Deep Brain Stimulation – Therapeutic Possibilities in Alzheimer's Disease
Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA, USA
Allegheny Health Network, 420 E North Ave, Suite 302, Pittsburgh, PA, USA
† These authors contributed equally to this work.
Academic Editor: Douglas G. Walker
Special Issue: Research on Neurodegenerative Diseases
Received: December 02, 2020 | Accepted: April 26, 2021 | Published: April 30, 2021
OBM Geriatrics 2021, Volume 5, Issue 2, doi:10.21926/obm.geriatr.2102170
Recommended citation: Fitzgerald E, Kusyk DM, Tomycz ND. Deep Brain Stimulation – Therapeutic Possibilities in Alzheimer’s Disease. OBM Geriatrics 2021; 5(2): 170; doi:10.21926/obm.geriatr.2102170.
© 2021 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and represents a significant cause of cognitive decline, disability, and mortality . As the population continues to age, the number of people living with dementia is expected to more than triple in the next 30 years . Ongoing clinical trials continue to investigate β-amyloid targeted therapy as well various other medications with anti-tau effects, neurotransmitter modification, anti-neuroinflammatory and neuroprotective effects, however the community remains without effective or disease-modifying drugs . There is a salient need for the development of novel, potentially disease-modifying therapeutic strategies.
Advances in neuroimaging and neurophysiology have informed our current understanding of AD as a progressive, widespread disruption of neural networks – particularly the memory circuit – due to synaptic loss, faulty neurotransmission, and neural atrophy. One of the more direct ways of probing and manipulating neural circuits in a clinical setting is deep brain stimulation (DBS). The specific mechanisms of DBS remain unclear. It has been initially suggested that high frequency stimulation acts a reversible lesion, however it is increasingly apparent that the reality is more complex, and that DBS exerts its effects through neuronal inhibition, disruption pathologic oscillations within neural networks, stimulating neural network reorganization as well as with possible neuroprotective effects . Regardless of its specific mechanisms, DBS remains a highly sophisticated means of probing and modulating neural circuits, and is being investigated as a therapeutic intervention for AD.
Here, we review AD pathophysiology as primarily a disease of disordered circuitry, evolving literature regarding the utility of DBS in patients with AD, and future directions for investigating this therapeutic modality. We performed a MEDLINE search for “(Alzheimer's Disease) AND (Deep Brain Stimulation)” with results filtered to human clinical trials, studies and randomized control studies. The resulting 15 results were found to accounts of six separate trials of DBS for AD in humans, and these are the trials which are reviewed below.
The Amyloid hypothesis remains the dominant theory of AD pathogenesis. Sequential cleavage of amyloid precursor protein (APP) by β‐ and γ‐secretase enzymes in the brain leads to the accumulation of pathologic β-amyloid peptide (Aβ) in extracellular plaques . Aβ accumulation appears to be the driving force behind the activation of microglial and astrocytic inflammation, oxidative injury, and the formation of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau . These downstream inflammatory and molecular changes contribute to progressive neurodegeneration, hippocampal atrophy, cholinergic neuronal loss, and synaptic dysfunction .
On a larger scale, research has uncovered multiple areas of dysfunction and degeneration in AD. A lot of focus has been placed on the mesial temporal lobe (MTL) and the hippocampus. After all, the MTL is the initial site of pathologic Aβ extracellular plaques in AD, and the first comprehensive hierarchical staging of AD by neuropathological examination revealed that the accumulation of neurofibrillary tangles occurs initially in the entorhinal cortex (EC) and then spreads to all isocortical association areas, including the hippocampal formation . The hippocampus in particular seems pivotal, since the first reported symptoms of AD are difficulty in remembering new information and episodic memory loss [2,3], which are hippocampus dependent . Additionally, hippocampal atrophy is widely observed in the majority of AD patients and is considered a characteristic physiological feature associated with cognitive deficits .
However, though the MTL and hippocampus have been the focus so far, AD has a diffuse array of effects which are sometimes hard to synthesize into one disease model. For example, though the MTL is the first area with histopathologic change, it is the posterior corpus callosum which is the most common site for early metabolic and perfusion abnormalities on functional imaging . Disease progression is also often accompanied with the atrophy of the fornix and mammillary body (MB) . Post-mortem analysis also has strong evidence for cholinergic neuronal loss in the nucleus basalis of Meynert (NBM) as well as the projection system between the vertical subdivision of the diagonal band of Broca (VBM) and hippocampus [10,11].
As more research highlights new areas affected by AD, a network approach to the disease can help organize therapeutic targets. Based on the areas already identified, at least 3 principal networks are at play in AD: the memory circuit of Papez, the cholinergic network of the basal forebrain, and the default mode network.
First described in 1937, the Papez circuit, also known as the medial limbic circuit, is traditionally described as the neural loop going from the hippocampal formation to the MB in the hypothalamus through the fornix, to the anterior nucleus of the thalamus (ATN), the cingulate gyrus and finally back to the hippocampus via the entorhinal cortex (EC) . First suggested to be part of the emotive circuitry of emotion, the circuit has since been shown to be more involved in the consolidation of declarative memory . Given the circuit’s role in memory, and the structural changes seen in its components in AD, it is clear its dysfunction has a large role to play in AD symptomatology .
Animal studies confirm the circuit’s role. In rodents, acute stimulation of the EC and ATN has been shown to promote neurogenesis of seemingly functional dentate gyrus neurons in the hippocampus, and EC stimulation reduced the plaque burden in an animal model of AD [14,15,16,17]. Stimulation of the fornix, EC, and ATN has also improved rodent performance on various memory tasks, including spatial memory and delayed non-match to sample task testing [14,15,18]. In animal models, the fornix has in particular presented itself as an important target. Stimulation of the fornix has demonstrated increased hippocampal neurotrophic factor, synaptic protein expression, and acetylcholine levels, in turn leading to hippocampal neurogenesis and improved memory function in rodents [16,19,20,21,22].
The cholinergic network of the basal forebrain (BF) is another neural network at the center of AD pathophysiology, after all, the mainstay of symptomatic treatment for AD is the use of centrally-acting acetylcholinesterase inhibitors (AChEIs), which are thought to provide symptomatic relief by potentiating cholinergic synaptic activity . Most cholinergic neurons in the mammalian brain are found in four regions: the brainstem nuclei, subset of thalamic nuclei, striatum, and BF nuclei. [23,24,25] Among them, the nbM of the basal forebrain constitutes the single largest source of cholinergic innervation to the entire cortical surface; whereas the VDB is the major source of cholinergic innervation to the hippocampus from the basal cholinergic nuclei [26,27]. This is a widely connected area. In particular, nbM neurons also receive other cortical input from the orbitofrontal cortex, anterior insula, temporal pole, entorhinal cortex, and medial temporal cortex broad projections involved in attention, arousal, learning and memory formation [28,29]. Degeneration of the nbM has been linked to neuropsychiatric symptoms in Parkinson’s disease, Dementia with Lewy Bodies, and AD [26,29,30].
In animal models, stimulation of the nbM in rats increased cortical cholinergic activity, and intermittent nbM stimulation in primates improved working memory, an effect which was inhibited by cholinergic antagonists [31,32]. Cholinergic activity has also been hypothesized to play a role in the clearance of Aβ in the cerebral cortex . DBS of the nbM may therefore provide neuroprotective and functional benefits in patients with AD.
The default mode network (DMN) is the final network to be reviewed in this manuscript. It refers to the functional co-activation of several regions during “resting-state” activities . Using functional MRI data, this putative network was demonstrated to include the PCC, bilateral inferior parietal cortex, left inferolateral temporal cortex, and ventral anterior cingulate cortex . This network is connected to the memory circuit of Papez and is involved in successful memory retrieval . Additionally, changes within this network may facilitate the deposition of Aβ, providing an important pathophysiologic link to AD [36,37]. As metabolism in these areas begins to decline, it may form a local environment favorable to amyloid deposition, cerebral atrophy, network dysfunction, and eventually clinical signs of dementia . Though a clear target for neuromodulation has not been identified in the DMN, it remains an important network to monitor as we delve into human clinical trials.
These findings highlight the clinical importance of studying the dynamic alterations in neural networks implicated in AD.
3. Human Studies
3.1 Neuromodulation of the Fornix
Presently, DBS of the fornix (DBS-f) is the most extensively investigated neuromodulation target in humans for AD. The target was discovered serendipitously – a patient undergoing an investigational electrode implantation in the hypothalamus for treatment of refractory obesity vividly recalled a personal experience during awake intraoperative testing . With post-operative imaging, the contacts which most reliably triggered recall were noted to be close to the patient’s fornix. On neuropsychological evaluation after 3 weeks of stimulation, the patient was found to have significant improvements on certain tests (e.g. the Wechsler Adult Intelligence Scale, the California Verbal Learning Test, and the Spatial Associate Learning task), as well as a double blinded associative memory task with the DBS “on” versus “off” . Radiographic assessment of the patient’s stimulation was limited, since the patient’s weight precluded an MRI or a PET scan. However, with sLORETA (standardized low-resolution electromagnetic tomography, an imaging modality based on multichannel surface EEG recordings), the activation of the hypothalamic electrode led to a significant increase in the activity in the ipsilateral mesial temporal lobe structures, including the hippocampus and the parahippocampal gyrus [18,38].
Though the previously mentioned patient was relatively young with no evidence of AD, the group’s experience with forniceal stimulation and memory augmentation led to a Phase 1 trial of DBS-f in AD (Table 1) . The study looked at continuous stimulation of the bilateral fornices in six patients on medical therapy with an AChEI with mild AD, as determined by the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). The study’s main outcome measure was the Alzheimer’s Disease Assessment Scale, Cognitive Subscale (ADAS-Cog); however they also analyzed a variety of other neuropsychiatric tests, and imaging studies .
Though they did not have a non-interventional arm, the group compared the outcomes of their study participants against expected evolution of these measures in larger population based studies – namely that the ADAS-Cog would increase 6-7 points a year and the MMSE would decrease by approximately 3 points a year [41,42]. At the end of the 12 months, the patients’ ADAS-Cog scores suggested better than expected cognitive function in two participants, expected decline in three patients, and worse than expected decline in one patient, while MMSE was better than expected for all patients . On 12-month imaging follow up, MRI showed increased hippocampal volume in the two patients with best cognitive outcome, and less hippocampal volume loss (−2.6%) compared to 25 matched controls with AD (−9.5%) .
Functional imaging analyses confirmed the network effects of DBS. On sLORETA, the ipsilateral MTL once again saw an increase in activity in response to bipolar DBS stimulation – first in the hippocampus and parahippocampal gyrus, then the cingulate gyrus, and then the precuneus area of the parietal lobe . PET studies showed an even wider effect. The scans showed significantly improved glucose utilization in the temporal and parietal lobes at 1 month, which was maintained at 12 months . This effect spanned multiple neural networks, with an increase in glucose metabolism in a frontal-temporal-parietal-striatal-thalamic network and a frontal-temporal-parietal-occipital-hippocampal network, as well as select nodes of the DMN [39,44].
This study was a promising foray into DBS-f for AD. In spite of its small sample size, it did convey some measure of benefit to patients with mild AD. Furthermore, imaging studies of these patients confirmed the network nature of AD as a disease, and, more importantly, the DBS can have widespread network effects in AD with bilateral forniceal stimulation. The DBS increased metabolism in not only areas affected by AD, but also in cortical regions that are relatively spared in the disease process. Importantly, since the procedure was safe and well tolerated, the results prompted further investigation.
The next step in DBS-f was a multi-center, double-blind, randomized, controlled Phase II trial to evaluate the safety of the intervention in patients with mild AD . Setting it apart from its Phase I counterpart, this study included a sham stimulation control arm whose participants were implanted with electrodes but underwent no stimulation for the first 12 months. The results are unimpressive at first glance, with the primary clinical outcome measures of ADAS-Cog and CDR showing no significant differences between active vs. sham groups at 12 months. However, when stratified by age, patients <65 years old (n=12) trended towards worse cognitive outcomes with DBS-f, but those ≥65 years old (n=30) trended towards a benefit. This trend continued when the study was unblended at 12 months, and all participants began to receive stimulation. Patients ≥65 years old receiving 24 months of active stimulation deteriorated less than patients ≥65 years old with delayed active stimulation. Patients <65 years old deteriorated more than older patients regardless of treatment arm . Some have suggested that this difference in outcome may be explained by a higher portion of the younger patients having early-onset autosomal dominant AD .
Age was also significant when looking at cerebral glucose metabolism through PET scans. As a whole, patients receiving stimulation did show increased metabolism at 6 months but that did not sustain at 12 months. However, with subgroup analysis, the researchers noted that cerebral glucose metabolism decreased in all patients <65 years old, whereas those ≥65 years old in the active stimulation arm showed increased metabolism by 14–20% at 12 months .
Of note, this study did report four acute serious device- or procedure-related safety events in three patients for a rate of 7.1% of events/patient (95% CI 1.5-19.5). One event involved implantable pulse generator (IPG) infection, one involved moving a DBS lead to the optimal position as defined by imaging, and the others both involved post-op nausea. No new neurological deficits or mortalities were caused by the surgical procedure . These values are in line with the known risk profile of DBS; therefore, this trial demonstrated safety, tolerability, and a possible clinical benefit of DBS-f in patients ≥65 years old with mild AD.
These studies have notable limitations and blind spots. First, these studies did not address the possible effects of stimulation parameters on treatment effect. Put in another way, it is unclear if the DBS was not effective because of an inherent limitation of the technique, or if it was set at an ineffective stimulation setting. Second, these studies raise the possibility that DBS-f may be an effective treatment modality, but only for select patients. The Phase I study suggested that the patients with milder AD showed a smaller decline in ADAS-cog scores, while the Phase II study suggested that older patients benefit the most [39,45,46]. Furthermore, other variables were noted but are harder to study, for example, patients with the strongest experiential memories on awake intraoperative testing seemed to do best in the Phase I study, however that is anecdotal without a more quantitative instrument .
Some of these questions will be addressed in an upcoming trial from the same research group. A larger phase IIb/III multi-center, double-blind, randomized, controlled trial is recruiting patients to assess safety and efficacy of DBS-f in patients ≥65 years old with mild AD. This study will measure primary clinical outcomes with the integrated Alzheimer's Disease Rating Scale (iADRS), glucose PET scanning at certain sites, and CSF biomarkers such as tau protein and Aß-amyloid. The investigators will also randomize patients in the active stimulation arm to 130 Hz vs 40 Hz stimulation, and switch patients to the more effective frequency after interim analysis .
3.2 Neuromodulation of the Cholinergic System
As previously discussed, atrophy of the basal forebrain cholinergic system, and particularly of the NBM are considered central to the pathophysiology of AD [11,30]. As such, just as symptomatic pharmacologic therapy for AD currently targets the cholinergic system; neuromodulation of the same offers another potential therapeutic target for DBS. In particular, Kuhn et al, chose to stimulate the NBM or Ch4 division of the basal forebrain cholinergic system (DBS-nbM), given it contains the largest group of cholinergic neurons, and it is significantly affected by AD . To test the intervention, Kuhn et al. organized a double-blind, sham-controlled, phase I clinical trial investigating bilateral low-frequency (20Hz) DBS-nbM in 6 patients with mild to moderate AD taking AChEIs ≥3 months (4 female, 2 male; age: 57-79; MMSE 18-26). Patients were randomized to receive 2 weeks of active vs. sham stimulation before crossing-over. This was followed by an 11-month open label phase with active stimulation in all six patients. The primary clinical outcome was ADAS-Cog score at 12 months, with several secondary outcome cognitive tests including the Mini-Mental State Examination (MMSE), the Stroop task, subtests of the Wechlser Memory Scale and the Wechlser Adult Intelligence Scale, as well as others .
The results are optimistic on neuropsychiatric evaluation. In their patient group, ADAS-cog scores worsened by an average of 3 points after 1 year of stimulation, while MMSE scores remained almost stable . As pointed out previously, this points to a rather slow progression of disease, since the natural history of AD has ADAS-cog scores increasing 6-7 points per year, and MMSE scores decreasing 3 points a year [41,42]. On functional imaging, the researchers noted a 2-5% increase in cortical glucose metabolism, focused in the amygdala, hippocampus and temporal regions .
As with DBS-f, it is still unclear how DBS-nbM exerts its effect on the physiology of AD patients. Current hypotheses range from the possible excitation of the nucleus to increase acetylcholine secretion, to the stabilization of oscillatory activity of the cholinergic circuits to induce synthesis of neutrophic factors [48,49,50]. Further research is needed to elucidate the mechanism of action of DBS-nbM as well as to aid in the selection of appropriate candidates for the treatment.
3.3 Neuromodulation of the Frontal Lobe
Instead of focusing on the neural networks involved in memory, Scharre et al. sought to use neuromodulation to improve executive function in AD patients, arguing that though memory issues are central to AD, it is the executive deficits which present a large care burden onto caretakers . To specifically target those symptoms, the group chose the Ventral Striatum/Ventral Capsule (VS/VC) as a target. Located at the base of the frontal lobes, the region encompassed by the VS/VC and the nearby nucleus accumbens and septal nuclei serve important roles in executive and behavioural self-regulatory functions . While the VS/VC region has not been used for the neuromodulation of AD, it had been used in other neurobehavioral conditions such as depression or obsessive-compulsive disorder [53,54,55,56,57].
Scharre et al. presented a non-randomized phase I prospective open label trial of three subjects with bilateral VC/VS stimulation with matched comparison groups from the AD Neuroimaging Initiative (ADNI) . In contrast to the studies previously reviewed in this manuscript, they used the Clinical Dementia Rating – Sum of Boxes (CDR-SB) as the primary endpoint. Based on their analysis, both patient 2 and patient 3 seemed to have a less severe decline than predicted based on a match cohort from the ADNI. Furthermore, the PET scans of the 2 responders showed increased metabolism in both the ventromedial and dorsolateral prefrontal cortical region, and the orbitofrontal regions. This is a drastically different metabolic pattern when compared to the results of both the DBS-f and DBS-nbM studies, which speaks to the different physiologic goals of the stimulation. Unfortunately, the Scharre et al. group did not provide neuropsychiatric assessments specific to executive decision making, and therefore more research is needed to determine with the functional PET imaging corresponds to executive improvements in AD patients
In summary, these studies show DBS-f increases cortical glucose metabolism in patients ≥65 years, preserves or increases hippocampal volume, reduces synaptic neuronal loss, and increases neural activity in the memory circuit and DMN [39,43]. Despite these objective findings, primary clinical outcomes provide conflicting data. The phase II cohort had no net improvements in ADAS-Cog and CDR-SB at 12 months . Sub-group analysis of the current evidence favors a potential positive clinical benefit for patients with mild AD over the age of 65 years, however the magnitude of this benefit is not yet entirely clear, and may be mild . Currently, there is no information on the effects of DBS-f on plaque burden, the functionality of neurons contributing to the increased hippocampal size, or the mechanisms underlying these observed changes. More data is also needed regarding long-term effects of continuous DBS-f on preserving cognitive function, memory, and quality of life.
DBS-nbM is still in the early stages of testing, and current evidence favors a possible stabilizing effect of ADAS-Cog scores when implicated early for patients with mild AD . More data is needed to determine optimal patient selection for this treatment modality, as current responses to DBS-nbM are heterogeneous.
The inherently complex circuitry involved causes stimulation parameters to be another potential area for future studies to address, given that the stimulation parameters are not titrated to an observable clinical effect as they are during treatment of movement disorders. Additionally, memory recall is partially an active function, and current stimulation modalities are limited by continuous stimulation. Future modalities could be developed to attempt to engage memory circuits more selectively to overcome this.
In addition to those mentioned above, there are a number of clinical trials around the world that are currently recruiting and investigating DBS for treatment of AD. Trials in Madrid and Beijing are recruiting patients to compare DBS-f to DBS-nbM (NCT03290274 and NCT03115814), and another group in Taiwan is recruiting to investigate DBS-nbM in 10 more patients (NCT03959124). At UCLA, a group is investigating the feasibility and efficacy of non-invasive DBS using Low Intensity Focused Ultrasound Pulsation (LIFUP) for patients with mild cognitive impairment and mild AD (NCT03347084). These trials are listed on clinicaltrials.gov, along with specific recruitment information for the specific interventions.
Dr. Nestor Tomycz contributed to the formulation of the project, and editing. Dr. Dorian Kusyk and Mr. Ethan Fitzgerald both equally contributed to the draft.
No funding to disclose.
The authors have declared that no competing interests exist.
- Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol. 2018; 25: 59-70. [CrossRef]
- Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013; 80: 1778-1183. [CrossRef]
- Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020; 27: 18. [CrossRef]
- O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci. 2011; 34: 185-204. [CrossRef]
- Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82: 239-259. [CrossRef]
- McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack Jr CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.Alzheimers Dement. 2011; 7: 263-269. [CrossRef]
- Yu DF, Yan HH, Zhou J, Yang XD, Lu YM, Han YY. A circuit view of deep brain stimulation in Alzheimer's disease and the possible mechanisms. Mol Neurodegener. 2019; 14: 33. [CrossRef]
- Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI.PNAS. 2004; 101: 4637-4642. [CrossRef]
- Copenhaver BR, Rabin LA, Saykin AJ, Roth RM, Wishart HA, Flashman LA, et al. The fornix and mammillary bodies in older adults with Alzheimer's disease, mild cognitive impairment, and cognitive complaints: A volumetric MRI study. Psychiatry Res Neuroimaging. 2006; 147: 93-103. [CrossRef]
- Vogels OJ, Renkawek K, Broere CA, Laak HJ, van Workum F. Galanin-like immunoreactivity within Ch2 neurons in the vertical limb of the diagonal band of Broca in aging and Alzheimer's disease. Acta Neuropathol. 1989; 78: 90-5. [CrossRef]
- Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer's disease. Biol Psychiatry. 2012; 71: 805-813. [CrossRef]
- Choi SH, Kim YB, Peak SH, Cho ZH. Papez circuit observed by in vivo human brain with 7.0T MRI super-resolution track density imaging and track tracing. Front Neuroanat. 2019; 13: 17. [CrossRef]
- Papez JW. A proposed mechanism of emotion. Arch Neur Psych. 1937; 38: 725-743. [CrossRef]
- Hamani C, Stone SS, Garten A, Lozano AM, Winocur G. Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone. Exp Neurol. 2011; 232: 100-104. [CrossRef]
- Stone SS, Teixeira CM, DeVito LM, Zaslavsky K, Josselyn SA, Lozano AM, et al. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci. 2011; 31: 13469-13484. [CrossRef]
- Toda H, Hamani C, Fawcett AP, Hutchison WD, Lozano AM. The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg. 2008; 108: 132-138. [CrossRef]
- Mann A, Gondard E, Tampellini D, Milsted JA, Marillac D, Hamani C, et al. Chronic deep brain stimulation in an Alzheimer's disease mouse model enhances memory and reduces pathological hallmarks. Brain Stimul. 2018; 11: 435-444. [CrossRef]
- Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol. 2008; 63: 119-123. [CrossRef]
- Gondard E, Chau HN, Mann A, Tierney TS, Hamani C, Kalia SK, et al. Rapid modulation of protein expression in the rat hippocampus following deep brain stimulation of the fornix. Brain Stimul. 2015; 8: 1058-1064. [CrossRef]
- Hao S, Tang B, Wu ZY, Ure K, Sun YL, Tao HF, et al. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.Nature. 2015; 526: 430-434. [CrossRef]
- Xia F, Yiu A, Stone SS, Oh S, Lozano AM, Josselyn SA, et al. Entorhinal cortical deep brain stimulation rescues memory deficits in both young and old mice genetically engineered to model Alzheimer's disease. Neuropsychopharmacology. 2017; 42: 2493-2503. [CrossRef]
- Hescham S, Temel Y, Schipper S, Lagiere M, Schonfeld LM, Blokland A, et al. Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis. Brain Struct Funct. 2017; 222: 1069-1075. [CrossRef]
- Yan HH, Pang P, Chen WQ, Zhu HZ, Henko KA, Li H, et al. The lesion analysis of cholinergic neurons in 5XFAD mouse model in the three-dimensional level of whole brain. Mol Neurobiol. 2018; 55: 4115-4125. [CrossRef]
- Ballinger EC, Ananth M, Talmage DA, Role LW. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron. 2016; 91: 1199-1218. [CrossRef]
- Li XN, Yu Bin, Sun QT, Zhang YL, Ren M, Zhang XY, et al. Generation of a whole-brain atlas for the cholinergic system and mesoscopic projectome analysis of basal forebrain cholinergic neurons. PNAS. 2018; 115: 415-420. [CrossRef]
- Mesulam MM, Mufson EJ, Levey AI, Wainer BH. Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol. 1983; 214: 170-197. [CrossRef]
- Mesulam MM, Mufson EJ, Levery AI, Wainer BH. Atlas of cholinergic neurons in the forebrain and upper brainstem of the macaque based on monoclonal choline acetyltransferase immunohistochemistry and acetylcholinesterase histochemistry. Neuroscience. 1984; 12: 669-686. [CrossRef]
- Mesulam MM, Mufson EJ. Neural inputs into the nucleus basalis of the substantia innominata (Ch4) in the rhesus monkey.Brain. 1984; 107: 253-274. [CrossRef]
- Philipposa K, Pablob A, Veerlea VV, Thibauta S. The nucleus basalis of meynert and its role in deep brain stimulation for cognitive disorders: A historical perspective. J Alzheimers Dis. 2019; 69: 905-919. [CrossRef]
- Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer's disease and senile dementia: Loss of neurons in the basal forebrain. Science. 1982; 215: 1237-1239. [CrossRef]
- Liu RF, Crawford J, Callahan PM, Terry Jr AV, Constantinidis C, Blake DT. Intermittent stimulation of the nucleus basalis of meynert improves working memory in adult monkeys. Curr Biol. 2017; 27: 2640-2646e4. [CrossRef]
- Kurosawa M, Sato A, Sato Y. Stimulation of the nucleus basalis of Meynert increases acetylcholine release in the cerebral cortex in rats. Neurosci Lett. 1989; 98: 45-50. [CrossRef]
- Ovsepian SV, Herms J. Cholinergic neurons-keeping check on amyloid beta in the cerebral cortex. Front Cell Neurosci. 2013; 7: 252. [CrossRef]
- Greicius MD, Krasnow B, Reiss AL, Menon V.Functional connectivity in the resting brain: A network analysis of the default mode hypothesis.Proc Natl Acad Sci U S A. 2003; 100: 253-258. [CrossRef]
- Jakobs M, Lee DJ, Lozano AM. Modifying the progression of Alzheimer's and Parkinson's disease with deep brain stimulation. Neuropharmacology. 2020; 171: 107860. [CrossRef]
- Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer's disease: Evidence for a relationship between default activity, amyloid, and memory.J Neurosci. 2005; 25: 7709-7717. [CrossRef]
- Palmqvist S, Schöll M, Strandberg O, Mattsson N, Stomrud E, Zetterberg H, et al. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun. 2017; 8: 1214. [CrossRef]
- Pascual-Marqui RD, Michel CM, Lehmann D. Low resolution electromagnetic tomography: A new method for localizing electrical activity in the brain. Int J Psychophysiol. 1994; 18: 49-65. [CrossRef]
- Laxton AW, Tang‐Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease.Ann Neurol. 2010; 68: 521-534. [CrossRef]
- Rosen WG, Mohs MR, Davis KL, A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984; 141: 1356-1364. [CrossRef]
- Ito K, Ahadieh S, Corrigan B, French J, Fullerton T, Tensfeldt T. Disease progression meta-analysis model in Alzheimer's disease.Alzheimers Dement. 2010; 6: 39-53. [CrossRef]
- Mayeux R, Sano M. Treatment of Alzheimer's disease.N Engl J Med. 1999; 341: 1670-1679. [CrossRef]
- Sankar T, Chakravarty MM, Bescos A, Lara M, Obuchi T, Laxton AW, et al. Deep brain stimulation influences brain structure in Alzheimer's disease. Brain Stimul. 2015; 8: 645-654. [CrossRef]
- Smith GS, Laxton AW, Tang-wai DF. Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease.Arch Neurol. 2012; 69: 1141-1148. [CrossRef]
- Lozano AM, Fosdick L, Chakravarty MM, Leoutsakos JM, Munro C, Oh E. A phase II study of fornix deep brain stimulation in mild Alzheimer's disease.J Alzheimers Dis. 2016; 54: 777-787. [CrossRef]
- Leoutsakos JM, Yan HJ, Anderson WS, Asaad WF, Baltuch G, Burke A, et al., Deep brain stimulation targeting the fornix for mild Alzheimer dementia (the ADvance trial): A two year follow-up including results of delayed activation. J Alzheimers Dis. 2018; 64: 597-606. [CrossRef]
- Viaña JNM, Bittlinger M, Gilbert F. Ethical considerations for deep brain stimulation trials in patients with early-onset Alzheimer’s disease. J Alzheimers Dis. 2017; 58: 289-301. [CrossRef]
- Kuhn J, Hardenacke K, Lenartz D, Gruendler T, Ullsperger M, Bartsch C, et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia.Mol Psychiatry. 2015; 20: 353-360. [CrossRef]
- Hardenacke K, Hashemiyoon R, Visser-Vandewalle V, Zapf A, Freund HJ, Sturm V, et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia: Potential predictors of cognitive change and results of a long-term follow-up in eight patients.Brain Stimul. 2016; 9: 799-800. [CrossRef]
- Kuhn J, Hardenacke K, Shubina E, Lenartz D, Visser-Vandewalle V, Zilles K, et al. Deep brain stimulation of the nucleus basalis of Meynert in early stage of Alzheimer's dementia. Brain Stimul. 2015; 8: 838-839. [CrossRef]
- Scharre DW, Weichart E, Nielson D, Zhang J, Agrawal P, Sederberg PB, et al. Deep brain stimulation of frontal lobe networks to treat Alzheimer's disease. J Alzheimers Dis. 2018; 62: 621-633. [CrossRef]
- Price JL, Drevets WC. Neurocircuitry of mood disorders.Neuropsychopharmacology. 2010; 35: 192-216. [CrossRef]
- Ho AL, Salib AM, Pendharkar AV, Sussman ES, Giardino WJ, Halpern CH. The nucleus accumbens and alcoholism: A target for deep brain stimulation. Neurosurg Focus. 2018; 45: E12. [CrossRef]
- Greenberg BD, Gabriels LA, Malone Jr DA, Rezai AR, Friehs GM, Okun MS, et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: Worldwide experience. Mol Psychiatry. 2010; 15: 64-79. [CrossRef]
- Chen L, Li N, Ge SN, Lozano AM, Lee DJ, Yang C, et al. Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open-label pilot study.Brain Stimul. 2019; 12: 175-183. [CrossRef]
- Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry. 2015; 78: 240-248. [CrossRef]
- Rezai AR, Sederberg PB, Bogner J, Nielson DM, Zhang J, Mysiw WJ, et al. Improved function after deep brain stimulation for chronic, severe traumatic brain injury. Neurosurgery. 2016; 79: 204-211. [CrossRef]