Rethinking NBM DBS: Intermittent stimulation improves sustained attention in Parkinson's disease

Degeneration of the Nucleus Basalis of Meynert (NBM) has been implicated in the cognitive decline in Parkinson's disease (PD) [[1]Ray N.J. Bradburn S. Murgatroyd C. Toseeb U. Mir P. Kountouriotis G.K. Teipel S.J. Grothe M.J. In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.Brain. 2018 Jan 1; 141: 165-176Crossref PubMed Scopus (105) Google Scholar] and has therefore been a target of interest for deep brain stimulation (DBS). We have previously published on the feasibility and safety of NBM and globus pallidus interna stimulation in PD with advanced cognitive impairment [[2]Sasikumar S. Cohn M. Harmsen I.E. Loh A. Cho S.S. Sáenz‐Farret M. Maciel R. Soh D. Boutet A. Germann J. Elias G. Single‐trajectory multiple‐target deep brain stimulation for parkinsonian mobility and cognition.Mov Disord. 2022 Mar; 37: 635-640Crossref PubMed Scopus (7) Google Scholar]. The NBM was programmed to performance on sustained attention as it is a sensitive marker of cholinergic activity [[3]Bentley P. Driver J. Dolan R.J. Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging.Prog Neurobiol. 2011 Sep 1; 94: 360-388Crossref PubMed Scopus (134) Google Scholar] and is crucial to several activities of daily living [[4]Schepers A.M. Schorrlepp L. de Vries J.D. de Kloe T. van der Linden D. Bijleveld E. Revisiting the link between the sustained attention to response task (SART) and daily-life cognitive failures.Conscious Cognit. 2023 Sep 1; 114103558Crossref PubMed Scopus (0) Google Scholar]. NBM stimulation had improved sustained attention acutely, but gains were not maintained after eight weeks of constant low-frequency NBM stimulation. Indeed, four of the six participants demonstrated further cognitive decline 1-year post-DBS. In the open-label period, participants remained on continuous NBM stimulation. Although optimal duration and frequency of NBM stimulation has not been established [[5]Rasmusson D.D. Clow K. Szerb J.C. Frequency-dependent increase in cortical acetylcholine release evoked by stimulation of the nucleus basalis magnocellularis in the rat.Brain Res. 1992 Oct 23; 594: 150-154Crossref PubMed Scopus (77) Google Scholar,[6]Montero-Pastor A. Vale-Martínez A. Guillazo-Blanch G. Martí-Nicolovius M. Effects of electrical stimulation of the nucleus basalis on two-way active avoidance acquisition, retention, and retrieval.Behav Brain Res. 2004 Sep 23; 154: 41-54Crossref PubMed Scopus (31) Google Scholar], studies in non-human primates reveal that continuous stimulation impaired performance in a working memory task [[7]Liu R. Crawford J. Callahan P.M. Terry A.V. Constantinidis C. Blake D.T. Intermittent stimulation of the nucleus basalis of Meynert improves working memory in adult monkeys.Curr Biol. 2017 Sep 11; 27: 2640-2646Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Rather, intermittent stimulation of 60 pulses per second, for 20 seconds every minute improved working memory function by 32–44 % [[6]Montero-Pastor A. Vale-Martínez A. Guillazo-Blanch G. Martí-Nicolovius M. Effects of electrical stimulation of the nucleus basalis on two-way active avoidance acquisition, retention, and retrieval.Behav Brain Res. 2004 Sep 23; 154: 41-54Crossref PubMed Scopus (31) Google Scholar], with longer intervals (6–30 seconds) resulting in more improvement than shorter intervals (1.5–8 seconds) [[8]Blake D.T. Terry A.V. Plagenhoef M. Constantinidis C. Liu R. Potential for intermittent stimulation of nucleus basalis of Meynert to impact treatment of alzheimer's disease.Commun Integr Biol. 2017 Nov 2; 10: 2640-2646Crossref Scopus (10) Google Scholar]. This benefit was appreciated up to 3 months later, even in the absence of stimulation. The same intermittent NBM stimulation parameters improved sustained attention [[9]Liu R. Crawford J. Callahan P.M. Terry A.V. Constantinidis C. Blake D.T. Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys.Neuropharmacology. 2018 Jul 15; 137: 202-210Crossref PubMed Scopus (16) Google Scholar]. To assess the effects of intermittent NBM stimulation in humans, we performed a double-blind study with three participants (converted to PD dementia) from our previous trial. Informed consent was obtained and the study was performed in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Of the six initially recruited participants, one had passed away from non-PD related causes, another had moved out of province, and one had advanced disease that precluded participation in baseline cognitive assessments. After adjusting for anatomical size differences in non-human primates, intermittent NBM stimulation was set to 3mA, 60us and 60Hz for 1 hour daily, cycling between 20 seconds ON and 40 seconds OFF stimulation (Fig. 1A; Fig. S2). Participants were either randomized to intermittent or continuous stimulation at the same time every day, followed by a four-week cross-over period (Fig. 1B; Table S1). The primary outcome was performance on cognitive measures, which was assessed in a blinded fashion at baseline, four- and eight-weeks (Table S2). As an exploratory outcome, we assessed gait parameters on a six-metre walkway (Zeno walkway® by Protokinetics, USA) at the same intervals, to assess the impact of NBM cholinergic stimulation on gait (Table S3). Our results indicate that compared to baseline, intermittent stimulation significantly improves sustained attention (B = 0.13, se = 0.05, p = 0.01) whereas continuous stimulation does not affect cognitive scores (B = 0.02, se = 0.05, p = 0.75) (Fig. 1C). Gains were not appreciated in other cognitive domains (Table S2). Fig. S1 demonstrates the mean difference in sustained attention scores under different NBM stimulation conditions, including data from our previous trial [[2]Sasikumar S. Cohn M. Harmsen I.E. Loh A. Cho S.S. Sáenz‐Farret M. Maciel R. Soh D. Boutet A. Germann J. Elias G. Single‐trajectory multiple‐target deep brain stimulation for parkinsonian mobility and cognition.Mov Disord. 2022 Mar; 37: 635-640Crossref PubMed Scopus (7) Google Scholar]. One participant (ID 1) experienced worsening visual hallucinations with intermittent NBM stimulation, which resolved in the cross-over period. Spatiotemporal gait parameters (including gait variability) remained unchanged between stimulation conditions. Although preliminary, these results confirm what has been previously reported in primates: that intermittent, not continuous, low-frequency stimulation of the NBM might improve cognition. Our group continues to follow these participants to assess long-term cognitive gains, but further studies will need to replicate this hypothesis in larger cohorts. Finally, the lack of gait improvement might indicate that cholinergic projections from the pedunculopontine nucleus, and not the basal forebrain, play a role in the motor manifestations of PD. 1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique. SS: 1A, 1B, 1C, 2A, 2B, 3A. MC: 1A, 1B, 1C, 2C, 3B. AY: 1B, 1C, 2A, 2B, 3B. KD: 2C, 3B. APS: 2C, 3B. DB: 1A, 1B, 3B. AF: 1A, 1B, 2C, 3B. A.B. reports receiving honoraria from the American Academy of Neurology and Abbvie, consultancy fees from Abbvie, Abbott and Boston Scientific, and research grant from Fernand Lazard Foundation. All disclosures are not relevant to the paper. A.S. is a consultant for Hoffman La Roche and received honoraria from GE Health Care Canada LTD, Hoffman La Roche. A.F. reports the following: Consultancies from AbbVie, Ceregate, Medtronic, Boston Scientific, Iota, Inbrain, Inbrain Pharma; Honoraria from Abbvie, Medtronic, Boston Scientific, Sunovion, Chiesi farmaceutici, UCB, Ipsen; grants from University of Toronto, Weston foundation, Abbvie, Medtronic, Boston Scientific, CIHR. This work was supported by the Chair in Neuromodulation (A.F.) at University of Toronto and University Health Network, Toronto, ON, Canada, Canadian Institutes of Health Research (S.S.), Krembil-Rossy Chair (A.S) and Canadian Institutes of Health Research (CIHR) (PJT- 173540) (A.S)

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