Neuromodulation is defined as ‘the therapeutic alteration of neuronal activity, electrically or pharmacologically’. Neuromodulation techniques are novel therapeutic techniques to treat a variety of nervous system disorders including movement disorders, traumatic brain injuries, chronic pain and functional disorders of the nervous system to name only a few. The development of these techniques is based on the fundamental concept of ‘neuroplasticity’.

Neurones are terminally differentiated cells, which means that nervous tissue has no or little capacity to recover following an insult. However, nervous tissue exhibits plasticity, which means nervous tissue can change its structure and function (physical and chemical properties) overtime in response to environmental diversity.1 The brain activity associated with a given function can move to a different location in the brain, thus regaining the lost function. There are three main forms of plasticity: synaptic plasticity, neurogenesis and functional compensatory processing.2 The brain compensates for damage by reorganising and forming new connections between intact neurones. In order to reconnect, neurones need to be stimulated through activity.

This discussion will focus on invasive and non-invasive neuromodulation devices, how they have been used in research, and how they may be applied in clinical practice.

Invasive neuromodulation techniques

Deep brain stimulation
Deep brain stimulation (DBS) is an invasive neuromodulation technique where a small device, similar to a cardiac pacemaker, is surgically implanted to deliver electrical stimulation to targeted areas of the brain, thus influencing the neuronal activity at the target site. It is not fully understood how DBS affects the brain but it appears to reduce neuronal activity like a lesion.3 DBS is now considered a routine treatment option for selected patients with advanced Parkinson’s disease, generalised dystonia, and essential tremor, which are not amenable to other treatment options.4

Randomised blinded trials have demonstrated that it can improve both motor function and quality of life in Parkinson’s disease as well as in primary generalised and segmental dystonia.5 There is evidence that DBS improves quality of life in Parkinson’s disease, more than the best medical management, once intrusive motor fluctuations have developed.6 Tourette’s syndrome may respond to DBS with improvement in severity and frequency of tics as well as reducing compulsive behaviour by as much as 95%.7,8 DBS may also be effective in treating a number of psychiatric disorders, including treatment refractory depression and OCD.9-11 Finally, DBS has been used for many years for the treatment of intractable pain.12 Careful patient selection and accurate electrode positioning are critical to success. Specific guidelines should be consulted and an experienced multidisciplinary team must be involved. 

DBS has the advantage that it can stimulate deep brain areas (eg. sub-thalamic nuclei) which non-invasive techniques cannot. However, DBS requires surgery which can lead to tissue damage, hardware complications, infections and complications related to brain stimulation. The risk of intracerebral haemorrhage is 1/200. It is rare for the intracerebral electrode to migrate from the target site. Surgical intervention into complex circuits, involved in motor, cognitive and limbic functions, could potentially cause severe psychological problems.13 Therefore, although DBS is a widely accepted therapy, it is an invasive and expensive procedure and hence should only be used as a last resort.

Epidural cortical stimulation
Epidural cortical stimulation is a method in which electrodes placed on the surface of the dura provide electrical pulses to the cortex. The surgery involves a mini-craniectomy for electrode placement. This allows electrical stimulation of the cortex without interference from the scalp and skull bone. The most common use of direct cortical brain stimulation is in epilepsy where it has been shown to reduce seizures.14 Cortical stimulation of the dorsolateral pre-frontal cortex has been used in major depressive disorder, resistant to other treatment options.15 Cortical stimulation has also been used in stroke recovery where it appears to be more effective in combination with rehabilitative training when compared to rehabilitation alone, by encouraging cortical plasticity.1

A recent review of invasive cortical stimulation for neuropathic pain concluded that the method is relatively safe and an effective treatment for relief of chronic neuropathic pain.17 However, it has the disadvantage of requiring a surgery and has complications similar to DBS such as electrode erosion and infections.17

Non-invasive neuromodulation techniques
In recent years two techniques have become available to stimulate the brain non-invasively through the skull: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Application of these methods changes the excitability of the cerebral cortex that lasts beyond the treatment period. There is a lack of consensus as to which technique is superior due to lack of comparative controlled trials. However, each technique has its own advantages and disadvantages.

Transcranial magnetic stimulation
Transcranial magnetic stimulation uses a large rapidly changing magnetic field to induce electrical currents in the brain, which in turn stimulates the neuronal tissue. TMS was developed by Anthony Barker and his colleagues in 1985.18 They demonstrated that the cerebral cortex can be stimulated non-invasively by a magnetic field applied at the surface of the skull through a stimulating coil. The depth of stimulation varies depending on the angle and shape of the coil with the deepest being around 5.5cm.19 TMS coils are capable of stimulating an area as small as 25 mm2. The figure 8 coil produces a more localised and shallower stimulation underneath the central segment of the figure 8 coil, whereas the double-cone coil is especially designed for stimulation of large (less focal) deeper cortical structures.20

Stimulators can deliver single pulse (single-pulse TMS), paired pulses or repeated pulses (rTMS) at frequencies of up to 50Hz and induce electric fields in the cortex of up to about 150V/m. Repetitive TMS (rTMS) is longer-lasting and its effects continue after stimulation is ceased.21 Stimulation at ≤ 1Hz is termed slow rTMS and stimulation at greater than 1Hz is termed fast rTMS. Repetitive pulses can increase or decrease cortical excitability, depending on the parameters of stimulation. It is generally agreed that low frequency TMS (≤1Hz) induces inhibition while high frequency stimuli (≥5Hz) are excitatory. 

When used in normal individuals TMS can make subjects perform better or worse on a cognitive task such as reaction time or signal detection.22 Such effects are generally short lasting. In fact, rTMS applied to Broca’s area led to facilitation of language, implying enhanced excitability in Broca’s area.23 In one study rTMS protocol applied to the prefrontal brain region led to facilitation of action naming.24 It is possible that most of these findings are due to rTMS increasing the subjects’ attention to the task at hand, as supported by studies, which show rTMS to ameliorate the symptoms of attention deficit disorder.25

TMS has been used in neurophysiology, as a primary brain mapping tool and as a potential treatment in neurology, psychiatric disorders, rehabilitation and pain.26 Extensive literature has demonstrated safety of TMS in terms of anatomy and biochemistry of the brain,27 provided appropriate guidelines are followed. Thousands of patients with neurological disorders and psychiatric illnesses have undergone TMS safely.28

The most common side effect is headache. TMS therapy gives a sensation like a woodpecker drilling into a tree. Cases of seizures have been reported but are very rare.29 Other rare side effects include excessive tiredness, concentration difficulties and mild transient memory difficulties. There are few other illness-specific side effects. In terms of limitations there are several unanswered and controversial questions regarding the optimal stimulation parameters, interval between each sessions and duration of therapy. TMS has limited spatial resolution but this can be overcome in some situations by combining TMS with techniques to improve spatial resolution, such as EEG.30 In addition, only cortical brain areas can be stimulated. 

Due to low electrical conductivity of skull, the ratio of the maximum current density in the scalp to the maximum current density in the brain is much lower in TMS as compared to tDCS. The downside of TMS equipment is their large size and high cost. A trained operator is required to stand beside the patient. The tDCS devices, in contrast, are light weight, portable and do not require constant attention of the therapist. TMS requires a power supply, whereas tDCS are battery operated, which allows the patients to mobilise freely while receiving the therapy.

Transcranial direct current stimulation
The use of electricity (or galvanisation—a term used for DC stimulation) to treat psychosis dates back to late 18th century. In the 1960s, animal experiments demonstrated that neuronal activity could be altered with DC stimulation of the cerebral cortex and these changes could last for several hours. These studies formed the basis of transcranial direct current stimulation (tDCS).

It involves delivering weak direct current (1-2mA) through a sponge electrode placed on the scalp for periods of 4–5 seconds to more than 20 minutes. The higher the current density, the stronger, deeper and longer is the cortical neuronal stimulation. The delivery of current is not generally perceived by the subjects. The scalp offers high electrical resistance and hence only a fraction of delivered current reaches the brain tissue where it polarises the cortical neurones. Theoretically, depending on the orientation of the neurones with respect to the current, the membrane potentials may be hyperpolarised or depolarised by a few millivolts.31

Transcranial direct current stimulation (tDCS) involves two electrodes; anode (positive electrode) and cathode (negative electrode) and a battery supplying nine volts of direct current. It has been postulated that anodal stimulation depolarises the neurons by 5–10mV from their typical resting membrane potential of 65mV. Neurones will then require less dendritic input to fire. The cathode slightly hyperpolarises the neurones and it will require increased dendritic input to fire. 

Another theory suggests that anodal stimulation decreases local gamma-aminobutyric acid (an inhibitory neurotransmitter) levels, thus increasing neuronal activity, while cathodal stimulation decreases local glutamate (an excitatory neurotransmitter) thus reducing neuronal activity. Initial studies in humans demonstrated that anodal stimulation diminished depressive symptoms while cathodal stimulation reduced manic symptoms.32 Anodal stimulation is the most common form of tDCS as brain stimulation is required in most applications. The ability to induce opposite effects (inhibition or facilitation) on different parts of the brain is an important advantage of tDCS. 

The major limitation of tDCS is being less localised than TMS, as the stimulus is delivered through a relatively large electrode (20–35cm2). tDCS is generally safe, however safety has not been established for longer duration and greater intensities.33 One study of 567 tDCS sessions in healthy volunteers reported mild tingling sensation as the most common adverse effect (70.6%). 

Moderate fatigue was reported by 35.3% of the subjects, whereas a light itching sensation and redness under the stimulation electrodes was felt by 30.4% of cases. Headache, nausea and insomnia were reported infrequently.34 There were no changes in EEG activity and hence there is no effect on seizure threshold. tDCs has a more reliable sham condition (for double blind clinical trials) compared to TMS. 

Research in terms of measuring effects of tDCS on brain tissue and its after-effects have been limited. It has been suggested that studies have largely under reported tDCS-related side effects and more systematic reporting of adverse effects has been proposed.

Potential role of TMS and tDCS in clinical psychiatry
TMS has been used with promising results in a variety of neuropsychiatric conditions. It has been hypothesised that TMS can increase or decrease activity in a specific brain area involved the disorder. However the exact mechanism through, which it offers therapeutic benefit is still poorly understood. TMS has been mostly used in the treatment of major depression, however increasing it is being explored in the treatment of anxiety disorders including post-traumatic stress disorders, obsessive compulsive disorder, schizophrenia and acute mania.35

Medically refractory depression
The idea to treat medically refractory depression with TMS comes from the use of electroconvulsive therapy in the treatment of medically resistant depression. Mood improvement is observed with the high frequency stimulation of dorsolateral prefrontal cortex. More commonly, TMS is applied to left dorsolateral pre-frontal cortex as reduced metabolism has been observed in this region in depressed patients. A large multi-centre randomised trial using TMS in medically refractive depression has been completed.36 US Food and drug administration has approved rTMS for the treatment of medically refractive depression, however NICE has approved TMS for research purposes only. Unlike medicines rTMS does not cause systemic side effects and unlike ECT it does not cause memory loss.

Antidepressant effects of daily prefrontal repetitive TMS is supported by an extensive body of randomised controlled trials,37-39 but the magnitude and duration of this effect remains controversial. There are other unanswered questions as to whether TMS can be used as a maintenance therapy to prevent relapses and whether it should be used in conjunction with conventional antidepressants. 

 In terms of using tDCS in depression, very few studies have reported the effect lasting beyond a few hours. However, one study in depression reported a holding effect of 30 days.40 Similarly there are uncertainties about the maintenance therapy. tDCS is also demonstrated to be effective in bipolar depressive disorders with effect persisting at 30 days, after five days of treatment.41 There is some evidence of therapeutic effect of TMS in mania.42

A variation of TMS called magnetic seizure therapy (MST) uses high intensity, high frequency TMS to induce a seizure in anaesthetised patients. MST is shown to alleviate symptoms in drug resistant depression but is believed to be less effective than ECT.43 MST has far less side effects in comparison, as shown by Kayser and colleagues44 who demonstrated that MST has a significantly shorter recovery time and reorientation time compared to ECT.

Anxiety/post-traumatic stress disorders
It has been reported that patients with post-traumatic stress disorder have increased blood flow and oxygen consumption in right limbic, paralimbic and frontal cortex when recalling the traumatic event. Slow magnetic stimulation of these structures has been reported to reduce anxiety symptoms in post-traumatic stress disorder and panic disorders.45 However, clinical sham-controlled trials are scarce.46 Many of these trials have supported the idea that TMS has a significant effect, but in some studies, the effect is small and short lived.47, 48 TMS remains an investigational intervention that has not yet gained approval for the clinical treatment of any anxiety disorder.

Obsessive-compulsive disorder
Obsessive-compulsive disorder is a psychiatric disorder characterised by irresistible impulses to carry out certain tasks repeatedly. Brain regions involved in this disorder include basal ganglia and orbitofrontal cortex. Some controlled studies have evaluated the effects of repetitive TMS (rTMS) in patients with obsessive-compulsive disorder (OCD). Greenberg observed that a single session of right prefrontal cortex stimulation produced a significant decrease in compulsive urges in OCD patients lasting over eight hours.49 Other studies have reported transitory improvements in mood but there are no observations for changes in anxiety or obsessions. There are currently insufficient data from randomised controlled trials to draw any conclusions about the efficacy of transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder.50

The use of deep brain stimulation of the nucleus accumbens has been explored in the treatment of treatment refractory OCD.51 However, research is too limited to recommend any clinical use.

Schizophrenia
Schizophrenia is a devastating psychiatric illness characterised by persecutory delusions, auditory hallucinations, and depression. Many small studies have used rTMS on the temporoparietal cortex to reduce auditory hallucinations in schizophrenia and showed a significant improvement when compared to sham stimulation.52 This is likely to be effective by reducing activity in the brain areas responsible for the auditory hallucinations. In comparison, other studies have shown that rTMS of the temporoparietal cortex did not have any effect on hallucinations compared to sham controls.53 Larger studies are required to fully evaluate the place of TMS in the management of schizophrenia.

Disorders of cognition
The use of TMS/tDCS has been explored in dementia and other cognitive disorders. It has been hypothesised that interaction between task execution and stimulation may improve or reduce cognitive performance. Studies and reviews have suggested rTMS as an effective treatment for Alzheimer’s disease especially during the later stages of the disease.54, 55 However, many of these studies used patients with ‘probable Alzheimer’s disease’, simultaneously used other treatments and had very few subjects. A study involving patients with Alzeimer’s disease showed that with anodal tDCS in temporoparietal areas, performance on memory tasks improved.56 There is currently insufficient data to recommend neuromodulatory techniques in cognitive neurorehabilitation.

Potential role of TMS and tDCS in clinical neurology
Stroke
Damage caused to the brain by a stroke can have a variety of neurological and psychological implications. Effective neurorehabilitation, with physiotherapy for example, has been shown to improve outcome in post-stroke patients. TMS and tDCS have been studied as adjuvant strategies in neurorehabilitation. Cathodal tDCS has been shown to improve object naming in dysphasic stroke victims when using stimulation over damaged left fronto-temporal cortex compared to sham controls.57 The basic idea is that patients with extensive stroke exhibit abnormally high inhibition from the intact hemisphere to the diseased hemisphere and modulating this inhibition (up regulation of excitability of the motor cortex of the diseased hemisphere and down regulation of excitability of the motor cortex of the intact hemisphere) with TMS or tDCS may improve motor function in post-stroke patients. This idea is supported by studies in animals where direct epidural cortical stimulation improved motor function.58 Human studies so far have reported relatively transient moderate performance improvements.59, 60 More studies are required synchronising TMS/tDCS with established stroke rehabilitation measures.

Role in neurophysiology
Single pulse TMS has long been used for the functional assessment of corticospinal tract by calculating central motor conduction time (CMCT). CMCT is helpful in the diagnosis of demyelinating (multiple sclerosis) and neurodegenerative (motor neurone disease) disorders even before clinical manifestations occur. TMS mapping technique can be used to predict prognosis in stoke by allowing estimation of the damaged area.61 TMS has also been used for intraoperative monitoring, to monitor functional integrity of brain during surgery. The connectivity between different brain areas can also be studied by combining TMS with functional neuroimaging. TMS has helped in our understanding of the role of different cortical regions in different behaviours as transient disruption of a given cortical activity with TMS leads to the change in the performance of a given behaviour.62 TMS can be used to create “virtual brain lesions” and the contribution of different regions of brain on performance in a specific task can be assessed (causal chronometry). For example, Mottaghy and colleagues created a virtual lesion of the dorsolateral prefrontal cortex (DLPFC) which reduced working memory, showing that the DLPFC is involved in working memory.63 The combination of rTMS with positron emission tomography or magnetic resonance spectroscopy has been used as a tool to investigate neurochemical functional anatomy.64

Role in Parkinson’s disease
There is anecdotal evidence that TMS applied to the pre-frontal cortex can improve motor symptoms in Parkinson’s disease by increasing dopamine release.65 However, other studies did not replicate the findings.66
Parkinson’s disease is often accompanied by cognitive impairment and loss of working memory. Studies have shown that anodal stimulation of the left DLPFC improves working memory and cognition in patients with Parkinson’s disease.67

Role in epilepsy and related disorders
TMS has been used for the treatment of epilepsy with controversial results.68 Electrical stimulation of the vagas nerve is an established intervention for medically refractory epilepsy.

Role in pain management
tDCS has been shown to reduce pain perception and modulates pain thresholds in healthy volunteers and in central and chronic pain disorders.69 For example, tDCS can ameliorate pain caused by traumatic spinal cord injury70 or fibromyalgia,71 when compared to sham stimulation. These modulations in pain perception have been shown to last weeks, although effectiveness reduce with time.70

Conclusion
Neuromodulation techniques are novel and interesting tools in neuroscience research, diagnostics and therapeutics. Although encouraging results have been reported in a number of neuropsycological disorders, current state of knowledge is insufficient to recommend widespread clinical use. The research is still at an early stage and more work is required to ascertain the most optimal stimulus parameters (intensity, frequency, dosage, site of stimulation and dosing schedule) and the safety of these techniques. In the absence of large randomised controlled trial TMS or tDCS cannot replace existing and validated therapies. However, it is highly likely that rTMS may become a routine treatment for depression. There are no studies that used TMS and tDCS in combined protocols. Another unanswered question is whether general or focal stimulation is required. If focal stimulation is used the most appropriate sites for stimulation have to be ascertained. Neuroimaging techniques such as positron emission tomography or functional magnetic resonance imaging are invaluable in informing the most appropriate site of brain to be stimulated in different disorders.

Conflict of interest: none declared

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