Monday, December 3, 2018

Deep Brain Stimulation of Orbitofrontal Cortex Relieves Depression

reposted from

Deep Brain Stimulation of Orbitofrontal Cortex Relieves Depression

The result of a study among patients with epilepsy strengthens the case for the importance of this brain region in determining mood.

Dec 3, 2018
Orbitofrontal cortex in green; cingulate, red; insula, purple; hippocampus, yellow; amygdala, cyan
Electrically stimulating the lateral orbitofrontal cortex, a brain area behind the eyes, improves the moods of people with depression, according to a study published yesterday (November 29) in Current Biology
The technique used by the researchers, led by Edward Chang of the University of California, San Francisco, is called deep brain stimulation (DBS), in which surgically implanted electrodes send electrical pulses to particular areas of the brain. The approach is already in use as a treatment for movement disorders such as Parkinson’s disease and tremors. But results on its ability to treat depression have been mixed, as NPR reports.
The researchers worked with 25 epilepsy patients who already had electrodes implanted into their brains as part of their treatments. Many of the study participants also had signs of depression as evaluated by mood tests the researchers administered, Science News reports. The investigators tried stimulating many areas of the brain, and they found that jolts to the lateral orbitofrontal cortex made patients with signs of depression—but not others who didn’t have symptoms—feel better right away.
“Wow, I feel a lot better. . . . What did you guys do?” study coauthor Kristin Sellers recalls a patient exclaiming after receiving the stimulation, she tells NPR
“Only the people who had symptoms [of depression] to start with improved their mood, which suggests that perhaps the effect of what we’re doing is to normalize activity that starts off abnormal,” adds another coauthor, Vikram Rao.
The effects wore off soon after the stimulation ended, NPR reports.
The latest study offers “more evidence that [DBS] is something that is real and will work for depression,” Al Fenoy, an associate professor of neurosurgery at the University of Texas Health Science Center at Houston Medical School, who was not involved in the work, tells NPR. Fenoy has found that stimulating a different region, which makes connections with the OFC, can also alleviate depression.
Chang’s team hopes to develop a device that could monitor the OFC and stimulate it as needed to regulate mood, according to a statement.  

Friday, November 9, 2018

Poster Highlight: Brain's reward system d

reposted from

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Nov 7

The Ventral Tegmental Area - Reward and Arousal

During this afternoon, one of my favorite poster sessions took place (Sleep systems, and sleep regulators). Here, a poster that grabbed my attention was titled “GABA and glutamate networks in the VTA regulate sleep and wakefulness” from Xiao Yu, a member of William Wisden 1’s lab at Imperial College London.

Dopamine (green) and GABA (red) expressing neurons in the mouse ventral tegmental area (VTA; outlined) studies by Xiao Yu and colleagues demonstrates that these neurons bidirectionally regulate sleep and wakefulness (Credit: Jeremy C Borniger, PhD; Stanford University)
The ventral tegmental area 1 (VTA) is largely known as the seat of the brain’s ‘reward’ system. This is because neurons in this area are the primary source of all the brain’s dopamine, a ‘feel good molecule’ that is responsible for the rewarding effects of drugs, sex, and all things fun. Neurons in this area signal reward by calculating the so called ‘reward prediction error’. This is the difference between an expected and unexpected reward. For example, if you expect to get one piece of candy from your mom, but then she gives you 100 pieces of your favorite treat, neurons in the VTA calculate the difference, fire, and release a large surge of dopamine proportional to the reward ‘error’. This signal acts to reinforce the behaviors that led to the unexpected reward. A ‘good’ error like this is a called a ‘positive prediction error’ while the opposite, where a reward is omitted when it is expected, is called a ‘negative prediction error’. Negative prediction errors result in less dopamine release, and therefore aversion to the behaviors that led to this unexpected ‘disappointment’. As you may well predict, drugs of abuse like cocaine, alcohol, heroin, and others elicit a strong positive prediction error, resulting in a lot of dopamine release and reinforcement of drug seeking behavior.
In addition to dopamine neurons in the VTA, there exists two other primary populations, one that expresses the inhibitory neurotransmitter GABA, and another that produce primarily glutamate, an excitatory neurotransmitter. Recent research has demonstrated that in addition to their roles in reward signaling, VTA-dopamine neurons strongly promote wakefulness, likely through their projections to the nucleus accumbens (NAc) (see image below). How other VTA populations relate to wake/sleep states remains unknown.

Activation of VTA-dopamine neurons (TH-positive) strongly promotes wakefulness. You can see that when these neurons are stimulated (by light sensitive ChR2 activation), the mice rapidly wake up (panels c,d,e)(Credit: Eban-Rothschild et al., 2016; Nature Neuroscience)
To investigate these other populations, Xiao Yu and colleagues used optogeneticschemogeneticsfiber photometry (Ca2+), and neuropharmacology to untangle the roles GABA and glutamate neurons in the VTA play in sleep/wake states.
First, they identified that most glutamate neurons in the VTA also express NOS1 (nitric oxide synthase 1), and therefore used NOS1 and vglut2-cre mice to specifically target these neurons for manipulation. VGLUT2 stands for ‘vesicular glutamate transporter 2’, and is expressed on virtually all subcortical neurons that signal via glutamate. Using viral vectors to specifically express the stimulatory (hM3Dq) or inhibitory (hM4Di) DREADDs, they demonstrated that stimulation of VTA-glutamate neurons strongly promotes wakefulness while inhibition of this population strongly promotes sleep. To investigate how these neurons promoted arousal, they stimulated their projections in different brain regions using optogenetics. They focused on two primary output regions, the lateral hypothalamus (which contains many sleep-related neural populations) ,and the nucleus accumbens. Stimulation of glutamate nerve terminals arriving from the VTA to the lateral hypothalamus strongly promoted wakefulness, while stimulation of similar fibers arriving at the NAc had a less pronounced effect. This suggests that VTA-glutamate neurons likely promote wakefulness via dual projections to the lateral hypothalamus and NAc. Importantly, the natural activity of these neurons (examined via fiber photometry) was shown to be highest during wakefulness and REM sleep compared to NREM sleep. This suggests that they normally change their firing rates during distinct vigilance states.

Example of a fiber photometry trace showing the activity of GABA neurons across sleep-wake states. As you can see, these neurons are mostly active during wakefulness and REM sleep compared to NREM sleep (wake = white background, NREM = blue, REM = red) (Credit: Jeremy C Borniger, PhD, Stanford University)
Similar experiments were done to examine the VTA-GABA population. Activation of these neurons (via DREADDs or optogenetics) strongly promoted sleep, while inhibition of this population powerfully promoted wakefulness. Activation of GABA nerve terminals from the VTA to the LH strongly promoted sleep, an opposite effect to that of glutamate stimulation in LH. This effect was partially inhibited when stimulations occurred in combination with a drug (gabazine) that inhibits GABA signaling. This suggests that it is GABA (and not other molecules) released by these neurons that is largely responsible for their effects of sleep/wake states. Finally, they hypothesized that this effect could be driven by GABA’s inhibitory influence over VTA-dopamine populations. By inhibiting VTA-GABA neurons in combination with dopamine blockade, they were able to (mostly) eliminate the effect of VTA-GABA silencing on wakefulness. This supports a model in which VTA-GABA neurons inhibit neighboring VTA-dopamine neurons in order to promote sleep.
This is an exciting research area as a major problems for drug abuse victims are insomnia and chronic fatigue, which inevitably lead to the reinstatement of drug seeking behavior. Sleep drugs targeting the VTA could really help rectify general sleep problems and specifically those related to drug abuse.
That’s it for now, I’ll post another sleep story later, as that’s sorta my field!

Jeremy C Borniger, PhD
Department of Psychiatry & Behavioral Sciences
Stanford University SoM
Twitter: @jborniger
website: 1

One Minute, One Slide: SFN's extreme sleep and circadian neurobiology DataBlitz event

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Nov 9
What can you show with one minute and one slide?

It turns out, quite a lot!
For the past 21 years, the NIH National Center on Sleep Disorders Research has hosted a DataBlitz at the annual SFN meeting, challenging 20 speakers to present their work in only 60 seconds, and with only a single slide. The night is then capped-off with a plenary speaker, respectifully given two slides and two whole minutes. When I received the email inviting me to present my sleep research at this year’s DataBlitz, having never previously attended I naively assumed this would be a formal evaluation of my data, and I agonized over how to pare down my data into its most salient puncta.
Well, talk about missing the mark…
The Sleep and Circadian Biology DataBlitz is anything but formal. Dr.'s Chris Leonard and Michael Twery introduced the concept to everybody with drinks in hand, and encouraged the audience to cheer wildly for the good speakers, but to boo vociferously at anyone who dared pass the 60 second mark. With that warning ringing in my ears, he passed the mike to the MC of the evening, Dr. Lisa Lyons, and we began our rapid fire dive into the cutting edge of circadian research.
I learned there are a number of unique approaches to communicating your entire paper in only one minute. The first is just to speak faster… Rebecca Northeast from University of Manchester walked us all the way through the brainstem’s involvement in circadian timekeeping and demonstrated single-cell cycling rhythmicity between the the area postrema and the nucleus of the solitary tract. Kevin Zhang explained the importance of peripheral light sensing for mice and humans alike, and pretty clearly walked through their new deep-brain photoreceptor Opn3.
Others, myself included, applied a whittling-down approach, and painfully distilled the past several years of our lives into a couple key figures. William Todd for example showed the circuit controlling time-dependent aggression propensity in mice, and explained its possible relevance to “sundowning” in Alzheimer’s patients. I could show only my most striking behavioral phenotype, and had to hand-wave through the rest of the model, and I still barely made it off the stage with 2 seconds left on the big clock.
Several talks really embodied brevity as the soul of wit, and turned their research story into short poems. Nadir Balba explained how light therapy can improve sleep quality in veterans with traumatic brain injuries using only four rhyming lines. Carolyn Jones needed only a limerick to tell the sad tale of a prairie vole who couldn’t form long-term social bonds due to cortical disruptions brought on by early-life sleep disruptions.

Our plenary speaker Dr. Luis de Lecea also chose the poetic route, and although he did run over his two minutes of alloted time, his verses and videos told the graphic story of hypocretin-positive neurons and their influence on sex drive in mice.

Even though I was only a first-timer, I was not alone in calling the 2018 DataBlitz a rousing success. Out of 615 sleep/circadian relevant abstracts at the SFN meeting, 21 presenters powered through a minute of rapid fire information presented to ~3-400 audience members. In under 30 minutes, 100 cumulative years of research on at least 7 model organisms was rushed, sang, and rhymed (with only 2 presenters running long and earning boos!) until the data overload could be washed down with sliders, wine, and beer.
I’ve only just gotten home and I’m already excited for DataBlitz 2019.

Benjamin Bell
PhD Candidate, Johns Hopkins School of Medicine
Sleep and Circadian Rhythms, Mark Wu Lab 1

Wednesday, November 7, 2018

Our presentation at Society for Neuroscience meeting in SanDiego

reposted from 

Dance for Parkinson’s Disease

During a Gairdner award lecture by Dr. Eric Kandel at the Toronto Reference Library, Kandel prescribed 2 miles of walking a day for protecting against age-related memory declines. Kandel, Nobel prize laureate and expert on the neurobiological basis of memory, described how his research demonstrates that osteocalcin mediates long-term memory formation. Osteocalcin is a hormone released from bones particularly during weight-bearing exercises such as walking.
Fast-forward one year to SFN 2018 in San Diego: Instead of walking, “Dr. Kandel, you should try dancing!” joked Dr. Joseph DeSouza, York University researcher who examines the effects of dance on Parkinson’s Disease.
“I do love some salsa!”, laughed Dr. Eric Kandel, now 88 years old.

(Left to right: Dr. Joseph DeSouza, Dr. Torsten Wiesel, Dr. Eric Kandel, and unknown)
Parkinson’s disease is a neurodegenerative disorder in which there is degeneration of dopaminergic cells in the substantia nigra which causes a host of motor symptoms such as tremors and slow, stiff movements. Dr. DeSouza’s poster presentation displays research conducted by PhD student Karolina Bearss. Their research examined the effect of dance lessons on the progression of Parkinson’s disease. They used both behavioural and neuroimaging methods which included Unified Parkinson’s Disease Rating Scale to measure the behavioural symptoms of the disease and functional neuroimaging to assess neural changes caused by training. They showed that weekly exercise classes protected against disease progression in the behavioural measure. The neuroimaging analysis is still ongoing however, the preliminary results suggest that the behavioural protection afforded by the dance lessons may be attributable to increased activation in the supplementary motor area.
Dance is a highly complex social activity which involves coordination of movements to an instructor and music. This workout for the body is certainly also a workout for the brain. While enjoying San Diego, hopefully you get to experience some of the local culture, put on your own dancing shoes, and experience some of the same benefits as the patients with Parkinson’s disease.

Dana Swarbrick
See more on Twitter: @DanaSwarbrick

Monday, October 29, 2018

Parkinson's Disease Therapeutics Conference summary and BLOG

Thank You for Attending the 12th Annual 
Parkinson's Disease Therapeutics Conference

Last Thursday, you joined more than 300 leaders from academia, industry and nonprofits at the only conference dedicated to the latest in Parkinson's drug development. We thank you for helping to create a successful and collaborative event and look forward to next year. 

For a wrap up on the event visit our blog

We also ask that you take a few minutes to complete a brief post-event survey. Your feedback will help us continuously improve our conference.

Interested in 2019 sponsorship opportunities?

Contact Evelia Johnston at for more information.

reposted from

FoxFeed Blog

Five Highlights from Our Conference Illustrate Momentum in Parkinson's Research

Posted by  
Krishna Knabe
Five Highlights from Our Conference Illustrate Momentum in Parkinson's Research
Last Thursday, The Michael J. Fox Foundation (MJFF) hosted a capacity crowd of leaders from industry, nonprofits and academia at our 12th annual Parkinson's Disease Therapeutics Conference, held in New York.
The conference kicked off with a welcome from MJFF CEO Todd Sherer, PhD, who spoke about the "incredible momentum" in Parkinson's research. He said: "Our ultimate goal is to develop new and better treatments for people with Parkinson's disease. That's why we are here -- to work collaboratively toward that goal."
In her opening remarks, this year's conference chair, Carole Ho, MD, of Denali Therapeutics thanked MJFF for "its amazing work supporting Parkinson's disease therapeutics with a patient focus." She went on to explain that the science of Parkinson's has evolved thanks in part to our deeper understanding of Parkinson's genetics, including GBA, PINK1 and LRRK2. Genetics were a focus for several presenters, including Dr. Ho's colleague Matthew Troyer, MD, who headlined the "Hot Topics in Parkinson's Disease Research" session.
Highlights from Dr. Troyer and other presenters follow:
  • Matthew Troyer, MD, of Denali Therapeutics presented, for the first time, data from the company's Phase 1 clinical trial of LRRK2 inhibitor DNL201. The drug was found to be generally safe and well-tolerated in study volunteers, with target and pathway engagement. Denali's trials are the first-in-human studies of LRRK2 inhibitors, and the positive data it shared was featured in "Forbes." Based on the positive results, Denali plans to initiate trials in Parkinson's disease patients with and without LRRK2 mutations.
  • Suzanne Pfeffer, PhD, from Stanford University presented research on how LRRK2 gene mutations affect our brains. She explained that LRRK2 modifies a type of Rab protein, which eventually leads to damage of brain cells. This finding provides important new targets for developing drugs to combat LRRK2 mutations and slow or stop Parkinson's disease.
  • Two presenters shared progress made possible by MJFF's landmark Parkinson's Progression Markers Initiative (PPMI). David Craig, PhD, of the University of Southern California and his colleagues used PPMI samples to develop the largest RNA sequencing data set ever made available. This extraordinary resource includes more than 1 billion reads per sample. Dr. Craig explained that, when combined with genetic data sets from PPMI, this RNAseq data could help identify genetic drivers of Parkinson's and other diseases. Kenneth Marek, MD, of the Institute for Neurodegenerative Disorders, summarized the breadth of data available to researchers through PPMI and presented information on the clinical predictors of Parkinson's disease risk identified through the study, including REM sleep behavior disorder, smell loss and certain genetic mutations.
  • Bastiaan Bloem, MD, PhD, from Radboud University shared his findings on the rapidly emerging field of wearable and digital measurement devices. In a series of studies, he and his colleagues demonstrated the feasibility and applicability of wearable sensors for Parkinson's. Wearable devices can address challenges of assessments done in doctor's offices -- which only capture a single moment of a complex, variable disease -- and provide a more complete picture of how patients experience Parkinson's.
MJFF investments are helping build a robust pipeline of drugs in development for Parkinson's disease. We look forward to sharing even more positive news at our conference next year.

Wednesday, October 10, 2018

We add it to drinking water for our teeth —

my colleague in the dept ....


We add it to drinking water for our teeth — but is fluoride hurting us?

Three new studies released today link fluoride exposure to ADHD and thyroid problems — and point to drinking water as the major source of exposure.

Two studies — one from Canada and one Mexico — released today point to potential health problems from fluoride, which, in a majority of U.S. communities, is purposefully added to drinking water to protect people's teeth.
The Canada study found that adults who are iodine deficient and have higher levels of fluoride in their system have a greater risk of an underactive thyroid. The Mexico study found mothers with higher fluoride exposure during pregnancy were more likely to have children with symptoms of ADHD. Both studies were published in the journal Environmental International.
A third study, published in Environmental Health Perspectives, found that among 1,566 pregnant women in Canada, fluoride levels in urine were almost two times higher for women who lived in regions where the element was added to their drinking water compared to pregnant women in regions with non-fluoridated water.
The studies call into question the practice of purposely adding fluoride to water or salt, which is done to prevent cavities and, to a lesser extent, osteoporosis. Many cities in the U.S. and Canada add fluoride to public drinking water and in Mexico it's added to some salt. Approximately 66 percent of people in the U.S. receive drinking water with added fluoride, according to the Centers for Disease Control and Prevention (CDC).
About 80 percent of fluoride exposure comes from water and beverages such as tea, which can leach fluoride from soil. Other sources include grapes and shellfish.
"I have grave concerns about the health effects of fluoride exposure," Ashley Malin, lead author of the Canada thyroid study and a researcher at the Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, told EHN. "And not just from my study but the other studies that have come out in recent years."

Fluoride, iodine and thyroids

Malin and colleagues had massive amounts of information from the Canadian Health Measure study. They looked at fluoride levels in the urine of nearly 7 million Canadians, as well as iodine deficiency and thyroid gland activity.
They found Canadians who were deficient in iodine—a mineral crucial for proper functioning of the thyroid — and who had high amounts of fluoride in their urine also had higher levels of thyroid stimulating hormones. Elevated levels of these hormones are a marker for a suppressed thyroid gland – commonly referred to as hypothyroidism, a condition that can cause a host of problems including fatigue, disrupted heart rates, and altered metabolism.
Small increases in thyroid stimulating hormones can be problematic, Malin said.
"Someone doesn't need to have full blown hypothyroidism to have an elevation in [thyroid stimulating hormones]. Research is showing more and more that subclinical elevations are associated with bad health effects," Malin said.
Iodine helps flush fluoride from the body so a deficiency leaves the body with more fluoride, which has been shown to interfere with certain enzymes important for thyroid function. This could explain why only iodine deficient Canadians seemed sensitive to fluoride impacts.
Malin said 18 percent of the nearly 7 million people they studied were iodine deficient. "We're talking about potentially [more than] a million people at risk of an underactive thyroid due to fluoride exposure."
But there are major health benefits of fluoride in water. According to the CDC, drinking fluoridated water reduces cavities (also called tooth decay) by about 25 percent in children and adults. The agency named water fluoridation one of its "Ten Great Public Health Achievements" of the 20th Century.
Dr. Manish Arora, a dentist and vice chairman of the Department of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai, told EHN via email that it "is important to balance these results with what we know about the benefits of water fluoridation as well."
"There have been tremendous gains in children's oral health worldwide over the past decades that, at least in part, can be attributed to the beneficial effects of fluoride," said Arora, who was not involved in any of the studies released today but is collaborating with some of the researchers on other projects.
While the new study doesn't prove fluoride impacts thyroid function, previous studies have linked the element to reduction thyroid hormones, and to elevated thyroid stimulating hormones and increased likelihood of hypothyroidism and diabetes in adults.

Behavior impacts

In the other study published today, researchers looked at 213 Mexican mother-children pairs and examined mothers' urine fluoride levels during pregnancy and assessed children for attention-deficit/hyperactivity disorder (ADHD) symptoms at ages 6 to 12. They found mothers with higher levels of fluoride during pregnancy were more likely to have children with ADHD symptoms, especially inattention.
It's not clear from this study why fluoride may impact child's behavior, but it could be driving thyroid hormone insufficiency in pregnant mothers (which can lead to problems in their unborn), or altering children's levels of dopamine, which moves signals from nerve cells to the brain and is vital for behavior development.
Christine Till, an associate professor and researcher at York University, told EHN one of her main concerns is that pregnant women are susceptible to iodine deficiency, which, according to the study from Canada, could leave the mothers-to-be with thyroid problems.
Also, fluoride easily crosses the placenta from mother to her unborn. The study is not the first to find a fluoride-behavioral link: A previous study linked the element to ADHD in U.S. children.
Dr. Howard Hu, co-author of the Mexico study and an epidemiological researcher at the University of Washington, told EHN the research from Canada on fluoride levels in pregnant women "makes the results of this study from Mexico even more applicable to what might be going on in North America."

To add or not to add

The evidence that fluoride may have negative impacts on health is building, Hu said, adding that one of the "most awkward features of this debate" is that it pits one branch of public health vs another.
Arora said "as a dentist and environmental health scientist, I feel this is an opportune moment in our professions to have an honest discussion."
"A question that is becoming increasingly important – is fluoridation of water supplies the best way to deliver the oral health benefits of fluoride?" Arora said. "For me, there is no 'one size fits all' answer to this. Socioeconomics, background risk and other aspects of the community have to be considered, but now is the time to have the scientific debate."
In a statement, the American Dental Association told EHN their National Fluoridation Advisory Committee would review the new studies, adding that "public health policy is based on a collective weight of scientific evidence, not the results of a single (or few) studies. The ADA remains committed to fluoridation of public water supplies as the single most effective public health measure to help prevent tooth decay."
Hu echoed Arora and said the answer in moving forward with fluoride is more nuanced than being pro- or anti-fluoride.
"Clearly this warrants additional research and consideration with how policies related to fluoride may need to be rethought," Hu said. "And not simply 'do we use fluoride or not,' but can we figure out a way to preserve the benefits while minimizing the potential adverse effects."
Till said she is "certain the safety of fluoride ingestion has not been proven."
"The problem is that it's an uncontrolled dose – everyone is exposed to different levels. It may be prudent for pregnant women to reduce ingesting fluoride during pregnancy."