Understanding: Photobiomodulation Therapy for AD

Paper: Effects of Home Photobiomodulation Treatments on Cognitive and Behavioral Function, Cerebral Perfusion, and Resting-State Functional Connectivity in Patients with Dementia: A Pilot Trial

Link to paper: https://pubmed.ncbi.nlm.nih.gov/31050950/

Chao, Linda L. “Effects of Home Photobiomodulation Treatments on Cognitive and Behavioral Function, Cerebral Perfusion, and Resting-State Functional Connectivity in Patients with Dementia: A Pilot Trial.” Photobiomodulation, Photomedicine, and Laser Surgery, vol. 37, no. 3, Mar. 2019, pp. 133–41. PubMed, https://doi.org/10.1089/photob.2018.4555.

Before I get into the discussion of topics directly linking to the implications and whatnot of the paper, I would like to share why this paper appealed to me from the beginning. I started independently learning about neuroscience about a month into the first semester of college as a biology major, curious about it at first because I wanted to dive deeper into the cell-signaling systems in which we learned in class. 

Over the course of the semester, I progressed through the fundamentals of neuroscience through an online course on HarvardX. The course touched on some of the “well-known” neurodegenerative/autoimmune disorders or conditions that affect synaptic reception, such as Myasthenia Gravis, Botulism, Parkinson’s disease and Alzheimer’s Dementia. When you consider the situation I was in, the burning curiosity seemed reasonable; as a pre-med student, I was eager to learn more about these diseases and why they were so significant. Everything so far has been about the fundamentals of the science behind biological systems and the chemistry involved; nothing technical about how changes to these systems brought by external or congenital factors apply to our lives. 

It was actually the day after I finished the course when, during a routine health checkup, I came into contact with this paper. I often think back to this, somewhat convincing myself that this was evidence of divine intervention. Since I was small, I’ve visited this clinic every couple of months, so the doctor was somewhat familiar with my presence. After mentioning I was back from my first semester of college, he asked what I was studying/what my interests are. What I didn’t expect was that he was actually a neurophysiologist! After discussing for quite some time about some deeper topics and the inner workings of being a doctor, he mentioned that he, along with a group of other Harvard MD alumni, is part of a research study focused on the effects of photobiomodulation therapy on patients with AD. I then asked to take part in the research. I gained hands-on experience with the tools and equipment involved, data collection, and analysis. The paper discussed is one of the pilot trials on which the basis of my mentor’s research was built. Research on this disease has captivated me ever since.

The first thing to do is to always research and define anything that may seem intimidating, like those huge words in the title.

Photobiomodulation includes the words “photo”, “bio”, and “modulation”. Combined, it literally means “using light to alter processes involved in living tissue”.

Cognitive and behavioral functions may seem like abstract concepts more qualitative than quantitative; we will see how that changes when we get into the abstract. But for now, all you need to know is what it literally means.

Cerebral perfusion translates to blood flow to and from the brain. Cerebral means in relation to the cerebrum, which is the largest part of our brain. Perfusion just means blood flow.

Resting-state connectivity literally describes connectivity during a state in which something is not actively performing a function. Thinking of it as measuring your heart rate when you are sleeping. Connectivity, in neuroscience, means how the different regions of a person’s brain synchronizes.

Alzheimer’s Dementia (AD) is the disease in question.

Altogether, the title reads: How does the process of “using light to alter processes involved in living tissue” affect an AD patient’s cognitive and behavioral function, brain’s blood flow, and synchronization of different brain regions when not being actively used to perform a task?

Background: Disease Characteristics

-Alzheimer’s Dementia Characteristics

Why this starts to link to PBM directly:

When you step back, many of the major problems in Alzheimer’s disease point to the same issue: neurons are not getting or using energy efficiently. Mitochondria struggle to produce enough ATP, oxidative stress damages cells, and reduced blood flow limits the delivery of oxygen and nutrients. These problems show up earliest at synapses, where energy demand is highest, leading to communication breakdown long before widespread cell death occurs.
This matters because it suggests that Alzheimer’s disease is not only a problem of protein buildup, but also a problem of impaired cellular metabolism and circulation. Photobiomodulation becomes relevant in this context because it is proposed to support mitochondrial function and blood flow, potentially helping neurons meet their energy needs even in the presence of ongoing pathology.

Synaptic loss disrupts coordinated communication across distributed brain regions. Long range connectivity weakens, neural oscillations become less synchronized, and functional networks such as those involved in memory and executive processing lose stability.

How Alzheimer’s Disease is measured in practice

The methodology of the paper presents many measures that researchers use to access different behavioral and cognitive functions.

1.ADAS-Cog

ADAS-Cog is a standardized, in person cognitive test administered by a trained evaluator. The person completes a set of structured tasks, and each task has predefined scoring rules. The test produces a single total score that reflects overall cognitive impairment.

It measures performance on tasks involving:

• learning and short term recall
• delayed recall and recognition
• language function such as naming objects and following commands
• praxis which is the ability to carry out learned actions such as drawing shapes or using objects correctly

2.Neuropsychiatric Inventory (NPI)

The NPI is typically a structured caregiver interview rather than a direct test of the patient alone. A clinician asks a caregiver about a defined set of symptom domains over a recent time window. For each domain, the caregiver reports whether the symptom is present and, if it is, rates its severity and frequency.

It measures the behavioral output of brain dysfunction across domains such as:

• apathy
• depression or dysphoria
• anxiety
• agitation or aggression
• irritability
• disinhibition
• hallucinations or delusions
• sleep and nighttime behavior changes
• appetite and eating changes

The MRI is a truly spectacular invention, functioning by generating powerful magnetic waves to align the hydrogen atoms in your body to a certain angle, then using the energy they release when they align themselves back as imaging. Its origin, as you could tell, came from nothing related to pre-med studies. Rather, it was a thesis on how nuclei behaved in space when under the influence of magnetic fields and radio waves. I highly recommend understanding how MRIs work.

3.Arterial Spin Labeling perfusion MRI

ASL MRI measures cerebral blood flow without contrast dye by using the water in blood as an internal tracer. The scanner applies a magnetic pulse that labels inflowing arterial blood upstream of the brain. After a short delay, that labeled blood flows into brain tissue. The scanner then acquires images and compares labeled and unlabeled conditions. Thus, this measures cerebral perfusion.

As mentioned before, perfusion is a direct proxy for the brain’s ability to deliver:

• oxygen
• glucose
• other nutrients

4. Resting state fMRI

Resting state fMRI measures brain activity indirectly through the BOLD signal, which reflects changes in blood oxygenation. The participant lies still and does not perform a task. The scanner records slow fluctuations in the BOLD signal across time.

BOLD stands for Blood Oxygen Level Dependent. In essence, it is used to determine which parts of a patient’s brain are using more blood flow and oxygen to fire signals. This effect is further enhanced because hemoglobin, the oxygen-carrier protein in our red blood cells, changes its magnetic properties depending on whether it is carrying oxygen. Deoxygenated hemoglobin is more disruptive to the MRI signal than oxygenated hemoglobin. The MRI then detects the resulting shift in oxygenation.

What the abstract is saying

This study aimed to test whether photobiomodulation (PBM) therapy delivered at home could improve cognitive, behavioral, and physiological measures in patients with dementia. The therapy used near-infrared light delivered transcranially and intranasally, meaning light was applied both through the scalp and through the nasal cavity in order to reach brain tissue.

The researchers designed the study to replicate and expand on an earlier case series that had suggested cognitive improvements after PBM treatment. In this study, eight participants with dementia were recruited and randomly assigned to either a control group receiving usual care or a group receiving PBM treatment. The PBM therapy was administered at home three times per week for 12 weeks using the Vielight Neuro Gamma device, and treatments were carried out by a study partner.

To evaluate whether the therapy had any measurable effect, the researchers used four types of assessments. Cognitive function was measured with the ADAS-Cog test, behavioral and neuropsychiatric symptoms were measured using the Neuropsychiatric Inventory, cerebral blood flow was measured using arterial spin labeling MRI, and functional brain connectivity was examined using resting-state fMRI. These tests allowed the researchers to look at changes not only in cognition and behavior but also in brain physiology and network communication.

After 12 weeks, the group receiving PBM therapy showed improvements in cognitive scores, behavioral symptoms, cerebral blood flow, and functional connectivity within parts of the default mode network, while the control group did not show similar changes. The authors therefore concluded that PBM therapy was well tolerated and that the results support the potential of PBM as a home treatment approach for individuals with dementia, although the small sample size means larger studies would be required to confirm the findings.

What the introduction is saying

The authors begin by pointing out that Alzheimer’s disease remains a major global health problem without a cure. Current medications used to treat Alzheimer’s disease mainly target symptoms and often come with significant side effects. More recent research has focused heavily on disease-modifying strategies aimed at removing amyloid beta or tau proteins, because these are the hallmark pathological features of Alzheimer’s disease.

However, the authors highlight an important gap: many patients with Alzheimer’s disease are already in moderate or advanced stages, where the primary concern is managing cognitive decline and behavioral symptoms rather than preventing early pathology. As a result, relatively less attention has been given to therapies that could improve brain function in these later stages.

The study introduces photobiomodulation (PBM) as a potential approach. PBM uses red or near-infrared light to influence biological processes. Previous experiments and cadaver studies suggest that near-infrared light can penetrate the scalp, skull, and meninges and reach brain tissue at depths of roughly 40 mm. Because of this penetration capability, PBM can potentially influence neural tissue when delivered transcranially.

The authors note that an earlier small case series reported improvements in cognitive function after 12 weeks of transcranial and intranasal PBM treatment in five dementia patients. The first goal of the present study is therefore to replicate and extend those findings in a randomized study.

The authors then discuss possible mechanisms behind PBM’s effects. One commonly proposed explanation is that PBM may increase cerebral blood flow and oxygen consumption, which could improve metabolic support for neurons.

Finally, the introduction explains why the researchers chose to examine functional connectivity in the default mode network (DMN). The DMN is a group of interconnected brain regions involved in baseline cognitive activity and internal thought processes. It includes structures such as the posterior cingulate cortex, precuneus, medial prefrontal cortex, and parts of the parietal and temporal lobes. Because connectivity within this network is known to decline as Alzheimer’s disease progresses, it serves as a useful indicator of network-level dysfunction.

Importantly, the PBM device used in this study was specifically designed so that its light-emitting diodes target key nodes within the default mode network.

*The study included only eight participants, all of whom were white and most of whom were female. Because of the very small sample size, this demographic distribution likely reflects recruitment limitations rather than intentional sampling, but it also means the findings should be interpreted cautiously and may not generalize broadly.*

“From the perspective of Dr. Michael Chiu, the significance of this research would likely go beyond whether PBM ‘works’ in a narrow clinical sense. He would probably say that what makes this line of study so compelling is that it approaches Alzheimer’s disease at the level of function rather than waiting for irreversible structural loss. If PBM can improve cerebral perfusion, support mitochondrial metabolism, and stabilize communication across large-scale brain networks, then it suggests that even in a disease defined by degeneration, there may still be meaningful physiological systems left to support. In that sense, the importance of PBM research is not only therapeutic but conceptual: it pushes researchers to think of Alzheimer’s disease not just as protein accumulation, but as a disorder of energy failure, disrupted signaling, and declining network coordination. He might also emphasize that this is why measures such as ADAS-Cog, NPI, ASL MRI, and resting-state connectivity matter so much together. They allow researchers to ask not only whether pathology exists, but whether the brain is still capable of responding, adapting, and functioning better under targeted intervention. Even if PBM ultimately proves to be only part of the answer, its significance lies in opening a path toward treatments that are noninvasive, physiologically grounded, and aimed at preserving quality of life in patients for whom conventional options remain limited.” – Dr. Michael Chiu (translated from Chinese)