Deep Brain Stimulation of the Memory Circuit: Improving Cognition in Alzheimer’s Disease

Abstract

Deep brain stimulation (DBS) is an effective invasive treatment for a wide range of neurological and psychiatric disorders. Neurosurgically implanted electrodes deliver stimulation of pre-programmed amplitude, frequency, and pulse width within deep brain structures; those settings can be adjusted at a later stage according to individual needs for optimal response. This results in variable effects dependent on the targeted region. An established treatment for movement disorders, the effectiveness of DBS in dementia remains under investigation. Translational studies have uncovered a pro-cognitive effect mediated by changes on cellular as well as network level. Several groups have attempted to examine the benefits of DBS in Alzheimer’s disease; differences in inclusion criteria and methodology make generalization of results difficult. This review aims to summarize all completed and ongoing human studies of DBS in Alzheimer’s disease. The results are classified by targeted anatomical structure. Future directions, as well as economical and ethical arguments, are explored in the final section.

Keywords

Alzheimer’s disease deep brain stimulation dementia memory neuromodulation neuropsychiatry

INTRODUCTION

Alzheimer’s disease (AD) is a prototypical neurodegenerative disorder primarily affecting cognition with consequent effects on quality of life. The cost of dementia in the UK is £26.3 billion/year, with the number of people with dementia in the UK forecasted to increase to over 1 million by 2025 and over 2 million by 2051 [1, 2]. Current treatments include pharmacological agents targeting various aspects of the underlying pathophysiology of the disease, including acetylcholinesterase inhibitors and NMDA receptor antagonists [3]. Limited efficacy combined with occasionally significant side effects associated with their use drives the need for development of alternative treatments. Attempts to develop novel disease- modifying pharmacological agents have unfortunately not been successful in Phase III trials [4]. Moreover, a shift in perception of AD from a biochemical abnormality of cholinergic and glutamatergic pathways to a neural circuit disorder has moved treatment targets toward whole networks [5]. This has created interest in neuromodulatory therapies such as deep brain stimulation (DBS). By optimizing neural circuit function, the impact of pathological protein accumulation may be attenuated.

DBS is an invasive neuromodulation technique, involving electrical stimulation of specific targeted brain regions through stereotactically implanted electrodes [6]. It is important to note, however, that the effects of stimulation may extend beyond the anatomical constraints of the targeted region through to wider network connections. In addition, the extent of stimulation may depend on the stimulus parameters used. Although now a routine treatment for movement disorders such as Parkinson’s disease, its efficacy and safety in cognitive and neuropsychiatric disorders is still under investigation [7].

Based on preliminary results by Laxton et al., several groups have attempted to explore the potential cognitive benefits of neuromodulation in humans [8]. In parallel, animal models of dementia have provided invaluable insight into the underlying mechanisms that drive cognitive change through DBS [9, 10]. Relevant evidence suggests that the beneficial effects on cognition could be driven by: 1) direct effect on neurotransmission as demonstrated by an increase in acetylcholine release [11, 12]; 2) enhanced neurogenesis [13, 14]; 3) release of neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor [15, 16]; and 4) restoring abnormal network activity [17, 18] (Fig. 1).

Fig. 1

The effect of Deep Brain Stimulation in Alzheimer’s Disease. I) Electrodes are stereotactically implanted in targeted anatomical region(s) of the brain; these are linked to the pulse generator, a device implanted subcutaneously in the chest wall that determines the settings of the electrical stimulation. The pro-cognitive effect is mediated via the following potential mechanisms: a) neurotransmission: increased levels of extracellular acetylcholine were detected with microdialysis following fornix DBS, b) neurogenesis: entorhinal cortex stimulation promotes creation of new granule cells that mature, integrate and become fully functional neurons of the memory circuit, c) neurotrophic factors: stimulation of the nucleus basalis of Meynert and the medial septum has been shown to increase brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels, respectively, and d) networks: DBS may reinstate aberrant network activity in memory circuit.

This short review will outline progress in the field of DBS in AD, primarily focusing on human studies.

SEARCH STRATEGY AND SELECTION CRITERIA

We searched PubMed for English language publications (last update February 2018), by entering the following search terms: “deep brain stimulation”, “dementia”. Search yielded 281 papers. Article titles and abstracts were scrutinized for suitability. All studies involving human subjects were included and then grouped by region of stimulation, defined as the anatomical brain region where DBS electrodes were implanted. It is important to note that there is likely to have been overlap of target regions in the studies reported, due to wider stimulation effects as discussed above. When no human studies were available for a specific anatomical target, relevant animal studies were taken into consideration. Moreover, studies investigating cognitive outcomes of DBS in other central nervous system disorders were considered. Studies identified in the reference lists of key articles were also included (Fig. 2).

Fig. 2

Search Synopsis. *when no human studies were available, animal studies were considered.

Finally, a search using similar keywords was conducted in https://clinicaltrials.gov to identify ongoing or completed clinical trials.

ANATOMICAL TARGETS (TABLE 1)

Table 1

Human studies on DBS in Alzheimer’s disease; by region

Region	Study	Diagnosis	n	Age	Stimulation Parameters	Results
Entorhinal Cortex	N/A	N/A	N/A	N/A	N/A	N/A
Fornix	Laxton [8]	probable AD	6	40–80	voltage = 3.0–3.5 V	a. mean increase of 4.2 points in the ADAS-cog over one year, b. decrease in the rate of decline in the MMSE.
					frequency = 130 Hz
					pulse width = 90 ms
	Fontaine [29]	mild AD	1	<70	voltage = 2.5 V	stabilization of cognitive scores after one year of chronic stimulation
					frequency = 130 Hz
					pulse width = 210 ms
	Lozano [33]	probable AD	42	45–85	voltage = 3.0–3.5 V	slowing of cognitive decline over one year in patients 65 years of age and older
					frequency = 130 Hz
					pulse width = 90 ms
Globus Pallidus	N/A	N/A	N/A	N/A	N/A	N/A
Hippocampus	N/A	N/A	N/A	N/A	N/A	N/A
Medial Septum	N/A	N/A	N/A	N/A	N/A	N/A
Nucleus Basalis of Meynert	Turnbull [42]	AD	1	74	voltage = 3V	no improvement in memory or cognition
					frequency = 50 Hz
					pulse width = 210 ms
	Kuhn [48]	mild-mod. AD	6	57–79	variable	a. ADAS-cog scores worsened by an average of 3 points after one year of stimulation, b. mean MMSE score remained almost stable.
Thalamus (Anterior Thalamic Nucleus)	N/A	N/A	N/A	N/A	N/A	N/A
Ventral Capsule/ Ventral Striatum	Scharre [53]	probable AD	3	45–85		a. all participants had less decline in the CDR-SB scores relatively to matched comparison groups, b. increased metabolism on brain FDG PET in frontal cortical regions

n, sample size; N/A, non-applicable; AD, Alzheimer’s disease; MMSE, Mini-Mental State Examination; ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive; CDR-SB, Clinical Dementia Rating-Sum of Boxes.

Entorhinal cortex (EC)

Several groups have investigated the effect of DBS on the EC, a region vulnerable to neurodegeneration in AD. In an experimental model of AD, DBS reversed a scopolamine-induced memory deficit in rats when stimulated at 100 Hz, 100μA, and 100μs pulse width [19]. Most recently, a group from China showed beneficial effects from high frequency DBS targeting the same structure, on spatial and recognition memory in a rat model of AD [20].

In an elegant animal study, Stone et al. attempted to elucidate the potential mechanisms underlying DBS’s cognitive effect. Based on the knowledge that neurogenesis is influenced by neural activity, they targeted EC in mice with stimulation parameters approximating the high-frequency DBS used in clinical practice. This resulted not only in enhanced neural activity— reflected in the elevated expression of the activity-regulated gene c-Fos— but also a 2-fold increase in neurogenesis that was specific to the dentate gyrus (DG); the effect correlated with the duration of the stimulation. The newly generated neurons followed a normal maturation process and became fully functionally integrated in the memory circuits. This proved to be beneficial for spatial memory, as measured by the water-maze task [14].

A few years later, the same group, using a single EC-DBS treatment on a transgenic model of AD in mice, reversed contextual fear and spatial memory deficits but also decreased the plaque load in their hippocampi and cortices [21].

In human studies targeting EC, a group researching pharmacoresistant epilepsy reported significant improvement in spatial learning by applying DBS, with a cycle of 5s on and 5s off at 50 Hz and a pulse width of 300μs, to the entorhinal region. Although participants came from a different diagnostic category, the authors highlighted that this cognitive enhancement was observed regardless of baseline memory performance, suggesting that there may be potential benefits to other clinical populations, including AD [22].

Fornix

It was not until 2008 and a chance finding that fornix became a focus of attention for DBS in memory disorders. While attempting to treat obesity through bilateral hypothalamic DBS, Hamani et al. noticed that their patient reported intense déjà vu episodes. All these episodes were stimulation-specific and were reproducible even in a double-blinded experiment. Post-operative imaging revealed an electrode contact position close to the fornix; this was considered to have been the most likely to cause of the déjà vu episodes [23].

This observation in a single patient triggered a seminal study by Laxton: a phase I trial of fornix DBS in AD. Six patients diagnosed with mild AD and on relevant pharmacological treatment received continuous stimulation of their hypothalami/fornices. Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) and Mini-Mental State Examination (MMSE) changes were selected as patient outcomes [24, 25]. Six patients showed a mean increase of 4.2 points in the ADAS-cog over one year, as well as a decrease in the rate of decline in the MMSE. Using sLORETA (standardized LOw-Resolution brain Electromagnetic Tomography, a method estimating cortical distribution of neuronal electrical activity) and positron emission tomography (PET) imaging, the researchers showed two major effects of DBS: 1) activation of the default mode network and 2) increase in glucose utilization in temporal and parietal cortex [8 , 27]. True to the notion that DBS exerts its effect over entire neural circuits rather than just local effects, quantitative MRI volumetry on the same cohort revealed that increases in overall hippocampal volume (in two patients reaching 5.6 and 8.2% respectively) were highly correlated with volume changes in the fornix and the mammillary bodies [28].

Fontaine et al. subsequently designed a study to assess feasibility of fornix DBS in AD. The study initially suffered difficulties finding eligible patients for screening, however this were overcome by increasing the upper age limit for eligibility from 65 to 70. Despite increasing the pool of eligible participants, acceptance rates remained extremely low. The authors make an interesting point when contrasting those low rates of acceptance of DBS by the patients with the relatively high acceptance rates by their respective relatives; they ascribe this not only to the invasiveness of the technique but also to anosognosia to both current cognitive impairment and the inevitable further cognitive decline. Ultimately only one patient entered the study; results show stabilization of cognitive scores (MMSE, ADAS-cog, Free and Cued Selective Reminding Test) following a year of chronic stimulation [29].

In a separate field, epilepsy, fornix DBS was used in 11 patients with the primary aims of reducing interictal epileptiform discharges and seizure frequency. As well as a reduction in frequency of hippocampal seizures, improved cognition was also noted after comparison of pre- and post- stimulation MMSE scores. Interestingly, recall improvement was noted between the second and third administration of MMSE and not on the MMSE obtained 1 h post-stimulation, possibly reflecting a delayed stimulation effect [30].

Encouraged by the positive effect on cognition of their Phase I trial, Lozano et al. published early results of a Phase II trial in 2016. This was a 12-month sham-controlled trial of fornix DBS in mild AD with n = 42. Initial reports suggest DBS of the fornix as a feasible and safe operation with similar rate of adverse events to studies previously reported in the DBS literature [31]. The authors note that although there was a clear increase in glucose metabolism in several brain areas (pre-central gyrus, post-central gyrus, temporal association cortex, hippocampus, parietal association cortex, occipital cortex and cerebellar hemispheres), i.e., evidence for a network enhancing effect, this did not translate in to clinical improvement as measured by cognitive scales (ADAS-Cog-13 and Clinical Dementia Rating-Sum of Boxes (CDR-SB)) [25, 32]. A subgroup analysis highlighted a differential effect of DBS depending on the age-subgroup with older patients (>65 years of age) showing greater clinical benefit [33].

Globus pallidus

Although there are no human studies focusing solely on improving cognition through DBS targeting the globus pallidus, potentially relevant results have been published in the movement disorders field. One group reported global cognitive deterioration at one year follow up post-DBS in a 75-year-old man with a nearly two-decade history of parkinsonism. This decline was evident even with the stimulator was switched off, suggesting stimulation was unlikely to have led directly to cognitive deterioration. Authors concluded that co-existence of Parkinson’s disease and dementia with Lewy bodies was the most probable cause in this case [34].

In 2004, Moro et al. first attempted bilateral globus pallidus internus DBS in a single patient with severe chorea due to Huntington’s disease (HD). Although the results were promising for optimization of movement control and improving activities of daily living, the authors did not report any significant changes in cognitive status [35].

Fielding et al. later hypothesized that inhibition of the globus pallidus externa could result not only in motor but cognitive improvement in HD. To test this hypothesis, they first generated a transgenic rat model of HD that carried a mutant fragment of the human huntingtin (HTT) gene [36]. They then applied bilateral globus pallidus DBS with some success in improving response inhibition (a marker of cognitive impairment in HD), suggesting that there may be a pro-cognitive effect of DBS targeting the globus pallidus [37].

Hippocampus

The hippocampi have a central role in memory performance. Flawed adult neurogenesis in the dentate gyrus is believed to be partly responsible for the cognitive deficits in AD and other cognitive disorders [38]. Interestingly, there are no human DBS AD studies directly targeting the hippocampi.

In a study investigating the effect of DBS in treatment resistant epilepsy, electrodes were implanted stereotactically in the entorhinal cortices and hippocampi of 7 subjects. They all underwent an innovative virtual reality based spatial learning task, in which they had to navigate through a virtual environment. Their performance was measured on and off stimulation. Interestingly, direct stimulation of the entorhinal cortex led to improvements on the spatial memory task, however hippocampal stimulation was ineffective [22].

Hippocampal stimulation was reinvestigated in a later study using a rat model of memory deficit. Compared with baseline testing in the absence of stimulation, acute DBS of the CA1 subregion of the hippocampus (100 Hz, 100μA, 100μs) improved performance in an object location task [19].

Medial septum

One widely used and validated animal model for AD is based on depletion of cholinergic neurons in rats by intracerebroventricular (ICV) 192 IgG-saporin injections. Researchers in Korea managed to successfully reverse spatial memory impairments in this model by applying mid-frequency (60 Hz) DBS to the medial septum. The authors suggested that the improvements in spatial memory were mediated through two distinct mechanisms; increases in hippocampal acetylcholine and increased neurogenesis, as measured by an acetylcholinesterase assay and doublecortin immunohistochemistry respectively [39]. Despite this promising result, trials targeting the medial septum are yet to be pursued in humans.

Nucleus basalis of Meynert (NBM)

As one of the main areas affected by neuronal loss, NBM is heavily implicated in AD pathology [40, 41]. As early as 1984, it became a potential DBS target in AD; in a pioneering study, Turnbull et al. unilaterally targeted the left NBM in a single patient but with no measurable cognitive benefit [42].

Some years later, a single patient with Parkinson’s disease dementia underwent bilateral implantation of electrodes into NBM, in combination with bilateral subthalamic nuclei (STN) electrodes. The parkinsonian symptoms responded well to conventional 130 Hz STN stimulation, whereas the apraxic features of his dementia improved only after NBM stimulation at less than 20 Hz [43, 44].

Based on these positive findings, Kuhn et al. in Cologne set out to investigate the effect of low frequency NBM-DBS in mild-moderate AD, as defined by DSM-IV, ICD-10 and NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association) scale [45 –47]. The investigators opted for an elaborate study design of two phases: phase I) a randomized sham-controlled DBS phase of one month where patients underwent two weeks of stimulation followed by two weeks off stimulation (sham); phase II) an open stimulation phase of eleven months, where stimulation settings were adjusted according to individual needs. Using the ADAS-Cog as the primary outcome measure, the authors concluded that four out of six patients responded with cognitive improvement. No significant side effects were observed [48, 49]. Interestingly, it was noted that certain patient factors, particularly disease severity and age, predicted response to stimulation on the primary outcome measure. To further explore these factors, the same group performed NBM-DBS on two younger patients (61 and 67) with milder AD. They subsequently concluded that optimal cognitive outcomes and slower disease progression may be expected when NBM-DBS is performed at an earlier disease stage and at younger age [50].

Thalamus

The anterior thalamic nucleus (ATN) is considered an effective DBS target for seizure control in intractable epilepsy. Moreover, as it is a component of the Papez circuit, targeting the ATN with DBS could have beneficial effects on cognition. In a novel paper, Yoon-Sang Oh et al. examined the cognitive effects of bilateral ATN DBS in 9 patients diagnosed with intractable epilepsy, using intermittent adjustments in stimulation parameters. Neurocognitive assessment at 12 months post-electrode implantation and the stimulator in the ON state, revealed a favorable effect of ATN DBS on word fluency and delayed verbal memory [51]. Based on the above findings, another group attempted to test the effect of bilateral stimulation of the ATN on cognition in an AD-rat model. Using the Morris water maze they compared performance on four different groups of rats (AD with stimulation, AD with sham stimulation, AD without electrode implantation, sham AD without electrode implantation). Stimulation parameters (130 Hz) were selected based on findings from other groups suggesting enhanced therapeutic effect with higher frequencies. The group receiving stimulation performed better, suggesting that high-frequency stimulation of the ATN may be useful for improving cognition in patients with AD [52].

Ventral capsule/ventral striatum (VC/VS)

Located adjacent to the deeper part of the frontal lobes, the VC/VS has the potential to modulate frontal networks affected in AD and hence improve behavioral and executive deficits. In a non-randomized phase I pilot study, Scharre et al. assessed the safety and feasibility of VC/VS DBS in AD for the first time. Three patients with probable AD, already on medication, received continuous stimulation for a minimum of 18 months, with no serious adverse events reported. Choosing the CDR-SB as their primary outcome measure, results suggested less decline in the DBS patients compared to matched AD controls. In fact, one of the participants showed significant functional improvement, regaining independence in various aspects of her daily living. FDG-PET performed in various time-points pre and post stimulation showed minimal changes in the frontal lobe metabolism for one of the participants, yet increased metabolism for the other two. Interestingly, the participant with the minimal changes, also showed minimal improvement in his CDR-SB scores [53].

ONGOING CLINICAL TRIALS (TABLE 2)

Table 2

Ongoing and completed clinical trials of DBS in Alzheimer’s disease and Lewy body dementia (source: clinicaltrials.gov)

Identifier	Type	Condition	Region	Estimated n	Age (years)	MMSE	Location	Status
NCT02263937	Double Blind, Randomized, Dual Center, Crossover, Pilot Trial	DLB	Bilateral Nucleus Basalis of Meynert	6	50–80	21–27	University College London	Complete (unpublished)
NCT01340001	Double Blind, Randomized, Crossover Trial	DLB	Bilateral Nucleus Basalis of Meynert	6	18–75	16–26	University Hospital, Rouen	Recruiting
NCT02253043	Single Group, Open Label	AD	___________	10	40–80	___________	Beijing Tiantan Hospital	Recruiting
NCT03115814	Prospective, Self-Control, Observational	AD	___________	6	40–80	0–10	Chinese PLA General Hospital	Recruiting

n, sample size; DLB, dementia with Lewy bodies; AD, Alzheimer’s disease.

Based on the preliminary results thus far, several clinical trials are underway. Searching the clinicaltrials.gov database for relevant trials (July 2017), we identified 5 trials: two completed with unpublished results at the time of writing and three in the recruitment stage. These are discussed in more detail below:

University College London (NCT02263937): Using a double blind, randomized, crossover design the researchers piloted the use of NBM-DBS in 6 patients with Lewy body dementia. (status: completed)

University Hospital Rouen (NCT01340001): this is a pilot Phase I study investigating the effect of NBM-DBS on patients presenting with cognitive and behavioral disorders of Lewy body dementia. (status: recruiting)

Beijing PINS Medical Co. (NCT02253043): this is a 12-month study to verify the long term effectiveness and safety of a bilateral DBS system produced by Beijing PINS Medical Co., Ltd. as a treatment option for cognitive, behavioral, and functional disability in patients with AD. The investigators aim to recruit 10 patients. (status: recruiting)

Chinese PLA General Hospital (NCT03115814): attempting to investigate the safety and effectiveness of DBS in severe AD, this group has set up a prospective, self-control Phase I trial aiming to recruit 6 patients. (status: recruiting)

We have attempted to make contact with all the above teams. No preliminary results were shared.

DISCUSSION

It is more than 30 years since a role for DBS in dementia has been postulated. Despite some promising results as outlined in this review, there is still significant progress to be made to define the role of DBS in dementia [54, 55]. A recent review of fornix DBS for AD raised several practical considerations that researchers should consider when designing a study, including the need for uniform selection criteria, and standardization of both stimulation parameters and cognitive assessments [56]. In addition, there are numerous barriers that investigators need to overcome before preforming successful DBS clinical research, including scarce funding, expensive regulatory burdens, industry control of investigative devices, and public scrutiny over financial conflicts of interest [57].

Adapting an invasive treatment approach in this vulnerable patient group has raised ethical concerns, including the inherent difficulty of obtaining informed consent from patients with advanced cognitive decline [58, 59]. The use of validated capacity-assessment tools and advance research directives may help overcome these hurdles [60]. Using a conceptual framework based on the principles for ethical assessment of new therapies (non-maleficence, beneficence, justice and respect for autonomy, subsidiarity and proportionality) Ovadia and Bottini argue that DBS in degenerative disorders, including dementia, should be restricted to investigational/experimental trials until significantly more data are available [61]. When patients are entered into DBS in dementia trials, robust planning should be in place to ensure adequate access to care after trial completion [60].

The legal issues around consent for DBS were also reviewed by a group in Germany; they emphasize the importance of including relatives in the whole decision-making process given that capacity to consent in often impaired in patients suffering from severe neuropsychiatric disorders. They raised the important question of whether pre-treatment consent remains valid for post-treatment adjustments to the device, such as stimulation settings and battery revisions [62].

Ethical and legal considerations aside, the relatively high financial burden of using and developing novel invasive treatments such as DBS needs to be addressed [63]. This could be mitigated against by reducing manufacturing cost of the devices and by reforming government funding policy to be more supportive of innovation in this field [64]. Using a decision analysis model, Mirsaeedi-Farahani et al. performed a cost-effectiveness analysis of DBS for AD. In the model, mild AD patients received either standard treatment or a combination of standard treatment and DBS, Success was defined as “immediate improvement to and 1-year maintenance of minimal stage AD”. The results suggest that, given the limited efficacy of current pharmacological treatments for mild AD, DBS requires a success rate of 3% to be as clinically effective as current treatments and a success rate of 80% to be less costly [65].

New innovations to DBS systems are currently emerging and may prove particularly relevant to disorders of memory and cognition (Table 3). These are discussed below:

Table 3

Advances in deep brain stimulation

Advances	Advantages
Directional Leads	Anatomically precise stimulation Less side effects
On-Demand Stimulation	Responds to the natural pattern of the illness
Novel Patterns of Stimulation	Simulates firing activity of specific brain regions
Biomarker-assisted patient selection	Identifying patients with higher chances of optimal response
DBS plus	Concurrent monitoring and delivery of other therapies
Intravascular Electrodes	Less invasive
Wireless Communication	Optimal charging and remote programming

Directional leads and field shaping (utilizing multiple independent or segmented contacts): this allows more anatomically precise stimulation, keeping current away from adjacent areas responsible for side effects while retaining the beneficial effects on the primary target [66].

On demand stimulation: current DBS practice involves infrequent manual stimulation parameters adjustment, thus failing to respond to the dynamic nature of neuropsychiatric disorders. Real Time Adaptive (Closed-loop) DBS is a proposed alternative that can monitor and respond dynamically to changes in recognized patterns of pathological activity [67].

Novel patterns of stimulation: c1. Theta-burst DBS of the fornix was used in a human study of four participants with treatment resistant temporal lobe epilepsy. This stimulation pattern simulates firing activity in the hippocampus and led to improvements in visuo-spatial memory [68], c2. A recent study using bilateral NBM-DBS in Rhesus monkey found that intermittent but not continuous stimulation led to working memory improvements; the authors concluded that this effect was mediated via optimization of cholinergic pathways [69].

Biomarker-assisted patient selection: Baldermann et al. used pre-operative structural MRI images to predict outcomes of NBM-DBS in AD patients; patients where fronto-parietal thickness was preserved had more favorable outcomes [70]. These findings support the use of biomarkers to select patients who are more likely to response to DBS.

DBS Plus: future iterations of DBS surgery could involve ancillary treatment, for example use DBS as a medium to introduce stem cells, autologous transplants, and gene modification as well as real-time monitoring of electrochemical activity [71].

Intravascular electrodes: endovascular DBS may be a useful complementary approach to stereotactic transcranial DBS for some indications [71, 72].

Wireless Communication: charging of implantable pulse generators has been a consistent issue in DBS surgery aftercare. Wireless charging offers a potential solution. [73].

Given the promising evidence for efficacy in the preliminary data obtained thus far, the need for further research in the field of DBS for AD is more prominent than ever. Well-designed studies are required to address the following objectives: 1) clarify the efficacy of DBS in AD, 2) improve mechanistic understanding of DBS action in AD, 3) establish an evidence base for biomarker-assisted patient selection and novel patterns of stimulation, and 4) evaluate promising DBS technological innovations [66, 74].

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-0212r1).

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