COLIN McManus still cannot stand the sound of sirens. The former police officer was stabbed while on duty one September afternoon in 1992. His attacker punctured his left lung, seized his radio and left him for dead in an alley. He survived and his physical wounds healed. But his mental scars were largely ignored. Back at work, his behaviour swung between recklessness and terror. Then one day, in jest, a colleague flicked out a car key and held it to McManus’s throat. Something snapped. “I ended up with the barrel of my gun pointed at his chest,” says McManus.
He did not fire, but McManus’s own behaviour scared him enough to make him seek treatment. He was suffering from post-traumatic stress disorder (PTSD), a condition that affects millions who have survived a life-threatening incident or witnessed violence. PTSD is a well-known condition, but less well known is the fact that PTSD is just one of a group of mental illnesses called anxiety disorders, characterised by paralysing terror that seriously hampers people’s lives (see “The anxiety disorders”).
Anxiety disorders are astonishingly common. In countries where researchers have made estimates, ranging from the US to Brazil to Turkey, their prevalence outstrips all other mental illnesses. In the US and Britain, about one in seven adults is affected in any given year (see Graphic), while as many as a quarter of us suffer sometime in our lives.
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Yet few such common illnesses are so neglected or trivialised. Although “shell shock” – an early name for PTSD – was recognised after the first world war, most forms of anxiety disorder were not medically acknowledged until the 1980s, and those who were affected were often just told to pull themselves together. Even today, many sufferers do not receive treatment. In one US study carried out in the 1990s, fewer than 40 per cent of sufferers had received professional help, often because they did not seek it.
At last, however, this ignorance and neglect is giving way to new insights as researchers begin to uncover the molecular and cellular bases for anxiety disorders. Research is identifying predisposing factors, including evidence that certain genes are involved. And, crucially, clinicians are finding that an anxiety disorder need not be a life sentence (see “The treatment jungle”).
At the heart of this new understanding is the normal emotion we call fear. Fear has an obvious biological function: it helps animals and people avoid danger. But in people with anxiety disorders the fear response somehow goes awry, escalating into a paralysing anxiety that grips them in inappropriate situations – in lifts, on escalators, at train stations, or when speaking in public, for example.
Researchers are also starting to understand how this happens. It turns out the brain stores its memories of fearful experiences in a near-indelible format that differs substantially from ordinary memory. In vulnerable people, it seems these fear memories can short-circuit rational thought and block normal behaviour.
“This is an exciting time,” says Luke Johnson, a neurobiologist at the Center for the Neuroscience of Fear and Anxiety at New York University. For the first time, he argues, researchers from animal laboratories and human clinics are pooling their results and finding common ground. “The work is really coming together.”
The first step to understanding anxiety disorders is to discover how the brain normally learns to fear. Some fears are instinctive – sudden loud noises, for example – but much of what we recognise as fear is learned: knives are sharp, dogs bite. By mapping the circuitry and biochemistry of this learned fear, researchers are beginning to find out what is different in people with anxiety disorders.
Ever since Pavlov experimented with his dogs, researchers have known that animals can be taught to associate a stimulus such as the ringing of a bell with an event such as feeding time. They can also be taught to associate a stimulus with a nasty event, such as an electric shock. People learn to fear certain stimuli in much the same way: the sound of a dentist’s drill, the smell of hospital disinfectant.
In the best-known experiments on so-called fear conditioning, rats learn to fear a harmless sound if it is always accompanied by an electric shock to their footpads. Psychologists call the sound the conditioned stimulus and the shock the unconditioned stimulus. The rat’s brain links the two, and soon enough the sound alone triggers fear. The animals respond with recognised fight-or-flight behaviour: they freeze and their blood pressure rises. In humans, learned fear induces feelings anyone would recognise – sweaty palms, a lurch in the stomach and prickling skin.
The link between the scary stimulus and this literal gut reaction is laid down as a special, primal kind of memory that neurobiologists called emotional memory. It is quite separate from the explicit or rational memory that also forms after the fearful experience – the sort of memory that can be described in words and set in place and time. Crucially, in both animals and humans, emotional memory is relatively indelible, whereas the explicit memory can be changed easily.
It now appears that, in at least some people with anxiety disorders, emotional memory seems to dominate explicit memory more than in healthy people. For McManus, a distant siren or the sight of a carving knife triggered an emotional memory that caused paralysing feelings of terror, even though his rational brain could tell him a thousand times that neither meant he was in mortal danger.
The study of emotional memory and its role in anxiety disorders began in the 1980s with the work of neurobiologist Joseph LeDoux, who now directs the Center for the Neuroscience of Fear and Anxiety. He wanted to find out exactly which regions of the brain were involved in learned fear. His experiments led him to a small structure in the forebrain called the amygdala. Today, the amygdala is one of the hottest research topics in neuroscience. “Every second person in the field wants to study it,” says Johnson.
LeDoux’s work showed that the amygdala is the place where the link between the unconditioned stimulus and the conditioned stimulus is formed, and where emotional memory is centred. When a rat hears the sound and receives a shock, nerve cells in the amygdala fire rapidly and frequently and synaptic connections there are permanently strengthened. Once laid down, these memories usually last a lifetime. The explicit memory of the fear is laid down separately, via the cortex and principally in the hippocampus.
LeDoux tracked the route that the conditioned stimulus takes to reach the amygdala. He found that, when a rat hears the feared tone, a signal travels via the auditory nerve to the thalamus, a clearing house for sensory and motor stimuli. The signal then continues via two routes, dubbed the high road and the low road. The high road takes the signal to the cortex, the part of the brain associated with conscious reasoning, and then to the amygdala. The low road takes the signal directly to the amygdala. The low road conveys less detailed information, but it gets there about twice as fast. If you are trying to avoid a predator, the difference can save your life.
Once the amygdala is alerted, the response kicks in immediately. Signals travel from the amygdala to the brainstem, the primitive part of the brain that controls involuntary fear. This triggers a “quick-and-dirty” fear response that starts before the cortex can plan more considered action. The physical responses that we associate with fear are triggered by low-road signals.
The intriguing question is why some people’s fear response seems to kick in too readily and too intensely. Why is it that some people respond to harmless stimuli as though they were real threats, and end up panicking on trains or in meetings? Why do some people exposed to trauma develop PTSD when others do not? The suspicion is growing that malfunctions of the amygdala may be part of the explanation. There is also some evidence from animals that different bits of the amygdala might be faulty in different forms of anxiety.
A healthy amygdala seems to be good at filtering out unthreatening stimuli, says Gregory Quirk at Ponce School of Medicine in Puerto Rico. Without this filtering, he suggests, animals and people would respond to all kinds of inappropriate fear cues such as moderate noises or, say, a dog on a leash. Quirk and other researchers argue that in some people the amygdala does not filter enough but, rather like a leaky valve, lets too much information in. In these individuals, even mildly scary stimuli can be terrifying, and paralysing emotional memories of fearful events may persist and overwhelm rational thought (Annals of the New York Academy of Sciences, vol 985, p 263). Once primed by one or more frightening experiences, a person with a leaky amygdala may become “hypervigilant”, perceiving many innocuous stimuli as frightening. At this point they are suffering from an anxiety disorder.
Here’s how it happens. Normally, the circuits that hard-wire emotional memories in the amygdala are held in check by relatively generous amounts of the neurotransmitter GABA. This is known as an inhibitory neurotransmitter: it allows negatively charged ions to enter each nerve cell, so that the nerve needs a stronger signal to make it fire.
It seems that the inhibitory effect of GABA is what enables the amygdala to filter out unthreatening stimuli. If GABA activity in the amygdala is blocked in rats, the animals get twitchy. In 1995 Anantha Shekhar, now at Indiana University School of Medicine in Indianapolis, injected a substance called bicuculline, which blocks GABA receptors, directly into rats’ amygdalas. The more bicuculline they received, the more the rats avoided social interaction, their heart rates increased and their blood pressure went up.
Then, last year, another team of researchers led by Nobel prizewinner Eric Kandel at Columbia University, New York, came up with new evidence to support the leaky amygdala hypothesis. They decided to investigate a gene that is expressed specifically in the amygdala and in the circuits that convey the conditioned stimulus to it. The gene encodes a molecule called gastrin-releasing peptide, which turns out to have receptors on a population of nerve cells called interneurons in the lateral nucleus of the mouse amygdala. These interneurons produce GABA, which inhibits the activity of neurons in circuits close by. When gastrin-releasing peptide binds to the interneurons they are activated and produce more GABA, so increasing the inhibitory effect.
Kandel’s team bred mice that lacked the receptor for gastrin-releasing peptide. In these mice, levels of GABA produced by the interneurons were lower, and the main circuits in the amygdala were less inhibited, firing more easily and building stronger synaptic connections than in normal mice. The animals were quicker to learn fear – the classical sound and electric shock – and their behaviour was more anxious (Cell, vol 111, p 905). “It was a shock,” says team member Gleb Shumyatsky. He had not expected that a single gene would have such an effect. “These mice have a specific enhancement of their memory for fear.”
The obvious question is whether this is relevant to humans. Several studies have shown that people with panic disorder and generalised anxiety disorder tend to have lower levels of GABA in the brain overall. Also, the benzodiazepines, a class of common anti-anxiety drugs including Valium, work on the GABA system. However, because GABA is widespread in the brain, these findings could be interpreted in many ways.
The team is now hoping to find mutations in the genes encoding gastrin-releasing peptide and its receptor in humans. “Our hypothesis would be that if you have a deficiency of the peptide or its receptor, perhaps you would have enhanced fear memory,” Shumyatsky says. Such individuals might have a lower threshold for anxiety, he speculates. Now the race is on to discover whether gastrin-releasing peptide or its receptor could be targeted by drugs.
Another line of evidence suggests that in anxiety disorders, mechanisms for overriding fear memories have gone wrong. Although these memories are difficult to modify, there is evidence from both animals and humans that the brain can overwrite them. In mice and rats, learned fear can be extinguished by carefully un-linking the conditioned and unconditioned stimuli. The animal is allowed to hear the sound that it associates with shock, but the shock does not come. After many repeats of this experience, the animal becomes less anxious on hearing the sound.
It seems that the prefrontal cortex plays a key role in forming this newly written memory, says Quirk. Rats whose prefrontal cortex is damaged can still extinguish a learned fear, but the next day they revert to their old, fearful behaviour. Quirk argues that in people with PTSD, the problem may be a failure of the prefrontal cortex to exert enough control over the amygdala. When psychiatrists expose Vietnam veterans with PTSD to reminders of their trauma, many of them show abnormally low levels of activity in the prefrontal cortex, whereas their amygdala is unusually active. In other words, the balance between rational and emotional memory has tipped too far. Something similar could be going on with other anxiety disorders.
But anxiety disorders cannot be blamed on the amygdala alone. Another key focus of interest is the neurotransmitter serotonin, which plays a central role in mood regulation. People with some forms of anxiety disorder have lower levels of serotonin. Prozac and other selective serotonin re-uptake inhibitors (SSRIs) keep levels of the neurotransmitter generally higher in the brain and are widely prescribed for anxiety as well as depression. Could an imbalance in serotonin levels play havoc with the brain’s perception of fear?
The answer seems to be yes, sometimes, particularly if the imbalance happens in infancy. Last year, Cornelius Gross at Columbia University found that depriving infant mice of some of their serotonin made them anxious as adults. In an ingenious experiment, the researchers bred genetically modified mice in which they could switch on and off the production of one type of serotonin receptor, 1A, at different stages of development simply by giving the mice an antibiotic.
In adult mice, switching off the receptors did not make the animals anxious. However, mice that received the antibiotic in the womb failed to make the receptors as newborns, and grew up anxious even after the receptor was switched back on. The finding implies that a pathway to anxiety is laid down during early development (Nature, vol 416, p 396).
There is other evidence that serotonin must be available to the brain in adequate amounts to protect it from anxiety. In January this year, Evan Deneris and his colleagues at Case Western Reserve University in Cleveland, Ohio, announced the results of studies on a gene called Pet-1, whose role seems to be fostering the development of neurons that produce and respond to serotonin. The team bred mice that lacked the gene. The result was dramatic: the animals had only a scattering of serotonin-producing neurons and made up to 90 per cent less of the neurotransmitter than usual. Compared with normal mice, these animals were significantly more anxious (Neuron, vol 37, p 233).
The team has not yet extended the studies to people. “But I would not be surprised if the Pet-1 gene plays a similar role in human anxiety,” says Deneris. Importantly, he says, the gene continues to be expressed in the adult mouse brain, suggesting that it helps maintain serotonin levels throughout life. It will be useful, he says, to investigate whether variation in Pet-1 genes between individuals affects their overall serotonin levels.
The search for genes involved in anxiety disorders has another, particularly bizarre twist. Two years ago, a Spanish team reported some astonishing results. They found an apparently powerful link between anxiety and double-jointedness, and blamed both traits on a longish stretch of DNA on the long arm of chromosome 15.
Xavier Estivill, now at the Centre for Genomic Regulation in Barcelona, and colleagues were intrigued by reports from psychiatrists that a high proportion of double-jointed people suffer from panic disorder or phobias. Double-jointedness is a common inherited trait, affecting as many as 15 per cent of the population. Estivill took DNA samples from seven Catalonian families known to have a high incidence of both double-jointedness and anxiety disorders. In an astounding 87 per cent of the double-jointed and 90 per cent of those with anxiety disorders, he found a duplication in a region of chromosome 15.
The team then analysed another 70 unrelated patients with either panic disorder or agoraphobia but not double-jointedness and, remarkably, found that 68 of them had the same duplication. By contrast, in a control set of 189 samples, just 14 had the duplication. Estivill concluded that the duplication strongly predisposes people to anxiety disorders (Cell, vol 106, p 367).
Powerful as the results seem, Estivill does not claim that he has found the cause of anxiety disorders. “There will be multiple mechanisms,” he says. The problem for Estivill is that some other teams have so far failed to repeat these findings. For example, a team at the Wessex Regional Genetics Laboratory in Salisbury, UK, used the same approach but found no significant link between anxiety disorders and double-jointedness.
Estivill admits that he has not found the gene or genes in the duplicated section responsible for the changes, or a mechanism to explain them. But he is pressing ahead, creating lines of transgenic mice that express various genes located in the duplicated region. Although he is keeping quiet so far about the details, he says that some of the animals developed unusual “panic-like” responses.
Anxiety disorders are complex diseases, and no one knows how far researchers will be able to pin down the complex interaction of genes, development and adult experience. What is certain is that, as the pieces of the jigsaw start to fit together, the prospects for sufferers are improving. As for Colin McManus, he has retired from the police early because of his ill health, but has recently had treatment and feels better than he has done for years. When one of his family carves the roast, he can see beyond the carving knife that for years paralysed him with terror. “It’s the person behind the knife, not the knife, that matters,” he says.
The anxiety disorders
Panic disorder: repeated panic attacks, often triggered by a specific stimulus. Sufferers may experience chest pain, palpitations and breathlessness.
Obsessive-compulsive disorder: normal life is impossible because of checking and re-checking rituals such as repeatedly checking doors are locked. Sufferers may also be plagued by intrusive and ugly thoughts.
Generalised anxiety disorder: endless and debilitating worry, and a tendency to fear the worst.
Phobia: specific phobias, such as fear of spiders or flying, or social phobias, including fear of appearing in public.
Post-traumatic stress disorder: numbness, emotional detachment, flashbacks and nightmares. Recent research suggests that repeated exposure to ongoing trauma, such as child abuse, can cause PTSD.
The treatment jungle
Different anxiety disorders are treated differently, and the treatments vary in credibility. In the UK, the National Institute for Clinical Excellence is reviewing the options and will report next year.
Some patients improve with the help of drugs. The benzodiazepines, such as Valium, can help in the short term, but they can cause long-term side effects. Also, these drugs rarely help the depression that often accompanies anxiety. Instead, serotonin-boosting drugs can be more effective in treating both anxiety and depression. But drugs do not work well for everyone, nor for all forms of anxiety disorder. Specific phobias, for example, are rarely helped by drugs.
One of the most effective treatments is cognitive-behavioural therapy (CBT) which helps a person to restructure their beliefs and fears rationally. The therapy may include exposure to the thing that they find most terrifying, to help correct their false beliefs. It also helps the patient to develop ways to manage their anxiety. For example, children with PTSD can be taught to think of the flashback as an image on TV, and to imagine getting the remote and switching it off.
In the long term, CBT has been shown to be more effective than drugs for some people. It is also more effective than other therapies, such as counselling, for several forms of PTSD, according to an analysis by Allison Harvey at the University of Oxford.
One controversial therapy for PTSD, called eye movement desensitisation and reprocessing (EMDR), was developed by Francine Shapiro in California in the mid-1990s. The patient is asked to focus on the most feared experience and describe it while the therapist moves a finger from side to side in their visual field. Or the therapist may tap the patient’s left and right hand alternately. In some studies, psychiatrists have reported that this treatment can reduce people’s symptoms.
How the therapy might work is unknown. Among those who say it has helped them is Colin McManus, the former police officer. However, rigorous comparisons of treatment methods show EMDR to have mixed results. It is more effective than counselling or doing nothing, but according to some recent reviews, across treatment groups, CBT seems to be better than EMDR and to have longer-lasting effects.