Category: Cognitive Science/Neuroscience

Near-infrared (NIR) light can easily pass through brain tissue with minimal scattering, allowing it to reach deep structures. There, up-conversion nanoparticles (UCNPs; blue) previously inserted in the tissue can absorb this light to generate shorter-wavelength blue-green light that can activate nearby neurons. (credit: RIKEN)

An international team of researchers has developed a way to shine light at new depths in the brain. It may lead to development of new, non-invasive clinical treatments for neurological disorders and new research tools.

The new method extends the depth that optogenetics — a method for stimulating neurons with light — can reach. With optogenetics, blue-green light is used to turn on “light-gated ion channels” in neurons to stimulate neural activity. But blue-green light is heavily scattered by tissue. That limits how deep the light can reach and currently requires insertion of invasive optical fibers.

The researchers took a new approach to brain stimulation, as they reported in Science on February 9.

1. They used longer-wavelength (650 to 1350nm) near-infrared (NIR) light, which can penetrate deeper into the brain (via the skull) of mice.
2. The NIR light illuminated “upconversion nanoparticles” (UCNPs), which absorbed the near-infrared laser light and glowed blue-green in formerly inaccessible (deep) targeted neural areas.*
3. The blue-green light then triggered (via chromophores, light-responsive molecules) ion channels in the neurons to turn on memory cells in the hippocampus and other areas. These included the medial septum, where nanoparticle-emitted light contributed to synchronizing neurons in a brain wave called the theta cycle.**

Non-invasive activation of neurons in the VTA, a reward center of the mouse brain. The blue-light sensitive ChR2 chromophores (green) were expressed (from an injection) on both sides of the VTA. But upconversion nanoparticles (blue) were only injected on the right. So when near-IR light was applied to both sides, it only activated the expression of the activity-induced chromophore cFos gene (red) on the side with the nanoparticles. (credit: RIKEN)

This study was a collaboration between scientists at the RIKEN Brain Science Institute, the National University of Singapore, the University of Tokyo, Johns Hopkins University, and Keio University.

Non-invasive light therapy

“Nanoparticles effectively extend the reach of our lasers, enabling ‘remote’ delivery of light and potentially leading to non-invasive therapies,” says Thomas McHugh, research group leader at the RIKEN Brain Science Institute in Japan. In addition to activating neurons, UCNPs can also be used for inhibition. In this study, UCNPs were able to quell experimental seizures in mice by emitting yellow light to silence hyperexcitable neurons.

Schematic showing near-infrared radiation (NIR) being absorbed by upconversion nanoparticles (UCNPs) and re-radiated as shorter-wavelength (peaking at 450 and 475 nm) blue light that triggers a previously injected chromophore (a light emitting molecule expressed by neurons) — in this case, channelrhodopsin-2 (ChR2). In one experiment, the chromophore triggered a calcium ion channel in neurons in the ventral tegmental area (VTA) of the mouse brain (a region located ~4.2 mm below the skull), causing stimulation of neurons. (credit: Shuo Chen et al./Science)

While current deep brain stimulation is effective in alleviating specific neurological symptoms, it lacks cell-type specificity and requires permanently implanted electrodes, the researchers note.

The nanoparticles described in this study are compatible with the various light-activated channels currently in use in the optogenetics field and can be employed for neural activation or inhibition in many deep brain structures. “The nanoparticles appear to be quite stable and biocompatible, making them viable for long-term use. Plus, the low dispersion means we can target neurons very specifically,” says McHugh.

However, “a number of challenges must be overcome before this technique can be used in patients,” say Neus Feliu et al. in “Toward an optically controlled brain, Science  09 Feb 2018. “Specifically, neurons have to be transfected with light-gated ion channels … a substantial challenge [and] … placed close to the target neurons. … Neuronal networks undergo continuous changes [so] the stimulation pattern and placement of [nanoparticles] may have to be adjusted over time. … Potent upconverting NPs are also needed … [which] may change properties over time, such as structural degradation and loss of functional properties. … Long-term toxicity studies also need to be carried out.”

* “The lanthanide-doped up-conversion nanoparticles (UCNPs) were capable of converting low-energy incident NIR photons into high-energy visible emission with an efficiency orders of magnitude greater than that of multiphoton processes. … The core-shell UCNPs exhibited a characteristic up-conversion emission spectrum peaking at 450 and 475 nm upon excitation at 980 nm. Upon transcranial delivery of 980-nm CW laser pulses at a peak power of 2.0 W (25-ms pulses at 20 Hz over 1 s), an upconverted emission with a power density of ~0.063 mW/mm2 was detected. The conversion yield of NIR to blue light was ~2.5%. NIR pulses delivered across a wide range of laser energies to living tissue result in little photochemical or thermal damage.” — Shuo Chen et al./Science

** “Memory recall in mice also persisted in tests two weeks later. This indicates that the UCNPs remained at the injection site, which was confirmed through microscopy of the brains.” — Shuo Chen et al./Science

Abstract of Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics

Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

MIT’s miniaturized system can deliver multiple drugs to precise locations in the brain, also monitor and control neural activity (credit: MIT)

MIT researchers have developed a miniaturized system that can deliver tiny quantities of medicine to targeted brain regions as small as 1 cubic millimeter, with precise control over how much drug is given. The goal is to treat diseases that affect specific brain circuits without interfering with the normal functions of the rest of the brain.*

“We believe this tiny microfabricated device could have tremendous impact in understanding brain diseases, as well as providing new ways of delivering biopharmaceuticals and performing biosensing in the brain,” says Robert Langer, the David H. Koch Institute Professor at MIT and one of the senior authors of an open-access paper that appears in the Jan. 24 issue of Science Translational Medicine.**

Miniaturized neural drug delivery system (MiNDS). Top: Miniaturized delivery needle with multiple fluidic channels for delivering different drugs. Bottom: scanning electron microscope image of cannula tip for delivering a drug or optogenetic light (to stimulate neurons) and a tungsten electrode (yellow dotted area — magnified view in inset) for detecting neural activity. (credit: Dagdeviren et al., Sci. Transl. Med., adapted by KurzweilAI)

The researchers used state-of-the-art microfabrication techniques to construct cannulas (thin tubes) with diameters of about 30 micrometers (width of a fine human hair) and lengths up to 10 centimeters. These cannulas are contained within a stainless steel needle with a diameter of about 150 micrometers. Inside the cannulas are small pumps that can deliver tiny doses (hundreds of nanoliters***) deep into the brains of rats — with very precise control over how much drug is given and where it goes.

In one experiment, they delivered a drug called muscimol to a rat brain region called the substantia nigra, which is located deep within the brain and helps to control movement. Previous studies have shown that muscimol induces symptoms similar to those seen in Parkinson’s disease. The researchers were able to stimulate the rats to continually turn in a clockwise direction. They also could also halt the Parkinsonian behavior by delivering a dose of saline through a different channel to wash the drug away.

“Since the device can be customizable, in the future we can have different channels for different chemicals, or for light, to target tumors or neurological disorders such as Parkinson’s disease or Alzheimer’s,” says Canan Dagdeviren, the LG Electronics Career Development Assistant Professor of Media Arts and Sciences and the lead author of the paper.

This device could also make it easier to deliver potential new treatments for behavioral neurological disorders such as addiction or obsessive compulsive disorder. (These may be caused by specific disruptions in how different parts of the brain communicate with each other.)

Measuring drug response

The researchers also showed that they could incorporate an electrode into the tip of the cannula, which can be used to monitor how neurons’ electrical activity changes after drug treatment. They are now working on adapting the device so it can also be used to measure chemical or mechanical changes that occur in the brain following drug treatment.

The cannulas can be fabricated in nearly any length or thickness, making it possible to adapt them for use in brains of different sizes, including the human brain, the researchers say.

“This study provides proof-of-concept experiments, in large animal models, that a small, miniaturized device can be safely implanted in the brain and provide miniaturized control of the electrical activity and function of single neurons or small groups of neurons. The impact of this could be significant in focal diseases of the brain, such as Parkinson’s disease,” says Antonio Chiocca, neurosurgeon-in-chief and chairman of the Department of Neurosurgery at Brigham and Women’s Hospital, who was not involved in the research.

The research was funded by the National Institutes of Health and the National Institute of Biomedical Imaging and Bioengineering.

* To treat brain disorders, drugs (such as l-dopa, a dopamine precursor used to treat Parkinson’s disease, and Prozac, used to boost serotonin levels in patients with depression) often interact with brain chemicals called neurotransmitters (or the cell receptors interact with neurotransmitters) — creating side effects throughout the brain.

** Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, is also a senior author of the paper.

*** It would take one billion nanoliter drops to fill 4 cups.

Abstract of Miniaturized neural system for chronic, local intracerebral drug delivery

Recent advances in medications for neurodegenerative disorders are expanding opportunities for improving the debilitating symptoms suffered by patients. Existing pharmacologic treatments, however, often rely on systemic drug administration, which result in broad drug distribution and consequent increased risk for toxicity. Given that many key neural circuitries have sub–cubic millimeter volumes and cell-specific characteristics, small-volume drug administration into affected brain areas with minimal diffusion and leakage is essential. We report the development of an implantable, remotely controllable, miniaturized neural drug delivery system permitting dynamic adjustment of therapy with pinpoint spatial accuracy. We demonstrate that this device can chemically modulate local neuronal activity in small (rodent) and large (nonhuman primate) animal models, while simultaneously allowing the recording of neural activity to enable feedback control.

Repeating a word: as the brain receives (yellow), interpretes (red), and responds (blue) within a second, the prefrontal cortex (red) coordinates all areas of the brain involved. (video credit: Avgusta Shestyuk/UC Berkeley).

Recording the electrical activity of neurons directly from the surface of the brain, using electrocorticograhy (ECoG)*, neuroscientists were able to track the flow of thought across the brain in real time for the first time. They showed clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response to a perception.

Here’s what they found.

For a simple task, such as repeating a word seen or heard:

The visual and auditory cortices react first to perceive the word. The prefrontal cortex then kicks in to interpret the meaning, followed by activation of the motor cortex (preparing for a response). During the half-second between stimulus and response, the prefrontal cortex remains active to coordinate all the other brain areas.

For a particularly hard task, like determining the antonym of a word:

During the time the brain takes several seconds to respond, the prefrontal cortex recruits other areas of the brain — probably including memory networks (not tracked). The prefrontal cortex then hands off to the motor cortex to generate a spoken response.

In both cases, the brain begins to prepare the motor areas to respond very early (during initial stimulus presentation) — suggesting that we get ready to respond even before we know what the response will be.

“This might explain why people sometimes say things before they think,” said Avgusta Shestyuk, a senior researcher in UC Berkeley’s Helen Wills Neuroscience Institute and lead author of a paper reporting the results in the current issue of Nature Human Behavior.

For a more difficult task, like saying a word that is the opposite of another word, people’s brains required 2–3 seconds to detect (yellow), interpret and search for an answer (red), and respond (blue) — with sustained prefrontal lobe activity (red) coordinating all areas of the brain involved. (video credit: Avgusta Shestyuk/UC Berkeley).

The research backs up what neuroscientists have pieced together over the past decades from studies in monkeys and humans.

“These very selective studies have found that the frontal cortex is the orchestrator, linking things together for a final output,” said co-author Robert Knight, a UC Berkeley professor of psychology and neuroscience and a professor of neurology and neurosurgery at UCSF. “Here we have eight different experiments, some where the patients have to talk and others where they have to push a button, where some are visual and others auditory, and all found a universal signature of activity centered in the prefrontal lobe that links perception and action. It’s the glue of cognition.”

Researchers at Johns Hopkins University, California Pacific Medical Center, and Stanford University were also involved. The work was supported by the National Science Foundation, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke.

* Other neuroscientists have used functional magnetic resonance imaging (fMRI) and electroencephelography (EEG) to record activity in the thinking brain. The UC Berkeley scientists instead employed a much more precise technique, electrocorticograhy (ECoG), which records from several hundred electrodes placed on the brain surface and detects activity in the thin outer region, the cortex, where thinking occurs. ECoG provides better time resolution than fMRI and better spatial resolution than EEG, but requires access to epilepsy patients undergoing highly invasive surgery involving opening the skull to pinpoint the location of seizures. The new study employed 16 epilepsy patients who agreed to participate in experiments while undergoing epilepsy surgery at UC San Francisco and California Pacific Medical Center in San Francisco, Stanford University in Palo Alto and Johns Hopkins University in Baltimore. Once the electrodes were placed on the brains of each patient, the researchers conducted a series of eight tasks that included visual and auditory stimuli. The tasks ranged from simple, such as repeating a word or identifying the gender of a face or a voice, to complex, such as determining a facial emotion, uttering the antonym of a word, or assessing whether an adjective describes the patient’s personality.

Abstract of Persistent neuronal activity in human prefrontal cortex links perception and action

How do humans flexibly respond to changing environmental demands on a subsecond temporal scale? Extensive research has highlighted the key role of the prefrontal cortex in flexible decision-making and adaptive behaviour, yet the core mechanisms that translate sensory information into behaviour remain undefined. Using direct human cortical recordings, we investigated the temporal and spatial evolution of neuronal activity (indexed by the broadband gamma signal) in 16 participants while they performed a broad range of self-paced cognitive tasks. Here we describe a robust domain- and modality-independent pattern of persistent stimulus-to-response neural activation that encodes stimulus features and predicts motor output on a trial-by-trial basis with near-perfect accuracy. Observed across a distributed network of brain areas, this persistent neural activation is centred in the prefrontal cortex and is required for successful response implementation, providing a functional substrate for domain-general transformation of perception into action, critical for flexible behaviour.

(credit: Nintendo)

For seniors, playing 3D-platform games like Super Mario 64 or taking piano lessons can stave off mild cognitive impairment and perhaps even prevent Alzheimer’s disease, according to a new study by Université de Montréal psychology professors.

In the studies, 33 people ages 55 to 75 were instructed to play Super Mario 64 for 30 minutes a day, five days a week for a period of six months, or take piano lessons (for the first time in their life) with the same frequency and in the same sequence. A control group did not perform any particular task.

The researchers evaluated the effects of the experiment with cognitive performance tests and magnetic resonance imaging (MRI) to measure variations in the volume of gray matter.

Increased gray matter in the left and right hippocampus and the left cerebellum after older adults completed six months of video-game training. (credit: Greg L. West et al./PLoS One)

• The participants in the video-game cohort saw increases in gray matter volume in the cerebellum (plays a major role in motor control and balance) and the hippocampus (associated with spatial and episodic memory, a key factor in long-term cognitive health); and their short-term memory improved. (The hippocampus gray matter acts as a marker for neurological disorders that can occur over time, including mild cognitive impairment and Alzheimer’s.)
• There were gray-matter increases in the dorsolateral prefrontal cortex (controls planning, decision-making, and inhibition) and cerebellum of the participants who took piano lessons.
• Some degree of atrophy was noted in all three areas of the brain among those in the passive control group.

“These findings can also be used to drive future research on Alzheimer’s, since there is a link between the volume of the hippocampus and the risk of developing the disease,” said Gregory West, an associate professor at the Université de Montréal and lead author of an open-access paper in PLoS One journal.

“3-D video games engage the hippocampus into creating a cognitive map, or a mental representation, of the virtual environment that the brain is exploring,” said West. “Several studies suggest stimulation of the hippocampus increases both functional activity and gray matter within this region.”

However, “It remains to be seen whether it is specifically brain activity associated with spatial memory that affects plasticity, or whether it’s simply a matter of learning something new.”

Researchers at the Memorial University in Newfoundland, and Montreal’s Douglas Hospital Research Centre were also involved in the study.

In two previous studies by the researchers in 2014 and 2017, young adults in their twenties were asked to play 3D video games of logic and puzzles on platforms like Super Mario 64. Findings showed that the gray matter in their hippocampus also increased after training.

Abstract of Playing Super Mario 64 increases hippocampal grey matter in older adults

Maintaining grey matter within the hippocampus is important for healthy cognition. Playing 3D-platform video games has previously been shown to promote grey matter in the hippocampus in younger adults. In the current study, we tested the impact of 3D-platform video game training (i.e., Super Mario 64) on grey matter in the hippocampus, cerebellum, and the dorsolateral prefrontal cortex (DLPFC) of older adults. Older adults who were 55 to 75 years of age were randomized into three groups. The video game experimental group (VID; n = 8) engaged in a 3D-platform video game training over a period of 6 months. Additionally, an active control group took a series of self-directed, computerized music (piano) lessons (MUS; n = 12), while a no-contact control group did not engage in any intervention (CON; n = 13). After training, a within-subject increase in grey matter within the hippocampus was significant only in the VID training group, replicating results observed in younger adults. Active control MUS training did, however, lead to a within-subject increase in the DLPFC, while both the VID and MUS training produced growth in the cerebellum. In contrast, the CON group displayed significant grey matter loss in the hippocampus, cerebellum and the DLPFC.