How to tell a missile from a pylon: a tale of two cortices

During the Second World War, analysts pored over stereoscopic aerial reconnaissance photographs, becoming experts at identifying potential targets from camouflaged or visually noisy backgrounds, and then at distinguishing between V-weapons and innocuous electricity pylons.

Now, researchers at the University of Cambridge have identified the two regions of the brain involved in these two tasks – picking out objects from background noise and identifying the specific objects – and have shown why training people to recognise specific objects improves their ability to pick out objects.

In a study funded by the Wellcome Trust, volunteers were given a series of 3D stereoscopic images with varying levels of background noise and asked first to find a target object and then to say whether the object was in the foreground or the background. During the task, researchers applied transcranial magnetic stimulation (TMS) – a technique whereby a magnetic field is applied to the head – to disrupt the performance of two regions of the brain used in object identification: the parietal cortex and the ventral cortex. Their results are published in the journal Current Biology.

The researchers showed that the parietal cortex was involved in selecting potential targets from background noise, while the ventral cortex was involved in object recognition. When TMS was applied to the parietal cortex, volunteers performed less well at selecting objects from the background; when the field was applied to the ventral cortex, they performed less well at identifying the specific objects.

However, the researchers found that after the volunteers had undergone training to discriminate between specific objects, the ventral cortex – which, until then, had only been used for this purpose – also became involved in selecting targets from noise, enhancing their ability to distinguish between objects. The reverse was not true – in other words, the parietal cortex did not become involved in object discrimination.

Dr Welchman, a Wellcome Trust Senior Research Fellow in the Department of Psychology, explains: “The parietal cortex and the ventral cortex appear to be involved in the overlapping tasks to a different extent. By analogy to the World War II analysts, the parietal cortex helped them spot suspect objects while the ventral cortex helped them distinguish the weapons from the pylons. But training these operatives to identify the weapons will have improved their ability to spot potential weapons in the first place.”

The research may have implications for therapies to help people with attentional difficulties. For example, people with damage to the parietal cortex, such as through stroke, are known to have difficulty in finding objects in displays, particularly when the display is distracting.

“These results show that training in clear displays modifies the brain areas that underlie performance in distracting situations. This suggests a route for rehabilitative training that helps individuals avoid distracting information by training individuals to make fine judgements,” he adds.

Selectively Rewiring the Brain’s Circuitry to Treat Depression

On Star Trek, it is easy to take for granted the incredible ability of futuristic doctors to wave small devices over the heads of both humans and aliens, diagnose their problems through evaluating changes in brain activity or chemistry, and then treat behavior problems by selectively stimulating relevant brain circuits.

While that day is a long way off, transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex does treat symptoms of depression in humans by placing a relatively small device on a person’s scalp and stimulating brain circuits. However, relatively little is known about how, exactly, TMS produces these beneficial effects.

Some studies have suggested that TMS may modulate atypical interactions between two large-scale neuronal networks, the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN). These two functional networks play important roles in emotion regulation and cognition.

In order to advance our understanding of the underlying antidepressant mechanisms of TMS, Drs. Conor Liston, Marc Dubin, and their colleagues conducted a longitudinal study to test this hypothesis.

The researchers used functional magnetic resonance imaging in 17 currently depressed patients to measure connectivity in the CEN and DMN networks both before and after a 25-day course of TMS. They also compared the connectivity in the depressed patients with a group of 35 healthy volunteers.

TMS normalized depression-related hyperconnectivity between the subgenual cingulate and medial prefrontal areas of the DMN, but did not alter connectivity in the CEN.

Liston, an Assistant Professor at Weill Cornell Medical College, further details their findings, “We found that connectivity within the DMN and between nodes of the DMN and CEN was elevated in depressed individuals compared to healthy volunteers at baseline and normalized after TMS. Additionally, individuals with greater baseline connectivity with subgenual anterior cingulate cortex – an important target for other antidepressant modalities – were more likely to respond to TMS.”

These findings indicate that TMS may act, in part, by selectively regulating network-level connectivity.

Dr. John Krystal, Editor of Biological Psychiatry, comments, “We are a long way from Star Trek, but even the current ability to link brain stimulation treatments for depression to the activity of particular brain circuits strikes me as incredible progress.”

Dubin, also an Assistant Professor at Weill Cornell Medical College, adds, “Our findings may inform future efforts to develop personalized strategies for treating depression with TMS based on the connectivity of an individual’s default mode network. Further, they may help triage to TMS only those patients most likely to respond.”

Visualising plastic changes to the brain

Painless therapy

Transcranial magnetic stimulation (TMS) is a painless, non-invasive stimulation method, where an electromagnetic coil held above the head is used to generate a strong magnetic field. This method is deployed to activate or inhibit specific brain regions. Even though the number of its medical applications is constantly on the increase, TMS’ precise neuronal mechanisms of action are not, as yet, very well understood. That is because imaging used for humans, such as fMRI (functional magnetic resonance imaging), do not possess the temporal resolution necessary for recording neural activities in milliseconds. More rapid measurement methods, such as EEG or MEG, on the other hand, are affected by the induced magnetic field, with the results that strong interferences are generated that cover important information regarding immediate TMS-based changes to brain activities.

Observing effect on neurons in real time

High-res images of TMS effects have now for the first time been successfully generated by RUB researchers in animal testing. The work group headed by PD Dr Dirk Jancke, Institut für Neuroinformatik, utilises voltage-sensitive dyes which, anchored in cell membranes, send out fluorescent light signals once neurons get activated or inhibited. By using light, the researchers avoided the problem of measurement of artefacts occurring due to magnetic fields. “We can now demonstrate in real time how one single TMS pulse suppresses brain activity across a considerable region, most likely through mass activation of inhibiting brain cells,” says Dr Jancke. With higher TMS frequencies, each additional TMS pulse generates an incremental increase in brain activity. “This results in a higher cortical activation state, which opens up a time window for plastic changes,” explains Dr Vladislav Kozyrev, the first author of the study.

Chances for patients

The increased neuronal excitability may be utilised to effect specific reorganisation of cell connections by means of targeted learning processes. For example, through visual training after TMS, the ability to identify image contours improves; moreover, a combination of these methods enhances contrast perception in patients with amblyopia - a disorder of sight acquired during child development. For many neurological diseases of the brain, such as epilepsy, depression and stroke, specific models have been developed. “Deployed in animal testing, our technology has delivered high spatiotemporal resolution imaging data of cortical activity changes,” says Dirk Jancke. “We are hoping that these data will enable us to optimise TMS parameters and learning processes in a targeted manner, which are going to be used in future to adapt this technology for medical treatment of humans.”

Electric Current to Brain Boosts Memory

Stimulating a particular region in the brain via non-invasive delivery of electrical current using magnetic pulses, called Transcranial Magnetic Stimulation, improves memory, reports a new Northwestern Medicine® study.

The discovery opens a new field of possibilities for treating memory impairments caused by conditions such as stroke, early-stage Alzheimer’s disease, traumatic brain injury, cardiac arrest and the memory problems that occur in healthy aging.

“We show for the first time that you can specifically change memory functions of the brain in adults without surgery or drugs, which have not proven effective,” said senior author Joel Voss, assistant professor of medical social sciences at Northwestern University Feinberg School of Medicine. “This noninvasive stimulation improves the ability to learn new things. It has tremendous potential for treating memory disorders.”

The study was published August 29 in Science.

The study also is the first to demonstrate that remembering events requires a collection of many brain regions to work in concert with a key memory structure called the hippocampus – similar to a symphony orchestra. The electrical stimulation is like giving the brain regions a more talented conductor so they play in closer synchrony. 

“It’s like we replaced their normal conductor with Muti,” Voss said, referring to Riccardo Muti, the music director of the renowned Chicago Symphony Orchestra. “The brain regions played together better after the stimulation.”

The approach also has potential for treating mental disorders such as schizophrenia in which these brain regions and the hippocampus are out of sync with each other, affecting memory and cognition.    

TMS Boosts Memory 

The Northwestern study is the first to show TMS improves memory long after treatment. In the past, TMS has been used in a limited way to temporarily change brain function to improve performance during a test, for example, making someone push a button slightly faster while the brain is being stimulated. The study shows that TMS can be used to improve memory for events at least 24 hours after the stimulation is given.

Finding the Sweet Spot

It isn’t possible to directly stimulate the hippocampus with TMS because it’s too deep in the brain for the magnetic fields to penetrate. So, using an MRI scan, Voss and colleagues identified a superficial brain region a mere centimeter from the surface of the skull with high connectivity to the hippocampus. He wanted to see if directing the stimulation to this spot would in turn stimulate the hippocampus. It did.

“I was astonished to see that it worked so specifically,” Voss said.

When TMS was used to stimulate this spot, regions in the brain involved with the hippocampus became more synchronized with each other, as indicated by data taken while subjects were inside an MRI machine, which records the blood flow in the brain as an indirect measure of neuronal activity.

The more those regions worked together due to the stimulation, the better people were able to learn new information.

How the Study Worked

Scientists recruited 16 healthy adults ages 21 to 40. Each had a detailed anatomical image taken of his or her brain as well as 10 minutes of recording brain activity while lying quietly inside an MRI scanner. Doing this allowed the researchers to identify each person’s network of brain structures that are involved in memory and well connected to the hippocampus. The structures are slightly different in each person and may vary in location by as much as a few centimeters.

“To properly target the stimulation, we had to identify the structures in each person’s brain space because everyone’s brain is different,” Voss said. 

Each participant then underwent a memory test, consisting of a set of arbitrary associations between faces and words that they were asked to learn and remember. After establishing their baseline ability to perform on this memory task, participants received brain stimulation 20 minutes a day for five consecutive days. 

During the week they also received additional MRI scans and tests of their ability to remember new sets of arbitrary word and face parings to see how their memory changed as a result of the stimulation. Then, at least 24 hours after the final stimulation, they were tested again.

At least one week later, the same experiment was repeated but with a fake placebo stimulation. The order of real stimulation and placebo portions of the study was reversed for half of the participants, and they weren’t told which was which.

Both groups performed better on memory tests as a result of the brain stimulation. It took three days of stimulation before they improved.

“They remembered more face-word pairings after the stimulation than before, which means their learning ability improved,” Voss said. “That didn’t happen for the placebo condition or in another control experiment with additional subjects.”

In addition, the MRI showed the stimulation caused the brain regions to become more synchronized with each other and the hippocampus. The greater the improvement in the synchronicity or connectivity between specific parts of the network, the better the performance on the memory test. “The more certain brain regions worked together because of the stimulation, the more people were able to learn face-word pairings, “ Voss said.

Using TMS to stimulate memory has multiple advantages, noted first author Jane Wang, a postdoctoral fellow in Voss’s lab at Feinberg. “No medication could be as specific as TMS for these memory networks,” Wang said. “There are a lot of different targets and it’s not easy to come up with any one receptor that’s involved in memory.”

The Future 

“This opens up a whole new area for treatment studies where we will try to see if we can improve function in people who really need it,“ Voss said.

His current study was with people who had normal memory, in whom he wouldn’t expect to see a big improvement because their brains are already working effectively.

“But for a person with brain damage or a memory disorder, those networks are disrupted so even a small change could translate into gains in their function,” Voss said.

In an upcoming trial, Voss will study the electrical stimulation’s effect on people with early-stage memory loss.

Voss cautioned that years of research are needed to determine whether this approach is safe or effective for patients with Alzheimer’s disease or similar disorders of memory.

A weighty discovery

Humans have developed sophisticated concepts like mass and gravity to explain a wide range of everyday phenomena, but scientists have remarkably little understanding of how such concepts are represented by the brain.

Using advanced neuroimaging techniques, Queen’s University researchers have revealed how the brain stores knowledge about an object’s weight – information critical to our ability to successfully grasp and interact with objects in our environment.

Jason Gallivan, a Banting postdoctoral fellow in the Department of Psychology, and Randy Flanagan, a professor in the Department of Psychology, used functional magnetic resonance imaging (fMRI) to uncover what regions of the human brain represent an object’s weight prior to lifting that object. They found that knowledge of object weight is stored in ventral visual cortex, a brain region previously thought to only represent those properties of an object that can be directly viewed such as its size, shape, location and texture.

“We are working on various projects to determine how the brain produces actions on the world,” explains Dr. Gallivan about the work he is undertaking at the Centre for Neuroscience Studies at Queen’s. “Simply looking at an object doesn’t provide the brain with information about how much that object weighs. Take for example a suitcase. There is often nothing about its visual appearance that informs you of whether it is packed with clothes or empty. Rather, this is information that must be derived through recent interactions with that object and stored in the brain so as to guide our movements the next time we must lift and interact with that object.”

According to previous research, the ventral visual cortex supports visual processing for perception and object recognition whereas the dorsal visual cortex supports visual processing for the control of action. However, this division of labour had only been tested for visually guided actions like reaching, which are directed towards objects, and not for actions involving the manipulation of objects, which requires access to stored knowledge about object properties.

“Because information about object weight is primarily important for the control of action, we thought that this information might only be stored in motor-related areas of the brain,” says Dr. Gallivan. “Surprisingly, however, we found that this non-visual information was also stored in ventral visual cortex. Presumably this allows for the weight of an object to become easily associated with its visual properties.”

In ongoing research, Drs. Gallivan and Flanagan are using transcranial magnetic stimulation (TMS) to temporarily disrupt targeted brain areas in order to assess their contribution to skilled object manipulation. By identifying which areas of the brain control certain motor skills, Drs. Gallivan and Flanagan’s research will be helpful in assessing patients with neurological impairments including stroke.

The work was funded by the Canadian Institutes of Health Research (CIHR). The research was recently published in Current Biology.

(Image caption: The light grey coil on the left is a conventional, commercially available TMS coil. The black coil on the right is the new, innovative version designed to fit a smaller non-human primate’s cranium and work with the neural monitoring device. Credit: Photo courtesy of Warren Grill.)

Watching Individual Neurons Respond to Magnetic Therapy

Engineers and neuroscientists at Duke University have developed a method to measure the response of an individual neuron to transcranial magnetic stimulation (TMS) of the brain. The advance will help researchers understand the underlying physiological effects of TMS — a procedure used to treat psychiatric disorders — and optimize its use as a therapeutic treatment.

TMS uses magnetic fields created by electric currents running through a wire coil to induce neural activity in the brain. With the flip of a switch, researchers can cause a hand to move or influence behavior. The technique has long been used in conjunction with other treatments in the hopes of improving treatment for conditions including depression and substance abuse.

While studies have demonstrated the efficacy of TMS, the technique’s physiological mechanisms have long been lost in a “black box.” Researchers know what goes into the treatment and the results that come out, but do not understand what’s happening in between.

Part of the reason for this mystery lies in the difficulty of measuring neural responses during the procedure; the comparatively tiny activity of a single neuron is lost in the tidal wave of current being generated by TMS. But the new study demonstrates a way to remove the proverbial haystack.

The results were published online June 29 in Nature Neuroscience.

“Nobody really knows what TMS is doing inside the brain, and given that lack of information, it has been very hard to interpret the outcomes of studies or to make therapies more effective,” said Warren Grill, professor of biomedical engineering, electrical and computer engineering, and neurobiology at Duke. “We set out to try to understand what’s happening inside that black box by recording activity from single neurons during the delivery of TMS in a non-human primate. Conceptually, it was a very simple goal. But technically, it turned out to be very challenging.”

First, Grill and his colleagues in the Duke Institute for Brain Sciences (DIBS) engineered new hardware that could separate the TMS current from the neural response, which is thousands of times smaller. Once that was achieved, however, they discovered that their recording instrument was doing more than simply recording.

The TMS magnetic field was creating an electric current through the electrode measuring the neuron, raising the possibility that this current, instead of the TMS, was causing the neural response. The team had to characterize this current and make it small enough to ignore.

Finally, the researchers had to account for vibrations caused by the large current passing through the TMS device’s small coil of wire — a design problem in and of itself, because the typical TMS coil is too large for a non-human primate’s head. Because the coil is physically connected to the skull, the vibration was jostling the measurement electrode.

The researchers were able to compensate for each artifact, however, and see for the first time into the black box of TMS. They successfully recorded the action potentials of an individual neuron moments after TMS pulses and observed changes in its activity that significantly differed from activity following placebo treatments.

Grill worked with Angel Peterchev, assistant professor in psychiatry and behavioral science, biomedical engineering, and electrical and computer engineering, on the design of the coil. The team also included Michael Platt, director of DIBS and professor of neurobiology, and Mark Sommer, a professor of biomedical engineering.

They demonstrated that the technique could be recreated in different labs. “So, any modern lab working with non-human primates and electrophysiology can use this same approach in their studies,” said Grill.

The researchers hope that many others will take their method and use it to reveal the effects TMS has on neurons. Once a basic understanding is gained of how TMS interacts with neurons on an individual scale, its effects could be amplified and the therapeutic benefits of TMS increased.

“Studies with TMS have all been empirical,” said Grill. “You could look at the effects and change the coil, frequency, duration or many other variables. Now we can begin to understand the physiological effects of TMS and carefully craft protocols rather than relying on trial and error. I think that is where the real power of this research is going to come from.”