBS performance. In contrast, iTBS applied to cerebellar DMN did not modulate performance. Reaction time measures on the gradCPT were unaffected by either TMS condition.
Acknowledgements
This work was supported by the US Department of Veteran Affairs through a Clinical Science Research & Development Career Development Award (grant number 1IK2CX000706-01A2) to M.E, Sidney Baer Jr. Foundation Awards to M.A.H and S.E.L., and the National Institutes of Health (grant number 1R01MH112706) to M.A.H.
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