According to the findings published last week in the journal Nature Medicine, the device works on adaptive deep brain stimulation (aDBS), a neuromodulation technique (technology that alters nerve activity by delivering electrical signals or pharmaceutical agents) in which stimulation parameters are adjusted in accordance with the clinical and neurological state of the patient. Different motor and cognitive symptoms correspond to different brain signals, which are called biomarkers.
A closed loop system, which is automatically regulated to maintain the desired state and in which action is dependent on outcome, aDBS reads these biomarkers and uses them as feedback variables to adjust stimulation parameters in real-time.
The study, led by Carina R Oehrn from UCSF’s Department of Neurological Surgery, is the first to assess adaptive stimulation in Parkinson’s disease patients during normal and unrestricted daily life. The purpose of the research was to determine how adaptive stimulation is better than conventional stimulation, and how the former can improve the quality of life for Parkinson’s disease patients.
The significance is that with the help of the device, both movement problems and insomnia can be managed in those suffering from Parkinson’s disease. Most importantly, patients can use the device while carrying out daily activities, without the fear of experiencing unwanted symptoms due to inadequate or excess stimulation.
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aDBS & movement control
DBS was first tried for Parkinson’s disease patients in 1986. It was used to stimulate the motor thalamus, a brain region involved in movement control where all sensory and motor information is relayed from the body to the brain.
The aDBS technique reads brain signals and determines which symptoms they correspond to. After picking up these signals, the device curbs them with electrical pulses, complementing the effects of medicines. In other words, bothersome symptoms, such as tremors and stiffness, are associated with an increase in the levels of certain brain signals. To relieve the patient of the motor problems, it is important to curtail those impulses. For this, aDBS can be used along with medicines.
A drug called levodopa is administered to Parkinson’s disease patients because it replaces dopamine in the brain cells that have lost their ability to produce the neurotransmitter, which controls movement and affects mood, motivation and sleep.
However, in several instances, excess dopamine is produced in the brain, resulting in uncontrolled movements (dyskinesia), such as tremors and erratic movements of the face, arm and legs.
The new device can help provide less stimulation when medications are active, so that the patient does not exhibit excess movements.
When the medicine’s effects wear off, the patient experiences anxiety, mood swings, pain and sleepiness, and a recurrence of dyskinesia. These symptoms occur because dopamine levels in the brain decrease. To restore them, the aDBS device can help stimulate dopamine-releasing neurons.
An interesting element is that patients can use another hand-held device, similar to a remote, to turn the treatment off or stop the adaptive mode of the implant.
As part of the trial, the UCSF researchers tested the device on four male participants, and compared the results to those of an already existing DBS technology called constant DBS (cDBS).
The four participants were recruited from outpatient clinics of the neurology and neurological surgery departments at UCSF from August 2018 to February 2022. All of them had Parkinson’s disease for 10-15 years, and belonged to the age group of 47-68 years.
In the standard-of-care neuromodulation technique cDBS, stimulation parameters remain constant, irrespective of the patient’s symptoms and associated changes in brain activity. The technology has several disadvantages because the constant level of electrical stimulation may understimulate or overstimulate regions of the brain, causing more harm than good.
This is where aDBS comes to the rescue. Unlike aDBS, cDBS cannot alleviate insomnia because it mostly controls daytime movement problems.
“We used the same hardware device for both standard-of-care cDBS therapy and the research aDBS therapy. Our study compared different software for applying stimulation using the same device,” Dr Stephanie Cernera, one of the authors of the paper and postdoc at UCSF, told ThePrint.
“Once the aDBS algorithm was turned on, the benefits of the self-modulating stimulation intensity would be almost immediate for certain motor symptoms. For instance, when a patient’s medications are working, their cDBS stimulation intensity may be too high and cause unwanted movements. However, in aDBS, the algorithm would detect that the patient’s medication is working, adjust stimulation amplitude accordingly, and reduce or stop these unwanted movements,” Dr Cernera added.
How aDBS can treat insomnia
A previous study, published in February 2024 in Nature Communications, led by Simon Little of the UCSF, showed that aDBS has the potential to treat insomnia in Parkinson’s disease patients.
As part of the research, Little and his team tested aDBS on four patients with Parkinson’s disease, and one with cervical dystonia (painful neurological conditions characterised by involuntary contraction of neck muscles).
The study showed that not only could aDBS recognise brain activity linked with various stages of sleep, but could also identify patterns that indicate if the person is likely to wake up at any point of time in the night.
Little’s first aDBS sleep study was published last year in the journal Brain Stimulation. The authors of the paper had concluded that stimulation of the brain while the patient is sleeping can help scientists understand sleep neurophysiology in Parkinson’s disease patients, and can also be used to develop therapies that target sleep symptoms.
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How the aDBS device was developed
In 2013, Philip Starr, a professor of neurological surgery at UCSF and one of the senior authors on the paper, had devised a method to detect and record abnormal brain rhythms associated with Parkinson’s disease. These abnormal signals are generated because dopamine-producing neurons become damaged or die.
In 2021, Starr and his colleagues identified patterns of brain rhythms corresponding to motor symptoms.
Starr and Little focused on developing a DBS system that can read varying dopamine levels, and for that, they started identifying brain signals corresponding to different movement problems.
The subthalamic nucleus (STN) is the deep brain region that coordinates movement, but the researchers decided not to study signals generated in this area.
This is because STN is the region cDBS stimulates. Had the researchers tried to study signals produced in STN, they would not have obtained any readings because cDBS stimulating that region would have caused the brain signals corresponding to motor problems to be muted.
Therefore, the researchers studied alternative signals in the motor cortex—a region not stimulated by cDBS—which is the optimal biomarker for signal fluctuations associated with unwanted symptoms in Parkinson’s disease patients.
Based on the signals collected, they developed a data analysis system that can convert the information into personalised algorithms unique to each patient.
“DBS leads were placed into the STN, which is a common brain target for DBS in patients with Parkinson’s disease. Standard-of-care cDBS stimulation settings are typically configured by a neurologist over the course of many months after the surgical placement of the device. It took additional weeks-months to identify the brain signals and additional settings for each patient’s aDBS algorithms,” Dr Cernera said.
Can aDBS go wrong?
While aDBS results in better symptom control compared to cDBS, the effectiveness of the former depends on the ability of the monitored brain signals to detect symptoms and change stimulation intensity accordingly.
However, Dr Cernera said that if the brain signals fail to accurately predict the patients’ symptoms, the stimulation intensity would remain in a safe range, as identified by the study neurologist. But this might inadequately address the patient’s symptoms.
“One way that the symptoms could be inaccurately predicted from the brain signals would be if the signals changed over time. Our study included at least 30 days of evaluating aDBS in each patient, and did not show any change in brain signals over time. This has been the longest study to ever perform aDBS in naturalistic settings,” Dr Cernera explained.
However, she added that more research will be needed to track the long-term effectiveness of aDBS algorithms and stability of these brain signals, a future focus area for the Starr laboratory.
Other diseases that aDBS can treat
According to Dr Cernera, if a symptom of a neurological disease has an associated brain signal and responds to changes in stimulation intensity or timing, it is possible that aDBS could manage these symptoms.
“The aDBS technique could potentially be applicable to a variety of motor and neuropsychiatric diseases. Currently, aDBS is being investigated for other movement disorders such as essential tremor and Tourette syndrome,” Dr Cernera said.
Essential tremor is a neurological condition that causes involuntary and rhythmic shaking of the hands, trunk, head, legs and voice. Tourette syndrome is a neurological condition that causes unwanted, uncontrolled, rapid and repeated movements (tics) and vocal sounds.
“We developed our aDBS algorithm with movement problems in mind and found that aDBS improved patients’ most bothersome motor symptom or movement problem compared to traditional DBS. We also monitored a variety of other non-movement symptoms, such as mood, anxiety, and found no difference in aDBS compared to cDBS,” Dr Cernera said.
“It is certainly possible that we might be able to affect non-movement symptoms by either identifying different brain signals or stimulating in a different way. This will be a focus of Dr. Oehrn’s laboratory at the University of California, Davis, where she is developing aDBS approaches for memory and mood in Parkinson’s disease,” she added.
In a statement released by UCSF, Starr said that aDBS has potential to manage symptoms of not just Parkinson’s, but also those of other neurological conditions, like depression and obsessive-compulsive disorder.
(Edited by Mannat Chugh)
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