LRRK2 Mutation Fires Up Immune Response, Harms Brain

27 Sep 2019

LRRK2 Controls Infection. Reovirus (brown) infects more neurons in LRRK2 knockout mice (right) than in wild-types (left). [Courtesy of Science Translational Medicine/AAAS.]

The LRRK2 variant, G2019S, increases a person’s chances of getting Parkinson’s disease, but may help protect against infection, according to research in the September 25 Science Translational Medicine. Scientists led by Michael Schlossmacher at the University of Ottawa, Canada, report that G2019S revved up the immune response in mice, improving survival from peripheral infections. In the brain, however, this response backfired, as immune cells released reactive oxygen species that exacerbated neurodegeneration and reduced survival. α-Synuclein in the brain also shot up, hinting that the combination of LRRK2 variant and environmental trigger might kick off Parkinson’s. Schlossmacher presented some of these data at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held in March 2018 in Turin, Italy (Apr 2018 conference news). 

• G2019S LRRK2 revs up the immune system, helping mice fight infection.
• Alas, this response releases α-synuclein in the brain and harms neurons.
• G2019S female mice survived blood infection better than males, but succumbed faster to encephalitis.

Schlossmacher’s group investigated the immune effects of LRRK2 because the kinase is mostly expressed in macrophages, monocytes, and microglia, and very little in the dopaminergic neurons that are lost in PD (Mar 2013 conference news). In the current study, joint first authors Bojan Shutinoski and Mansoureh Hakimi examined postmortem human tissue and surgical biopsies to find robust LRRK2 expression in white blood cells that had infiltrated inflamed human brains, including brainstems infected with HIV and cortices harboring rabies virus. In PD brainstems, LRRK2 was mostly expressed by leukocytes inside blood vessels, not by neurons or glia.

To find out what LRRK2 does in immune cells, the authors turned to mice. They infected about 50 adult animals with Salmonella typhimurium, which causes lethal sepsis. Female, but not male, LRRK2 knockout mice struggled to fight off the infection, accumulating a fivefold higher bacterial load than did wild-types. The reason for this sex difference remains murky. All the mice died within three weeks of infection. Despite greater bacterial proliferation, female LRRK2 knockouts survived as long as did male knockouts and wild-type mice.

The G2019S variant had opposite, and more dramatic, effects than the knockouts. G2019S knock-in micehandily squelched the infection, with bacterial loads in both females and males reaching but a tenth and a fifth, respectively, of what they did in wild-type. Because the effect was stronger in females, the authors used them for subsequent analyses of Salmonella infection.

They found that the protective effect of G2019S against Salmonella depended on myeloid cells, since depletion of monocytes and neutrophils abolished it. In infected females, G2019S myeloid cells generated more reactive oxygen species in the spleen and brain than did those myeloid cells in wild-type mice. The net effect was to improve survival, with female G2019S heterozygotes and homozygotes living an additional seven and 12 days, respectively, after blood infection than did controls.

What would happen with a brain infection? The authors sprayed reovirus in the noses of about 200 newborn mouse pups. The virus rapidly spread to the brain, causing encephalitis that killed half of the wild-type pups within three weeks. As with the blood infection, female LRRK2 knockouts fared poorly. They accumulated more reovirus in the brain than did males, and only a quarter survived to three weeks. Males, on the other hand, survived as well as controls.

Unexpectedly, female G2019S knock-ins also fared worse than wild-types. Both male and female knock-ins mounted a robust immune response—three times as many leukocytes infiltrated the brain as in wild-type mice, and peak viral loads only reached a tenth as high. Even so, female G2019S mice succumbed readily to the infection, having three times the risk of dying as female controls, whereas male knock-ins survived as well as controls. Altogether, the data from this study suggest that female mice mount a more robust LRRK2-mediated immune response than males, which protects them from a peripheral infection, but backfires in the brain, causing increased neuronal damage and death, the authors noted.

In addition, G2019S knock-ins produced 50 percent more α-synuclein in their brains than did wild-types. Unlike the other analyses, males and females were similar in this regard. The findings hint at a connection to Parkinson’s disease, suggesting that a brain infection could kick off α-synuclein accumulation. Schlossmacher and others have proposed that α-synuclein acts as an antimicrobial agent (Oct 2016 news; May 2017 news; Jul 2017 news). Notably, researchers have found a gender difference in people who carry the G2019S variant, with women more likely to develop Parkinson’s than men (Cilia et al., 2014; Marder et al., 2015; San Luciano et al., 2017). In general, men are more likely to get the disease.

The findings could focus attention on the potential role of systemic inflammation in PD, given that a blood infection boosted reactive oxygen species in the brain, the authors said. “We believe LRRK2’s role in immunity will spur interest in the role of the peripheral immune system in shaping brain health. Maybe modulating the peripheral immune response will benefit PD patients,” Shutinoski and Hakimi wrote to Alzforum.—Madolyn Bowman Rogers

Race For a Cure

September 27, 2019

Ticket Prices:

$125/person thru September 1st

$150/person thru Night of Event

*Fee includes admission for one to the Kickin' Party, with free drinks and food from local restaurants, plus admission to the Parkinson's Research Breakfast at The Southern Hotel on Saturday, Oct. 19th from 9-11am.

For more information: www.kickinparkinsons.com

Go to:  https://kickinparkinsons.com

https://www.eventbrite.com/e/kickin-parkinsons-a-kickin-party-tickets-62679080818

Ohio man's bike ride for Parkinson's disease takes him to San Diego

 Sep 27, 2019     By: Jermaine Ong

(KGTV) - An Ohio man’s journey around the country to raise money and awareness for Parkinson’s disease has taken him to the San Diego area.

Joe Motz completed the first half of his 6,500-mile bicycle trek when he rolled into San Diego on Friday morning.

Motz turned 65 years old on Aug. 2, and as a way to celebrate his birthday, he decided to go on the bike ride in hopes of raising $650,000 for those suffering from Parkinson’s, specifically in the Cincinnati area.

He told 10News’ Scripps sister station WCPO: “Parkinson’s patients will say ‘You know what Joe? I don’t know from one day to the next when I get up, I’ll feel like I’m concrete -- I can’t move -- I can’t do basic things like button my shirt,’” he said. “‘Then the next day I’ll be okay for a while.’”

On the Gearing Up For Good website, Motz said, “My goal is to provide greater access to people with Parkinson’s and other neurological diseases to these integrative health services.”

Motz began his ride in his hometown of Anderson Township, just outside of Cincinnati, on his birthday. He said he expected the journey to take about 90 days.

After heading north into North Dakota, Motz made his way south through Colorado, Utah and Arizona, before reaching California.

The back half of Motz’s bike ride will take him through Arizona, New Mexico and Texas, before he pedals home to Ohio.

To celebrate Motz’s arrival in America’s Finest City, a special happy hour event is being held at Thorn Brewing Co. in North Park on Sept. 27, from 4 p.m.-6 p.m.

https://www.10news.com/news/local-news/ohio-mans-bike-ride-for-parkinsons-disease-takes-him-to-san-diego

Research Treating Parkinson's by restoring a waste-clearing mechanism

by Angus Liu | Sep 27, 2019 

Stanford University scientists identified a compound that appears to reverse a defect implicated in Parkinson's disease. (alex-mit/iStock/Getty Images Plus)

Scientists at the Stanford University School of Medicine have identified a molecular defect that seems common among almost all patients with Parkinson’s disease. The marker could help diagnose the neurodegenerative disorder earlier, they argue, and it has already helped them pinpoint a promising drug candidate.

Parkinson’s can be classified as either sporadic or an inherited type caused by genetic mutations. In a study published in Cell Metabolism, the Stanford team showed that the the failure of cells to effectively remove an enzyme called Miro1 was observed in a large proportion of tissue samples from both types of Parkinson’s patients, as well as those at high risk.

With the help of artificial intelligence-based drug discovery specialist Atomwise, the team screened millions of small molecules that could target Miro1. The most promising compound they found cleared out the protein and stalled neurodegeneration in fruit flies. Xinnan Wang, the study's senior author, has founded a company, CuraX, hoping to push the compound or a close analog into clinical trials in a few years.

Parkinson’s is caused by the death of dopamine-producing nerve cells, which help transmit motion-regulating signals between neurons. One prevailing theory holds that the problem is caused by defects in the cell’s energy factories, called mitochondria. Dopaminergic neurons in the brain need a lot of energy, and they produce toxic byproducts that are harmful to mitochondria. Our body clears out the damaged mitochondria by degrading Miro.

In the new study, Wang’s team collected fibroblasts from 83 Parkinson’s patients (including both familial and sporadic) and five asymptomatic close relatives considered to be at high risk. The researchers disrupted the cells’ mitochondria in lab dishes, which should have caused Miro degradation and clearance of the damaged mitochondria.

However, the researchers found that Miro persisted in 78 of the 83 Parkinson’s fibroblasts and all five high-risk samples. That problem didn't occur in either control samples or those taken from patients with other movement disorders.

Atomwise then used its AI algorithm to help the scientists screen over 6.8 million drugs for molecules that would bind to Miro in a way that would promote its separation from mitochondria. They selected one candidate that significantly reduced fruit flies’ Miro levels without causing toxicities.

In fibroblasts from a patient with sporadic Parkinson’s, the drug improved Miro clearance. And in three different fly strains engineered to develop Parkinson’s-like climbing difficulties, it prevented the death of dopaminergic neurons. It also preserved climbing ability in two of the fly strains, the researchers reported.

Targeting mitochondria has always been an area of interest in Parkinson’s research. A team from Capital Medical University in Beijing and the University of Iowa recently focused on filling the energy gap left by dysfunctional mitochondria. The researchers found that terazosin, a treatment for prostate enlargement, might be able to do the job.

Wang and colleagues believe the Miro defect could serve as a marker to help diagnose Parkinson’s earlier in the disease process. Currently, when a person starts to show symptoms of the disease, about half of the dopaminergic neurons in the brain have already died.

What’s more, Mrio1 could prove to be a promising drug target for treating the disease, the study’s authors argued. “Our hope is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who’ve tested positive for the Miro-removal defect but don’t yet have Parkinson’s symptoms, they’ll never get it,” Wang said in a statement.

https://www.fiercebiotech.com/research/treating-parkinson-s-by-restoring-a-waste-clearing-mechanism

Parkinson’s Foundation to Present Spanish-language Conference Oct. 19

SEPTEMBER 27, 2019     BY MARY CHAPMAN 

The Parkinson’s Foundation’s fourth annual Spanish-language conference, set for Oct. 19 in Norwalk, California, will provide the latest information about Parkinson’s disease treatment and management.

Called “Hacia Adelante: Navegando el Mar del Parkinson’s” (“Forward: Sailing the Parkinson’s Sea”), the free conference is for patients, families, and healthcare providers interested in learning how to live well with Parkinson’s. All sessions and activities will be conducted in Spanish.

“Parkinson’s is more prevalent in Hispanics than in any other U.S. ethnic group, but studies confirm that many Hispanics are underserved when it comes to accessing necessary Parkinson’s information, treatment and care,” Fernando Cubillos, MD, the foundation’s senior director of research programs, said in a press release.

“As part of our mission to tackle this problem head on, we’re providing this conference to better empower and serve Latinos living with the disease through expert care, education and advocacy that is patient and community centered.”

In addition to presentations by a host of expert physicians and advocates, the event will include question-and-answer sessions, community resources, exercise and dance demonstrations, live music performances, and complimentary meals and parking. Grammy and Latin Grammy award-winning music producer Sebastian Krys will talk about his experience with Parkinson’s. The conference will take place from 9 a.m. to 3 p.m. at the DoubleTree by Hilton, 13111 Sycamore Drive.

Conference topics were chosen by the community. They include symptom management, healthcare system navigation, exercise, remaining motivated in the face of Parkinson’s, and caregiving as a family. Register here or by calling the bilingual Parkinson’s Foundation helpline at 800-473-4636.

On a related topic, the foundation presents a new episode of the podcast, “Substantial Matters: Life and Science of Parkinson’s,” every other Tuesday. In one episode — “What We’ve Learned from the Hispanic Parkinson’s Community” — Claudia Martinez, the Hispanic outreach coordinator at the Muhammad Ali Parkinson Center in Phoenix, describes the methods she uses to help Hispanic patients get the best possible care.

The most common neurodegenerative disease after Alzheimer’s, Parkinson’s affects nearly 1 million U.S. residents and 10 million globally. In the United States alone, 60,000 new cases are diagnosed annually.

The Parkinson’s Foundation works to enhance patient care and advance research toward a cure.

https://parkinsonsnewstoday.com/2019/09/27/parkinsons-foundation-presenting-spanish-speaking-conference-oct-19/

Stress Can Result in Resisting Sanctuary

 SEPTEMBER 27, 2019    BY DR. C

BOOM! Abruptly out of bed, I’m disoriented by flashing lights reflecting on the bedroom walls. I sit on the edge of the bed and look out onto what should be morning sun, bringing to life the cheery reds of bee balm against a backdrop of white birches. Instead, the sky is black. I thought it was night, but the clock says it’s morning. Rain hammers out a discordant melody on our metal roof. It’s a gloomy, wet, cold day. It sure would be nice to stay curled up under the covers.

Neo shouts at a volume comparable to the thunder, “Heck, no! You have only two days until your big research presentation.”

I snap back, “I know! I know!” The cotton oasis beckons me to go fetal. Neo is quite annoyed with me.

“What are you thinking?” Neo inquires.

“Oh, nothing. You’re right. I should look over the presentation, but I can’t get motivated to do so. I’m so nervous that I can’t even turn on my computer,” I say, almost in a whisper, as I reach to pull the covers over myself.

“Oh, no, you don’t. Get out of bed and let’s face this fear. What’s there to be afraid of? You know the material and you enjoy public speaking.” Neo doesn’t understand this latest development in my Parkinson’s.

I retort, “It’s not that at all. It’s about my physical ability to do it. This summer, my Parkinson’s symptoms got worse, and there are times when I cannot perform motor tasks. There is nothing I can do to stop these motor dysfunctions. What if one happens right when it’s my turn to stand and give my presentation?”

“So your fear of failure due to the possibility of motor freezing is preventing you from doing anything at all?” Neo replies with a slight sneer.

Somewhat defeated, I offer, “I could go back to bed.”

Neo points out, “That’s not going to solve anything. Why not enter your sanctuary for a while? You know that helps.” He is saying what I already know, but it is not motivating me to act.

“Really?” I counter. “Look outside. It’s not exactly walk-in-the-park weather. Besides, my focus should be on how to make my presentation better.” I move to the bathroom and start getting ready for the day.

Neo insists, “Embracing sanctuary is not affected by the weather. Your senses and your mind can still take in all that sanctuary offers, even in the rain.”

I feel my emotions start to escalate. “I don’t feel like calming down. I need the emotional energy to light up enough passion so I can break the chain of procrastination and the fears about my Parkinson’s symptoms.” I dress and head to the kitchen for breakfast.

Neo surveys my actions as I drop part of my breakfast on the floor. “You think you are more physically capable if you are all energized and full of passion?” It’s a good thing Neo is incorporeal and safe from any unintended physical harm.

“I—” Pausing, I stare off at nothing in particular. “I guess not. But it feels familiar and, in that way, safe. I can’t quiet down enough to use sanctuary right now. Each time I move toward quieting, the pain gets so loud it’s unbearable. That’s certainly not conducive to getting my presentation ready.” I pace the floor as I continue to mutter about the presentation that’s due in two days.

Neo points out the obvious: “Man, you are seriously stressed.” He is adept at recognizing when the situation is going downhill quickly. “Time in the sanctuary does help with stress. You know that stress unattended will just intensify all your Parkinson’s symptoms — physical, mental, emotional, and psychological. That big rock you’re throwing at yourself creates too many ripples in the pond.”

Between mouthfuls of granola and orange juice, I say, “I don’t have the time. Perhaps another day I could handle this. I can’t look at that reflecting pond right now. I’m afraid that I will hate what I see.”

“I know,” Neo says. “The path is always here when you want to walk it, and I’m with you.” Neo and I watch the rain let up, leaving behind garden flowers painted with iridescent droplets that reflect the beams of sunlight poking through the storm clouds.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

https://parkinsonsnewstoday.com/2019/09/27/resisting-sanctuary-motor-tasks-stress/

Accordion Pill Enables Higher Optimal Doses of Levodopa Than Sinemet, Data Show

 SEPTEMBER 27, 2019     BY JOSE MARQUES LOPES PHD

Patients with Parkinson’s disease who were treated with Accordion Pill Carbidopa/Levodopa (AP-CD/LD) tolerated a higher dose of levodopa and experienced less variability in plasma levels of this standard therapy than those on Sinemet.

Those are the top-line results from a Phase 3 clinical trial and data from a pharmacological study.

The effectiveness of levodopa may wear off with chronic treatment, resulting in the reappearance of motor complications, known as “off” periods. As this is associated with levodopa’s limited absorption in the upper gastrointestinal tract, Intec Pharma developed AP-CD/LD, which includes a gastric retention and release system to enable both immediate and controlled release. This controlled release mode prolongs the discharge of the medication into the stomach to eight to 12 hours, which may improve absorption.

The double-blind ACCORDANCE study (NCT02605434) is comparing AP-CD/LD with Merck’s Sinemet, an immediate release formulation of CD/LD. A total of 320 patients with advanced Parkinson’s were included in the double-blind part of the study (65.6% men, average disease duration 8.7 years), with the final visit occurring last May.

All eligible participants were on a daily levodopa dose within 400 and 1,300 mg and experienced at least 2.5 hours of off periods. After study completion, the patients could join a 12-month open-label safety extension study of AP‑CD/LD.

After two periods of six weeks each to stabilize and optimize patients on Sinemet and then on AP-CD/LD, the patients were assigned randomly to either approach over 13 weeks, with a two-week follow-up.

Two AP-CD/LD doses were tested: 50 mg of carbidopa, with 400 or 500 mg of levodopa, two or three times daily. Similar to the baseline percentage of daily off time, the patients’ mean age did not differ significantly between the two groups: 62.8 years in the AP-CD/LD group and 64.9 years in patients receiving IR-CD/LD.

At the recent  International Congress of Parkinson’s and Movement Disorder Society (MDS 2019),  R. Michael Gendreau, MD, PhD, Intec’s chief medical officer, presented the scientific poster “Patients Experiencing Motor Fluctuations with Parkinson’s Disease: Participant Characteristics in the ACCORDANCE Phase 3 Efficacy and Safety Trial of Accordion Pill-Carbidopa/Levodopa.” The presentation showed that patients on AP-CD/LD tolerated higher daily doses of levodopa than those taking Sinemet.

Specifically, 86.2% of patients taking AP-CD/LD achieved an optimal levodopa dose of 1,200 mg or greater, compared to only 19.7% among those on Sinemet.

Previous results from ACCORDANCE showed that, compared with Sinemet, AP-CD/LD did not provide greater reduction in daily off periods, benefits in “on” time without troublesome dyskinesia (involuntary body movements), or improved motor function scores, as assessed with the  Unified Parkinson’s Disease Rating Scale.

In a press release, Gendreau said that this lack of significant benefits of AP-CD/LD may have been due to confounding effects from patients whose dose was increased to the maximum (50/500 mg).

An analysis of lower doses showed a greater difference in mean daily off time between AP-CD/LD and IR-CD/LD in participants who were not dose-limited during the Accordion Pill titration process.

“This suggests that for many participants, AP doses higher than those available in this study may have been necessary to achieve optimal efficacy,” said Gendreau.

Also at MDS 2019, Jeffrey A. Meckler, Intec’s vice chairman and CEO, presented the study, “Pharmacokinetics of Accordion Pill-Carbidopa/Levodopa Following Multiple Doses in Patients with Parkinson’s Disease.” That presentation showed a pharmacokinetic (PK) comparison of AP-CD/LD 50/500 mg three times per day and the immediate release form (37.5/150 mg) five times daily in 12 patients. (Of note, PK refers to how a compound is absorbed, distributed, metabolized and eliminated by the body.)

After treatment with the immediate release form on day 1, the patients were instructed to take AP-CD/LD until day 8, when they returned to the clinic in the off state and received AP-CD/LD three times over 10 hours.

In line with Phase 2 findings — which also showed reduced motor fluctuations — preliminary results showed that AP-CD/LD provided less variability in levodopa’s plasma levels. Overall, as variable plasma levodopa levels have been associated with motor complications, the findings “suggest that treatment with AP-CD/LD may reduce motor complications,” the team wrote. AP-CD/LD was well-tolerated and no serious adverse side effects were reported.

“We believe the data underscored the potential of AP-CD/LD in PD while highlighting its long-term safety data,” said Meckler. “We have initiated a formal process for partnering AP-CD/LD in PD and this enhanced exposure will be important as we seek to partner AP-CD/LD for continued late-stage clinical development and commercialization in [Parkinson’s] patients.”

https://parkinsonsnewstoday.com/2019/09/27/accordion-pill-optimal-doses-levodopa-sinemet/

A model for brain activity during brain stimulation therapy

SEPTEMBER 27, 2019    by University of Pennsylvania

Graphical Abstract Optimizing direct electrical stimulation for the treatment of neurological disease remains difficult due to an incomplete understanding of its physical propagation through brain tissue. Here, we use network control theory to predict how stimulation spreads through white matter to influence spatially distributed dynamics. We test the theory’s predictions using a unique dataset comprising diffusion weighted imaging and electrocorticography in epilepsy patients undergoing grid stimulation. We find statistically significant shared variance between the predicted activity state transitions and the observed activity state transitions. We then use an optimal control framework to posit testable hypotheses regarding which brain states and structural properties will efficiently improve memory encoding when stimulated. Our work quantifies the role that white matter architecture plays in guiding the dynamics of direct electrical stimulation and offers empirical support for the utility of network control theory in explaining the brain’s response to stimulation. DOI:https://doi.org/10.1016/j.celrep.2019.08.008

Brain stimulation, where targeted electrical impulses are directly applied to a patient's brain, is already an effective therapy for depression, epilepsy, Parkinson's and other neurological disorders, but many more applications are on the horizon. Clinicians and researchers believe the technique could be used to restore or improve memory and motor function after an injury, for example, but progress is hampered by how difficult it is to predict how the entire brain will respond to stimulation at a given region.

In an effort to better personalize and optimize this type of therapy, researchers from the University of Pennsylvania's School of Engineering and Applied Science and Perelman School of Medicine, as well as Thomas Jefferson University Hospital and the University of California, Riverside, have developed a way to model how a given patient's brain activity will change in response to targeted stimulation.

To test the accuracy of their model, they recruited a group of study participants who were undergoing an unrelated treatment for severe epilepsy, and thus had a series of electrodes already implanted in their brains. Using each individual's brain activity data as inputs for their model, the researchers made predictions about how to best stimulate that participant's brain to improve their performance on a basic memory test.

The participants' brain activity before and after stimulation suggest the researchers' models have meaningful predictive power and offer a first step towards a more generalizable approach to specific stimulation therapies.

The study, published in the journal Cell Reports, was led by Danielle Bassett and Jennifer Stiso, a neuroscience graduate student and a member of Bassett's Complex Systems Lab.

Memory is just one area where electrical stimulation therapy is thought to have promise, but more basic research on how to coax brain activity into the desired state is needed.

"There are patterns of activity across the entire brain when you're remembering something, and those patterns look different depending on how well you're doing," Stiso says. "We know electrical stimulation can change those patterns, but how to change them into the pattern associated with better performance isn't clear."

With a collaboration between neurologists at the Hospital for the University of Pennsylvania and Thomas Jefferson University Hospital, the researchers found epilepsy patients with implanted electrodes who were willing to volunteer to receive targeted stimulation during direct brain recordings while they awaited surgery.

While their brain activity was being recorded, the patients participated in basic memory tests, which entailed hearing and recalling a list of words.

"We then used features of those individuals' brain activity, and the pattern of connections between their brain regions, to model what would happen to the whole brain when we stimulate a specific region," Stiso says. "A lot of memory research is focused on specific regions of the brain, like the hippocampus, but we think these therapies need to take a much larger network of regions into account."

Combined with data from other stimulation experiments conducted with these epilepsy patients, these models suggested which specific patterns of brain activity and connections would be most beneficial when the stimulation was targeted to improve memory.

"Using in silico experiments, we found that stimulation that had been optimized based on the model pushed the brain towards states of good memory performance," says Bassett.

"Ultimately, we're trying to figure out where and how much to stimulate each person's brain to reach the brain-wide patterns associated with the specific goal of a given therapy," Stiso says. "This type of study is an important, early step towards developing a fast, generalizable model of an individual's response to a specific stimulation therapy."

More information: Jennifer Stiso et al. White Matter Network Architecture Guides Direct Electrical Stimulation through Optimal State Transitions, Cell Reports (2019). DOI: 10.1016/j.celrep.2019.08.008

Journal information: Cell Reports

https://medicalxpress.com/news/2019-09-brain-therapy.html

Kiri and Sky: 'Everyone has their challenges and Parkinson's is ours'

Sharon Stephenson     Sep 28 2019

Kiri and Sky Elworthy. Sky was diagnosed with Parkinson's when he was 39.

Kiri and James (known as Sky) Elworthy are both 49 and have been married for 25 years. They have four children aged between 18-28. James, who has Parkinson's disease, has run an 850ha sheep/beef farm near Martinborough since 1993 while Kiri is the co-owner of the Tora Coastal Walk.

KIRI: I grew up near Riversdale, not too far from Sky, but somehow we never met. I went to Lincoln University but at the end of my first year got pregnant with my daughter Margot. I moved home and when she was 6 months old, we moved to Wellington so I could complete a BA. Flatting, studying and being a single mother was challenging, but everyone was so supportive I started an MA in Museum Studies.

About halfway through, I went to a 21st in Gladstone that Sky had crashed. He was tall and good-looking and I was like: "OMG who is that guy?" I was gutted he was with a beautiful woman but was so relieved when I found out she was his sister. One of his friends told Sky not to go near me because I had a kid! Thankfully he ignored that advice and it was fireworks between us from the start; I know love at first sight is a cliche, but that's how it was with us.

Within two weeks, we were joined at the hip. We married a year later and three children soon followed. We had the total privilege of bringing up our kids in a beautiful rural environment. My mother-in-law started the Tora Walk in 1995 and I took it over from her four years later. At the beginning, it was manageable with young kids and a farm, because we weren't fully booked. Now we get thousands of walkers every season.

When Sky was diagnosed with Parkinson's 10 years ago, it was a real shock. We had a perfect life – great kids, jobs we loved and a fantastic relationship. But everyone has their challenges and this is ours. Sky now has a facial twitch which can be hard for him to manage and sometimes it makes him less social than he was. We got kicked out of a Wellington bar recently because they thought he was intoxicated and wouldn't believe he had a medical condition.

But Sky is incredibly determined and he'll never give up. He manages to stay positive, although we run a tag-team so if he's down I'll be upbeat and vice versa. He underwent deep brain surgery in July and so far we're really pleased with the progress. It's looking like he'll have some great results in the long run.

As we've gotten older, we've learnt not to sweat the small stuff. Before, we would have had a huge barney but now we let it go. One of the biggest arguments we've ever had was over Sky's many books. I'm a neat freak and got angry about his mess so started throwing them at him. Eventually he tidied them up and now we can laugh about it.

"It's been a tough 10 years but it's made Kiri and I a lot more honest and forgiving of each other," says Sky.

SKY: I'm the second oldest of four children, born into a farming family. After school I did a bit of shepherding, then went to Massey, where I discovered females!

I spent a bit of time driving around Australia and working on dairy farms, but when Mum rang to say they'd bought the farm next door and could I run it for them, I came home. I lived on my own in the farmhouse, which soon became party central.

In 1994, my sister Cecil asked me to come to a 21st with her. I didn't know the people but tagged along. I met Kiri at the bar and we started talking. She laughed at all my jokes and was easy on the eye, with this amazing lion's mane of hair. She'll hate me for saying this, but at the time I thought: "I'll have a crack at that one!"

Kiri told me she had a 3-year-old daughter from a previous relationship which didn't bother me at all. I knew straight away that she was the one – it just felt right being with her.

After that, we'd spend most weekends together and a one night during the week. We'd also write each other old-fashioned love letters.

We moved in together less than a year after meeting and got married soon after. We both wanted kids and Kiri is a great mother. She's also incredibly loyal and funny. In fact, the worst thing I can say about her is that she spends hours in the shower washing that mane of hair I was so attracted to! We only have one bathroom so it can take forever to get in there.

I got Parkinson's when I was 39, which has meant some rough times. It started as a tremor one day and never really stopped. It affects my mobility, so even walking a few paces can feel like dragging myself through a bowl of porridge. I'm still a sole operator on our farm, but my sons Guy and Rupert help me out a lot.

It's early days, but so far the deep brain surgery has helped with my facial twitch and general mobility. It also means I can reduce my medication, which is great. It's been a tough 10 years but some good has come out of the bad: it's made Kiri and I a lot more honest and forgiving of each other and also brought the family closer. We all spend a lot more time together these days.

Kiri and I have always been able to laugh about stuff and that's been one of the things that makes our relationship work. We've also learned to let things go and forgive, because life's too short to hold onto grudges and arguments.

https://www.stuff.co.nz/life-style/love-sex/115896102/kiri-and-sky-everyone-has-their-challenges-and-parkinsons-is-ours