Clicking Sound After Craniotomy
Having cranial surgery can be scary. Many patients say they hear strange sounds, like a clicking noise. But what is a craniotomy, and why do some people hear this sound?
A craniotomy involves temporarily removing a section of the skull to access the brain. About 31% of patients say they hear sounds in their head after surgery. They often describe it as a ‘clicking’ sound. We aim to explain this to those who have had or will have this surgery.
Key Takeaways
- Craniotomy involves removing a portion of the skull to access the brain.
- A significant percentage of patients report hearing clicking sounds post-surgery.
- The clicking sound can be a cause of concern for patients after cranial surgery.
- Understanding the reasons behind this phenomenon can provide relief.
- We will delve into the causes and implications of clicking sounds after craniotomy surgery.
Understanding Craniotomy Procedures

a photorealistic image of a craniotomy procedure being performed in a modern operating room. The patient’s head is shaved and the scalp is exposed, with the surgeon carefully making an incision using a surgical scalpel. The surgeon’s hands are visible, wearing sterile gloves and wielding various surgical instruments like bone saws, forceps, and retractors. The room is well-lit, with bright overhead lighting and a crisp, clean atmosphere. The focal point is on the exposed skull, with the surgeon’s hands and the surrounding medical equipment in focus. The background is blurred, but visible elements include medical monitors, trays of instruments, and other medical staff assisting with the procedure.
To understand the clicking sound after a craniotomy, first learn what it is. A craniotomy is a surgery where part of the skull is taken off to reach the brain. It’s key for many brain surgeries.
Definition and Purpose of a Craniotomy
A craniotomy removes a bone flap from the skull. This lets surgeons work on the brain. It’s done to ease brain pressure, remove tumors, or fix blood vessel issues.
Types of Craniotomy Procedures
There are different craniotomy surgeries, including:
- Traditional Craniotomy: This removes a big part of the skull.
- Keyhole Craniotomy: It’s a smaller, less invasive method.
- Awake Craniotomy: Done with the patient awake to check brain function.
The Bone Flap Concept
The bone flap is a key part of craniotomy surgery. It’s the skull section taken off and put back after surgery. It’s secured with plates, screws, or other methods.
Difference Between Craniotomy and Craniectomy
Craniotomy and craniectomy both remove skull parts. But, the main difference is the bone flap’s return. In a craniotomy, it’s put back. In a craniectomy, it’s not put back right away and might be left out or put back later.
Normal Post-Craniotomy Recovery Process
A detailed timeline depicting the post-craniotomy recovery process, showcasing the gradual healing and progress over time. The foreground features a close-up of a patient’s head, with the surgical incision visible and sutures in place, indicating the initial stage of recovery. The middle ground shows the patient’s gradual progress, with images of the patient walking, engaging in physical therapy, and undergoing neurological examinations. The background incorporates medical imagery such as brain scans, diagnostic equipment, and hospital settings, conveying the comprehensive nature of the recovery journey. The lighting is soft and natural, creating a sense of warmth and reassurance. The overall composition and mood evoke a sense of hope and the resilience of the human body in the face of a major neurosurgical procedure.
The recovery after a craniotomy is complex. It includes immediate care, healing of the skull and brain, and managing side effects. Knowing this helps patients and their caregivers get ready for what’s ahead.
Immediate Recovery Timeline
Right after surgery, patients stay in the ICU. Here, they are watched closely for any problems. How long they stay in the ICU can vary but is usually a few days.
Once moved to a regular room, patients start to get more active. They do this with the help of their healthcare team.
Expected Physical Sensations
Recovery brings many physical feelings. These include swelling, bruising, and pain at the surgery site. Doctors use medicine to help with these feelings.
Patients might also feel headaches, tiredness, and nausea. These feelings are usually short-lived and get better as they heal.
Healing of the Skull and Brain
The skull and brain start to heal right away. The bone flap, put back after surgery, takes weeks or months to fully heal.
Brain swelling goes down in a few weeks. But, it can take longer for the brain to fully recover. This depends on the person’s health and the surgery’s complexity.
Common Side Effects During Recovery
Side effects include pain, swelling, and bruising at the surgery site. Some might feel weak, numb, or have changes in thinking.
Side Effect | Typical Duration | Management Tips |
Pain | Several weeks | Follow prescribed pain management regimen |
Swelling/Bruising | 2-4 weeks | Apply cold compresses as directed |
Neurological Symptoms | Varies | Rehabilitation therapy as recommended |
Understanding the recovery process helps patients and their caregivers. They know what to expect and when to get medical help.
Clicking Sound After Craniotomy
A close-up view of a craniotomy incision, with a visible metallic clip or staple holding the skin together. The image should capture the moment of a subtle clicking sound, as the patient’s head moves slightly, causing the metallic components to gently reverberate. The lighting should be soft and natural, highlighting the details of the surgical site. The background should be blurred, focusing the viewer’s attention on the incision and the underlying structures. The overall mood should convey a sense of medical precision and the delicate nature of the post-operative experience.
After a craniotomy, some patients hear a clicking sound. This can be confusing and worrying. We will look into what this sound is, when it happens, and what people have said about it.
Description of the Clicking Sound
The sound is often described as a repetitive click or tap. It can be soft or loud, depending on the surgery. Some compare it to a ticking clock or a metallic click.
The sound might be steady or change in frequency and loudness over time.
When the Clicking Typically Occurs
The sound usually starts during recovery after surgery. It might begin right away or a few days or weeks later. The timing and sound can depend on the surgery type, materials used, and how quickly the bone heals.
Patient Experiences with Craniotomy Clicking
People have different experiences with the clicking sound. Some say it’s louder in certain positions or when doing specific things. Others link it to their heartbeat or breathing.
This shows how complex and varied this phenomenon is.
Patient Activity | Effect on Clicking Sound |
Changing head position | May alter the sound’s intensity or frequency |
Engaging in strenuous activities | Can increase the clicking sound |
Resting or sleeping | May reduce or eliminate the clicking sound |
Frequency and Duration Patterns
The clicking sound’s frequency and length can differ a lot. Some hear it all the time, while others only sometimes. How long it lasts also varies, from weeks to months.
Knowing these patterns helps in managing what patients expect and how to care for them.
Medical Explanations for Post-Craniotomy Clicking
A close-up view of a titanium plate implanted in the side of a person’s head, following a craniotomy surgical procedure. The metallic plate appears shiny and reflective, with a slight curvature to fit the contours of the skull. The skin around the incision site is slightly reddened, indicating recent healing. Soft, even lighting illuminates the scene, casting subtle shadows that accentuate the surgical details. The background is blurred, keeping the focus on the titanium plate and the surrounding scalp. The overall mood is one of clinical precision and the aftermath of a successful medical intervention.
The clicking sound after a craniotomy can be caused by several medical factors. It’s important for patients to understand these causes. This helps them manage their expectations and recovery.
Bone Flap Movement
The movement of the bone flap is a main reason for the clicking sound. During a craniotomy, a part of the skull, called the bone flap, is removed. This allows doctors to access the brain. After the surgery, the flap is put back in place.
But sometimes, the bone flap might not fit perfectly or might move a bit. This can cause a clicking or tapping sound.
Factors influencing bone flap movement:
- Improper fixation techniques
- Post-operative swelling
- Patient activities that strain the head
Titanium Plate Interactions
Titanium plates are used in cranial surgeries to hold the bone flap in place or to repair skull defects. The metal plates can sometimes make clicking sounds. This happens when the plate isn’t perfectly aligned with the skull or when there’s movement or friction.
Tissue and Fluid Dynamics
Changes in intracranial pressure and fluid movement in the cranial cavity can also cause clicking sounds. For example, pneumocephalus, where air gets into the cranial cavity, might explain these sounds.
Key factors include:
- Presence of air or gas within the cranial cavity
- Fluid shifts or changes in intracranial pressure
- Tissue healing and scar formation
Neurological Factors
In some cases, the clicking sound might be due to neurological reasons. This includes the healing of nerves or changes in brain activity. These factors are less common but should be considered, especially if other neurological symptoms are present.
Neurological considerations:
- Nerve regeneration or irritation
- Changes in brain activity or seizure activity
- Other neurological symptoms accompanying the clicking
Common Causes of Clicking Sounds After Brain Surgery
A detailed close-up view of the human skull, highlighting the craniotomy site and surrounding anatomy. The image should convey a sense of medical precision, with a focus on the causes of the clicking sound often experienced after brain surgery. Showcase the key structures responsible, such as the bone, dura mater, and any potential fluid buildup or scar tissue formation. Utilize warm, natural lighting to create a clinical yet approachable atmosphere, captured through a high-resolution lens at a slightly elevated angle to provide a comprehensive understanding of the subject matter.
It’s important to know why patients hear clicking sounds after brain surgery. This helps ease their worries and ensures they recover well. The clicking sound can come from the surgery itself and how the body heals.
Normal Healing Processes
The body’s healing process is a main reason for clicking sounds. As the body heals, the bone flap and tissues might move. This movement can cause a clicking or tapping sound.
This sound can happen because of the changing pressure inside the skull. Some patients say they feel the bone flap move a bit.
Surgical Fixation Methods
The way the bone flap is fixed during surgery can also cause clicking sounds. Titanium plates and screws are often used to hold the bone flap in place. But sometimes, these devices can rub against bone or tissue, making sounds.
Anatomical Factors
How a person’s body is different can also play a role. The size and where the craniotomy is done can affect healing. The patient’s overall body shape also matters.
Influence of Patient Activities
What patients do can also affect the clicking sounds. Actions like bending, straining, or even moving their head can make the bone flap or screws move. This movement can cause a clicking sound.
Knowing these reasons helps patients deal with the clicking sounds after surgery. It also helps doctors give better advice and reassurance.
Differentiating Normal vs. Concerning Clicking Sounds
A close-up photograph of the back of a human head, showcasing the intricate structure of the skull and the subtle, rhythmic clicking sounds that occur after a craniotomy procedure. The scene is illuminated by a soft, directional light, casting gentle shadows and highlighting the texture of the bone. The focus is sharp, allowing the viewer to clearly observe the delicate movements and vibrations within the skull. The image conveys a sense of medical precision and the profound connection between the human body and the technological advancements that allow us to peer into its inner workings.
It’s key for patients to understand the difference between normal and concerning clicking sounds after a craniotomy. Knowing the warning signs is crucial for seeking medical help when needed.
Characteristics of Normal Clicking
Normal clicking sounds are usually soft and intermittent. They might be more noticeable when you move or change positions. These sounds often come from the body’s healing process and may go away with time.
Warning Signs That Require Medical Attention
Some clicking sounds are harmless, but others can signal problems. Warning signs include louder or more frequent clicking, pain, swelling, or redness at the surgical site. Also, watch for changes in weakness, numbness, or trouble speaking.
Changes in Clicking Patterns Over Time
It’s important to watch for changes in clicking patterns. If the clicking gets softer or less frequent, it’s a good sign. But, if it stays the same or gets worse, see your neurosurgeon to check for any issues.
Associated Symptoms to Monitor
Keep an eye out for symptoms like headaches, dizziness, or nausea. These, along with clicking sounds, might mean you need to see a doctor. Writing down when these symptoms happen and how bad they are can help your doctor during check-ups.
When to Contact Your Neurosurgeon About Clicking
A high-resolution, photorealistic image of a person’s head, showing a close-up view of the back of the neck and the base of the skull. The skin has a slight reddish hue, indicating inflammation or irritation. The focus is on the area where the skull has been surgically opened, with visible scarring and a subtle clicking sound emanating from the site. The lighting is natural, casting soft shadows that accentuate the contours of the anatomy. The background is blurred, keeping the attention on the focal point of the image. The overall mood is one of concern and medical necessity, conveying the importance of seeking professional medical advice regarding the clicking sound.
Knowing when to talk to your neurosurgeon about a clicking sound after a craniotomy is key. Some clicking is normal while healing. But, some situations need medical help.
Concerning Symptoms Accompanying Clicking
If you have symptoms like more pain, swelling, signs of infection, or fever with the clicking, call your neurosurgeon. “Patients should report any increasing wound pain, swelling, or signs of infection.” Quickly telling your doctor about these symptoms can stop bigger problems.
Changes in Frequency or Intensity
Changes in the clicking sound’s frequency or loudness mean you should see your neurosurgeon. If the sound gets louder or more frequent, or if you have other symptoms, get medical help. This could mean you need more tests or a change in treatment.
Documentation Tips for Medical Appointments
Before you call your neurosurgeon, write down your symptoms. Note when the clicking happens, how long it lasts, and what might make it better or worse. This info helps your doctor understand your situation better.
Emergency Situations vs Routine Follow-up
It’s important to know when to call for an emergency and when to wait for a regular check-up. Severe headaches, confusion, or weakness need quick help. For less urgent issues, a follow-up appointment is fine.
“If you’re unsure about the severity of your symptoms, it’s always best to err on the side of caution and seek advice.”
Diagnostic Approaches for Post-Craniotomy Clicking
Healthcare professionals use different tools to figure out the clicking noise after brain surgery. Finding the cause of these sounds is key to treating the patient right.
Physical Examination Techniques
A detailed physical check is usually the first step. Doctors look at the patient’s overall health for any signs of trouble. They check for tenderness or swelling at the surgery site and check the brain’s function.
Imaging Studies Used
Imaging tests are vital in finding the cause of the clicking. Computed Tomography (CT) scans help spot issues like air in the skull or movement of the bone flap. Studies show CT scans can find air in the skull in patients with clicking sounds.
Other Diagnostic Considerations
Doctors also look at the patient’s medical history. They check for past surgeries or conditions that might cause the clicking sound.
Ruling Out Complications
It’s important to check for complications. Doctors evaluate symptoms and test results to see if the clicking is serious. This could be due to infection or faulty hardware.
Treatment Options for Problematic Clicking Sounds
When clicking sounds after a craniotomy become a problem, there are several treatment options. The right treatment depends on the cause of the clicking, the patient’s health, and how bad the symptoms are.
Conservative Management Approaches
First, doctors might try conservative management to help with the clicking sounds. This can include:
- Watching the clicking sound for any changes
- Avoiding things that make the clicking worse
- Using relaxation techniques to deal with stress and anxiety from the clicking
- Sound masking techniques, like white noise machines or apps, to make the clicking less noticeable
Some people find relief through other methods. For example, drinking pineapple juice might help because of its anti-inflammatory effects.
Medical Interventions
If conservative management doesn’t work, doctors might try medical interventions. These can include:
- Medicines to reduce inflammation or help with neurological symptoms
- Physical therapy to improve movement and reduce pain
- Targeted injections to reduce swelling or inflammation around the surgery site
Surgical Solutions When Necessary
If the clicking sound is due to a specific problem, like bone flap movement or titanium plate issues, surgery might be needed. Surgical options can include:
- Revising the bone flap to make sure it’s fixed right
- Changing or replacing titanium plates or other devices
- Fixing any other issues that cause the clicking sound
Emerging Treatment Modalities
New treatments are being developed as medical technology improves. These might include:
- Advanced materials for fixing the skull that reduce clicking sounds
- Minimally invasive procedures to fix specific causes of clicking
- New rehab techniques to help patients deal with and lessen clicking sounds
We will keep an eye on and use new treatments that look promising for fixing clicking sounds after craniotomy.
Managing Daily Life with Craniotomy Clicking
Living with a clicking sound after a craniotomy can be tough. But, there are ways to handle it. With the right strategies and lifestyle changes, you can lessen its effect on your daily life.
Practical Coping Strategies
Dealing with the clicking sound requires both physical and mental approaches. Relaxation techniques like deep breathing, meditation, or yoga can help. Keeping a symptom journal also helps track when the clicking happens and what might cause it.
- Practice relaxation techniques daily
- Maintain a symptom journal to track patterns
- Stay hydrated to maintain overall health
Sound Masking Techniques
Sound masking can help manage the clicking sound, especially in quiet places. Using a white noise machine or a fan can mask it. Listening to soothing music or nature sounds through headphones can also be helpful.
Physical Activity Modifications
It’s important to stay active after a craniotomy, but some changes might be needed. Avoid heavy lifting or bending as they can make the symptom worse. Instead, try gentle exercises like walking or stretching.
Activity | Recommendation |
Heavy Lifting | Avoid |
Gentle Walking | Recommended |
Bending | Avoid |
Stretching | Recommended |
Sleep Management Approaches
Sleep problems are common for those with a clicking sound after a craniotomy. A consistent sleep schedule and a relaxing bedtime routine can improve sleep. Using sound masking at night can also reduce the sound’s effect on sleep.
By using these strategies, patients can manage their daily lives better with craniotomy clicking. This improves their overall quality of life.
Psychological Impact of Post-Craniotomy Clicking
The sounds after a craniotomy can really affect patients. The constant clicking can make them feel more anxious and stressed. This can slow down their recovery.
Anxiety and Stress Responses
Many patients with post-craniotomy clicking feel more anxious and stressed. They worry about the sound and its impact on their health. This worry can make them feel uneasy.
Some common signs of anxiety and stress include:
- Increased heart rate and blood pressure
- Difficulty sleeping or insomnia
- Irritability and mood swings
- Preoccupation with the clicking sound
Cognitive Behavioral Techniques
Cognitive behavioral techniques (CBT) can help manage the psychological effects of post-craniotomy clicking. These methods help patients see the clicking sound in a different light. They also reduce anxiety.
Some CBT strategies include:
- Keeping a journal to track the clicking sound and associated emotions
- Learning relaxation techniques such as deep breathing or progressive muscle relaxation
- Challenging negative thoughts and replacing them with more positive, realistic ones
Support Groups and Resources
Support groups and resources are key for patients dealing with post-craniotomy clicking. Talking to others who have gone through similar experiences can offer comfort and reassurance.
Some valuable resources include:
- Online forums and support groups for craniotomy patients
- Mental health professionals specializing in post-surgical recovery
- Educational materials on managing anxiety and stress
Communication with Family and Caregivers
It’s important for patients to talk openly with their family and caregivers about post-craniotomy clicking. Sharing their feelings and concerns can help them get emotional support and practical help.
We suggest that patients:
- Openly discuss their feelings and concerns with loved ones
- Educate family and caregivers about post-craniotomy clicking and its psychological impact
- Seek help when needed, whether it’s emotional support or assistance with daily tasks
Patient Stories: Experiences With Craniotomy Clicking
Patient testimonials show a wide range of experiences with clicking sounds after craniotomy. They highlight the need for personalized care. These stories give valuable insights into recovery and what affects patient outcomes.
Case Studies and Testimonials
Many patients have shared their experiences with clicking sounds after craniotomy. For example, one patient heard a clicking sound that matched their heartbeat. Another felt a clicking sensation when changing positions.
“The clicking sound was initially alarming, but as I understood it was related to my bone flap healing, I became more comfortable.” – A patient testimonial. These stories stress the importance of clear communication and support during recovery.
Resolution Timelines
The time it takes for clicking sounds to go away varies a lot. Some people hear the sound for just a few weeks, while others experience it for months. The type of surgical fixation and healing rate can affect how long it lasts.
- Early resolution: Clicking sound diminishes within 6-8 weeks post-surgery.
- Gradual improvement: Clicking sound decreases over several months.
- Variable patterns: Clicking sound may persist or change in character over time.
Quality of Life Considerations
The clicking sound can affect people’s quality of life differently. Some get used to it, while others find it bothersome. It can affect sleep or concentration. Understanding these impacts is key to providing good care.
Strategies for managing the clicking sound include:
- Sound masking techniques
- Relaxation and stress management
- Adjusting daily activities to minimize the sound’s impact
Lessons Learned from Patient Experiences
Patient stories show the importance of tailored care and support. By understanding the different experiences of craniotomy patients, healthcare providers can better meet their needs.
Key takeaways from patient experiences include the need for:
- Clear and personalized communication about potential post-surgical sensations.
- Ongoing support to address concerns and adapt to changes during recovery.
- Holistic care approaches that consider both physical and psychological well-being.
Long-term Outlook for Patients Experiencing Clicking
It’s important to know what to expect when you hear clicking sounds after a craniotomy. These sounds can last differently for everyone. Many things can affect how long you hear them.
Typical Duration of Symptoms
Studies show that clicking sounds usually last about four days after surgery. But, it can be shorter or longer for some people. Some might only hear them for a few days, while others could have them for weeks or months.
Factors Affecting Persistence of Clicking
Several things can make clicking sounds last longer. These include:
- The type of surgical procedure performed
- The presence of any complications during or after surgery
- The patient’s overall health and healing process
- The use of specific materials in the surgical repair, such as titanium plates
Knowing these factors can help both patients and doctors. It helps in planning how to deal with the sounds for less time.
Research on Long-term Outcomes
Research on long-term effects of clicking sounds after surgery is helpful. A detailed look at patient data shows:
Duration of Clicking Sounds | Percentage of Patients |
Less than 1 week | 40% |
1-4 weeks | 30% |
1-3 months | 20% |
More than 3 months | 10% |
Adaptation and Habituation Over Time
Many people find that they get used to the sound over time. This makes it easier to live with. It improves their life quality a lot.
In summary, the time you hear clicking sounds after surgery can change. Knowing what affects it and how you can get used to it helps in recovery.
Prevention Strategies for Minimizing Post-Craniotomy Clicking
To reduce post-craniotomy clicking, we need a mix of advanced surgery and patient cooperation. Understanding why clicking happens after surgery helps us find ways to make it less common.
Surgical Techniques and Considerations
The way a craniotomy is done is key to avoiding clicking later. Advanced fixation methods like titanium plates and screws help keep the bone flap in place. This reduces movement and clicking sounds. Also, careful handling of soft tissues and precise closure can lower the risk of complications that might cause clicking.
Patient Compliance with Post-Op Instructions
Following post-operative instructions is vital to avoid clicking after a craniotomy. We tell patients to avoid heavy lifting, bending, or hard work. Following a gentle recovery plan can greatly lower the chance of complications, including clicking sounds.
Emerging Technologies in Cranial Fixation
The field of cranial fixation is always getting better, thanks to new technologies. Advances in materials and engineering have brought innovative devices. These offer more stability and lower the risk of clicking. These new tools promise better results and fewer clicking sounds for patients.
Preoperative Discussions with Surgeons
Talking to surgeons before surgery is crucial. It helps set expectations and plan for recovery. By discussing individual risks and making a care plan, we can lower the chance of clicking and other problems. Patients should ask questions and clear up any doubts about their surgery and recovery.
Conclusion
We’ve looked into the issue of clicking sounds after a craniotomy. This is a worry for many who have this surgery. But, it’s usually not something to worry about and often goes away on its own.
It’s important for patients to know what to expect after a craniotomy. Knowing that the clicking sound is part of healing can reduce stress. We’ve talked about why this happens, like bone movement and how titanium plates work.
Being well-informed helps patients deal with their recovery better. It’s key to talk openly with your neurosurgeon. If the clicking sound is worrying, get medical help. With the right care, most people recover well from a craniotomy.
FAQ
What is a craniotomy and why is it performed?
A craniotomy is a surgery where a part of the skull is removed to reach the brain. It’s done to ease brain pressure, remove growths, or fix blood vessel problems.
What is a bone flap in the context of craniotomy?
A bone flap is a skull section removed during surgery. It’s put back after the brain work is done. It’s fixed with plates, screws, or other methods.
Is a clicking sound normal after a craniotomy?
Yes, some people hear a clicking sound after surgery. It might be from the bone flap moving or the titanium plates. But, always tell your neurosurgeon if you notice it.
What causes the clicking sound after craniotomy?
The clicking sound can come from different things. It might be the bone flap moving, the titanium plates, or how tissues and fluids move. Each person’s case is different.
When should I be concerned about the clicking sound after craniotomy?
Be worried if the sound comes with pain, swelling, or fever. Or if it changes in sound or gets louder. Talk to your neurosurgeon if you notice anything odd.
How is the clicking sound after craniotomy diagnosed?
Doctors use physical checks, CT or MRI scans, and other tests to figure out the cause. Your neurosurgeon will look at the sound and find out why it’s happening.
What are the treatment options for problematic clicking sounds after craniotomy?
Treatment can be watching and waiting, making lifestyle changes, or medical or surgical steps. It depends on why the clicking is happening.
How can I manage daily life with clicking sounds after craniotomy?
Try sound masking, adjust your physical activities, and manage your sleep. These can help you deal with the clicking sound better.
Can the clicking sound after craniotomy be a sign of a complication?
Usually, it’s not a big worry, but sometimes it can mean a problem like infection or bone flap issues. Always check in with your neurosurgeon.
How long does the clicking sound typically last after craniotomy?
The sound’s length varies. It might go away in weeks or months. It depends on the surgery, how you heal, and your body’s response.
Are there strategies to minimize the occurrence of clicking sounds after craniotomy?
Yes, there are ways. Use precise surgery, follow instructions, try new technologies, and talk to your surgeon before surgery. This can help reduce risks.
References
National Center for Biotechnology Information. Evidence-Based Medical Insight. Retrieved from https://pubmed.ncbi.nlm.nih.gov/27328839/