A Pilot Clinical Trial Investigating Deep Brain Stimulation of the Pedunculopontine Nucleus for the Treatment of Alzheimer's Disease
Phase: NA
Conditions: Alzheimer Disease
Sponsor: University Health Network, Toronto

DBS-PPN-AD CAPCR ID#: 24-5380 
 
 
 
 
PILOT CLINICAL TRIAL PROTOCOL 
 
 
A Pilot Clinical Trial Investigating the Safety, Feasibility 
and Proof of Concept of Deep Brain Stimulation of the 
Pedunculopontine Nucleus for the Treatment of Alzheimer’s 
Disease 
 
Dr. Taufik A. Valiante MD PhD FRCS 
 
 
Krembil Brain Institute, Toronto Western Hospital, 
University Health Network 
 
 
 
 
Protocol Version # 3.0 
 2025

DBS-PPN-AD CAPCR ID#: 24-5380 
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General Information 
 
Title:  
A Pilot Clinical Trial Investigating Deep Brain Stimulation of the 
Pedunculopontine Nucleus for the Treatment of Alzheimer’s 
Disease 
 
Funding:  
Alzheimer Society of Canada and Brain Canada Foundation 
 
Principal Investigator: 
Dr. Taufik A. Valiante 
 
 
 
 
taufik.valiante@uhn.ca  
 
 
 
Collaborators:  
 
Dr. Ahmad Elsawy 
ahmad.elsawy3@uhn.ca 
 
Dr. Mary Pat McAndrews 
mary.mcandrews@uhn.ca 
 
Dr. David Tang-Wai 
david.tang-wai@uhn.ca 
 
Dr. Bernadette Mdawar 
Bernadette.mdawar@camh.ca 
 
Dr. Richard Wennberg 
richard.wennberg@uhn.ca 
 
Dr. Hamed Azami 
Hamed.Azami@camh.ca 
 
Coordinators:  
 
Delaney Sharp 
delaney.sharp2@uhn.ca  
 
Steven Carcone 
 
 
 
 
steven.carcone@uhn.ca 
 
Research Activities Address: Krembil Discovery Tower 
60 Leonard Ave. 
Toronto, ON M5T 0S8 
 
Clinical Site Address:  
Toronto Western Hospital 
399 Bathurst Street, West Wing 4-436 
Toronto, ON M5T 2S8 
T: 416-603-5460

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Contents 
1.0 Background ............................................................................................................................... 1 
1.1 Rationale ............................................................................................................................... 2 
1.1.2 GOs, Theta-Gamma Coupling, and Parvalbumin Interneurons in Cognition ................ 2 
1.1.3 Disruption of GOs, Theta-Gamma Coupling, and PVINs Function in AD ................... 2 
1.1.4 GOs Entrainment as a Disease-Modifying Intervention in AD ..................................... 2 
1.1.5 Neural Circuitry Identifying the PPN as a Key Neuromodulation Target ..................... 3 
1.1.6 Preliminary Data from DBS-PPN Studies ..................................................................... 4 
1.2 Novelty & Significance......................................................................................................... 6 
1.2.1 Limitations of Anti-Amyloid Therapies and the Promise of DBS-PPN ........................ 6 
1.2.2 Comparative Efficacy of Non-Invasive Methods .......................................................... 6 
1.2.3 Emerging GABAergic agents ........................................................................................ 6 
1.2.4 Previous DBS Trials ...................................................................................................... 7 
1.2.5 Broader Implications ...................................................................................................... 7 
2.0 Objectives ................................................................................................................................. 8 
2.1 Assess the Safety, Feasibility, and Preliminary Efficacy of DBS-PPN in AD ................. 8 
2.2 Establish Proof-of-Concept for DBS-PPN’s Ability to Modulate PVINs Function and its 
Potential Effects on Electrographic Markers Associated with AD ......................................... 8 
3.0 Hypotheses ................................................................................................................................ 8 
3.1 DBS-PPN Attenuates the Electrographic Signature of AD .............................................. 8 
3.2 DBS-PPN Modulates Electrographic Surrogates of Molecular Clearance Mechanisms in 
AD ........................................................................................................................................... 8 
3.3 DBS-PPN Improves Cognitive Function by Addressing the Electrographic Deficits 
Associated with AD ................................................................................................................ 8 
4.0 Study Methodology ................................................................................................................... 9 
4.1 Design ................................................................................................................................... 9 
4.2 Patient Selection.................................................................................................................... 9 
4.2.1 Recruitment .................................................................................................................... 9 
4.2.2 Consent Process ............................................................................................................. 9 
4.2.3 Inclusion Criteria ......................................................................................................... 10 
4.2.4 Exclusion Criteria ........................................................................................................ 10 
4.3 Intervention ......................................................................................................................... 10 
4.4 Outcome Measures.............................................................................................................. 11 
4.4.1 Safety ........................................................................................................................... 11 

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4.4.2 Feasibility ..................................................................................................................... 14 
4.4.3 Electrographic Measures .............................................................................................. 14 
4.4.4 Cognitive Measures ..................................................................................................... 15 
4.4.5 Participant’s Evaluation of Intervention ...................................................................... 16 
5.0 Study Timeline ........................................................................................................................ 16 
6.0 Statistical Considerations ........................................................................................................ 17 
7.0 Quality Control & Quality Assurance Procedures .................................................................. 17 
8.0 Ethical Considerations ............................................................................................................ 18 
8.1 Termination of Participation/Withdrawal Criteria .............................................................. 18 
8.2 Potential Risks .................................................................................................................... 18 
8.2.1 Surgical Risks .............................................................................................................. 19 
8.2.3 Stimulation-Related Risks (Adjustable with Programming) ....................................... 19 
8.2.4 Risk of Study-related Procedures................................................................................. 19 
8.3 Risk Mitigation ................................................................................................................... 20 
8.3.1 Close Monitoring ......................................................................................................... 20 
8.3.2 Follow-up Visits........................................................................................................... 20 
8.3.3 Informed Consent......................................................................................................... 20 
9.0 Data Management & Record Keeping .................................................................................... 20 
10.0 Deliverables, Significance & Benefits .................................................................................. 21 
10.1 Potential Benefits .............................................................................................................. 21 
10.1.1 Benefits to Participants .............................................................................................. 21 
10.1.2 Benefits to the Community/Public: ............................................................................ 21 
10.1.3 Benefits to UHN & The Krembil Brain Institute: ...................................................... 22 
11.0 References ............................................................................................................................. 24 
 
 
 
 

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Protocol Summary 
Full Title 
A Pilot Clinical Trial Investigating Deep Brain Stimulation of the Pedunculopontine Nucleus for 
the Treatment of Alzheimer’s Disease 
Short Title 
DBS-PPN-AD 
Design 
Multi-centre, single-cohort, non-randomized prospective pilot trial 
Sample Size  
N= 6 
Study Population  
Adults 60 years and older, diagnosed with Alzheimer’s Disease. 
Accrual Period 
Up to 36 months. 
Study Duration 
Up to 48 months. 
Intervention 
Medtronic Model B35200 Percept™ PC Neurostimulator with BrainSense™ Technology deep 
brain stimulation device. The system delivers electrical stimulation to targeted regions of the 
brain, defined by anatomy or physiology, to suppress the symptoms associated with a neurologic 
disorder treatable by brain stimulation. The neurostimulator generates electrical current that is 
conducted through DBS extensions and leads to the distal lead electrodes. The electrical current 
leaves the lead's electrodes and interacts with the targeted brain tissue to achieve the desired 
effect. 
Primary Objectives 
i. 
Feasibility 
Determined by assessing recruitment trends, adherence to study protocol and attrition 
rates; 
ii. 
Safety 
Assessed by monitoring adverse events, serious adverse events, or unanticipated 
problems related to the DBS device. 
 
 
 

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Secondary Objectives 
i. 
Electrographic Measures 
GO and theta-gamma coupling will be used as surrogates for PVIN activity. DBS-
PPN ability to restore GO and theta-gamma coupling will be used as proof of concept 
for its ability to upregulate PVIN within the hippocampal-neocortical network. 
ii. 
Cognitive Measures 
Cognitive assessments will be used to correlate the anticipated effects of DBS-PPN to 
improvement in cognitive performance using the: Clinical Dementia Rating (CDR) 
Scale; the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-
Cog); the Montreal Cognitive Assessment (MoCA);  the Neuropsychiatric Inventory 
(NPI);the Sleep Disorders Inventory (SDI); and Quality of Life in Alzheimer’s 
Disease (QoL-AD).

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Summary 
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that gradually impairs 
memory, cognitive abilities, and daily functioning, placing a significant burden not only on 
patients but also on caregivers and the healthcare system. Despite extensive research, current 
treatments provide only symptomatic relief without halting or reversing the disease’s 
progression. 
Recently, a new class of treatments has emerged, targeting amyloid—a protein that accumulates 
abnormally in the brains of AD patients and is believed to play a role in the disease’s pathology. 
While anti-amyloid therapies, such as Leqembi (lecanemab), have shown potential in targeting 
amyloid deposits, their clinical benefits remain modest. These drugs offer limited improvements 
in symptoms and come with a risk of significant side effects, including infusion reactions in 
around 25% of patients, as well as brain swelling and bleeding—collectively known as amyloid-
related imaging abnormalities (ARIA)—affecting about 20% of users. Furthermore, these 
treatments necessitate frequent intravenous infusions and regular brain imaging, significantly 
increasing costs and limiting accessibility. 
The limited efficacy, potential for adverse effects, and high costs have led to varied regulatory 
responses across countries. The Therapeutic Goods Administration (TGA) in Australia declined 
to approve Leqembi, citing an insufficient risk-benefit balance given the risks of ARIA. This 
mirrors the European Medicines Agency's (EMA) stance, which also opted not to approve the 
drug, expressing similar concerns regarding its risk-benefit profile. In the UK, the Medicines and 
Healthcare products Regulatory Agency (MHRA) granted approval, yet the National Institute for 
Health and Care Excellence (NICE) has withheld a recommendation for funding by the National 
Health Service (NHS), effectively limiting access to private care. Japan has approved Leqembi 
for an initial round of treatment under national insurance, but subsequent doses require out-of-
pocket payment. These decisions highlight a cautious global stance toward anti-amyloid 
therapies, raising ethical considerations regarding equitable access and the true impact of these 
treatments on AD progression. 
Amid these developments, interest is growing in alternative approaches to treating AD by 
modulating brain wave activity, specifically gamma oscillations. Gamma oscillations are brain 
rhythms associated with cognition and memory, both of which are compromised in AD. Studies 
suggest that enhancing gamma activity could help slow AD progression. Techniques like visual 
or auditory stimulation can increase gamma waves, but their effects are often limited to sensory 
areas and may not fully engage the brain’s natural gamma activity, potentially limiting 
therapeutic benefit. 
This study investigates a novel approach using deep brain stimulation (DBS) to target the 
pedunculopontine nucleus (PPN), a region involved in generating and regulating gamma 
oscillations across the brain. By stimulating the PPN, we aim to enhance gamma activity in a 
more widespread and natural manner, potentially improving memory and cognition in AD 
patients. Preclinical studies have demonstrated that gamma enhancement has disease modifying 
effects in AD. While DBS of the PPN for AD is an emerging field, DBS itself is a well-
established treatment for movement disorders and certain types of epilepsy, with expanding 
applications in other neurological conditions. In Parkinson’s disease, for instance, PPN 

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stimulation has been associated with cognitive improvements and better sleep quality—benefits 
that could address similar deficits in AD and support cognitive health. 
This study explores DBS-PPN as a promising intervention for AD, aiming to enhance cognition 
and overall quality of life for patients.  

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1.0 BACKGROUND 
Alzheimer's disease (AD) is an insidious and devastating neurodegenerative condition that 
affects millions worldwide, placing a considerable burden on patients, families, and healthcare 
systems. In Canada, over 650,000 individuals are currently living with AD or another form of 
dementia. This number is expected to more than double by 2030, underscoring the urgent need 
for effective treatments that can slow or halt the disease progression.1-3 
In 2020, the total annual economic burden of dementia in Canada was estimated to be $40B, 
including the impact upon informal caregivers (e.g., family members), which was estimated to be 
$25B. This includes costs from lost productivity (absenteeism and early retirement) and 
consideration of an estimated 472 million caregiving hours. If current trends continue, the annual 
economic burden could grow by 275% over the next 30 years.4 
Recent advances in amyloid-depleting therapies represent a significant breakthrough in 
Alzheimer’s research; however, their clinical benefits remain limited.5 These treatments have 
demonstrated modest improvements in slowing cognitive decline, often accompanied by 
substantial drawbacks, including notable side effects, high costs, and logistical challenges.5-8 For 
instance, frequent MRI surveillance for amyloid-related imaging abnormalities (ARIA) and 
biweekly intravenous administration are required, imposing a strain on healthcare systems that 
may lack the capacity to deliver such intensive care on a wide scale.5-7 These challenges 
accentuate the necessity for alternative treatments that are accessible, safe, and effective for a 
broader patient population. 
Over the last decade, emerging evidence has identified neuronal hyperexcitability as a critical 
factor in the pathogenesis of AD.9,10 The loss of both the number and function of inhibitory 
interneurons has been shown to exacerbate amyloid deposition, leading to further interneuron 
impairment and creating a vicious cycle of inexorable cognitive decline.9,10 Stimulation of 
interneurons at gamma frequencies has demonstrated disease-modifying effects in several 
preclinical studies.11-14 Entraining gamma oscillations (GOs), the electrophysiological signature 
of interneuron activity,15 has not only mitigated aberrant amyloid production but has also 
enhanced microglial and glymphatic clearance of amyloid deposits.11,12 Furthermore, it has 
restored deficits in theta-gamma coupling, an emerging electrophysiological biomarker in AD 
crucial for successful memory processing in the hippocampus.13,14,16 
The pedunculopontine nucleus (PPN), located in the brainstem, is recognized as a principal 
driver of endogenous GOs in the brain.17 Our study aims to utilize deep brain stimulation (DBS) 
of the PPN to entrain inherent GOs, thereby harnessing the disease-modifying effects observed in 
preclinical studies. We support our proposal by identifying a neural network through which PPN 
stimulation would drive inhibitory interneurons and entrain the resultant GOs across extensive 
brain networks including the hippocampus, a key structure pertinent to memory and AD.18 
Furthermore, DBS of the PPN (DBS-PPN) has shown cognitive improvements in Parkinson’s 
dementia patients with a firmly established safety profile, an important observation that has 
largely gone unnoticed in the cognitive neuromodulation field.19-21 Thus, our study is grounded 
in robust preclinical and clinical evidence supporting the feasibility and safety of DBS-PPN in 
AD. Additionally, our study has been peer-reviewed by an expert panel of the Alzheimer’s 
Society Research Program (ASRP), which has endorsed this project through the ASRP/Brain 
Canada Proof of Concept Grant (2024).22  

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1.1 Rationale 
1.1.2 GOs, Theta-Gamma Coupling, and Parvalbumin Interneurons in Cognition 
Cognitive processes such as memory encoding, attention, and sensory processing rely on GOs 
which occur in the 30-100 Hz  frequency range.23,24 These fast rhythms allow for precise 
coordination of neural activity across cortical networks.23,24 Parvalbumin interneurons (PVINs), a 
subtype of GABAergic interneurons, play a key role in generating and maintaining gamma 
oscillations by providing fast, rhythmic, and temporally precise inhibition to pyramidal 
neurons.15,25 This action helps regulate the timing of excitatory signals, allowing neurons to fire 
in synchrony.15,23 Moreover, the interaction between GOs and slower theta rhythms (4-8 Hz), 
known as theta-gamma coupling, is crucial for organizing information flow in the brain.26,27 
Theta-gamma coupling enables the brain to segment and prioritize information, with gamma 
oscillations encoding fine details within theta cycles.26,27 This coupling, facilitated by PVINs, 
underlies key cognitive functions such as working memory, navigation, and attention by 
enhancing the temporal coordination between hippocampal and cortical circuits.28-30 
1.1.3 Disruption of GOs, Theta-Gamma Coupling, and PVINs Function in AD 
The disruption of GOs and theta-gamma coupling is closely associated with cognitive decline in 
AD, particularly memory deficits and impaired attention.16,23,31 PVINs dysfunction, driven by 
neurodegeneration and the accumulation of amyloid-beta and tau pathology, undermines the 
ability of neural circuits to generate gamma rhythms.9,10 This loss leads to impaired theta-gamma 
coupling, which is crucial for the synchronization of hippocampal and cortical activity during 
cognitive tasks.16,28,31 The loss of PVINs reduces inhibitory control over excitatory neurons, 
leading to network hyperexcitability and desynchronization.9,10 The breakdown in theta-gamma 
coupling disrupts the brain's ability to encode and retrieve memories, as well as process 
information efficiently.16,26,31 Furthermore, studies suggest that impaired GOs may accelerate 
amyloid-beta deposition and tau pathology, contributing to a vicious cycle of neural network 
degradation, ultimately exacerbating the cognitive decline in AD (Fig. 1).9,10 
 
Figure 1: Aβ deposits impair the GABAergic parvalbumin interneurons (PVIN) inhibitory drive over glutamatergic 
pyramidal cells leading to excitatory neurotoxicity. The hyperexcitable pyramidal cells produce more Aβ creating a 
vicious cycle with inexorable cognitive decline. 
 
1.1.4 GOs Entrainment as a Disease-Modifying Intervention in AD 
Several studies have explored the potential of GOs entrainment as a therapeutic approach to 
modify the progression of Alzheimer's disease (AD), with a focus on reducing amyloid burden, 
restoring network dynamics, and enhancing amyloid-beta clearance.32 A pioneering study by 
Iaccarino et al. (2016) demonstrated that non-invasive stimulation of GOs, using 40 Hz light 
flicker in a mouse model of AD, led to a significant reduction in amyloid-beta plaques.12 This 
reduction was attributed to increased activation of microglia, the brain's resident immune cells, 

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which are crucial for clearing amyloid deposits. The study further suggested that gamma 
entrainment reestablished the balance between excitatory and inhibitory signaling, particularly 
by enhancing the activity of PVINs, which are essential for generating gamma rhythms. The 
restoration of PVINs function contributes not only to the normalization of network oscillations 
but also to the regulation of neural plasticity and cognitive performance.32 
Subsequent studies have expanded on these findings by demonstrating that gamma entrainment 
can promote not only amyloid-beta clearance but also tau pathology reduction, which is another 
hallmark of AD.33,34 Chronic gamma stimulation, delivered through auditory or visual sensory 
stimulation, has been shown to recruit microglia and astrocytes, both of which are implicated in 
the clearance of pathological protein aggregates.33,34 The enhanced activity of these glial cells, 
triggered by synchronized GOs, increases their phagocytic capacity, leading to a reduction in 
amyloid-beta levels in the hippocampus and other cortical areas. Additionally, gamma 
stimulation has been linked to improved cerebrospinal fluid flow, which is critical for waste 
clearance from the brain, including amyloid-beta peptides.11 Importantly, the therapeutic effects 
of gamma entrainment extend to the restoration of theta-gamma coupling, which is often 
disrupted in AD due to PVINs dysfunction.13,14 By reestablishing the precise timing of neuronal 
firing and network synchronization, gamma stimulation helps restore the brain's capacity for 
efficient information processing and memory encoding.32 These promising findings highlight the 
potential of GOs entrainment as a disease-modifying intervention in AD, offering a novel 
approach to targeting both the pathological and functional aspects of the disease. 
1.1.5 Neural Circuitry Identifying the PPN as a Key Neuromodulation Target  
The PPN located in the dorsolateral mesopontine tegmentum, plays a critical role in modulating 
GOs in the brain, acting as a key mediator of bottom-up control mechanisms.17 The PPN’s 
ascending glutamatergic projections, particularly targeting the basal forebrain, have been 
identified as the primary drivers of gamma oscillatory activity.35 Studies have demonstrated that 
this PPN-basal forebrain pathway is pivotal for the initiation and regulation of GOs, which are 
essential for various cognitive functions, including attention and memory.36 These projections 
stimulate cholinergic and GABAergic neurons within the basal forebrain, leading to widespread 
gamma entrainment across cortical and subcortical regions.36 This makes the PPN an essential 
hub for the regulation of higher-order neural processes.37 
Harmoniously, the basal forebrain is known to synchronize GOs through its extensive and direct 
projections to PVINs in both neocortical and hippocampal regions.38,39 PVINs are crucial in 
generating and sustaining gamma rhythms due to their ability to precisely modulate excitatory 
pyramidal neuron activity.25 By influencing PVIN function, the basal forebrain facilitates the 
entrainment of GOs across the neocortical-hippocampal network, which is critical for the 
encoding and retrieval of memory.18 This interconnected system of the PPN, basal forebrain, and 
PVINs forms a coordinated neural circuit that supports cognitive processes through the 
modulation of gamma rhythms.18 
In this framework, PPN glutamatergic projections upregulate the activity of the basal forebrain, 
which in turn recruits and synchronizes PVINs, thus driving gamma oscillatory activity 
throughout cortical and hippocampal networks (Fig. 2).18 

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Figure 2: Pedunculopontine nucleus (PPN) is the main driver of gamma oscillations in the brain. PPN achieves this 
through ascending glutamatergic projections to the basal forebrain (BF), which in turn sends direct projections 
upregulating PVIN and the ensuing gamma oscillations within the hippocampal-neocortical network. [Left] Aβ 
deposits impair gamma oscillations and PVIN function of synchronizing pyramidal cells firing within the 
hippocampal-neocortical network, hampering memory processing and cognition. [Right] Deep brain stimulation 
(DBS) of the PPN would augment PVIN activity which has been shown to decrease the Aβ burden, restore gamma 
oscillations, and rescue memory in AD preclinical studies. 
This cascading effect places the PPN at the core of a neuromodulatory network capable of 
enhancing cognitive function, particularly memory processing. Given its central role in 
regulating GOs, the PPN emerges as a highly promising target for neuromodulation therapies in 
AD, where GOs disruption is linked to cognitive decline. 
This integrative neural network model underscores the PPN’s role in orchestrating PVINs-driven 
gamma activity and its relevance to memory circuits. This model underscores the PPN’s 
influence not only on basal forebrain and hippocampal circuits but also on the coordination of 
cortical regions, positioning it as a key factor in understanding memory-related dysfunctions in 
neurodegenerative diseases like AD (further details are available in our preprint). Importantly, 
this points to the potential of PPN-targeted therapies for restoring normal gamma oscillatory 
function and mitigating the cognitive deficits associated with AD.18 
1.1.6 Preliminary Data from DBS-PPN Studies 
DBS-PPN traditionally investigated in Parkinson’s disease (PD) for motor symptoms, has also 
been shown to have significant non-motor benefits, particularly in areas related to sleep and 
cognition.19-21 Studies indicate that DBS-PPN can improve the quality of sleep in PD patients, 
significantly increasing REM sleep which is critical for memory consolidation and cognitive 
function.19-21,40-43 The PPN, as a key structure within the reticular activating system, plays an 
essential role in regulating arousal and maintaining the sleep-wake cycle.17,36 Stimulating the 
PPN has been found to improve sleep architecture, facilitating a more restorative sleep that, in 
turn, supports cognitive performance.19-21,44,45 
Some studies that included cognitive assessments alongside sleep measurements reported 
improvements in certain cognitive domains, particularly those related to executive function and 
attention.19-21 For example, Costa et al. found that DBS-PPN stimulation significantly reduced 
response times in an n-back task, indicating enhanced processing speed, though accuracy 
remained unchanged.46 Cervalo et al. demonstrated improvements in delayed recall, executive 

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function, verbal long-term memory, and verbal fluency with DBS-PPN.40 Fischer et al. reported 
that low-frequency DBS-PPN stimulation enhanced basal attentional processing in patients with 
Parkinsonian disorders, increasing tonic alertness, a key factor in sustained attention.47 Ricciardi 
et al. presented a case where deactivating DBS-PPN led to a decline in cognitive functions such 
as short-term memory, verbal fluency, and object naming.19 Upon reactivating the stimulation, 
the patient's cognitive performance, including attention and memory, returned to baseline, 
restoring their prior cognitive profile and autonomy. 
The connection between sleep disturbances and AD is indeed well-established. Poor sleep 
quality, particularly a reduction in REM sleep, is both a risk factor and a consequence of AD 
pathology.48,49 Disrupted sleep accelerates the accumulation of amyloid-beta and tau proteins, 
key pathological features of AD, due to the impaired functioning of the glymphatic system 
during sleep.48,50 Conversely, these pathological proteins further disrupt sleep architecture, 
creating a bidirectional relationship that exacerbates cognitive decline (Fig. 3).48,5039,41 
 
 
Figure 3: Bidirectional relationship between sleep disruption and Alzheimer’s disease 
Studies indicate that a 1% reduction in REM sleep heightens dementia risk by 9%, underscoring 
REM’s crucial role in cognitive health.49 DBS-PPN has been shown to almost double REM sleep 
duration without impacting other disease stages, suggesting it may help slow AD progression by 
enhancing REM sleep.43 These findings highlight the potential of interventions targeting REM as 
a strategy to mitigate AD risk. 
In this context, findings from DBS-PPN in Parkinson's patients are highly relevant to 
Alzheimer's research. Improved sleep measures, such as increased REM, could potentially delay 
or mitigate cognitive decline in AD by enhancing neural plasticity, promoting synaptic health, 
and facilitating the clearance of neurotoxic proteins during sleep.42,43,48,50 Given the PPN's role in 
modulating both GOs and sleep-wake cycles, DBS-PPN presents a compelling neuromodulatory 
approach for addressing cognitive symptoms in AD.17 By restoring a healthy sleep architecture, 
PPN stimulation could interrupt the vicious cycle of poor sleep and accumulating amyloid 
pathology, thus preserving cognitive function in neurodegenerative conditions.18-21,43,48,50 
In conclusion, this intersection of improved sleep, GOs, and cognition provides a holistic 
therapeutic approach that targets not only symptomatic aspects of AD but also the underlying 
neural network disruptions that drive disease progression. 

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1.2 Novelty & Significance 
1.2.1 Limitations of Anti-Amyloid Therapies and the Promise of DBS-PPN 
Recently developed anti-amyloid drugs, which have shown cognitive improvements for the first 
time after decades of failure, have been well received both within and outside the scientific 
community.5 However, the initial excitement has been tempered by concerns about their limited 
clinical impact, significant side effects, and poor cost-effectiveness.5,6,8 Unlike these therapies, 
DBS-PPN represents a novel approach by addressing the underlying pathological processes that 
lead to amyloid-beta deposition, such as neuronal hyperexcitability and the disruption of 
glymphatic clearance during sleep, rather than directly targeting amyloid-beta itself.18 This could 
not only prove to be a more efficient and effective strategy, but also avoids the brain 
inflammation associated with monoclonal antibodies directly targeting amyloid-betadeposits.51-53 
Such inflammation can lead to brain edema and hemorrhage, known as ARIA, which occur in 
about 20% of patients.51-53 The high incidence of ARIA necessitates frequent MRI surveillance, 
further compounding the logistical and financial burdens of anti-amyloid therapies.53 For 
example, the total cost of Lecanemab, including safety monitoring, can reach up to $88,728 USD 
per patient per year.54 In contrast, DBS-PPN has one-time operative and device costs estimated at 
$20,000 to $26,000 USD.55 Thus, DBS-PPN could offer a more effective, more feasible, and 
safer option at a significantly lower cost. 
1.2.2 Comparative Efficacy of Non-Invasive Methods 
Our proposal to entrain GOs using neuromodulation has been investigated, albeit through a non-
invasive approach known as Gamma ENtrainment Using Sensory Stimulation (GENUS).56 
GENUS is a technique that uses sensory inputs, such as 40 Hz auditory or visual stimuli, to 
induce GOs in the brain.56 While GENUS has shown some promise, it is limited to effects within 
specific sensory regions of the brain, which may not be sufficient given the widespread nature of 
AD.56-59 This method requires extensive treatment sessions, leading to patient non-compliance 
and potential disruptions to daily routines due to the cognitive load imposed by the auditory and 
visual stimulation.56 Additionally, the benefits of GENUS are often short-lived, necessitating 
frequent sessions to maintain efficacy, and individual responses can vary significantly based on 
sensory processing capabilities.56 In contrast, DBS-PPN offers a more targeted and sustained 
approach, engaging widespread brain networks, including critical areas like the hippocampus, 
without the need for exhaustive treatment sessions or environmental adjustments.18 This ensures 
better patient compliance and reduces the impact on daily life, making DBS-PPN a potentially 
more effective and practical solution for addressing the cognitive deficits associated with AD. 
Furthermore, studies indicate that GENUS elicits gamma-like oscillations that lack the same 
stability, coherence, and network-wide engagement of the brain’s native GOs.58 Conversely, 
DBS-PPN directly targets neural structures that generate native GOs, leading to more stable and 
widespread entrainment.17,18 This distinction is crucial for Alzheimer's research, as consistent 
engagement of endogenous GOs may be necessary to achieve meaningful cognitive 
improvements. 
1.2.3 Emerging GABAergic agents 
Emerging GABAergic treatments aim to restore inhibitory tone by enhancing PVINs activity, 
thereby addressing the neural hyperexcitability linked to AD progression.10 However, these 
pharmacological approaches are often accompanied by systemic side effects, including sedation, 
dizziness, motor incoordination, and cognitive impairment, which pose significant risks, 
particularly for elderly patients already vulnerable to cognitive decline. In contrast, our DBS-

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PPN approach offers a more targeted strategy by specifically GOs and enhancing PVINs activity 
in a spatially selective manner, minimizing the widespread and non-specific effects associated 
with GABAergic drugs.18 Directly modulating PVINs via PPN stimulation bypasses the systemic 
disruptions associated with pharmacological treatments, providing continuous, long-term 
modulation without the daily fluctuations or compliance issues commonly encountered with oral 
medications. 
1.2.4 Previous DBS Trials 
Prior DBS trials targeting the nucleus basalis of Meynert (NBM) and the fornix for Alzheimer’s 
disease have yielded inconclusive results.60 DBS-NBM was based on the cholinergic hypothesis, 
which has been challenged by findings indicating that cholinergic degeneration occurs later in 
the disease process.61,62 Fornix DBS stemmed from an incidental finding in a patient undergoing 
DBS for obesity who experienced vivid autobiographical memory recall upon fornix 
stimulation.63,64 This reliance on a non-specific observation, without a comprehensive 
understanding of the underlying neural networks, led to less favorable outcomes.65,66 In contrast, 
our DBS-PPN approach is supported by robust preclinical and clinical evidence highlighting: (1) 
the disease-modifying effects of GOs entrainment, (2) the critical role of PPN in this process, 
and (3) the cognitive benefits observed in humans.11-13,17,19,34 Additionally, the proposed trial 
utilizes GOs entrainment and theta-gamma coupling as objective electrophysiological outcome 
measures to evaluate the disease modifying potential of DBS-PPN.16,27,31,67 
1.2.5 Broader Implications 
This pilot study serves as a precursor to a multicenter randomized controlled trial (RCT) that 
could establish the first disease modifying neuromodulatory treatment for AD. It also opens 
up opportunities to investigate DBS-PPN in other dementias, such as frontotemporal dementia 
and Parkinson's dementia, where PVINs dysfunction is observed.19,68 The findings may extend 
beyond dementia, with relevance to conditions characterized by GOs and PVINs impairments, 
including epilepsy, schizophrenia, and autism.69-71 Ultimately, this study aims to contribute to 
our understanding of brain excitation/inhibition networks, which play a crucial role in normal 
brain function and are significant in various neurological disorders.69-71 
 
 

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2.0 OBJECTIVES  
2.1 Assess the Safety, Feasibility, and Preliminary Efficacy of DBS-PPN in AD 
This aim focuses on evaluating the safety, tolerability, and feasibility of DBS-PPN as a 
neuromodulatory intervention for patients with AD. The goal is to gather essential data for the 
design of a future multicenter RCT. We will also assess preliminary efficacy by measuring 
electrophysiological outcomes and cognitive function. 
2.2 Establish Proof-of-Concept for DBS-PPN’s Ability to Modulate PVINs Function and its 
Potential Effects on Electrographic Markers Associated with AD 
This study aims to demonstrate that DBS-PPN enhances PVINs function, thereby restoring GOs 
and theta-gamma coupling in patients with AD.13,14,17,18 While the molecular effects of DBS-
PPN, such as amyloid-beta clearance, will not be directly measured, electrographic outcomes 
will serve as surrogate markers, supported by preclinical studies showing a link between GOs 
and molecular processes involved in amyloid-beta clearance.11,12,34 
3.0 HYPOTHESES 
3.1 DBS-PPN Attenuates the Electrographic Signature of AD 
GOs and theta-gamma coupling are critical neural rhythms that underpin successful memory 
processing.23,26,27 Disruptions in these oscillatory patterns have been linked to cognitive deficits 
in AD patients.16,23,67 Preclinical studies indicate that stimulation of PVINs at gamma frequencies 
restores theta-gamma coupling and improves memory in AD models.13,14 We hypothesize that 
DBS-PPN will enhance PVINs function, restoring impaired GOs and theta-gamma coupling in 
AD patients, thereby attenuating the electrographic imprint of AD.18 
3.2 DBS-PPN Modulates Electrographic Surrogates of Molecular Clearance Mechanisms in 
AD 
Amyloid-beta deposition is a key pathological hallmark of AD, stemming from an imbalance 
between amyloid-beta production and clearance.72 In preclinical models, gamma-frequency 
stimulation of PVINs has been shown to enhance microglial activity, promoting amyloid-beta 
clearance and reducing its burden.12 Furthermore, gamma entrainment appears to decrease 
aberrant amyloid-beta production by restoring the excitation/inhibition balance in the brain.12,34 
GOs are also linked to the enhancement of the glymphatic system, which facilitates amyloid-beta 
clearance.11 Although molecular changes will not be directly measured in this study, we 
hypothesize that DBS-PPN will modulate electrographic signatures (GOs and theta-gamma 
coupling) as surrogates for these molecular clearance mechanisms.18 
3.3 DBS-PPN Improves Cognitive Function by Addressing the Electrographic Deficits 
Associated with AD 
Cognitive decline in AD, particularly memory impairment, is closely associated with disruptions 
in GOs and theta-gamma coupling.16,23 By enhancing PVINs function through DBS-PPN, we 
expect to restore these neural rhythms and subsequently improve cognitive performance in AD 
patients. We hypothesize that improved electrographic markers will correspond to gains in 
memory and overall cognition, providing evidence of DBS-PPN’s therapeutic potential in AD. 

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4.0 STUDY METHODOLOGY 
4.1 Design 
This pilot study is designed as a single-centre, single-cohort, open-label, non-randomized 
prospective clinical trial. The open-label nature means that both the researchers and the 
participants will be aware of the intervention being administered, which is DBS targeting of the 
pedunculopontine nucleus (PPN). The trial will recruit a small group of participants to evaluate 
the safety, feasibility, and preliminary efficacy of DBS-PPN in treating AD. 
The rationale for the choice of a single-cohort, open-label design allows for a focused, initial 
exploration of the intervention's effects without the complexities and costs associated with larger, 
multi-center, randomized controlled trials (RCTs). This design is appropriate for a pilot study 
where the primary goals are to gather preliminary data on feasibility and safety, and to identify 
any potential issues that could affect a larger trial in the future. 
4.2 Patient Selection 
4.2.1 Recruitment 
The study will recruit a small number of participants (N=6) who meet specific inclusion and 
exclusion criteria. Each participant will serve as their own control, with outcome measures 
compared before and after DBS-PPN intervention. Recruitment will be performed through the 
Toronto Dementia Research Alliance (TDRA). Established in 2012, the TDRA is a collaboration 
among the University of Toronto, Baycrest, the Centre for Addiction and Mental Health 
(CAMH), Ontario Shores Centre for Mental Health Sciences (Ontario Shores), Sunnybrook 
Health Sciences Centre, Unity Health Toronto, and UHN.  
The TDRA and the Alzheimer Society of Toronto (AST) have teamed up to make ongoing 
studies in AD more accessible to prospective participants, as their website provides a Research 
Studies section where patients and their caregivers can find information about AD studies that 
are open for participation. Prospective participants can browse for studies in plain language, or if 
they are not sure which study to sign up for, there is a questionnaire to help match them to a 
study. Click here to review their brochure. Any information entered and stored through these 
questionnaires will only be used for the purpose of connecting the patient with the specific study 
and providing the study team with the patient’s contact information. The electronic forms and 
systems will be protected with standard safeguards as per CAMH privacy policy and will only be 
accessed by the TDRA team. 
We aim to recruit a minimum of two patients per year to reach our goal of recruiting six patients 
in under 36 months, which is the threshold we will require to proceed with a larger RCT in the 
future. 
4.2.2 Consent Process 
Potential participants will be identified through the Toronto Dementia Research Alliance 
(TDRA). Initial contact will be made by the research team to provide information about the 
study. 
Patients expressing interest will be referred to the neurosurgery/neuropsychology clinic at TWH 
(Dr. McAndrews) to screen for study eligibility based on our inclusion and exclusion criteria set 
forth below. If deemed eligible, informed consent will be obtained by the coordinator and 
baseline outcome measures will be collected (Figure 3; cognitive/electrophysiological/PET 

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scan). DBS-PPN implantation will be scheduled within 2 months of obtaining informed consent 
(Figure 3).  
The study coordinator or designated study staff will obtain informed consent from participants. 
Detailed explanations of the study will be provided, and any questions or concerns will be 
addressed. 
4.2.3 Inclusion Criteria 
i. 
 Adults over 60 years old; 
ii. 
Satisfied the diagnostic criteria of the National Institute of Aging - Alzheimer’s 
Association criteria for probable AD; 
iii. 
Clinical dementia rating scale global score of ≤ 1; and 
iv. 
Not taking an acetylcholinesterase inhibitor and/or memantine, or taking a stable dose 
for at least six months; 
v. 
Fluent in English; 
vi. 
Caregiver available. 
4.2.4 Exclusion Criteria 
i. 
Pre-existing structural brain abnormalities (e.g., significant white matter disease, tumor, 
infarction, or intracranial hematoma); 
ii. 
Other neurologic or psychiatric diagnoses, or medical comorbidities that would preclude 
patients from undergoing surgery; 
iii. 
Non-fluent in English (it will be very difficult to conduct standard cognitive tests in 
English on non-fluent English speakers. In addition, language barrier is significant hurdle 
in providing standard care with communication and cognition being a main outcome 
measure). 
 
4.3 Intervention 
The study will employ Deep Brain Stimulation (DBS), a neuromodulation therapy involving the 
precise application of electrical impulses to targeted brain regions to modulate neural activity. 
DBS is delivered through a surgically implanted neurostimulator, similar in function to a cardiac 
pacemaker, and is used to manage symptoms of specific neurological disorders. 
Surgical Procedure: The DBS implantation procedure targeting the PPN involves a 
neurosurgical operation performed under general anesthesia. During the procedure, thin 
electrodes are implanted in the PPN with the aid of advanced pre-operative imaging (MRI and 
CT scan) to confirm precise targeting. These electrodes are connected to a neurostimulator 
device implanted subcutaneously in the chest. This device generates and transmits electrical 
impulses to the PPN, which can be adjusted to optimize therapeutic outcomes. A post-operative 
CT scan is used to confirm location of the implanted electrodes. 
Postoperative Recovery: Following the procedure, patients are expected to stay overnight for 
monitoring, with most returning home the next day. A gradual return to normal activities is 
anticipated within 3 to 6 weeks, allowing time for recovery and initial device programming 
adjustments. 

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Device and Regulatory Information: This study will use the Medtronic Model B35200 
Percept™ PC Neurostimulator with BrainSense™ Technology, a licensed device approved by 
Health Canada in 2020. Although the device is licensed for specific uses, it will be applied here 
for an off-label indication by targeting the PPN, which falls outside its standard approved 
indications. Given that this study is independently conducted and not sponsored by the 
manufacturer, it qualifies for an exemption from Health Canada’s Investigational Testing 
Authorization (ITA) requirements. Per Health Canada’s guidance on ITA applications (section 
2.3.2.2), studies employing licensed devices off-label are exempt from ITA requirements if they 
are not manufacturer-sponsored (see link).21,64,73-75 
4.4 Outcome Measures 
The primary outcomes will focus on safety and feasibility metrics, serving to inform the design 
of a subsequent RCT. The secondary outcomes will assess electrophysiological and cognitive 
measures, providing proof-of-concept for the potential disease-modifying effects of DBS-PPN.  
4.4.1 Safety   
DBS is a neurosurgical procedure that utilizes stereotactic techniques to implant an electrode in a 
specific brain target, delivering electrical stimulation via a pulse generator.76 As a minimally 
invasive intervention, most patients are discharged the day after surgery and can resume normal 
activities within 3–6 weeks.77 DBS is considered a low-risk procedure and has become a widely 
accepted treatment for several neurological conditions, including Parkinson’s disease and drug-
resistant epilepsy.76 
The most frequent complication associated with DBS is infection, occurring in approximately 
3% of cases, with the most severe being intracranial hemorrhage or stroke, which remains rare 
(<1%).76,78 Importantly, the incidence of complications is significantly reduced in high-volume 
centers. Toronto Western Hospital is internationally recognized for its expertise in DBS 
surgeries. 
The use of DBS-PPN has been reported in over 100 published cases, establishing a favorable 
safety profile, including demonstrated tolerability in the pediatric population.74,79 However, it is 
important to note that DBS-PPN is considered an off-label application for Alzheimer’s disease. 
This study aims to further validate the safety and tolerability of DBS-PPN in individuals with 
Alzheimer’s, laying the groundwork for a subsequent multi-center RCT. 
Possible adverse events (AEs), serious adverse events (SAEs), or unanticipated problems related 
to the DBS device, related surgery and/or stimulation will be closely monitored and managed as 
per standard of care and definitions and classifications set forth in the following subsections. 
4.4.1.1 Definition and Classification of Adverse Events (AEs) 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the medical device which includes: 
a. Events related to the investigational medical device or the comparator; and 
b. Events related to the procedures involved. 
 
An SAE is an event that: 
a. Led to death; 

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b. Led to serious deterioration in the health of the subject, that either resulted in: 
i. 
A life-threatening illness or injury; 
ii. 
A permanent impairment of a body structure or a body function; 
iii. 
In-patient or prolonged hospitalization; or 
iv. 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.\ 
c. Led to foetal distress, foetal death or a congenital abnormality or birth defect; 
d. Could have led to death or a serious deterioration were it to recur. 
 
4.4.1.2 AE Severity 
All AEs will be assessed by the study team using The Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 published by the U.S. Department of Health and Human 
Services (November 27, 2019) grading system. For AEs not included in the CTCAE defined 
grading system, the following guidelines will be used to describe severity: 
• Grade 1, Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; 
• Grade 2, Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental activities of daily life (ADL)*; 
• Grade 3, Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**; 
• Grade 4, Life-threatening consequence; urgent intervention indicated; or 
• Grade 5, Death related to AE. 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
4.4.1.3 AE Relationship to Study Intervention 
For all collected AEs, the study team will determine the AE’s causality based on temporal 
relationship, alternative explanations (e.g. concurrent disease or other drugs) and clinical 
judgment. The degree of certainty about causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study device use and 
cannot be explained by concurrent disease or other drugs, chemicals, or devices; 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after implantation/use of the study device, is 
unlikely to be attributed to concurrent disease or other drugs, chemicals or devices; 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after implantation/use of the study device. However, 
other factors may have contributed to the event (e.g., the participant’s clinical condition, 
other concomitant events). Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related,” as appropriate; 

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• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to implantation/use of the study device makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
implantation/use of the study device) and in which other drugs, chemicals, devices or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments); or 
• Not Related – The AE is completely independent of implantation/use of the study device, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
4.4.1.4 AE Outcome 
The outcome of the AE will be defined according to the following: 
• Recovered/ Resolved: The event has fully resolved at the end of the study*; 
• Recovering/ Resolving: The event is improving but has not fully resolved at the end of 
the study*; 
• Recovered/ Resolved with sequelae: The event has resolved, but retained pathological 
conditions resulting from the prior disease or injury; 
• Not recovered/ not resolved: The event is ongoing at the end of the study*; 
• Fatal: This event is determined to be the cause of death; and 
• Unknown: Outcome information could not be obtained. 
*or at the time of last observation 
 
 

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4.4.2 Feasibility 
4.4.2.1 Recruitment Rates 
The effectiveness of recruitment strategies will be assessed by monitoring the rate at which 
eligible participants are enrolled. The target enrollment is six participants within a 36-month 
period. Recruitment progress will be regularly reviewed to identify potential barriers and 
optimize outreach methods. 
4.4.2.2 Adherence to Study Protocol 
To ensure procedural consistency across participants, adherence to the study protocol will be 
systematically monitored. Any protocol deviations will be documented and evaluated for their 
potential impact on study outcomes, ensuring the reliability and reproducibility of findings. 
4.4.2.3 Attrition Rates 
Participant retention will be assessed through an analysis of attrition rates, with particular 
attention to identifying the causes of dropout. Understanding these factors will provide critical 
insights into the feasibility of sustaining long-term participant engagement in future large-scale 
RCTs. 
4.4.2.4 Feedback from Participants and Caregivers 
Exit interviews will be conducted with participants and their caregivers to gather qualitative data 
on their experiences with the intervention and the research processes. This feedback will be 
instrumental in refining both the intervention and study design for subsequent trials. 
4.4.3 Electrographic Measures 
Objective electrophysiological outcome measures will be utilized to provide proof-of-concept for 
the disease-modifying potential of DBS-PPN. The ability of DBS-PPN to restore neural 
oscillations associated with cognition will serve as evidence not only for potential memory 
enhancement but also as a surrogate marker for improved amyloid-beta and tau clearance, as 
demonstrated in preclinical studies. 
4.4.3.1 GOs Power and Synchrony 
Description: 
GOs are primarily generated by PVINs and play a key role in memory and cognitive processing. 
In AD, the disruption of these oscillations is associated with cognitive decline, impaired 
microglial function, and a reduction in glymphatic clearance efficiency. Restoring gamma power 
and synchrony may not only enhance cognition but also promote amyloid-beta and tau clearance, 
through upregulating microglial responses and improving glymphatic system function. 
Measurement: 
GOs power spectral density and synchrony will be assessed using scalp EEG and MEG during 
DBS-PPN "on" and "off" epochs. These recordings will be collected during resting-state periods 
at the first follow-up visit, 4 weeks post-implantation (see device programming section). 
Increases in gamma activity during the "on" state will be evaluated to determine the effectiveness 
of DBS-PPN in entraining neural rhythms essential for cognitive restoration and 
amyloid/tauclearance. 
Significance: 
Preclinical studies have shown that gamma stimulation at 40 Hz promotes the activation of 
microglia, which are essential for clearing amyloid plaques and tau, and enhances CSF-ISF 
exchange within the glymphatic system, aiding amyloid/tau clearance. Given that impaired 

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gamma rhythms contribute to both cognitive deficits and the accumulation of AD-related 
pathology, restoring GOs offers a promising avenue for improving memory function and slowing 
disease progression. 
4.4.3.2 Theta-Gamma Coupling During N-Back Memory Task 
Description: 
Theta-gamma coupling captures the interaction between slower theta rhythms (4–8 Hz) and 
faster GOs. This dynamic coordination is essential for memory encoding and retrieval, with 
particular relevance during working memory tasks such as the n-back task. Emerging evidence 
identifies theta-gamma coupling as a biomarker in AD, correlating with the degree of cognitive 
decline and reflecting the functional status of hippocampal-prefrontal networks . This 
methodology has been pioneered, with published data, by our collaborators at CAMH.16,31,67,80 
Measurement: 
Theta-gamma coupling will be measured using EEG and MEG recordings during an n-back task, 
which engages working memory and cognitive flexibility. Comparisons will be made between 
"on" and "off" states of DBS-PPN to evaluate whether stimulation enhances coupling and 
improves task performance. The analysis will focus on brain regions critical to memory 
processes, such as the hippocampus and prefrontal cortex, given their involvement in encoding 
and retrieval functions. This will be conducted at the first follow-up visit, 4 weeks post-
implantation (see device programming section). Thereafter the device will be turned “on” for 
the rest of the study and theta-gamma coupling will be examined at subsequent follow-up visits 
at 3, 6, 9, and 12 months to monitor long-term changes in cognitive performance. These 
longitudinal assessments will help determine whether DBS-PPN elicits sustained improvements 
in neural coupling and working memory performance, reflecting potential therapeutic benefits 
over time. 
Significance: 
Deficits in theta-gamma coupling are closely linked to impaired memory encoding and retrieval 
in AD, making it a key target for interventions aimed at cognitive restoration.16,26,31,67 PVINs, 
through their inhibitory control, play a crucial role in coordinating theta and gamma 
oscillations.13,14,28 DBS-PPN, by modulating PVINs activity, may enhance theta-gamma 
coupling, improving temporal coordination within memory-related networks, such as the 
hippocampus and prefrontal cortex.18 By upregulating PVINs function, DBS-PPN holds potential 
for improving working memory and cognitive flexibility, offering mechanistic insights into how 
stimulation influences memory networks. Longitudinal theta-gamma coupling assessments will 
provide data on the durability of DBS-PPN’s effects and monitor disease progression over time. 
4.4.4 Cognitive Measures 
Cognitive assessments will be employed to correlate the anticipated effects of DBS-PPN with 
improvements in cognitive performance. The following validated tools will be used: 
• 
Clinical Dementia Rating (CDR) – Sum of Boxes (CDR-SB): 
The CDR-SB will be used to provide a more granular assessment of cognitive and 
functional performance. It evaluates six domains, including memory, orientation, and 
problem-solving, and generates a total score that better captures subtle changes in disease 
severity.81,82 
• 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog): 
The ADAS-Cog is a widely used tool to measure cognitive dysfunction in Alzheimer’s 

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disease (AD). It assesses domains such as memory, language, and praxis, and is sensitive 
to detecting cognitive changes over time.82,83 
• 
Montreal Cognitive Assessment (MoCA): 
The MoCA is a 30-item screening tool designed to detect early cognitive impairments 
across multiple domains. It is particularly effective in measuring executive functions, 
attention, memory, and visuospatial abilities, offering high sensitivity for identifying mild 
cognitive impairment.84 
• 
Neuropsychiatric Inventory (NPI): 
The NPI assesses behavioral and neuropsychiatric symptoms frequently observed in AD, 
such as agitation, depression, and apathy. It is administered through a structured 
interview with caregivers, who report on the presence, frequency, and severity of 
symptoms, making it sensitive to treatment-related changes.85 
• 
Sleep Disorders Inventory (SDI): 
The SDI expands upon the sleep-related item from the NPI. It captures the frequency, 
severity, and caregiver burden of sleep disturbances through caregiver reports.6 Sleep 
disorders are common in AD and contribute to behavioral and emotional difficulties in 
both patients and caregivers.86 
• 
Quality of Life in Alzheimer’s Disease (QoL-AD): 
The QoL-AD is a validated tool designed to assess quality of life in individuals with 
Alzheimer’s disease. It consists of both patient and caregiver versions, capturing 
perceptions of physical health, social interaction, and emotional well-being. Including this 
measure will provide a broader understanding of how DBS-PPN impacts both cognitive 
and non-cognitive aspects of the patient’s life.87 
  
4.4.5 Participant’s Evaluation of Intervention 
DBS-PPN-AD Trial Exit Interview: Interview conducted at end of the study to assess patients’ 
and caregivers’ evaluation of the pilot study, including their experience in the trial, benefits of 
DBS-PPN AD to emotion and cognition, and recommendations for83-86,88 
5.0 STUDY TIMELINE 
The study will span 12 months, with key milestones including patient recruitment, DBS-PPN 
implantation, DBS activation, and follow-up assessments at 3-month intervals. These follow-up 
visits will assess safety, feasibility, electrographic,and cognitive outcomes. DBS-PPN 
implantation will be performed within two months after obtaining informed consent from 
patients (Figure 3). 
 

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Figure 3. Study timeline and Schedule of Research Activities. Cognitive Assessments and Questionnaires: Clinical 
Dementia Rating Scale (CDR); Alzheimer's Disease Assessment Scale - Cognition Subscale (ADAS-Cog); Montreal 
Cognitive Assessment (MoCA); Neuropsychiatric Inventory (NPI); Sleep Disorder Inventory (SDI); Quality of Life 
in Alzheimer's Disease (QoL-AD). * Ideally, an MRI is done in a 1-hour hospital visit 1-4 weeks before the surgery, 
but can be done on day of surgery. **Visit 3 may be divided into two sessions within the same week. 
 
6.0 STATISTICAL CONSIDERATIONS 
The planned sample size (N=6) is consistent with similar pilot clinical trials in the literature.62,64 
Descriptive summaries of variables will be provided where appropriate. Variance and confidence 
intervals of the outcome measures will be used to guide the power analysis of a larger RCT. Each 
patient will serve as their own control and repeated measures ANOVA will be used for the 
analysis of outcome measures change over the 12 months course of the study. All statistical tests 
will be performed at the 0.05 level. 
Safety will be assessed by analyzing the rates of procedure-related WHO grade 3-5 AEs and 
summarized descriptively. Additional summaries may be performed. 
 
7.0 QUALITY CONTROL & QUALITY ASSURANCE PROCEDURES 
Site monitoring will be conducted to ensure that the rights and well-being of participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and 
with applicable regulatory requirement(s). 

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The study coordinator will ensure that the study is conducted and documented properly by 
carrying out the activities outlined in International Council for Harmonisation E6, Section 5.18.4 
and as detailed in the study Monitoring Plan. 
Types of monitoring will include: 
• targeted data verification 
• confirmation of completion of eCRFs in REDCap 
• query resolution 
• eligibility criteria review 
• adverse event review 
• screening/enrolment data 
 
8.0 ETHICAL CONSIDERATIONS 
This trial will be conducted in compliance with the protocol, Good Clinical Research Practice 
(GCP) and all applicable regulatory requirement(s). The protocol, informed consent form, 
recruitment materials, and all participant materials will be submitted to the UHN REB for review 
and approval. Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled. Any amendment to the protocol will require review and approval by the 
UHN REB before the changes are implemented to the study. All changes to the consent form 
will be REB approved; a determination will be made regarding whether previously consented 
participants need to be re-consented. 
Participants will be provided with detailed information about the study, including its purpose, 
procedures, potential risks, and benefits. Informed consent will be obtained prior to participation. 
8.1 Termination of Participation/Withdrawal Criteria 
The following criteria apply to participants who have been enrolled in the study. An enrolled 
participant will be automatically withdrawn from the study if their treatment plan is modified 
such that they no longer meet the study eligibility criteria. A participant may verbally withdraw 
at any time by contacting the PI (surgeon) or appropriate study staff (e.g. study coordinator, 
surgeon’s administrative coordinator). 
The PI may terminate a patient’s participation in the study if: any clinical AE, laboratory 
abnormality, or other medical condition or situation occurs such that continued participation in 
the study would not be in the best interest of the participant. 
Reasons for withdrawal or termination will be recorded in the participant’s study record. 
All data collection relating to a withdrawn or terminated participant will cease at the time of 
withdrawal/termination. Clinical care in all withdrawn or terminated participants will continue as 
per standard of care. Any participant that withdraws or is terminated prior to completion of the 
Month 9 visit will be replaced. 
8.2 Potential Risks 
The risks of DBS surgery can generally be grouped into surgical, device-related, and stimulation-
related complications. 

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8.2.1 Surgical Risks 
Infection 
 Approximately 3% of patients experience infection at the site of implantation. This may require 
removal or replacement of the DBS hardware in severe cases. 76,78 
76,78 
Intracranial Hemorrhage/Stroke 
 There is a risk of bleeding in the brain, which can lead to stroke. The incidence of stroke or 
significant hemorrhage in DBS procedures is less than 1%, which can lead to neurological 
deficits or, rarely, death (0.2%). Small bleeds are often asymptomatic, but larger bleeds can 
cause significant issues depending on the area affected.  
Seizures 
Seizures occur in about <1% of patients as a rare postoperative complication.  
 
Hardware-related Complications 
 Lead fractures or displacement occur in around 2% of cases which may require surgical 
correction. 
8.2.2 Device-Related Risks 
 Device Infection 
As with surgical risks, device-related infection occurs in around 3% of patients, often requiring 
antibiotic treatment or device related. 
 Battery Issues 
Patients require battery replacement every few years, depending on usage, which involves minor 
surgical procedures and carries similar infection risks. 
8.2.3 Stimulation-Related Risks (Adjustable with Programming) 
 Adverse Effects 
 Potential reversible side effects associated with DBS stimulation and implantation include 
sensory phenomena, oscillopsia “shimmering vision”, limb myoclonus, headache, dizziness, and 
urinary incontinence. 
8.2.4 Risk of Study-related Procedures 
8.2.4.1 CT Risk 
As part of this study, you will undergo imaging of your brain using a CT scan. CT scans involve 
exposure to a small amount of ionizing radiation, which carries a very low risk of potential harm.  
Additionally, some people may experience claustrophobia or discomfort during the scan. 
Commonly, patients experience a warm feeling or a metallic taste in the mouth during the 
injection of the contrast dye. These side effects disappear quickly and do not require any 
treatment. More rarely, patients may experience short-term side effects such as nausea, vomiting, 
headache, rash. You may develop an allergic reaction to the dye used for the CT scan.  
 If you are eligible for the study, safety checks will be conducted before any imaging, and a 
healthcare professional will be available to address any concerns during the procedures 
 

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8.2.4.2 EEG and MEG Risk  
EEG and MEG are safe, non-invasive methods to monitor brain activity. EEG uses small 
electrodes on the scalp to detect electrical signals, while MEG measures the magnetic fields 
generated by brain activity without direct contact. Both are painless, but patients may experience 
mild discomfort from wearing the EEG cap or lying still during the MEG scan, which could 
cause slightly anxiety or restlessness. Our team will prioritize patient comfort and monitor for 
any signs of distress throughout these procedures.  
 
  8.2.4.3G MRI Risk  
An MRI scan is painless but noisy. If you have any metal in your body, for your safety, please 
tell the staff. There is no radiation. Some people may feel a little ‘closed-in’ the MRI machine, 
but you will be able to speak with someone at all times and can stop the test at any time. 
Gadolinium contrast is not safe to use in people who have kidney problems.  If you have had a 
problem with your kidneys, please inform the study team of this problem before the procedure. 
There is a small risk quantify of allergic reaction with gadolinium that can include symptoms of 
itchiness or rash. Rarely, a serious reaction may develop involving your kidneys leading to 
hardened skin lesions all over your body and stiffening of your joints. You must seek medical 
attention immediately if you develop any symptoms of allergic reaction. 
 
 
8.3 Risk Mitigation 
8.3.1 Close Monitoring 
Participants will be closely monitored for any adverse events. Any serious adverse events will be 
managed promptly according to standard clinical procedures. 
8.3.2 Follow-up Visits 
Regular follow-up visits will help in early detection and management of any complications. 
8.3.3 Informed Consent 
Participants will be fully informed of the potential risks before consenting to the study 
9.0 DATA MANAGEMENT & RECORD KEEPING 
UHN’s validated REDCap instance will be used to capture study assessments and data 
[electronic case report forms (e-CRFs)]. REDCap is a secure web platform for building and 
managing online databases and surveys. REDCap's streamlined process for rapidly creating and 
designing projects offers a vast array of tools that can be tailored to virtually any data collection 
strategy. Electrophysiological data (including related PET scan files) will be uploaded into an 
electronic image database created in UHN’s MS OneDrive. 
The study coordinator or other delegated study staff will enter data into the eCRFs. Training will 
be provided for the electronic data capture (EDC) system. All study staff using the EDC system 
must have the necessary education, training, and experience or any combination of these. The 
program manager will be responsible for documenting employee education, training, and 
previous experience that pertain to the EDC system for all staff using the EDC system. The 
program manager must maintain adequate security of the EDC system, including documentation 
that all users have been trained and a list of authorized users. To ensure all data entries can be 
tracked, all personnel responsible for data entry must obtain a unique user identification (user 

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ID) and password before any data can be entered in the eCRFs. Authorized study staff will be 
assigned a unique user ID only after receiving training. 
Data collection is the responsibility of the program manager and PI. They are responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
Source documents include: 
• Signed informed consent forms 
• Study data collection questionnaires 
• Electrophysiological data 
• PET scan files 
• Participant’s medical files (MRN, EPIC) 
• DBS device-specific data, i.e. make, model, DBS parameter settings 
 
Data reported in the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and captured in a progress note and 
maintained in the participant’s official study record. 
In Canada, essential study documents will be maintained for a period of 25 years, in accordance 
with section C.05.012 of Canada’s Food and Drug Regulations - Division 5 “Drugs for clinical 
trials involving human subjects''. 
10.0 DELIVERABLES, SIGNIFICANCE & BENEFITS 
This pilot study sets the stage for a multicenter RCT with the potential of providing the first 
disease modifying neuromodulatory treatment for AD. Moreover, it paves the way for exploring 
DBS-PPN in other forms of dementia, for example frontotemporal dementia where PVIN 
dysfunction has been reported, and Parkinson’s dementia where preliminary evidence supports a 
beneficial role.15,32. Our findings could be translatable to other pathologies where GO and 
PVIN impairment is a common denominator such as epilepsy, schizophrenia, and autism.33–35  
This study will teach us immensely about the brain excitation/inhibition networks that are the 
nucleus of normal brain functioning and are at the center of a broad spectrum of brain 
pathologies. 
10.1 Potential Benefits 
10.1.1 Benefits to Participants 
Improvement in Cognitive Function 
Participants may experience improvement in cognitive functions, such as memory and attention, 
due to enhanced PVIN function and modulation of gamma oscillations. 
Reduction in AD Symptoms 
The intervention has the potential to reduce the molecular and electrographic imprints of AD, 
thereby alleviating symptoms associated with the disease. 
10.1.2 Benefits to the Community/Public: 
Advancement in AD Treatment 
Successful results from this pilot study could pave the way for a new, effective treatment 
modality for AD, potentially benefiting hundreds of thousands of Canadians. 

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Economic Impact 
If DBS-PPN proves to be effective, it could reduce the overall burden of AD on the Canadian 
healthcare system by decreasing the need for long-term care and associated healthcare costs. 
10.1.3 Benefits to UHN & The Krembil Brain Institute: 
These following benefits underscore the potential of this pilot study to catalyze significant 
advancements in AD treatment and neuromodulation: 
Research Leadership & Innovation 
This study positions the Krembil Brain Institute at the forefront of ground-breaking research in 
neuromodulation and AD treatment. Leading such innovative research enhances Krembil's 
reputation as a pioneer in developing novel therapeutic strategies, attracting top-tier talent and 
fostering a culture of excellence and innovation. 
Increased Funding & Grant Opportunities 
Positive outcomes from this pilot study are likely to attract additional funding and grant 
opportunities from national and international funding bodies, including government agencies 
(CFI, CIHR), private foundations, and industry partners. This can significantly boost the 
institute’s research budget, enabling further advancements and expansion of research programs. 
Strategic Collaborations & Partnerships 
Success in this pilot study could lead to strategic collaborations with other leading research 
institutions, pharmaceutical companies, and medical device manufacturers. These partnerships 
can facilitate knowledge exchange, resource sharing, and joint ventures in large-scale clinical 
trials and research projects. 
Publication & Academic Prestige 
Ground-breaking results from this study are expected to result in high-impact publications in 
prestigious scientific journals. Such publications not only enhance the academic prestige of UHN 
and Krembil, but also contribute to the global scientific community’s understanding of AD and 
neuromodulation. 
Clinical Impact & Patient Care 
Establishing DBS-PPN as a viable treatment for AD could significantly improve patient care 
protocols and outcomes. The institute’s involvement in this research translates to direct clinical 
benefits for patients treated at its affiliated hospitals, reinforcing its commitment to improving 
patient care through cutting-edge research. 
Economic Benefits & Cost Savings 
By demonstrating the cost-effectiveness of DBS-PPN compared to existing treatments (can be 
proposed in the larger RCT), the institute can position itself as a leader in developing 
economically viable healthcare solutions. This can lead to substantial cost savings for healthcare 
systems, enhancing the institute’s value proposition to healthcare providers and policymakers. 
Educational & Training Opportunities 
Leading this research project provides invaluable educational and training opportunities for 
medical students, residents, and fellows. It fosters a learning environment that emphasizes 
translational research and clinical application, preparing the next generation of clinicians and 
researchers. 

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Long-term Institutional Growth 
The success of this pilot study and potentially a subsequent larger RCT can, catalyze long-term 
growth for the Krembil Research Institute, enabling the establishment of new research centres, 
recruitment of additional expert faculty, and expansion of research infrastructure. 
 

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