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Model may explain how deep brain stimulation treats Parkinson’s
People with Parkinson’s disease and their doctors confront many unknowns, including the answer to exactly how deep brain stimulation (DBS) relieves some of the motor symptoms patients experience.
In a new study, scientists at Boston University and The Picower Institute for Learning and Memory at MIT present a detailed model explaining the underlying circuit dynamics, providing an explanation that, if experimentally confirmed, could improve the therapy further.
Among the things that are known about Parkinson’s disease is that a deficit of the neuromodulator dopamine is associated with abnormally high beta-frequency rhythms (brain waves at a frequency of about 20 Hz).
DBS, involving the delivery of high-frequency electrical stimulation to a brain region called the subthalamic nucleus (STN), apparently suppresses these elevated beta rhythms, restoring a healthier balance with other rhythm frequencies and better movement control.
The new biophysically-based computational model described in the Proceedings of the National Academy of Sciences posits that the beneficial effect of DBS arises from how it interrupts a vicious cycle promoting runaway beta in a circuit loop between the STN and a region called the striatum.
In 2011, study co-author Michelle McCarthy, research assistant professor of mathematics and statistics at BU, used mathematical models to show how, in the absence of dopamine, runaway beta might arise in the striatum from excessive excitement among striatum-dwelling cells called medium spiny neurons (MSNs).
The model, led by Picower Institute postdoc Elie Adam, builds on McCarthy’s finding.
Joining Adam and McCarthy are co-authors Emery N Brown, Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT and Nancy Kopell, William Fairfield Warren Distinguished Professor of Mathematics and Statistics at BU.
The quartet’s work suggests that under healthy conditions, with adequate dopamine, cells in the striatum called fast-spiking interneurons (FSIs) can produce gamma-frequency rhythms (30-100 Hz) that regulate the beta activity of the MSNs.
But without dopamine, the FSIs are unable to limit the MSN activity and beta comes to dominate a whole circuit loop connecting the STN to the FSIs, to the MSNs, to other regions and then back to the STN.
“The FSI gamma is important to keep the MSN beta in check,” Adam said. “When dopamine levels go down, the MSNs can produce more beta and the FSIs lose their ability to produce gamma to quench that beta, so the beta goes wild.
“The FSIs are then bombarded with beta activity and become conduits for beta themselves, leading to its amplification.”
When DBS high-frequency stimulation is applied to the STN, the model shows, that replaces the overwhelming beta input received by the FSIs and restores their excitability.
Reinvigorated and freed from those beta shackles, the interneurons resume producing gamma oscillations (at about half the DBS stimulation frequency, typically at 135 Hz) that then suppress the beta activity of the MSNs.
With the MSNs no longer producing too much beta, the loop leading back to the STN and then to the FSIs is no longer dominated by that frequency.
“DBS stops the beta from propagating towards FSIs so that it is no longer amplified, and then, by additionally exciting FSIs, restores the ability of FSIs to produce strong gamma oscillations, that will in turn inhibit beta at its source,” Adam said.
The model reveals another important wrinkle. Under normal circumstances, different levels of dopamine help shape the gamma produced by the FSIs. But the FSIs also receive input from the brain’s cortex.
In Parkinson’s disease, where dopamine is absent and beta becomes dominant, the FSI’s lose their regulatory flexibility, but amid DBS, with beta dominance disrupted, the FSIs can instead become modulated by input from the cortex even with dopamine still absent.
That allows them a way to throttle the gamma they provide to the MSNs, and enable a harmonious expression of beta, gamma and theta rhythms.
By providing a deep physiology-based explanation of how DBS works, the study may also offer clinicians clues to how to make it work best for patients, the authors said.
The key is finding the optimal gamma rhythms of the FSIs, which may vary a bit from patient to patient.
If that can be determined, then tuning the DBS stimulation frequency to promote that gamma output should ensure the best results.
Before that can be tested, however, the model’s fundamental findings need to be validated experimentally. The model makes predictions necessary for such testing to proceed, the authors said.
The National Institutes of Health provided funding for the research.
Brain recordings show tirzepatide briefly silences food noise in one woman with obesity, but the effect appears temporary.
A rare brain study using implanted electrodes found that tirzepatide, sold as Mounjaro and Zepbound, quiets brain signals linked to constant thoughts about food, but the effect appears temporary.
Researchers monitored brain activity in a 60-year-old woman with severe obesity who had electrodes surgically implanted as part of a clinical trial for treatment-resistant obesity.
The patient, identified as “Participant 3”, struggled with obsessive thoughts about food, leading to ordering takeaway or continual snacking even when she wanted to resist.
She reported eating large amounts until uncomfortably full, particularly pre-packaged cupcakes, fast-food roast beef sandwiches and French fries.
The woman had tried to manage her obesity through bariatric surgery, medication, behavioural therapy and weight-loss drugs.
She had also been prescribed dulaglutide, a GLP-1 inhibitor (a class of drugs that mimic hormones regulating blood sugar and appetite), which did not affect her weight or food preoccupation.
When prescribed tirzepatide for her type 2 diabetes before the brain surgery, the team gained a rare opportunity to observe how the drug alters brain signals tied to eating behaviour in real time.
Casey H. Halpern, is professor of neurosurgery and head of the division of stereotactic and functional neurosurgery at the Perelman School of Medicine at the University of Pennsylvania.
The researcher said: “Brain surgery to implant the electrodes is invasive, and thus it is extremely rare to study human brain activity in this way.
“This participant was already taking tirzepatide when she enrolled in the trial, but before any stimulation was delivered, giving us a unique opportunity to make foundational observations about how the drug alters brain signals.”
The electrodes were implanted in the nucleus accumbens (NAc), a region that helps regulate motivation and guides decisions around pleasure-seeking and impulse control.
Prior work shows that in people with obesity and binge eating disorder, signalling in this circuit is dysregulated.
After she reached her full dose of tirzepatide following surgery, the participant reported no food preoccupation and her NAc activity was quiet.
After five months, NAc activity returned to levels consistent with obesity, along with reports of severe food preoccupation, suggesting the drug’s effect was temporary.
In contrast, trial participants not taking tirzepatide showed the expected elevated NAc activity and frequent episodes of food preoccupation throughout monitoring.
Up to 60 per cent of people with obesity report experiencing “food noise”, meaning persistent thoughts about food that drive distress and dysregulated eating behaviours.
Binge eating disorder affects at least three million people in the US and is considered the country’s most common eating disorder.
“Until we better understand their action on the brain, it’s far too soon to call GLP-1 and GIP inhibitors miracle drugs for more conditions beyond type 2 diabetes and obesity,” Halpern said.
GIP inhibitors work alongside GLP-1 to regulate blood sugar and appetite.
Tirzepatide targets both GLP-1 and GIP receptors and was developed to manage type 2 diabetes.
“GLP-1 and GIP inhibitors are amazing medications at doing what they were developed for – managing blood sugar in people with type 2 diabetes and weight loss in obesity,” said study investigator Kelly Allison, professor of psychiatry and director of the Center for Weight and Eating Disorders.
“This research shows us that they might be useful to manage food preoccupation and binge eating, but not in their current form.”
The clinical trial involves implanting intracranial electroencephalography (iEEG) electrodes, a technique that records electrical activity in the brain, similar to devices used to treat drug-resistant epilepsy and Parkinson’s disease.
The electrodes record NAc activity as participants encounter foods that typically trigger binge eating episodes.
Halpern’s previous research identified distinctive electrical activity in the NAc that arises just before food preoccupation and the urge to binge, but not when someone is simply hungry before a normal meal.
A pilot trial showed that delivering high-frequency stimulation to the NAc when craving-linked signals occurred could prevent binge eating behaviours.
“Although this study only featured the data from one person taking tirzepatide, it provides compelling data about how GLP-1 and GIP inhibitors alter electrical signals in the brain,” said co-first author Wonkyung Choi, a PhD candidate in Halpern’s lab.
“These insights should inspire further research into developing a treatment better tailored to the impulsivity traits of obesity and related eating disorders that is safe and long-lasting.”
Childhood loneliness increases the risk of dementia in later life, according to new research.
Adults who recalled being lonely and without a close friend in childhood faced a 41 per cent higher risk of developing dementia, even if they were no longer lonely as adults.
People who frequently felt lonely without close friends during youth showed accelerated cognitive decline — a worsening of memory and thinking — and started middle age with lower scores on these skills.
Researchers from universities in China, Australia and the US, including Harvard and Boston universities, analysed data from 13,592 Chinese adults tracked from June 2011 to December 2018.
The critical factor was the subjective feeling of loneliness itself. Those who reported often feeling lonely as children had a 51 per cent higher dementia risk, even if some had close friends.
However, those who only lacked close friends but did not feel lonely showed no significant difference in risk.
Nearly half of roughly 1,400 adults in the study reported being lonely and without close friends during childhood.
The 4.2 per cent who experienced both faced the highest risk of cognitive decline.
The link to dementia remained strong even for people who were no longer lonely in adulthood, suggesting early-life isolation can have lasting effects on brain health.
During childhood, the brain develops rapidly and is vulnerable to harm. Loneliness acts as a chronic stressor, flooding the developing brain with harmful hormones that can damage memory centres, and it reduces stimulation from social play and peer interaction that helps build robust neural networks.
A separate 2024 study of more than 10,000 older adults found that specific childhood hardships — including poverty, disruptive home environments or parental addiction — were directly linked to poorer cognitive function later in life.
Youth loneliness appears to be rising, partly linked to widespread social media use.
Among girls, 64 per cent aged five to seven, 67 per cent aged eight to 10, and 73 per cent aged 11 to 13 reported feelings of loneliness last year. More than a quarter of boys aged 11 to 17 in the US report feeling lonely.
Children face growing social isolation, with one in four Americans now eating every meal alone — a rate that has surged by over 50 per cent since 2003. Sharing meals with friends and family helps build bonds and positive memories in youth.
Fewer children are playing outside or joining team sports.
A recent study reported that one in three children do not play outside on school days, and one in five do not do so even at weekends.
The 2024 research found a direct, dose-dependent relationship between childhood adversity and cognitive problems in adults — the greater the early trauma, the greater the later risk.
For each significant increase in early trauma, individuals faced an eight per cent higher risk of daily memory issues and scored lower on objective tests of mental speed and focus.
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