Anxiety Disorders are among the most common mental health issues and can be disabling, preventing a person from living a life that they want. Neurofeedback for Anxiety Disorders Management is the most healthy way of treatment and allow reshape and rewire the brain, not just mask the symptoms.
Anxiety is a normal and often healthy emotion. Anxiety is a natural human reaction that involves the mind and body. It serves an important basic survival function. Anxiety is an alarm system that is activated whenever a person perceives danger or threat. When a person feels threatened, under pressure, or are facing a stressful situation the body makes automatic fight-or-flight response. Because anxiety makes a person alert, focused, and ready to head off potential problems, a little anxiety can help us do our best in situations that involve performance and motivate to solve problems.
But anxiety that’s too strong and long-lasting can interfere with doing our best. Too much anxiety can cause people to feel overwhelmed, tongue-tied, or unable to do what they need to do. When a person regularly feels disproportionate levels of anxiety, then it is likely to cross the line from normal anxiety into the territory of an anxiety disorder and it might become a medical disorder. Anxiety Disorders are among the most common mental health issues and can be disabling, preventing a person from living a life that they want. But the good things are that Anxiety Disorders are highly treatable. Neurofeedback for anxiety disorders management is very effective with long-lasting results.
Symptoms of Anxiety Disorders
To treat anxiety it is necessary to timely recognize the symptoms and manifestations. The symptoms may not go away on their own and if left untreated, they can start to take over the person’s life. It’s important to seek support early if you’re experiencing anxiety.
Anxiety disorders often are a group of related conditions and symptoms may vary from person to person. One person can get panicky at the thoughts of some problem, others may struggle with a disabling fear or uncontrollable, intrusive thoughts, someone else may suffer from intense anxiety attacks that strike without warning. Yet another may live in a constant state of tension, worrying about anything and everything. But despite their different forms, all anxiety disorders illicit an intense fear or worry out of proportion to the situation at hand.
The symptoms of anxiety disorder often include the following:
- restlessness, and a feeling of being “on-edge”;
- uncontrollable feelings of worry;
- increased irritability;
- concentration difficulties;
- sleep difficulties, such as problems in falling or staying asleep.
In addition to the primary symptom of excessive and irrational fear and worry, other common emotional symptoms of an anxiety disorder include:
- Feelings of apprehension or dread;
- Watching for signs of danger;
- Anticipating the worst;
- Trouble concentrating;
- Feeling tense and jumpy;
- Irritability;
- Feeling like your mind’s gone blank.
But anxiety is more than just a feeling. As a product of the body’s fight-or-flight response, anxiety also involves a wide range of physical symptoms, including:
- Pounding heart;
- Sweating;
- Headaches;
- Stomach upset;
- Dizziness;
- Frequent urination or diarrhea;
- Shortness of breath;
- Muscle tension or twitches;
- Shaking or trembling;
- Insomnia
Because of these physical symptoms, anxiety sufferers often mistake their disorder for a medical illness. They may visit many doctors and make numerous trips to the hospital before their anxiety disorder is finally recognized.
Types of Anxiety Disorders
There are different types of anxiety. The most common is the follow.
Generalized Anxiety Disorder (GAD)
A person feels anxious on most days, worrying about lots of different things, for a period of six months or more.
If constant worries and fears distract a person from his day-to-day activities, or he is troubled by a persistent feeling that something bad is going to happen, this person may be suffering from generalized anxiety disorder (GAD). People with GAD are chronic worrywarts who feel anxious nearly all of the time, though they may not even know why.
Anxiety related to GAD often manifests in physical symptoms like chest pain, headache, tiredness, tight muscles, insomnia, stomach upset or vomiting, restlessness, and fatigue. Generalized anxiety can lead a person to miss school or avoid social activities. With generalized anxiety, worries can feel like a burden, making life feel overwhelming or out of control.
Social Anxiety Disorder
A person with a social anxiety disorder has an intense fear of being viewed negatively by others, being criticized, embarrassed or humiliated, even in everyday situations, such as speaking publicly, eating in public, being assertive at work or making small talk. It is also known as social phobia.
Social anxiety disorder can be thought of as extreme shyness. In severe cases, social situations are avoided altogether. Performance anxiety is the most common type of social phobia.
Phobias and Irrational Fears
A person with phobia feels unrealistic or exaggerated fear of a particular object, activity or situation that in reality presents little to no danger. He may go to great lengths to avoid the object of the fear. Unfortunately, avoidance only strengthens the phobia.
There are many different types of phobias. Common phobias include fear of animals (such as snakes and spiders), fear of flying, fear of heights, and etc.
Panic Attacks and Panic Disorder
A person has panic attacks, which are intense, overwhelming and often uncontrollable feelings of anxiety combined with a range of physical symptoms. Someone having a panic attack may experience shortness of breath, chest pain, dizziness, and excessive perspiration. Sometimes, people experiencing a panic attack think they are having a heart attack or are about to die.
If a person has recurrent panic attacks or persistently fears for more than a month, they’re said to have panic disorder. Panic disorder is characterized by repeated, unexpected panic attacks, as well as fear of experiencing another episode. Agoraphobia is an intense fear of panic attacks that causes a person to avoid going anywhere a panic attack could possibly occur.
Other Conditions Where Anxiety is Present
Obsessive-Compulsive Disorder (OCD)
A person has ongoing unwanted/intrusive thoughts and fears that cause anxiety and seem impossible to stop or control. Although the person may acknowledge these thoughts as silly, they often try to relieve their anxiety by carrying out certain behaviors or rituals.
For a person with OCD, anxiety takes the form of obsessions (bad thoughts) and compulsions (actions that try to relieve anxiety). For example, a fear of germs and contamination can lead to constant washing of hands and clothes.
Post-Traumatic Stress Disorder (PTSD)
Post-traumatic stress disorder (PTSD) can happen after a person experiences a traumatic or life-threatening event (e.g. war, assault, accident, disaster). Symptoms of PTSD can include difficulty relaxing, nightmares or flashbacks of the event, hypervigilance, startling easily, withdrawing from others, and avoidance of anything related to the event. PTSD is diagnosed when a person has symptoms for at least a month.
Separation Anxiety Disorder
While separation anxiety is a normal stage of development, if anxieties intensify or are persistent enough to get in the way of school or other activities, your child may have a separation anxiety disorder. Children with a separation anxiety disorder may become agitated at just the thought of being away from mom or dad and complain of sickness to avoid playing with friends or going to school.
Anxiety Disorder Risk Factors
Researchers are finding that both genetic and environmental factors contribute to the risk of developing an anxiety disorder. Although the risk factors for each type of anxiety disorder can vary, some general risk factors for all types of anxiety disorders include:
- Temperamental traits of shyness or behavioral inhibition in childhood;
- Exposure to stressful and negative life or environmental events in early childhood or adulthood;
- A history of anxiety or other mental illnesses in biological relatives;
- Some physical health conditions, such as thyroid problems or heart arrhythmias, or caffeine or other
substances/medications can produce or aggravate anxiety symptoms. - Inflammation affects subcortical and cortical brain circuits associated with motivation and motor activity as well as cortical brain regions associated with arousal, anxiety, and alarm.
There is a surprising specificity on the impact of inflammation on behavior. Researches show that inflammation not only occurs in depression but also in multiple other psychiatric diseases including anxiety disorders, bipolar disorder, personality disorders, and schizophrenia. These data suggest that inflammation is transdiagnostic in nature, occurring in subpopulations of patients within a number of psychiatric disorders. It is revealed that Yoga and alpha meditation increases parasympathetic outflow and consequently decrease inflammation.
A physical health examination is helpful in the evaluation of a possible anxiety disorder.
Self Test for Anxiety
This Self-Assessment Test for Anxiety called the General Anxiety Disorders screening tool with the 7 questions (GAD-7). It can help you find out if you might have an anxiety disorder that needs treatment. It calculates how many common symptoms you have and, based on your answers, suggests where you might be on a scale, from mild to severe anxiety.
Hamilton Anxiety Rating Scale (HAM-A) for Rating by Clinicians
The Hamilton Anxiety Rating Scale (HAM-A) was one of the first rating scales developed to measure the severity of anxiety symptoms and is still widely used today in both clinical and research settings. The scale is intended for adults, adolescents, and children and should take approximately ten to fifteen minutes to administer.
The major value of HAM-A is to assess the patient’s response to a course of treatment, rather than as a diagnostic or screening tool. By administering the scale serially, a clinician can document the results of drug treatment, psychotherapy or neurofeedback.
The scale consists of 14 items; each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety).
Brain Region and Anxiety Disorders from Neurofeedback Management Perspective
Normally, the brain manages our fear and anxiety without allowing them to interfere with our daily functioning. If there’s a nearby threat, different areas of the brain help us make sense of the threat by amplifying or quelling our anxiety and fear.
The various anxiety disorders involve many different areas of the brain. These areas reflect both the uniqueness of each of these disorders and the features that they have in common. Anxiety is the result of interaction between a number of different brain regions — a fear network. No one brain region drives anxiety on its own. Instead, interactions among many brain areas are all important for how we experience anxiety. Contemporary models of anxiety disorders have primarily focused on amygdala-cortical interactions. We only feel anxiety when signals from the amygdala overpower the cognitive brain, and into our consciousness. If you can rationalize that, then cognitive brain network overtakes and suppresses the emotional fear network.
Symptoms of anxiety disorders are thought to result in part from a disruption in the balance of activity in the emotional centers of the brain rather than in the higher cognitive centers.
The higher cognitive centers of the brain reside in the frontal lobe.
The prefrontal cortex (PFC) is responsible for executive functions such as planning, decision making, predicting consequences for potential behaviors, and understanding and moderating social behavior.
The orbitofrontal cortex (OFC) codes information, controls impulses and regulates mood. This region is crucial for the self-regulation of emotions and the relearning of stimulus-reinforcement associations.
Medial OFC is implicated in fear of extinction. Successful treatment of spider phobia is primarily accompanied by functional changes of the medial OFC.
In contrast to mOFC, anterolateral OFC (lOFC) has been associated with negative affects and obsessions and thus dysfunctional lOFC may underlie different aspects of certain anxiety disorders.
The ventromedial PFC (vmPFC) is involved in reward processing and in the visceral response to emotions.
In the healthy brain, these frontal cortical regions regulate impulses, emotions, and behavior via inhibitory top-down control of emotional-processing structures. Ventromedial prefrontal cortex to dampen the signals coming from the amygdala. Patients with damage to this brain region are more likely to experience anxiety since the brakes on the amygdala have been lifted.
The emotional-processing brain structures are referred to as the limbic cortex.
It includes the insular cortex and cingulate cortex. The limbic cortex integrates the sensory, affective, and cognitive components of pain and processes information regarding the internal bodily state. Dysfunction in the posterior cingulate cortex (PCC) may play an important role in anxiety psychopathology.
A relative gray matter deficit was found in the right anterior cingulate cortex of patients with panic disorder (PD) compared with controls. Deactivation in PCC while listening to threat-related words alternating with emotionally neutral words. Dorsal anterior cingulate cortex (dACC), amplifies fearful signals coming from the amygdala. When anxious patients are shown pictures of fearful faces, the dACC, and amygdala ramp up their interaction, producing palpable anxiety. People without anxiety show little to no response.
A relative increase in gray matter volume was found also in the left insula of patients with panic disorder (PD) compared with controls.
The hippocampus is another limbic system structure. It has tonic inhibitory control over the hypothalamic stress-response system and plays a role in negative feedback for the hypothalamic–pituitary–adrenal (HPA) axis. Because all old memories depend on the hippocampus, this structure is involved in anxiety disorders that are generated by memories of painful experiences, such as post-traumatic stress disorder (PTSD).
Studies do show that people who have suffered the stress of incest or military combat have a smaller hippocampus. This atrophy of the hippocampus might explain why such people experience explicit memory disturbances, flashbacks, and fragmentary memories of the traumatic events in question. Research shows that the hippocampus is also smaller in some depressed people. Stress, which plays a role in both anxiety and depression, may be a key factor here since there is some evidence that stress may suppress the production of new neurons (nerve cells) in the hippocampus.
The amygdala processes emotionally salient external stimuli and initiates the appropriate behavioral response. The amygdala is responsible for the expression of fear and aggression as well as species-specific defensive behavior, and it plays a role in the formation and retrieval of emotional and fear-related memories. The amygdala plays a central role in anxiety disorders. It warns us when danger is present in our environment and triggers the fear reaction and then the fight or flight reaction to get us out of it.
Some studies have shown that monkeys with damage to the amygdala were unusually stoic in the face of scary stimulus, like a nearby snake.
The amygdala is implicated in generating fear responses, whereas cortical regions, specifically the mOFC and the vmPFC, are implicated in fear extinction. The central nucleus of the amygdala is heavily interconnected with cortical regions including the limbic cortex. It also receives input from the hippocampus, thalamus, and hypothalamus. It plays an important role in anxiety disorders that involve specific fears, such as phobias. Researchers have also observed that a group of very anxious children had a larger amygdala, on average than a group of normal children.
The amygdala act as a sensor of threats or a lack of control, communicating the need for a reaction to the hypothalamus. The hypothalamus, in turn, releases corticotropin-releasing hormone (CRH), which binds to the adenohypophysis that then produces the adrenocorticotrophic hormone (ACTH). ACTH binds to the adrenal cortex and adrenal medulla.
Researchers show that additional structures showing differential increases of gray matter were the left superior temporal gyrus, the midbrain, and the pons.
Additionally to the differences in the size of various brain structures, abnormally high or low activity in a particular region of the brain may be another kind of anomaly that results in anxiety disorders.
In addition to the activity of each brain region, it is also important to consider the neurotransmitters providing communication between these regions.
Increased activity in emotion-processing brain regions in patients who have an anxiety disorder could result from decreased inhibitory signaling by gamma-amino-butyric-acid (GABA) or increased excitatory neurotransmission by glutamate. Well-documented anxiolytic and antidepressant properties of drugs that act primarily on monoaminergic systems have implicated serotonin, norepinephrine, and dopamine in the pathogenesis of mood and anxiety disorders.
Neurofeedback for Anxiety Disorders
Chronic anxiety and stress can increase catecholamine release, decrease growth hormones, and aberrantly activate immune and inflammatory cascades. As such, stress and anxiety can directly influence illness progression and can lead to irritable bowel syndrome exacerbations and increased cardiovascular risk. Increased frequency of general anxiety disorder has been found in people with asthma, cancer and chronic pain.
This comorbidity of anxiety with chronic illness can cause increased morbidity, mortality and decreased quality of life. Poorly controlled anxiety reduces the quality of life of many healthy individuals and is a key symptom of numerous neuropsychiatric and psychosomatic conditions.
For young children who perceive the world as a threatening place, a wide range of conditions can trigger anxious behaviors that then impair their ability to learn and to interact socially with others. Chronic and intense fear early in life affects the development of the stress response system and influences the processing of emotional memories.
Traditional treatment for anxiety includes psychological treatments such as cognitive therapy, cognitive behavioral therapy, exposure therapy, and self-help groups, as well as pharmacological modalities such as benzodiazepines and antidepressants.
The most common anxiety treatment is psychotherapy. Psychotherapy, specifically Cognitive Behavioral Therapy (CBT), has been shown through research to be very effective in addressing the symptoms associated with anxiety.
Although anxiety medication may temporarily help with anxiety relief, they usually don’t address the root cause, as well as negatively reinforce avoidant behaviors instead of learning how to deal with stress and uncomfortable feelings. Medications just treat the symptoms and do not correct the source of the problem in the brain. Besides, many anxiolytics may cause addictions.
Neurofeedback for Anxiety disorders management is almost such effective as medication and helps reduce or eliminate the use of these medications.
Neurofeedback is all about teaching the brain to self-regulate and reduce or completely eliminate symptoms of anxiety disorders. Neurofeedback works at the subconscious level, which is control 90 to 95% of the time. Through a process of measurement and reinforcement, you learn to regulate your brainwave activity. Quite simply, you are reinforced for changing brainwaves at a subconscious level through the use of computers. Almost any brain, regardless of its level of function (or dysfunction), can be trained to function better. Research has shown that the long-term effects of neurofeedback in anxiety disorders are stable over time, in difference with the anxiolytic medication that has an effect short period after discontinuation.
The first step in Neurofeedback for anxiety disorders treatment is to have an evaluation and measurement of brainwaves in different areas of the brain and reveal their functioning and activity. EEG shows any brain areas where there is too much or too little activity. It could also show which areas are not communicating well with other areas. Certain brainwave patterns are associated with certain neuropsychological functions and conditions. In this aspect, very precision results may be obtained by qEEG brain mapping.
The qEEG analysis allows specialists to see exactly excessive activation in part of the fear network in the brain in anxiety disorders. Once we see the source of the problem, we target that area for change through neurofeedback brain training. This allows you to reshape your brain, not just mask your symptoms.
People suffering from anxiety disorders often have over-activation in brain regions such as the right insula, hippocampus, and amygdala. Theory today suggests that anxiety disorders involve deficits in cognitive skills, such as the control of attention and these cognitive aspects of the disorders are the most likely targets for neurofeedback for anxiety disorders management, whose effects are thought to be mediated mostly by cognitive skill enhancement.
From a neurofeedback management perspective, alpha band (8-12 Hz) asymmetry with prevalence in the left frontal cortex has emerged as the most prominent electroencephalographic (EEG) correlate of both anxiety and depression in right-handed people, followed by excessive band power in beta 1 (12-20 Hz) and beta 2 waves (20-30 Hz) in the right parietal lobe. There is also research that shows the association of anxiety disorders with High-Beta in conjunction with a decrease of Low Beta activity in temporal lobes.
Neurofeedback for anxiety disorders enables people to consciously control changed activation of the brain, reducing their anxiety levels. Anxiety disorders neurofeedback management since first studied has used a wide enough range of EEG target frequency-bands and protocols. This includes frequencies in the alpha, beta and theta ranges, comprising almost half the typically measured spectrum of frequencies.
Healthy alpha asymmetry and regulation of alpha powers bands with the Neurofeedback have been successfully used to treat anxiety disorders and depression. Whereas increasing the power of sensorimotor rhythm (SMR) bands (12-15 Hz) over the sensorimotor cortex – has been used successfully to improve memory and sleep quality. Increase the alpha/beta3 ratio (9.5-12 Hz/23-38 Hz) at parietal lobe lead to improvement of anxiety, depression, and sleep quality, as well as some improvement in executive functions.
The combination of both protocols the SMR followed by alpha/beta3 ratio leads to an overall improvement in the symptoms reported by patients with anxiety disorders. The neurofeedback training protocol usually lasts 20 sessions, during which the individual is trained to increase beta 1 (12-15 Hz) at C4 with eyes open, followed by closed-eyes training designed to increase the alpha/beta 3 ratio (9.5-12 Hz/23-38 Hz) at P4. Researches show marked improvement in anxiety, depression, and sleep quality, as well as some improvement in executive functions.
EEG biofeedback protocols for the treatment of anxiety disorders have included alpha enhancement (e.g., Hardt & Kamiya, 1978), theta enhancement (e.g., Sittenfield et al., 1976), and alpha-theta enhancement (Peniston & Kulkosky, 1991) paradigms. Information regarding the location of sensors, frequency bands to be reinforced/inhibited, and type of feedback is provided below.
Fp1 (Left Prefrontal Cortex):
Location: Frontal pole, 10% of the distance from the nasion (bridge of the nose).
Relevance: Involved in cognitive control and emotional regulation. Increasing alpha activity here can promote relaxation.
Fp2 (Right Prefrontal Cortex):
Location: Frontal pole, 10% of the distance from the Nasion.
Relevance: Associated with stress and anxiety responses. Training can help balance activity and reduce anxiety symptoms.
F3 (Left Dorsolateral Prefrontal Cortex – DLPFC):
Location: Frontal lobe, 30% of the distance from the nasion to the inion and 20% from the midline.
Relevance: Involved in cognitive control and emotional regulation. Enhancing alpha or SMR activity here can reduce anxiety.
F4 (Right Dorsolateral Prefrontal Cortex – DLPFC):
Location: Frontal lobe, analogous to F3 on the right side.
Relevance: Balancing activity with F3 can help regulate anxiety-related imbalances.
Cz (Central Midline):
Location: The scalp vertex, halfway between the nasion and inion and equally spaced between the left and right preauricular points (just above the ears).
Relevance: Often used as a reference or ground electrode in neurofeedback sessions, also involved in general arousal and relaxation.
Alpha enhancement protocol
- Sensor location – O1, Oz (most common); C3, C4 (less common).
- Reinforced frequencies – 8-13 Hz.
- Reinforced EEG pattern – Percentage of time patient produces alpha amplitudes above a threshold
(e.g., 10 microvolts), or patient pro¬duction of alpha amplitudes above a set point
(e.g., 19-21 microvolts). - Feedback modality – Auditory (tones and/or verbal feedback); eyes are typically closed during training.
- Timing of sessions – Ranges from daily to weekly.
Theta enhancement protocol
- Sensor location – Oz or C4.
- Reinforced frequencies – Maintaining 3.5- to 7.5-Hz activity above a preset microvolt threshold, while suppressing 8- to 12-Hz pro-duction below a specified microvolt threshold
- Feedback modality – Primarily auditory with eyes closed; visual feedback has been provided in instances where surface electromyographic (EMG) feedback is also provided.
- Timing of sessions – Daily to weekly.
During the Neurofeedback procedure, the computer measures brainwave activity through the electrodes that placed on the scalp (watch video). When input falls into acceptable and healthy parameters, the system generates pleasant stimuli (audio or video feedback) to reinforce the change. Typically a movie plays consistently with a ding for each time a pre-set goal is achieved. This process is very pleasant, and since the brain craves this simple reinforcement, it typically begins changing within a few seconds of the commencement of the session. This operant conditioning is continued over numerous sessions of neurofeedback to reinforce transient changes in brain function using the patient’s own input as a guide. Through this process of reinforcement, the brain begins to regulate, and you see symptom reduction. With neurofeedback, it is possible to break open subconscious fears or worries and thus treat them. This is often the only way to gain access to the origin of anxiety/panic attacks.
Most people require two Neurofeedback sessions a week and the number of sessions varies based on the person and particular issue. While some people notice a reduction of symptoms after the first session, others may experience a gradual reduction of symptoms over time. The effects are often felt within the first few sessions; further training allows these to become permanent. Neurofeedback management of anxiety disorders calms the CNS so that a child, teen, or individual with anxiety can learn to manage stress in healthy ways.
After obtaining stable results with the help of neurofeedback specialists people with anxiety can continue to perform neurofeedback management of anxiety disorders upon their needs with the help of home use neurofeedback devices. They are very simple to use and adapted for alpha and beta neurofeedback training, i.e. for relaxation and concentration. Additionally, the constant use of these devices will improve short-term and long-term memory, quality of sleep, and stress resistance.
References:
E.I. Martin, K.J. Ressler, E. Binder, C.B. Nemeroff. The Neurobiology of Anxiety Disorders: Brain Imaging, Genetics, and Psychoneuroendocrinology. Psychiatr Clin North Am. 2009 September; 32(3): 549–575. doi:10.1016/j.psc.2009.05.004.
Mennella, Patron, & Palomba. (2017). Frontal alpha asymmetry neurofeedback for the reduction of negative affect and anxiety. Behaviour Research and Therapy, 92, 32-40.
Dias, Á. M. & van Deusen, A. (2011). A new neurofeedback protocol for depression. The Spanish Journal of Psychology, 14(01), 374-384.
F.Blaskovits, J.Tyerman, M.Luctkar-Flude. Effectiveness of neurofeedback therapy for anxiety and stress in adults living with a chronic illness: a systematic review protocol. JBI Database of Systematic Reviews and Implementation Reports: July 2017, Volume 15, Issue 7, p 1765–1769. doi: 10.11124/JBISRIR-2016-003118
Scheinost, D., Stoica, T., Saksa, J., Papademetris, X., Constable, R. T., Pi_enger, C., & Hampson, M. (2013). Orbitofrontal cortex neurofeedback produces lasting changes in contamination anxiety and resting-state connectivity. Translational Psychiatry, 3(4), e250. doi:10.1038/tp.2013.24
Simkin, D. R., Thatcher, R. W., & Lubar, J. (2014). Quantitave EEG and neurofeedback in children and adolescents: anxiety disorders, depressive disorders, comorbid addiction, and attention-deficit/hyperactivity disorder, and brain injury. Child and adolescent psychiatric clinics of North America, 23(3), 427-464.
J.S. Gomes, D.V. Ducos, H.Akiba, Á.M. Dias. A neurofeedback protocol to improve mild anxiety and sleep quality. Brazilian Journal of Psychiatry, vol.38 no.3 São Paulo July/Sept. 2016, 38:264-265. http://dx.doi.org/10.1590/1516-4446-2015-1811
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145052/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852103/
https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)70305-0/fulltext
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