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. 2018 Sep 3:12:614.
doi: 10.3389/fnins.2018.00614. eCollection 2018.

Nucleus Basalis of Meynert Stimulation for Dementia: Theoretical and Technical Considerations

Deepak Kumbhare  1   2 , Viktoras Palys  1   3 , Jamie Toms  1   4 , Chathurika S Wickramasinghe  5 , Kasun Amarasinghe  5 , Milos Manic  5 , Evan Hughes  6 , Kathryn L Holloway  1   4
Affiliations

Nucleus Basalis of Meynert Stimulation for Dementia: Theoretical and Technical Considerations

Deepak Kumbhare et al. Front Neurosci. .

Abstract

Deep brain stimulation (DBS) of nucleus basalis of Meynert (NBM) is currently being evaluated as a potential therapy to improve memory and overall cognitive function in dementia. Although, the animal literature has demonstrated robust improvement in cognitive functions, phase 1 trial results in humans have not been as clear-cut. We hypothesize that this may reflect differences in electrode location within the NBM, type and timing of stimulation, and the lack of a biomarker for determining the stimulation's effectiveness in real time. In this article, we propose a methodology to address these issues in an effort to effectively interface with this powerful cognitive nucleus for the treatment of dementia. Specifically, we propose the use of diffusion tensor imaging to identify the nucleus and its tracts, quantitative electroencephalography (QEEG) to identify the physiologic response to stimulation during programming, and investigation of stimulation parameters that incorporate the phase locking and cross frequency coupling of gamma and slower oscillations characteristic of the NBM's innate physiology. We propose that modulating the baseline gamma burst stimulation frequency, specifically with a slower rhythm such as theta or delta will pose more effective coupling between NBM and different cortical regions involved in many learning processes.

Keywords: Parkinson’s disease dementia; basal nucleus of Meynert; deep brain stimulation; diffusion tensor imaging; neuronal oscillations; quantitative electroencephalography.

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Figures

FIGURE 1
FIGURE 1
(A) This figure was originally published in Mesulam and Geula (1988). These coronal slices of the human brain from Mesulam and Geula (1988) demonstrate the locations of the ChAT positive neurons in the sub-nuclei of the Ch4 complex (NBM) within the context of the basal ganglia anatomy. Permission was granted by John Wiley and Sons (license number: 4330331169891). ac, anterior commissure; Am, amygdaloid nuclei; an, ansa lenticularis; aP, ansa peduncularis; Ch4a, anterior sector of Ch4; Ch4ai, anterointermediate sector of Ch4; Ch4al, anterolateral subsector of Ch4; Ch4am, anteromedial subsector of Ch4; Ch4id, interomediodorsal subsector of Ch4; Ch4iv, interomedioventral subsector of Ch4; Cl, claustrum; cp, cerebral peduncle; eml, external medullary lamina of the globus pallidus; ent, entorhinal cortex; Fx, fornix; GP, globus pallidus; GPe, globus pallidus (external segment); GPi, globus pallidus (internal segment); Hp, hippocampal formation; Hy, hypothalamus; IC, internal capsule; iml, internal medullary lamina of the globus pallidus; IN, insular cortex; itp, inferior thalamic peduncle; nst, nucleus of the stria terminalis; oc, optic chiasm; ot, optic tract; PO, preoptic area; pt, putamen. (B) Illustration of different NBM territories in the axial (i) and coronal (ii) plane, based on the range of coordinates described in the following NBM studies in rats. Boix-Trelis et al. (2006) observed increased C-Fos expression in cingulate, parietal, piriform and perirhinal cortices, but not in entorhinal cortex or amygdala nuclei when stimulated NBM sub regions around 0.95–1.8 mm posterior to bregma and 2.8 mm lateral to midline (black asterisks) (Boix-Trelis et al., 2006). Weinberger et al on the other hand showed that the activity of NBM in posterior 2.3 mm and lateral 3.3 mm (blue asterisks) is strongly correlated to auditory cortex (Weinberger et al., 2009, 2013). On the other hand, the barrel cortex is more predominantly affected by NBM stimulation in the region posterior 0.8 mm, L 2.6 mm (red asterisks). Visual cortex, has been estimated to be influenced by an NBM sub-region around posterior 2.8 and lateral 4 mm (Goard and Dan, 2009) (green asterisks). Buzsáki and Wang (2012) have noted that the NBM stimulation changes in EEG are in agreement with the anatomical findings, which provides additional evidence that the NBM projection to the cortex is topographically specific. The GP and STN region (yellow and pink regions respectively) are also shown for reference.
FIGURE 2
FIGURE 2
This figure from Gratwicke et al. (2013) demonstrates the NBM and its major cholinergic pathways in human brain. A, amygdala; AC, anterior commissure (lateral aspect); C, caudate; Cg, Cingulate gyrus; F, frontal lobe (medial surface); GPi, globus pallidus (internus); IN, insular cortex; NBM, nucleus basalis of Meynert; Oc, occipital lobe (medial surface); OF, orbitofrontal cortex; P, putamen; Pr, parietal lobe (medial surface). Permission was granted by Elsevier (license number: 4325321354014).
FIGURE 3
FIGURE 3
The entire left NBM has been seeded in a patient who subsequently underwent placement of a Left GPI DBS. The post-operative CT has been merged and the lead extracted to demonstrate the relative position of a standard GPI lead in relation to the bulk of the NBM outflow tracts. The bilateral NBM nuclei are reconstructed as described in the text and shown here in blue. The optic chiasm (yellow) and midline aspect of the anterior commissure (red) are shown for perspective. Frontal, temporal (via uncinate fasciculus) and parieto-occipital fibers are visualized.
FIGURE 4
FIGURE 4
Topographical maps of QEEG from three patients with DBS leads in different nuclei (GPI, STN, VIM), using the Electrical Geodesics Inc. data acquisition system. (A) Subtraction plot of beta band (12–30 Hz) activity in the “On” minus “Off” stimulation conditions using optimal DBS lead configurations and parameters for in (A1) GPI (A2) STN (A3) VIM during the awake resting condition. (B) Topoplots for EEG beta band for single patient using the (B1) Optimal (1,2), (B2) contact 0, and (B3) contact 3 of DBS electrode demonstrating differential modulation of different sub-regions in the cortex.
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