Donna Chisholm goes under the wire for science.
Iam wired, not for sound, but for a signal far more subtle – a brain wave from the right frontal cortex that has possibly been triggered deep in my hippocampus. It will appear as a slight oscillation on my EEG tracing; an unconscious response so slight that if I blink my eyes rapidly or grind my teeth, it will be lost in a cacophony of electrical noise.
For internationally noted University of Otago anxiety researcher Professor Neil Mcnaughton, who is monitoring this test at his Dunedin lab, the signal is the culmination of 50 years’ work. This brain wave – his brain wave – will, he believes, become the world’s first biomarker of anxiety.
The result will have nothing to do with how stressed I feel or my ability to “succeed” at the computer test Mcnaughton has designed. “We can do this with lizards if necessary.” This is good news. Lizards are apparently less intelligent than dolphins, orangutans, bears, parrots, donkeys, cats, raccoons and even naked mole rats.
The beauty of Mcnaughton’s rightclick, left- click, stop-go test is that it is providing new insights into the anxious brain – without the owner of the brain knowing any anxietyrelated circuitry is firing up at all.
Anxiety, he says, is not fear, but rather the adaptive reactions that help us to approach danger rather than flee from it. Think of a hungry rat that wants food but must weigh up the risk of the cat sitting next to it. The brain rhythm Mcnaughton has found – first in rats and now in tests on people – controls goal-conflict responses and is reduced by anti-anxiety drugs even if they don’t work for depression, phobia, panic or obsession.
Critically, says Mcnaughton, the biomarker will allow us to define a biological type of anxiety. At present, he says, guidelines for the diagnosis of mental disorders lump together symptoms to define them. “Nobody has ever got a biological definition of any mental disorder – we may have the first one of these.
The key problem at the moment is the way these are diagnosed. You have a group of things that we currently call high temperature spotty disorder. We should be able to end up effectively with a test which allows you to say, okay, this thing here is German measles.”
In EEG recordings from human volunteers, Mcnaughton has been able to accurately identify groups who have been given small doses of anti-anxiety drugs, based only on the levels of this right-frontal brain wave, which reflects the goal- conflict aspect of anxiety.
“My main claim to fame is to have attempted to nail down the idea that the hippocampus, which most people talk about as being to do with controlling memory, is actually a key area controlling anxiety. What I think we are dealing with is a mechanism that essentially can keep defensive, fearful, anxious memories going.
“This adds a parallel anxiety system (moving towards danger/ risk assessment) to the established fear systems (moving away from danger). It sees anxiety and fear as almost opposites of each other, rather than being two words for the same fundamental thing.
“The hippocampus is not only strongly connected to the amygdala but also to lower ( hypothalamus) and higher ( prefrontal cortex) areas involved in fear and anxiety.”
So, to the test. It is, as Mcnaughton promises, so simple as to be almost tedious. Left click on the mouse when a left-facing arrow appears on screen, right click when the right-facing arrow appears. But when a beep sounds, do not click. The speed of the beep is adjusted so that sometimes it will be easy to stop, sometimes almost impossible, or evenly balanced 50-50. It’s those 50-50 calls which generate the anxiety-related response. Tellingly, the signal is unaffected by the annoyance of failure. Which is just as well: expletives punctuate my test.
“You are trying to stop reliably every time there is a stop signal, and a lot of the time you can’t and that’s irritating, but a real advantage of the test is that we aren’t exposing people to a major threat. This task, in terms of its nature and surroundings, is very unthreatening. Then we arrange conflict, which is the key part of my theory.”
My EEG suggests I am not particularly, or overtly, anxious. I am, unremarkably, boringly average, having a similar-sized signal “bump” to Mcnaughton’s “middle of the road” group. “We expect clinical cases to have a much larger positive bump, with a spread to the lower frequencies.”
But what does all this mean for patients? Surely it isn’t viable for every patient to go through a brain scan to be diagnosed with anxiety? While that may be true of the present test, there is the prospect of cheap, clip-on EEG headsets. “By the time we are down this track, there may well be EEG systems that you could hand to your patient and use for neuro-feedback training.”
His research is also being used to better define and target the patients who score most highly on the anxiety brain signals, to then see if he can devise a questionnaire that identifies them as being anxious compared to having other types of mental disorder.
“The problem is different people are being given different drugs and some of the drugs work for different people some of the time, so the clinicians have to keep swapping round. The question is whether they can be given the right ones first off.”
Mcnaughton, who co-authored a seminal work in the field, The Neuropsychology of Anxiety, with renowned Oxford University psychologist Jeffrey Gray (who died in 2004), is recruiting people who identify themselves as being anxious but are not on drugs to treat it, and healthy controls, to take part in the EEG trials, which have the backing of a $1 million Health Research Council grant, in Auckland and Dunedin. Anyone who’s interested can find out more by emailing firstname.lastname@example.org.
The brain response typically associated with anxiety is known as “fight or flight”. This reaction starts in the amygdala – the centre for emotional processing – which sends an SOS to the hypothalamus, the command centre.
One of the troops the hypothalamus dispatches in response to stress and anxiety is the corticotropin-releasing hormone known as CRH. Ultimately, the hormonal cascade through the adrenal and pituitary glands shows up in our blood with increased levels of cortisol. We need these physiological changes to help us cope with the danger, but when the change becomes chronic, or occurs inappropriately, the stage is set for anxiety and stress disorders.
A few streets away from Mcnaughton’s lab, at the University of Otago’s Centre for Neuroendocrinology, Associate Professor Greg Anderson and Dr Karl Iremonger have come to regard CRH neurons as the equivalent of the Prime Minister, and the many and varied processes that act on them
“What I think we are dealing with is a mechanism that essentially can keep defensive, fearful, anxious memories going.”
as the PM’S specialist advisers and Cabinet. Anderson has also identified a key member of the Cabinet with a previously unrecognised but important role – to continue the analogy, a kind of biochemical Minister for Anxiety, known in scientific circles as RFRP neurons.
Anderson stumbled on the idea that RFRP might be affecting stress about five years ago, when he was researching (in rat models) their role in suppressing fertility.
“We were looking at situations where people are known to be infertile – before puberty, postmenopause, generally when lactating, and perhaps when stressed – to see whether this chemical might be ramped up. Some situations didn’t fit our hypothesis. There were times we were expecting to find high levels of this chemical and they were really low. But a much better explanation for the levels we were seeing was that they seemed to reflect whether the animals were anxious or not,” he says.
The RFRP neurons seemed to be “really ramped up” when the animals were stressed. “If the RFRP neurons are chronically elevated, it means the CRH neurons are chronically elevated.”
About five years ago, Anderson’s group developed a chemical, known as GJ14, which stops RFRP acting on its receptor on the CRH neuron. In 2015, they published their research showing how the drug completely reversed the anxiety-promoting effects of RFRP, and changed the behaviour of the mice treated with it. The behavioural tests are relatively simple – mice prefer dark enclosed spaces rather than being exposed in lighted areas and the activities are monitored in a light-
When we’re under stress, physiological changes in our bodies help us cope with the danger, but when the change becomes chronic, or occurs inappropriately, the stage is set for anxiety and stress disorders.
dark box. Mice treated with GJ14 spent significantly more time in the open than mice infused with RFRP.
The discovery has changed Anderson’s research focus, from fertility to anxiety, and his team is now working to find out if the drug can successfully cross the blood-brain barrier (at the moment it’s injected into the brain), which would be essential if it’s to be clinically effective.
Adding to the excitement of the find is that the drug appears to be “wonderfully without adverse side effects” and isn’t on the research radar of any other scientists in the field, internationally.
Another advantage is that it’s highly specific in its target. Earlier in the research, Anderson says they tested another drug that blocked RFRP but also blocked other related receptors, causing unwanted side effects such as potential fertility complications.
“Only one in 1000 research drugs will make it into clinical use; we are realistic about that. We will have to line our drug up against the SSRIS [antidepressants] and benzodiazepines [anti-anxiety drugs] and show ours is better in order to get a drug company excited about developing it further.”
Iremonger says a key goal of the research is to understand how stress neurons function. We already know about the cyclic nature of the reactions in the brain – that stress activates the CRH neurons, which activate the stress hormone levels, which feed back to the brain and regulate how the brain functions. “The problem seems to be that it’s not just a single stress that’s the problem. Most people can cope with those quite well – it’s chronic elevations in the cortisol which change brain activity in a detrimental way.”
He’s also looking at how neural structures within brain cells change after long-term exposure to cortisol. “Other labs around the world have shown quite convincingly that in the emotional circuits, you get quite dramatic changes in structure after long-term exposure to cortisol and to stress.”
Dr Karl Iremonger (left) and Associate Professor Greg Anderson at the University of Otago’s Centre for Neuroendocrinology.
University of Otago anxiety researcher Professor Neil Mcnaughton.
Expletives alert: Donna Chisholm takes the test.