Large-scale study of brain volume finds genetic links to Parkinson’s disease and ADHD

Researchers from USC and the QIMR Berghofer Medical Research Institute in Australia conducted an international study that revealed hundreds of genetic variants that shape the brain.
Researchers from USC and the QIMR Berghofer Medical Research Institute in Australia conducted an international study that revealed hundreds of genetic variants that shape the brain.

In one of the largest-ever studies of DNA and brain volume, researchers have identified 254 genetic variants that shape key structures in the “deep brain,” including those that control memory, motor skills, addictive behaviours and more.

The research is supported by the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium. This international effort, based at the Keck School of Medicine of USC, brings together over 1,000 research labs across 45 countries. The goal is to identify genetic variations that impact the structure and function of the brain.

“A lot of brain diseases are known to be partially genetic. From a scientific standpoint, we are aiming to identify the specific changes in the genetic code that cause these,” stated Paul M. Thompson, PhD, who is the associate director of the USC Mark and Mary Stevens Neuroimaging and Informatics Institute and the principal investigator for ENIGMA.

“By conducting research worldwide, we are beginning to pinpoint what has been referred to as ‘the genetic essence of humanity,’” he stated.

Identifying brain regions that are larger or smaller in certain groups, such as people with a specific brain disease, compared to others, can help scientists begin to understand the causes of brain dysfunction. Discovering the genes that control the development of those brain regions provides further insight into how to intervene.

In a recent study partly funded by the National Institutes of Health, a team of 189 researchers from around the world gathered DNA samples and conducted magnetic resonance imaging brain scans to measure volume in key subcortical regions, also known as the “deep brain,” from 74,898 participants. They then conducted genome-wide association studies (GWAS) to identify genetic variations linked to various traits or diseases. The study found gene-brain volume associations that are associated with a higher risk for Parkinson’s disease and attention-deficit/hyperactivity disorder (ADHD).

“There is strong evidence that ADHD and Parkinson’s have a biological basis, and this research is a necessary step to understand and eventually treat these conditions more effectively,” said Miguel Rentería, PhD, an associate professor of computational neurogenomics at the Queensland Institute of Medical Research (QIMR Berghofer) in Australia and principal investigator of the Nature Genetics study.

“Our findings suggest that genetic influences that underpin individual differences in brain structure may be fundamental to understanding the underlying causes of brain-related disorders,” he said.

Studying the deep brain

The researchers analyzed brain volume in key subcortical structures, including the brainstem, hippocampus, amygdala, thalamus, nucleus accumbens, putamen, caudate nucleus, globus pallidus and ventral diencephalon. These regions are critical for forming memories, regulating emotions, controlling movement, processing sensory data from the outside world, and responding to reward and punishment.

GWAS revealed 254 genetic variants associated with brain volume across those regions, explaining up to 10% of the observed differences in brain volume across participants in the study. While previous research has clearly linked certain regions with disease, such as the basal ganglia with Parkinson’s disease, the new study reveals which gene variants shape brain volume with greater precision.

“This paper, for the first time, pinpoints exactly where these genes act in the brain,” providing the beginnings of a roadmap for where to intervene said Thompson,

Some diabetes drugs tied to lower risk of dementia, Parkinson’s disease

A randomized, controlled trial led by Mass General Brigham researchers demonstrates that cognitive behavioral therapy can significantly reduce the impact of fibromyalgia pain

A study suggests that a certain class of drugs used to treat diabetes may be linked to a reduced risk of dementia and Parkinson’s disease.

The study examined SGLT2 inhibitors, also known as gliflozins, which lower blood sugar by prompting the kidneys to excrete sugar through urine.

“We are aware that neurodegenerative diseases such as dementia and Parkinson’s disease are becoming more prevalent as the population ages. People with diabetes are at a higher risk of cognitive impairment. It is encouraging to see that this category of drugs may offer some protection against dementia and Parkinson’s disease,” stated study author Minyoung Lee, MD, PhD, from Yonsei University College of Medicine in Seoul, South Korea.

The retrospective study examined individuals with type 2 diabetes who initiated diabetes medication from 2014 to 2019 in South Korea. Individuals using SGLT2 inhibitors were compared with those using other oral diabetes drugs, ensuring that the two groups had similar ages, other health conditions, and diabetes-related complications. The researchers then monitored the participants to determine whether they developed dementia or Parkinson’s disease. The individuals taking SGLT2 inhibitors were monitored for an average of two years, while those taking the other drugs were monitored for an average of four years.

Among the 358,862 participants with an average age of 58, 6,837 people developed dementia or Parkinson’s disease during the study. For Alzheimer’s disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10,000 person-years, compared to 63.7 cases for those taking other diabetes drugs. Person-years represent both the number of people in the study and the amount of time each person spends in the study. For vascular dementia, which is dementia caused by vascular disease, the incidence rate for people taking the SGLT2 drugs was 10.6 cases per 10,000, compared to 18.7 for those taking the other drugs. For Parkinson’s disease, the incidence rate for those taking the SGLT2 drugs was 9.3 cases per 10,000, compared to 13.7 for those taking the other drugs. After researchers adjusted for other factors that could affect the risk of dementia or Parkinson’s disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer’s disease and a 20% reduced risk of Parkinson’s disease. Those taking the drugs had a 30% reduced risk of developing vascular dementia.

Hitting the target with non-invasive deep brain stimulation: Potential therapy for addiction, depression, and OCD

Researchers at EPFL have successfully tested a novel technique for probing deep into the human brain, without surgery, for potential therapeutic purposes.

Non-invasive stimulation of the striatum

A model image of the targeted deep brain zone, the striatum, a key player in reward and reinforcement mechanisms. CREDIT EPFL

Neurological disorders, such as addiction, depression, and obsessive-compulsive disorder (OCD), affect millions of people worldwide and are often characterized by complex pathologies involving multiple brain regions and circuits. These conditions are notoriously difficult to treat due to the intricate and poorly understood nature of brain functions and the challenge of delivering therapies to deep brain structures without invasive procedures.



In the rapidly evolving field of neuroscience, non-invasive brain stimulation is a new hope for understanding and treating a myriad of neurological and psychiatric conditions without surgical intervention or implants. Researchers, led by Friedhelm Hummel, who holds the Defitchech Chair of Clinical Neuroengineering at EPFL’s School of Life Sciences, and postdoc Pierre Vassiliadis, are pioneering a new approach in the field, opening frontiers in treating conditions like addiction and depression.

Their research, leveraging transcranial Temporal Interference Electric Stimulation (TMS), specifically targets deep brain regions that are the control centres of several important cognitive functions involved in different neurological and psychiatric pathologies. The research highlights the interdisciplinary approach that integrates medicine, neuroscience, computation, and engineering to improve our understanding of the brain and develop potentially life-changing therapies.

“Invasive deep brain stimulation (DBS) has already successfully been applied to the deeply seated neural control centres to curb addiction and treat Parkinson’s, OCD or depression,” says Hummel. “The key difference with our approach is that it is non-invasive, meaning that we use low-level electrical stimulation on the scalp to target these regions.”

Vassiliadis, lead author of the paper, a medical doctor with a joint PhD, describes tTIS as using two pairs of electrodes attached to the scalp to apply weak electrical fields inside the brain. “Up until now, we couldn’t specifically target these regions with non-invasive techniques, as the low-level electrical fields would stimulate all the regions between the skull and the deeper zones—rendering any treatments ineffective. This approach allows us to selectively stimulate deep brain regions that are important in neuropsychiatric disorders,” he explains.

The innovative technique is based on temporal interference, initially explored in rodent models, and now successfully translated to human applications by the EPFL team. In this experiment, one pair of electrodes is set to a frequency of 2,000 Hz, while another is set to 2,080 Hz. Thanks to detailed computational models of the brain structure, the electrodes are specifically positioned on the scalp to ensure that their signals intersect in the target region.

At this juncture, the magic of interference occurs: the slight frequency disparity of 80 Hz between the two currents becomes the effective stimulation frequency within the target zone. The brilliance of this method lies in its selectivity; the high base frequencies (e.g., 2,000 Hz) do not stimulate neural activity directly, leaving the intervening brain tissue unaffected and focusing the effect solely on the targeted region.

This latest research focuses on the human striatum, a key player in reward and reinforcement mechanisms. “We’re examining how reinforcement learning, essentially how we learn through rewards, can be influenced by targeting specific brain frequencies,” says Vassiliadis. By stimulating the striatum at 80 Hz, the team found they could disrupt its normal functioning, directly affecting the learning process.

The therapeutic potential of their work is immense, particularly for conditions like addiction, apathy and depression, where reward mechanisms play a crucial role. “With addiction, for example, people tend to over-approach rewards. Our method could help reduce this pathological overemphasis,” Vassiliadis, also a researcher at UCLouvain’s Institute of Neuroscience, points out.

Furthermore, the team is exploring how different stimulation patterns can disrupt and potentially enhance brain functions. “This first step was to prove the hypothesis of 80 Hz affecting the striatum, and we did it by disrupting its functioning. Our research also shows promise in improving motor behaviour and increasing striatum activity, particularly in older adults with reduced learning abilities,” Vassiliadis adds.

Hummel, a trained neurologist, sees this technology as the beginning of a new chapter in brain stimulation, offering personalized treatment with less invasive methods. “We’re looking at a non-invasive approach that allows us to experiment and personalize treatment for deep brain stimulation in the early stages,” he says. Another key advantage of tTIS is its minimal side effects. Most study participants reported only mild sensations on the skin, making it a highly tolerable and patient-friendly approach.

Hummel and Vassiliadis are optimistic about the impact of their research. They envision a future where non-invasive neuromodulation therapies could be readily available in hospitals, offering a cost-effective and expansive treatment scope.

Learning and remembering movement


From the moment we are born, and even before that, we interact with the world through movement. We move our lips to smile or to talk. We extend our hand to touch. We move our eyes to see. We wiggle, we walk, we gesture, we dance. How does our brain remember this wide range of motions? How does it learn new ones? How does it make the calculations necessary for us to grab a glass of water, without dropping it, squashing it, or missing it?

Technion Professor Jackie Schiller from the Ruth and Bruce Rappaport Faculty of Medicine and her team examined the brain at a single-neuron level to shed light on this mystery. They found that computation happens not just in the interaction between neurons (nerve cells ), but within each individual neuron. Each of these cells, it turns out, is not a simple switch, but a complicated calculating machine. This discovery, published recently in the Science magazine, promises changes not only to our understanding of how the brain works, but better understanding of conditions ranging from Parkinson’s disease to autism. And if that weren’t enough, these same findings are expected to advance machine learning, offering inspiration for new architectures.

Movement is controlled by the primary motor cortex of the brain. In this area, researchers are able to pinpoint exactly which neuron(s) fire at any given moment to produce the movement we see. Prof. Schiller’s team was the first to get even closer, examining the activity not of the whole neuron as a single unit, but of its parts.

Every neuron has branched extensions called dendrites. These dendrites are in close contact with the terminals (called axons) of other nerve cells, allowing the communication between them. A signal travels from the dendrites to the cell’s body, and then transferred onwards through the axon. The number and structure of dendrites varies greatly between nerve cells, like the crown of one tree differs from the crown of another.

The particular neurons Prof. Schiller’s team focused on were the largest pyramidal neurons of the cortex. These cells, known to be heavily involved in movement, have a large dendritic tree, with many branches, sub-branches, and sub-sub-branches. What the team discovered is that these branches do not merely pass information onwards. Each sub-sub-branch performs a calculation on the information it receives and passes the result to the bigger sub-branch. The sub-branch than performs a calculation on the information received from all its subsidiaries and passes that on. Moreover, multiple dendritic branchlets can interact with one another to amplify their combined computational product. The result is a complex calculation performed within each individual neuron. For the first time, Prof. Schiller’s team showed that the neuron is compartmentalised, and that its branches perform calculations independently.

“We used to think of each neuron as a sort of whistle, which either toots, or doesn’t,” Prof. Schiller explains. “Instead, we are looking at a piano. Its keys can be struck simultaneously, or in sequence, producing an infinity of different tunes.” This complex symphony playing in our brains is what enables us to learn and perform an infinity of different, complex and precise movements.

Multiple neurodegenerative and neurodevelopmental disorders are likely to be linked to alterations in the neuron’s ability to process data. In Parkinson’s disease, it has been observed that the dendritic tree undergoes anatomical and physiological changes. In light of the new discoveries by the Technion team, we understand that as a result of these changes, the neuron’s ability to perform parallel computation is reduced. In autism, it looks possible that the excitability of the dendritic branches is altered, resulting in the numerous effects associated with the condition. The novel understanding of how neurons work opens new research pathways with regards to these and other disorders, with the hope of their alleviation.

These same findings can also serve as an inspiration for the machine learning community. Deep neural networks, as their name suggests, attempt to create software that learns and functions somewhat similarly to a human brain. Although their advances constantly make the news, these networks are primitive compared to a living brain. A better understanding of how our brain actually works can help in designing more complex neural networks, enabling them to perform more complex tasks.

Disease-modifying antirheumatic drugs do not seem to protect people with rheumatoid arthritis against Parkinson’s disease


The autoimmune disorder rheumatoid arthritis has been associated with a lower risk of Parkinson’s disease (PD) in previous studies, with antirheumatic drugs as one possible explanation. However, most of the disease-modifying antirheumatic drugs (DMARDs) were not associated with the risk of PD in individuals with rheumatoid arthritis, a new register-based study from the University of Eastern Finland shows. An exception was the use of chloroquine or hydroxychloroquine which associated with a lower risk of PD. The findings were published online on January 21, 2022, in Neurology®, the medical journal of the American Academy of Neurology.

Risk factors for PD are still unclear. Rheumatoid arthritis has been linked to PD with conflicting findings, and both risk lowering and increasing findings have been reported. The medications used to treat rheumatoid arthritis could be one possible explanation for the potential lower risk of PD in individuals with rheumatoid arthritis but there are only few previous studies.

According to the newly published study, previous use of methotrexate, sulfasalazine, gold preparations or immunosuppressants at least three years before the PD diagnosis was not associated with the risk of PD in individuals with rheumatoid arthritis. However, users of chloroquine or hydroxychloroquine had a 26% lower relative risk of PD. Different comorbidities, such as cardiovascular diseases and diabetes, along with age, sex, and duration of rheumatoid arthritis, were controlled for in the study.

Chloroquine and the more commonly used hydroxychloroquine have various effects on the immune system. These medicines have been found to have antiparkinson potential in animal models of PD. According to researchers, the possible protective association of chloroquine and hydroxychloroquine should be further investigated.

This study was conducted as part of the FINPARK study, which covers 22,189 community-dwelling Finns with PD and a matched comparison cohort. The study was limited to persons who had been diagnosed with rheumatoid arthritis at least three years before PD.