Motivation and emotion/Book/2015/Trans-cranial direct current stimulation and depression

Overview
Depression is a psychological disorder that affects millions of people worldwide and is the leading cause of disability. Beyondblue (n.d.) state that 1 million Australian adults have depression in any one year and that 1 in 6 people experience depression at some point in their lives. Most people tend to recover from a depressed mood over time but when the mood extends for several weeks and causes a loss of enjoyment in previously enjoyable activities a major depressive disorder (MDD) may be considered. A number of treatments exist for MDD, such as cognitive behavioural therapy (CBT), psychopharmacology, psychoanalysis and many others. With each treatment there is an associated cost in terms of time, expense or side effects. However, there has been much excitement and research into a treatment known as trans-cranial direct current stimulation (tDCS). Whilst there has been mixed results in the research, the promise of a treatment that is cheap, easy to administer and has zero or only low level temporary side effects has meant the technology is receiving a lot of attention.

Depression
Most people recognise the term depression but few understand the difference between sadness, having a depressed mood for a few days and clinical depression. Clinical depression is defined in The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013) and is referred to as Major Depressive Disorder (MDD). To differentiate other types of depression, in particular Bipolar Depression, the disorder may also be referred to as Unipolar Depression. To be diagnosed with MDD five or more of the following symptoms need to be present for at least a 2 week period, and include either a depress mode or a loss of interest or pleasure:
 * Depressed mood most of the day, nearly every day.
 * Diminished interest or pleasure in all or most activities most of the day, nearly every day.
 * Weight loss or gain without dieting or increase or decreased appetite, nearly every day.
 * Insomnia or hypersomnia nearly every day.
 * Psychomotor agitation or retardation nearly every day.
 * Fatigue or loss of energy nearly every day.
 * Feelings of worthlessness, or excessive or inappropriate guilt nearly every day.
 * Diminished ability to think, concentrate or make decisions nearly every day.
 * Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or suicide attempt or a plan for committing suicide.

These symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning and are not the result of substance abuse or a general medical condition.

Theories of depression
Depression is a complex disorder that appears to have more than one causal factor and two models attempt to explain the interconnectedness of some of these factors. The biopsychosocial model defined by Engle (1977) suggests that causes of depression are biological, psychological and social and that there is an interdependence of causes, the mind and body are connected and cannot be treated individually. The biopsychosocial model attempts to make sure that clinicians consider all factors when considering diagnosis and treatment. The second model is known as the diathesis-stress model and was proposed by Ingram & Luxton (2005). In this model the diathesis are the vulnerabilities for the development of depression. These vulnerabilities take some factors from the biopsychosocial model. However, the amount of environmental stress required to trigger the disorder depends on the inherent vulnerabilities each individual has. An individual with little vulnerability may find that a significant life stressor, such as loss of a loved one, does not trigger depression. Yet another individual with more vulnerability may trigger depression in the same scenario.

Biological
Several studies suggest that an imbalance in the neurotransmitters serotonin, norepinephrine and dopamine are found within individuals with MDD. Serotonin is responsible for sleep, aggression, sexual behaviour and mood. Norepinephrine is responsible for recognition and response to stressful situations. Dopamine is the reward mechanism of the brain and is active when people feel good. Brain imaging studies have also identified areas of the brain that are either more active or less active in people with MDD. Using Positron Emission Tomography (PET), Functional Magnetic Resonance Imaging (fMRI) and Computed Axial Tomography (CT) researchers have found that areas of the prefrontal cortex are less active and less able to regulate negative emotions whilst other areas of the prefrontal cortex are more active and respond more to negative stimuli.

Psychological
There have been three major movements in the study of psychology over the past 100 years, psychoanalytic, behavioural and cognitive and each movement has attempted to define causes and treatments for depression. However, psychodynamics and the behaviourism have largely been replaced by the cognitive approach to psychology. The cognitive approach suggests that depression is caused by a fault in the way we think and judge situations and events. Within cognitive research a number of theories have been proposed to explain depression such as Aaron Beck’s Cognitive Theory of Depression, Albert Ellis’ Cognitive Theory of Depression, Bandura’s Social Cognitive Theory of Depression and Seligman’s Learned Helplessness theory. Each theory takes a slightly different approach to the same problem, that depressed individuals have a negative view of themselves, the environment and the future and that these views are often reinforced through social interactions.

Social
Social factors are most often associated with the trigger event that causes the initial or secondary major depressive episode. For example, the death of a loved one, loss of a job, marital problems, breakdown of friendships and serious abuse, neglect. Additionally, traumatic events where you may have been involved or have been a witness, such as murder, violence or war may also trigger an episode. In the diathesis-stress model social factors tend to be the trigger events and will generally only trigger an episode if the individual has a high enough vulnerability.

Treatments for depression
There are many treatments for MDD available with varying levels of efficacy and costs. Some example treatments are discussed below.

Pharmacological
A number of antidepressant medications are available for the treatment of MDD. These medications work on different neurotransmitter targets and chemical mechanisms, such as Selective Serotonin Reuptake Inhibitors (SSRI) as well as other reuptake inhibitors (SNRI), tricyclics (TCA) and monoamine oxidase inhibitors (MAOI). However, one of the major concerns with the use of medical interventions is the short- and long-term side effects of the drugs. Individuals may experience stronger suicidal tendencies when first starting these drugs and other side effects include problems with sleep, sexual function and weight gain to name a few. Often medication also takes some weeks before it becomes fully effective.

Cognitive behavioural therapy
Cognitive Behavioural Therapy (CBT) is a treatment for depression based on the cognitive theories of Aaron Beck and Albert Ellis. In CBT, depression is thought of as a learned behaviour based on dysfunctional thinking and maladaptive behaviour. Since this process is learned, CBT seeks to teach people to detect the dysfunctional thinking and replace these thoughts with better alternatives and thereby learn new behaviours.

Brain stimulations
Although most people assume that electric shock treatments are from the dark ages and remember the movie one flew over the cuckoos nest as a particularly gruesome treatment the reality is that electroconvulsive therapy (ECT) is still in use and is approved as a treatment for MDD. Modern use is quite painless as the patient is anesthetised and given muscle relaxers. However, there are side effects including memory loss. This treatment is generally only considered for extreme cases where other treatments have failed. The technology works by applying a strong electric current to the patient that causes most neurons to fire and cause a seizure.

Another newer technique, trans-cranial magnetic stimulation (TMS) uses a precise magnetic field applied to the skull to induce an electric field within the brain. The electric field is able to trigger the firing of neurons within a specific area of the brain and generally will not trigger a seizure. The patient is awake and the procedure is generally painless. TMS is approved for clinical use in the treatment of MDD. TMS is difficult to setup and is costly. The treatment is also not suitable for people with metal implants, pacemakers or even tattoos with metallic inks are not approved for use with TMS.

What is trans-cranial direct current stimulation?
Trans-cranial Direct Current Stimulation (tDCS) is a form of brain stimulation that uses low voltage direct current to excite or inhibit areas of the brain that lead to changes in the functioning of that area.

How does it work?
The basic function of the tDCS system is to send an electric field through a region of the brain to elicit a change in brain function. An electric field is induced in the patient by placing an anode and cathode at various positions on the scalp, neck or shoulders of the patient. A small direct current (1-2 milliamps) is connected to the system to produce an excess of electrons at the anode and a decrease in electrons at the cathode (Peterchev, et al, 2012). This imbalance in electric charge causes electrons to flow through the brain from the anode to the cathode. The participant is connected to the system for 20 to 30 minutes per session.

Exactly how the electric field effects brain functioning is not entirely clear but at present the leading mechanism is that the electric field changes the polarization of the neural membrane (Peterchev, et al, 2012). The effect of this polarisation continues after the current has been removed for a period of time related to the length of the applied current. Stagg & Nitsche (2011) also describe the tDCS as affecting resting membrane potential. The changes to the resting potential either depolarise or hyperpolarise the neuronal membrane but the effects are at sub threshold levels and do not directly cause a neuron to fire. This effect for the anode can be thought of as increasing the gain of the system such that smaller inputs can be enough to enable the neuron to fire and making the system more sensitive. The opposite effect is true for the cathode with the system decreasing sensitivity such that a greater signal is required to cause the neuron to fire.

Equipment and safety
The equipment required to perform tDCS is inexpensive, small and portable. This makes it ideal for clinical practice, Doctor’s offices, small rural and remote hospitals, clinics and possibly home use. All that is required to start with tDCS is a controller, batteries, two electrodes, two sponges, wetting agent (sodium chloride), a headband to hold everything in place and a tape measure. Due to the small voltages being used in the system there is very low risk of harm in the use of tDCS. The existing research has found that in the early trials the tightness of the headband and the wetting agent were contributing factors in localised burning, dry and itchy scalps under the electrodes (Palm, et al., 2012). These side effects were not serious and caused no long-term damage. The recommended use of a saline solution has reduced the occurrence and severity of these side effects. During use people often report a tingling or itching sensation under the electrodes but these fade away during the session or once the current is stopped.

Clinical
The Food and Drug Administration (FDA) in North America is responsible for approving medical devices and treatments and has not certified tDCS as a suitable treatment for any medical or psychological disorder. However, a number of devices that are suitable for use in tDCS have been approved by the FDA as safe and are being used in research as off label devices. Other countries have similar governing bodies and as yet none have certified tDCS for clinical use.

DIY and brain hacking
One of the benefits of the system is that the components are easy to acquire, build and run. In fact, the system runs off a small 9 volt battery. Due to the low cost and ease of access, a do-it-yourself (DIY) movement has sprung up around the technology (Wexler, 2015). There are a number of companies promoting the benefits of tDCS based on a selective sample of studies and this can lead to the industry as a whole being called into question due to dubious and misleading claims from companies out to make money. There is also concern that some DIY users may be experimenting with voltages, currents and length of sessions with unknown consequences or side effects. In this regard DIY use should be cautioned.

Positioning system
One of the important aspects of the existing research is that the position of the electrodes determines which area of the brain is either excited or inhibited. Since different regions of the brain control varying cognitive and behavioural functions, deciding which to stimulate and which to inhibit to have the desired outcome is dependent on precise positioning. To ensure that research is reproducible the 10-20 system of electrode placement used in EEG tests and experiments is most often used in tDCS research. The electrode locations are identified with the lobe and hemisphere locations. The first letters represent the (F)rontal, (T)emporal, (P)arietal, (C)entral and (O)ccipital lobes. The number following represents the hemispherical location such that odd numbers represent the left hemisphere and even the right hemisphere. A letter ‘z’ indicates zero or the centre line.

Potential uses for tDCS
The number of potential uses for tDCS is great and while results are mixed research continues. Below is a list of some examples:
 * Memory
 * Mathematics comprehension
 * Language acquisition
 * Depression
 * Schizophrenia
 * Pain
 * Concentration and focus
 * Addiction

Theories
According to research and theories into the neurobiological basis of MDD it has been found that there are functional and structural changes that can be associated with MDD (Maletic, et al, 2007). Maletic, et al (2007) describe how the prefrontal cortex and the limbic system are connected in mood regulation via the ventromedial prefrontal cortex (VMPFC), lateral orbital prefrontal cortex (LOPFC), the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulated cortex (ACC). The DLPFC has been found to be underactive in patients with MDD and the VMPFC and LOPFC are overactive. Maletic, et al (2007) mentions that hyperactivity in the VMPFC is associated with anxiety, pain and depressive ruminations whereas an underactive DLPFC produces deficits in attention and working memory as well as retardation of motor function and apathy. For this reason a majority of tDCS trial focus on placing the anode at the left DLPFC in an attempt to excite this area that is often underactive in MDD sufferers. In fact, Disner, et al, (2011) also explain how many of these neural mechanisms can be integrated into Beck’s cognitive theory of depression and thereby start to link cognitive ideas of top-down cognitive control with subcortical emotional processing areas.

Research
Research into the use of tDCS as a form of treatment for MDD is widespread however results have been mixed. In one study by Dell’Osso, et al. (2010) they found that in a trial of patients with MDD or Bipolar Disorder (BD) there was significant reduction in Hamilton Depression Rating Scale (HAM-D) scores over the duration of the study. They selected the participants in the study who were having a major depressive episode and who were being treated with antidepressant medication. Also, the participants selected were either partially responding or not responding to the medication that was being taken at full dose for the previous 8 weeks. During the study participants remained on their medication. Participants were treated twice a day for 5 days at 2mA intensity for 20 minutes. No significant side effects were reported. The anode was placed at the left DLPFC and the cathode at the contralateral cortical area. Whilst the results showed a significant improvement, the study can be criticised for lack of sham/control condition and randomised selection of participants into these groups and was very limited in size (n = 23). Both of these factors call in to question the efficacy of the results. Unfortunately, the literature is populated with many examples of experiments with these conditions (Horvath, Carter, Forte, 2014). Whilst the study conditions are not ideal, the possibility that tDCS may be an effective treatment for some partial and non-responders is encouraging given that the results were also seen within a short period of time.

In a study by Rigonatti, et al. (2008) using tDCS in a sham controlled randomised double blind experiment they found that active tDCS had a significant reduction in depressive scores on the Beck Depression Inventory (BDI) compared to the sham tDCS condition. The study is also significant for comparing the effect of tDCS with a common antidepressant fluoxetine. The results of the comparison between tDCS and fluoxetine were similar at the conclusion of the 6-week study but tDCS was effective after the first 2 weeks and provided a faster benefit. The participants were selected based on a diagnosis of MDD. The patients were not on antidepressant medication during the two months prior to the trial or during the trial, apart from the fluoxetine condition. The study used 2mA intensity for 20 minutes for 10 days. The anodal electrode was placed over the left DLPFC and the cathodal electrode over the contralateral supraorbital area. Whilst the number of participants is still small and the fluoxetine trial was open and contained no placebo-controlled condition the strength of the results would indicate that tDCS is worthy of further study with larger populations.

However, in a randomised double blind sham controlled study by Palm, et al. (2012) they found no significant difference between active tDCS versus sham tDCS. The trial is interesting in that the participants selected were treatment resistant and had tried several antidepressants with no success. This study also used a design whereby each participant was allocated to the active or sham condition for the first treatment phase. The follow up treatment phase the groups were reversed (active->sham vs sham->active). Each group had 10 active and 10 sham sessions and each session was 20 minutes. Additionally, the first 10 participants use a session of 1mA intensity and the remainder used 2mA of intensity. Anode placement was at the left DLPFC and the cathode over the right supraorbital area. HAM-D and BDI were used to assess improvement additional cognitive and emotional scales were also used. Although the results revealed that active tDCS was not significantly different to sham tDCS there was an increase in subjective positive mood rating and a downward trending for less negative emotions. They suggested that this was a sign that tDCS did have some effect on emotional regulation. Other cognitive task measures were also not significant. Palm et al. (2012) suggested that the results should not be generalised to all tDCS use. As with most other studies of tDCS this study also suffers from a small sample size. Additionally, the patients were treatment resistant to multiple antidepressants so the time course may need to be longer to show an effect. Palm et al. (2012) also point out that the test participants were on average older than previously examined test participants. This study also confirmed that subjective evaluations of emotional regulation and is a promising signal that the areas targeted being targeted are having an effect on mood.

Efficacy
Past results suggest that efficacy for tDCS is unclear, with world certifying bodies still not endorsing a procedure or treatment regime that includes tDCS. This is also to be expected since the revival of the technology is still in the early phases and many studies are exploratory in nature and are attempting to understand the meaningful factors involved. Many of the studies also have small numbers of participants. This is the finding within each of the studies but more broadly across a number of meta-analyses. Berlim, et al. (2012) found in their meta-analysis that active tDCS was no more effective at treating MDD than sham tDCS when considering response and remission rates. The analysis only included studies that where randomised double blind and sham controlled. The participants in the selected studies must not have started an antidepressant treatment at the same time but were included if antidepressant use was stabilised prior to the study and was also acceptable if the treatment continued during the trial. Only 6 studies were suitable for inclusion and a total of 200 participants with MDD were included in the analysis. Berlim, et al. (2012) indicate that whilst some of the studies showed the opposite outcome they were comparing results based on change from baseline to end of treatment instead of response and remission rates as per their study. Due to the larger total participants in the meta-analysis Berlim, et al., (2012) conclude that their study has greater statistical power. An interesting consideration that was not discussed in the limitations was that two of the trials included patients who were higher in treatment resistance and from that could be argued that the populations were not equivalent and this may have contributed to the limited differences in response and remission rates.

In contrast, the consensus from one more recent meta-analysis showed that tDCS was effective for MDD, with increased success likened to higher dosages and sessions, augmentation with antidepressants such as sertraline, and those with more severe levels of depression. It was also found that tDCS is less effective for treatment-resistant depression (Brunoni et al., 2016) - which could explain the results found in the analysis by Berlim, et al., (2012). However, results from one more recent study showed that tDCS when paired with cognitive emotional training yielded significant results, even for treatment-resistant patients. This highlights the potential for neuroplasticity to achieve full effect when the dysfunctional brain areas are active during stimulation (Martin et al., 2018). Perhaps the most important work in the field of tDCS to date is the meta-analysis conducted by Lefaucheur and colleagues in 2017. What separates this review from the others is in its careful selection and ranking of data - only choosing studies that were placebo-controlled, with daily tDCS treatment and 10 or more participants. The studies were also structured hierarchically based on their strength of evidence and reliability. This allowed for a more reliable measure, where the results of the review showed probable efficacy for treatment. Still nonetheless, in order for this measure to change to a definitive efficacy and bring tDCS to clinical practice, more larger scale trials are needed as the present literature doesn’t contain enough high-standard studies consisting of over 25 participants.

Conclusion
It is still early days for tDCS treatment and while some of the results are mixed and inconclusive there is enough early positive signs to suggest that with further studies on duration, power, length of overall treatments and electrode placements that tDCS could prove to be another option for the treatment of depression. It may be that tDCS becomes a standalone treatment or used in combination with other treatments but either way the promise of a cheap and effective solution to depression is worth the continued investment in tDCS.

Overall, more investigation is needed in order to understand the effects of tDCS on underlying mechanisms, specifically in the cortico-subcortical regions. More neuroimaging before these experiments is required to know which specific biomarkers to target using tDCS and to also find which individual or genetic profiles are more susceptible to treatment. More research also needs to delve into the cognitive benefits and narrow down consistent results in regards to independent versus paired treatment with cognitive training programs. Studies should also expand upon the best dosage schedule, intensity, electrode size and also investigate the impact and consequences of missing clinical sessions.