Research Articles: Behavioral/Cognitive Stimulation of the posterior cingulate cortex impairs episodic memory encoding https://doi.org/10.1523/JNEUROSCI.0698-19.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.0698-19.2019 Received: 19 February 2019 Revised: 29 May 2019 Accepted: 10 July 2019 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2019 the authors Stimulation of posterior cingulate impairs memory ͳ Title: Stimulation of the posterior cingulate cortex impairs episodic memory encoding ʹ ͵ Abbreviated title: Stimulation of posterior cingulate impairs memory Ͷ ͷ Authors and affiliations: Vaidehi S. Natu1, Jui-Jui Lin1, Alexis Burks1, Akshay Arora1, Michael D. Rugg2, ͸ Bradley Lega1 ͹ 1Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390 ͺ 2Center for Vital Longevity, University of Texas at Dallas, TX, 75080 ͻ ͳͲ Corresponding Author: Vaidehi S. Natu, Department of Neurological Surgery, Dallas, 75930, ͳͳ [email protected] ͳʹ ͳ͵ Conflict of Interest: The authors declare no competing financial interests. ͳͶ Keywords: deep brain stimulation, stereo electroencephalography, posterior cingulate cortex, episodic ͳͷ memory, hippocampus, functional connectivity ͳ͸ ͳ͹ Manuscript information: ͳͺ Number of pages: 24 ͳͻ Number of Figures: 4 ʹͲ Number of words: ʹͳ Abstract: 236 ʹʹ Introduction: 650 ʹ͵ Discussion: 1482 ʹͶ ʹͷ Authors’ Contributions. VSN analyzed patient data and wrote the manuscript; JJ performed data ʹ͸ collection and analyzed data. AB and AA contributed to data collection; MR contributed to discussions on ʹ͹ the manuscript. BL performed patient surgeries, implanted and localized electrodes in patients, oversaw ʹͺ all components of the study, and wrote the manuscript. All co-authors have read and approved the ʹͻ submitted manuscript. ͵Ͳ Acknowledgements: This research was funded by NINDS grants R01 NS107357-02 to BL. ͵ͳ ͵ʹ Significance Statement (120/120 words) ͵͵ Cognitive impairment and memory loss are critical public health challenges. Deep brain ͵Ͷ stimulation (DBS) is a promising tool for developing strategies to ameliorate memory disorders by ͵ͷ targeting brain regions involved in mnemonic processing. Using DBS, our study sheds light on the lesser- ͵͸ known role of the posterior cingulate cortex (PCC) in memory encoding. Stimulating the PCC during ͵͹ encoding impairs subsequent recall memory. The degree of impairment is predicted by stimulation- ͵ͺ induced hippocampal gamma oscillations and functional connectivity between PCC and hippocampus. Our 1 Stimulation of posterior cingulate impairs memory ͵ͻ findings provide the first causal evidence implicating PCC in memory encoding and highlight the PCC as a ͶͲ favorable target for neuromodulation strategies, using a-priori connectivity measures to predict Ͷͳ stimulation effects. This has significant implications for developing therapies for memory diseases. Ͷʹ Ͷ͵ Abstract (236/250) ͶͶ Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory Ͷͷ processing, making it a potential target for responsive neuromodulation strategies outside of the Ͷ͸ hippocampal network. However, causal evidence for the role PCC plays in memory encoding is lacking. In Ͷ͹ human female and male participants (N=17) undergoing seizure mapping, we investigated functional Ͷͺ properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography (stereo Ͷͻ EEG). We used a verbal free recall paradigm in which the PCC was stimulated during presentation of half ͷͲ of the study lists, while no stimulation was applied during presentation of the remaining lists. We ͷͳ examined whether stimulation affected memory and modulated hippocampal activity. Results revealed ͷʹ four main findings. (i) Stimulation during episodic memory encoding impaired subsequent free recall, ͷ͵ predominantly for items presented early in the study lists. (ii) PCC stimulation increased hippocampal ͷͶ gamma band power. (iii) Stimulation-induced hippocampal gamma power predicted the magnitude of ͷͷ memory impairment. (iv) Functional connectivity between the hippocampus and PCC predicted the ͷ͸ strength of the stimulation effect on memory. Our findings offer causal evidence implicating the PCC in ͷ͹ episodic memory encoding. Importantly, the results indicate that stimulation targeted outside of the ͷͺ temporal lobe can modulate hippocampal activity and impact behavior. Furthermore, measures of ͷͻ connectivity between brain regions within a functional network can be informative in predicting ͸Ͳ behavioral effects of stimulation. Our findings have significant implications for developing therapies to ͸ͳ treat memory disorders and cognitive impairment using DBS. ͸ʹ ͸͵ Introduction (650/650) ͸Ͷ Deep brain stimulation (DBS) is a powerful tool used clinically to target dysregulated neural ͸ͷ circuits and to treat neurological disorders including Parkinson’s disease, essential tremor, psychiatric ͸͸ illnesses, and epilepsy (Limousin et al., 1998; Perlmutter et al., 2006; Kringelbach et al., 2007; Ressler et ͸͹ al., 2007; Bronstein et al., 2011). Several studies have applied DBS to patients undergoing treatment for ͸ͺ epilepsy for understanding the effects of stimulation on human memory (Coleshill et al., 2004; Lacruz et ͸ͻ al., 2010; Suthana et al., 2012; Fell et al., 2013; Jacobs et al., 2016; Ezzyat et al., 2017; Ezzyat et al., 2018; ͹Ͳ Kucewicz et al., 2018; Goyal et al., 2018; Inman et al., 2018). Electrical stimulation applied to core memory ͹ͳ regions including the hippocampus and entorhinal cortex impairs memory (Jacobs et al., 2016; Goyal et al., ͹ʹ 2018) (with some exceptions showing memory enhancement (Suthana et al., 2012; Suthana and Fried, 2 Stimulation of posterior cingulate impairs memory ͹͵ 2014)). These findings indicate causal importance of cortical structures and implicate DBS as an ideal ͹Ͷ method for developing neuromodulation strategies to treat memory disorders (Johnson et al., 2013). ͹ͷ The posterior cingulate cortex (PCC) is a deep cortical region that supports episodic memory ͹͸ processing. The majority of the evidence on PCC’s role in memory processing comes from non-invasive ͹͹ neuroimaging studies showing reduced neural activation for successfully remembered than forgotten ͹ͺ items (negative subsequent memory effect, SME) during memory encoding (Otten et al., 2001; Daselaar ͹ͻ et al., 2004; Uncapher et al., 2006; Miller et al., 2008; Duverne et al., 2009; Huijbers et al., 2011). The PCC ͺͲ also exhibits increased activation during successful episodic retrieval (Maddock et al., 2001; Cabeza et al., ͺͳ 2004; Wagner et al., 2005; Sestieri et al., 2011; Huijbers et al., 2011; Rugg et al., 2013). Additionally, ͺʹ evidence of PCC’s dense anatomical connections with medial temporal cortex and memory impairments ͺ͵ associated with (a) reduced metabolism in the PCC and (b) abnormal functional connectivity between PCC ͺͶ and hippocampus (Minoshima et al., 1997; Greicius et al., 2004; Zhou et al., 2008; De Vogelaere et al., ͺͷ 2012; Leech et al., 2014; Papma et al., 2017) make the PCC an excellent neuromodulation target for ͺ͸ cognitive enhancement. Despite fMRI evidence, progress on PCC’s role in memory encoding using ͺ͹ electroencephalography (EEG) remains limited as PCC is buried deep inside the medial surface of the brain. ͺͺ Recent intracranial EEG (iEEG) work using grid electrodes reported that the posterior medial cortex (PMC), ͺͻ including the PCC, shows increase in high gamma band activity in the PMC during memory retrieval ͻͲ (Foster et al., 2012; Foster et al., 2013; Foster et al., 2015; Fox et al., 2018) providing evidence for PMC’s ͻͳ role in memory cognition. Here we used DBS and iEEG to: (i) examine the role of PCC in episodic memory ͻʹ encoding and (ii) determine if PCC could be used as a target region for memory enhancement. ͻ͵ Based on prior fMRI findings (e.g., Otten et al., 2001; Duverne et al., 2009; Daselaar et al., 2004) ͻͶ that episodic memory encoding is facilitated when neural activity in the PCC is attenuated, we reasoned ͻͷ that high-frequency stimulation delivered to PCC during encoding might enhance memory. To test this ͻ͸ prediction, we stimulated the PCC (Fig. 1) using robotically-placed stereotactic EEG electrodes implanted ͻ͹ for seizure mapping (Lin et al., 2017; Lega et al., 2017). The stereo EEG technique allows: (i) precise ͻͺ targeting of deep brain regions (Fig. 1b) and (ii) simultaneous acquisition of oscillatory recordings from ͻͻ neighboring regions, such as the hippocampus (Fig. 1c). We employed a free recall memory task in which ͳͲͲ participants memorized a list of sequentially presented words during an encoding period, and then ͳͲͳ following a brief distraction period, attempted to freely recall the words. PCC was stimulated during the ͳͲʹ entire encoding period for half of the study lists, while no stimulation was applied during remainder of the ͳͲ͵ lists. We examined if: (i) stimulation induced memory enhancement or impairment, (ii) stimulation ͳͲͶ induced modulations in hippocampal oscillations, and (iii) there was a relationship between behavioral ͳͲͷ and neural effects of stimulation. ͳͲ͸ ͳͲ͹ Figure 1 approximately