The double-blind study is the first of its kind to investigate the effectiveness of rTMS in treating CUD in people with schizophrenia, and was supported by the U.S. National Institute on Drug Abuse (NIDA) and the CAMH Foundation.

“People with schizophrenia have very high rates of cannabis use disorder compared to the general population, and there is strong evidence that cannabis use worsens psychiatric symptoms and quality of life in these people,” said senior author CAMH clinician scientist Dr. Tony George. “Despite the known harmful effects, there is currently no approved treatment for CUD with or without schizophrenia. These results indicate rTMS may be a safe and effective way to reduce cannabis among people with schizophrenia.”

Until relatively recently, brain stimulation technologies like rTMS were used primarily for treatment-resistant depression. However, studies have now found rTMS to be effective in reducing drug use and cravings for several substance use disorders in the general population.

Study participants were given rTMS treatment at the Temerty Centre for Therapeutic Brain Intervention at CAMH five times a week for four weeks targeting the brain’s the dorsolateral prefrontal cortex (DLPFC), which is associated with the brain’s reward system and executive function.

Those who were given rTMS reported a reduction in cannabis use by up to 60 per cent after 28 days as well as reduced cravings, compared to controls receiving sham rTMS.

The authors state that one of the reasons there is currently no effective treatment for CUD in people with schizophrenia is that people with schizophrenia or other mental illnesses are usually excluded from CUD clinical trials. Dr. George says that CAMH is uniquely positioned to do this kind of research:

“In addition to our ability to conduct clinical trials with brain stimulation at the Temerty Centre, CAMH also has one of the largest schizophrenia outpatient clinics in North America as well as state-of-the-art addiction treatment programs,” said Dr. George. “All those factors make CAMH one of the few places in the world that can lead a study like this.”

“It was a difficult study to recruit for given the intensity of time commitment required by patients,” said study lead author Dr. Karolina Kozak Bidzinski. “However, the awareness patients had of the negative effects cannabis was having on their lives, the expected benefits of reducing their use and noticing the various positive outcomes that would surface throughout the duration of the trial, enabled such a high number of patients to complete the study. Hopefully this work paves the way for more research into investigating the effects of rTMS as a treatment for cannabis use disorder in people with schizophrenia.”

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Shell ring villages were coastal communities built around fishing, as indicated by their sitting next to shellfish estuaries, and their large mounds of mollusk shells which remain to this day. Shell rings formed some of the earliest human village settlements along the U.S. South Atlantic coast but were abandoned at the end of the Late Archaic around 4,000 years ago. While scholars have proposed socio-ecological explanations, there has been limited examination of the physical evidence for these.

Garland, Thompson and colleagues analyzed the biochemistry and paleobiology of mollusk shells found at three abandoned shell rings on Sapelo Island in Georgia, U.S. For example, they measured the size of oyster shells as an indicator of the health of the environment and compared oxygen isotope values to determine salinity conditions. They integrated their findings with chronological data — such as tree ring analyses — using a Bayesian chronological model, to determine environmental fluctuations over time.

The researchers found that the three Sapelo shell rings, known as Ring I, Ring II and Ring III, were occupied in the Late Archaic for varying, sometimes overlapping, periods. Ring II appeared to be the oldest and longest-lasting, founded around 4290 years ago and being occupied until 3950 years ago, with Ring I lasting around 150 years in the middle of this period. Ring III was the newest and outlasted the others, before abandonment around 3845 years ago. While Rings I and II featured large oyster shells, those at Ring III were significantly smaller, indicating a decrease in oyster shell size over time. Smaller oysters tend to be less healthy or younger, so this may indicate a depletion in oyster stocks and/or oyster health. Oxygen isotopes also indicated significantly lower salinity conditions by the time of Ring III as compared to Rings I and II.

The analysis suggests that the inhabitants of the shell ring villages experienced environmental fluctuations, especially around the occupation of Ring III. Coastal settlement may have initially been an adaptation to climate change as a way to effectively manage fisheries — which are highly sensitive to such changes. However, by the time of occupation of Ring III, fishing may have become unsustainable, leading to dispersals to other settlements and other forms of subsistence.

The authors believe that their work provides “comprehensive evidence for correlations between large-scale environmental change and societal transformations on the Georgia coast during the Late Archaic period.”

The authors add: “The emergence of village life and adaptation to coastal environments are significant transitions in human history that have occurred at various times and places across the globe. Our research shows that Indigenous peoples who established North America’s first coastal shell ring villages some 4200 years ago were resilient and, through cooperation and collective action, were able to adapt to environmental instability and resource shortfalls.”

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“We were surprised by this fascinating phenomenon that mitochondria appear to have a dual purpose: their well-established metabolic role producing energy, as well as this optical effect,” said the study’s lead investigator, Wei Li, Ph.D./B.M., who leads the NEI Retinal Neurophysiology Section.

The findings also address a long-standing mystery about the mammalian retina. Despite evolutionary pressure for light to be translated into signals and pass instantly from the retina to the brain, the trip is hardly direct. Once light reaches the retina, it must pass through multiple neural layers before reaching the outer segment of photoreceptors, where phototransduction (the conversion of light’s physical energy into cellular signals) occurs. Photoreceptors are long, tube-like structures divided into inner and outer segments. The last obstacle a photon must traverse before moving from the inner to the outer segment is an unusually dense bundle of mitochondria.

Those bundles of mitochondria would seem to work against the process of vision either by scattering light or absorbing it. So, Li’s team set out to investigate their purpose by studying cone photoreceptors from the 13-lined ground squirrel.

Unlike other animal models used for vision research, the 13-lined ground squirrel’s retina comprises mostly cones, which see color, as opposed to rods that enable night vision. Li’s team studies the 13-lined ground squirrel to better understand the causes of human eye diseases that primarily affect cone photoreceptors.

The researchers used a modified confocal microscope to observe the optical properties of living cone mitochondria exposed to light. Far from scattering light, the tightly packed mitochondria concentrated light along a thin, pencil-like trajectory onto the outer segment. Computational modeling using high-resolution mitochondrial reconstructions corroborated the live-imaging findings.

“The lens-like function of mitochondria also may explain the phenomenon known as the Stiles Crawford effect,” said first author of the paper, John Ball, Ph.D., a staff scientist in the Retinal Neurophysiology Section.

Scientists measuring retinal responses to light have long observed that when light enters the eye near the center of the pupil, it appears brighter compared to light of equal intensity entering the eye near the edge of the pupil.

In this study, Li found that the lens-like effect of mitochondria followed a similar directional light intensity profile. That is, depending on light source location, the mitochondria focused light into the outer segment of the cell along trajectories that mirrored those observed from the Stiles-Crawford effect.

Linking mitochondria’s lens-like function to the Stiles-Crawford effect has potential clinical implications. The long-observed effect may now be used as the basis for non-invasively detecting retinal diseases, many of which are thought to involve mitochondrial dysfunction at their origin. For example, patients with retinitis pigmentosa have been reported to have abnormal Stiles-Crawford effect even when they have good visual acuity. More research is needed to explore the structural and functional changes in cone mitochondria and their manifestations in detectable optic features.

Finally, the findings provide new insights into how our eyes may have evolved.

Like the mitochondria in Li’s study, within the photoreceptors of birds and reptiles, tiny oil droplets are located in the portion of the inner segment closest to the outer segment, and they are thought to serve an optical role. Furthermore, the mitochondrial “microlens” in mammalian cone photoreceptors confers a functionality reminiscent of that achieved by the compound eye of arthropods like flies and bumblebees.

“This insight conceptually bridges compound eyes in arthropods with the camera eyes of vertebrates, two independently evolved image-forming systems, demonstrating the power of convergent evolution,” Li said.

The study was funded by the NEI Intramural Research Program.

Video: https://youtu.be/BPWXpam_mcU

The study also found that, at a time when mental health problems soared due to financial woes, supply shortages and nonstop news coverage of the virus, people sought solace in the great outdoors, with one-third spending more time there than they did pre-COVID.

“This research shows how critical it is to keep parks and green spaces open in times of crisis,” said senior author Colleen Reid, an assistant professor of geography in the Institute for Behavioral Science. “It also shows that, as a public health measure, more effort should be made to put in green spaces and make them accessible.”

For the study, the authors presented about 1,200 Denver-area residents with a 30-minute survey gauging their mental health and their perceptions of green space near their home, including: how much there was, whether they could see it, whether it was accessible, how much they used it and its quality. They also collected aerial satellite imagery to objectively quantify greenery in respondents’ neighborhoods.

The survey ran from November 2019 to January 2021.

Once COVID-19 emerged and lockdowns ensued, Reid added additional questions, providing a rare opportunity to also look at how the pandemic influenced mental health over time and what was most stressful about it.

“Not surprisingly, we found that the pandemic impacted mental health negatively,” said co-author Emma Rieves, a master’s student in the Department of Geography. “But we also found that green space could have a powerful protective effect, even at a time of such extraordinary stressors.”

Supply shortages and job losses stressed people out

Surprisingly, the study found no association between being diagnosed with COVID and having poor mental health. But respondents reported that having symptoms, no diagnosis and no way to test was distressing.

Those who lost income or felt they were working in an unsafe environment were also more likely to be stressed or depressed, while the strongest source of mental health problems was a fear of supply shortages (including toilet paper and food).

People who spent a lot of time scrolling the internet looking at the news reported poorer mental health. In contrast, merely having abundant green space nearby, as measured by satellite images, was associated with lower depression scores.

To get the most benefit out of nearby green space, the study found, people had to get out and use it. Those who used green space most had significantly lower anxiety and depression.

“There are many dimensions of green space, and our study looked closely at how these dimensions impact mental health,” said Rieves, noting that policymakers often rely solely on objective measures, like satellite images or proximity to parks when assessing whether to invest in more greenery in a community.

On a satellite image, Rieves points out, a large patch of greenery could actually be a weed-filled lot. A ‘nearby park’ could be on the other side of a busy highway.

“It’s not just about being able to see trees from your home. The amount, quality and accessibility of that green space matters,” said Rieves.

Many public agencies closed public green spaces, including neighborhood playgrounds and national parks, at the onset of the pandemic for fear that the virus could be easily spread via surfaces. Once parks reopened, with places like gyms, bars and churches still closed, Coloradans flocked to the outdoors: 33% of respondents reported spending more time in parks or on trails than the year before.

The ‘biophilia hypothesis’

The study adds to a growing body of evidence suggesting that green space can have a measurable impact on health.

According to one theory, known as the ‘biophilia hypothesis,’ humans innately tend to seek connections with green spaces, where the calming environment influences stress hormones in a way that promotes healing and fends off disease.

“The idea is that we have evolved with nature, and only in the recent past have we been living in the concrete jungle,” said Reid.

One famous 1984 study even found that when hospital patients had rooms with a window looking out on green space, their wounds healed faster and they required less pain medication than those looking out on a brick wall.

Reid cautioned that correlations between green space and health have been scrutinized, in part because people with higher incomes and, thus, better access to healthy food and health care may also be more able to afford to live near green spaces.

To address that, Reid’s study took sociodemographic factors into account, along with the many unique circumstances that have emerged during COVID.

After controlling for all the factors, the benefits still remained clear: “Spend more time outside,” Rieves said. “Pandemic or no pandemic, it’s good for your mental health.”