Serendipitous Stimulation of Nucleus Basalis of Meynert—The Effect of Unintentional, Long-Term High-Frequency Stimulation on Cognition in Parkinson’s Disease

There is a growing interest in deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) as a potential therapeutic modality for Parkinson’s disease dementia (PDD). Low-frequency stimulation has yielded encouraging results in individual patients; however, these are not yet sustained in larger studies. With the aim to expand the understanding of NBM-DBS, we share our experience with serendipitous NBM-DBS in patients treated with DBS of the internal Globus pallidus (GPi) for Parkinson’s disease. Since NBM is anatomically located ventral to GPi, several GPi-treated patients appeared to have the distal contact of DBS-electrode(s) positioned in the NBM. We hypothesized that unintentional high-frequency NBM-DBS over a period of one year would result in the opposite effect of low-frequency NBM-stimulation and cause cognitive decline. We studied a cohort of 33 patients with bilateral high-frequency DBS in the GPi for Parkinson’s disease, of which twelve were unintentionally co-stimulated in NBM. The subgroups of unintentional unilateral (N = 7) and bilateral NBM-DBS (N = 5) were compared to the control group of bilateral GPi-DBS (N = 11). Here, we show that unintentional high-frequency NBM-DBS did not cause a significantly faster decline in cognitive function. Further research is warranted for characterizing the therapeutic role of NBM-DBS.

Current Research on Deep Brain Stimulation and Cognitive Impairment in Parkinson’s Disease

Cognitive impairment is one of the common non-motor complications in Parkinson’s disease. The underlying mechanism remains elusive due to multiple reasons. As a result, treatment options for cognitive decline in Parkinson’s disease are limited and not as effective as those for motor symptoms. Recent advances in neuroscience have developed new models for the pathophysiology of Parkinson’s disease dementia, based on which clinical research have showed promising results. The role of multiple neurotransmitter systems in cognitive impairment have been emphasized. The change in different functional neural networks (including microscale, mesoscale, and macroscale) resulting from abnormal neurobiochemical environment partly explains the clinical picture. Accordingly, neuromodulation methods can be good candidates for symptomatic management. Several preliminary studies on deep brain stimulation have demonstrated positive results. The nucleus basalis of Meynert, a hub in the cognitive network, is chosen by most studies as the stimulation target. Deep brain stimulation for motor symptoms, on the other hand, may also cause or aggravate patients’ cognitive dysfunction. Their influence on cognition is multifaceted and should be taken into account during patient selection, target design, and programming.

Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract

Objective:Determine the relationship between diffusion microstructure and early changes in Alzheimer’s disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain.Methods:Diffusion MRI scans were collected on cognitively normal participants (CN), patients with early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, four magnocellular regions of the basal forebrain (e.g. nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples.Results:FW was significantly higher in EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; pfdr<0.05). FW was significantly higher in AD compared to CN in all the examined regions (mean Cohen d = 1.41; pfdr<0.01). Additionally, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all five cognitive impairment metrics, and neurofilament light chain levels (mean r2 = 0.10; pfdr<0.05).Conclusions:These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and non-invasive early marker of structural changes related to cognitive impairment.

Effects of Cigarette Smoking on Resting-State Functional Connectivity of the Nucleus Basalis of Meynert in Mild Cognitive Impairment

Background: Mild cognitive impairment (MCI) is the prodromal phase of Alzheimer’s disease (AD) and has a high risk of progression to AD. Cigarette smoking is one of the important modifiable risk factors in AD progression. Cholinergic dysfunction, especially the nucleus basalis of Meynert (NBM), is the converging target connecting smoking and AD. However, how cigarette smoking affects NBM connectivity in MCI remains unclear.Objective: This study aimed to evaluate the interaction effects of condition (non-smoking vs. smoking) and diagnosis [cognitively normal (CN) vs. MCI] based on the resting-state functional connectivity (rsFC) of the NBM.Methods: After propensity score matching, we included 86 non-smoking CN, 44 smoking CN, 62 non-smoking MCI, and 32 smoking MCI. All subjects underwent structural and functional magnetic resonance imaging scans and neuropsychological tests. The seed-based rsFC of the NBM with the whole-brain voxel was calculated. Furthermore, the mixed effect analysis was performed to explore the interaction effects between condition and diagnosis on rsFC of the NBM.Results: The interaction effects of condition × diagnosis on rsFC of the NBM were observed in the bilateral prefrontal cortex (PFC), bilateral supplementary motor area (SMA), and right precuneus/middle occipital gyrus (MOG). Specifically, the smoking CN showed decreased rsFC between left NBM and PFC and increased rsFC between left NBM and SMA compared with non-smoking CN and smoking MCI. The smoking MCI showed reduced rsFC between right NBM and precuneus/MOG compared with non-smoking MCI. Additionally, rsFC between the NBM and SMA showed a significant negative correlation with Wechsler Memory Scale-Logical Memory (WMS-LM) immediate recall in smoking CN (r = −0.321, p = 0.041).Conclusion: Our findings indicate that chronic nicotine exposure through smoking may lead to functional connectivity disruption between the NBM and precuneus in MCI patients. The distinct alteration patterns on NBM connectivity in CN smokers and MCI smokers suggest that cigarette smoking has different influences on normal and impaired cognition.

Cholinergic white matter pathways in dementia with Lewy bodies and Alzheimer’s disease

Dementia with Lewy bodies and Alzheimer’s disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 Alzheimer’s disease dementia, 48 dementia with Lewy bodies, 35 mild cognitive impairment with Alzheimer’s disease, 38 mild cognitive impairment with Lewy bodies, and 71 controls. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes, and dementia conversion in the mild cognitive impairment groups. We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P &lt; 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (β=-0.22, P = 0.06) and worse performance on an attention task (β = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression (hazard ratio [95% confidence interval], medial pathway: 2.51 [1.24–5.09]; lateral pathway: 2.54 [1.24–5.19]). Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P &lt; 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (β = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (β=-0.47, P = 0.003). We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer’s disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment.

Global and network functional connectivity of nucleus basalis of Meynert is strengthened in blind individuals

Vision loss causes dramatic changes in brain function which are thought to facilitate behavioral adaptation. One interesting prospect is that the cholinergic signals are involved in this blindness-induced plasticity. Critically, the nucleus basalis of Meynert is the principal source of the cholinergic signals, however, no studies have yet investigated whether the nucleus basalis of Meynert is altered in blindness. Therefore, here we examined its structure, cerebrovascular response, and the resting-state functional connectivity in blind individuals. We found that the global signal of the nucleus basalis of Meynert as well as its network connectivity with the visual, language, and default mode network is significantly enhanced in early blind individuals. On the other hand, its structure and cerebrovascular response remain unchanged in early blind individuals. Further, we observed that less visual experience predicts stronger global and network connectivity of the nucleus basalis of Meynert. These results suggest that the nucleus basalis of Meynert develops a stronger neuromodulatory influence on the cortex of blind individuals at both global and network levels.

Structural (dys)connectivity associates with cholinergic cell density of the nucleus basalis of Meynert in Alzheimer's disease

Cognitive deficits in Alzheimer's disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-β and phosphorylated-tau pathology at autopsy. To better understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimer's disease, we utilized a combined post-mortem in-situ MRI and histopathology approach. A total of 19 Alzheimer's disease (10 amnestic and 9 non-amnestic) and 9 non-neurological control donors underwent 3T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed for amyloid-β, phosphorylated-tau and choline acetyltransferase. Compared to controls, we observed an MRI-derived volume reduction and altered microstructural integrity of the nucleus basalis of Meynert in Alzheimer's disease donors. Furthermore, decreased cholinergic cell density was associated with reduced integrity of the nucleus and its tracts to the temporal lobe, specifically to the temporal pole of the superior temporal gyrus, and the parahippocampal gyrus. The association between cholinergic cell density and alteration to cortical tracts was specific for amnestic, compared to non-amnestic Alzheimer's disease donors. Our study illustrates that the nucleus basalis of Meynert is severely affected in amnestic Alzheimer's disease, both in terms of pathology within the nucleus, but also in terms of damage to its cortical projections, specifically to the temporal lobe, which may contribute to the observed cognitive deterioration.