Brain stimulation: a therapeutic approach for the treatment of neurological disorders

Abstract Brain stimulation has become one of the most acceptable therapeutic approaches in recent years and a powerful tool in the remedy against neurological diseases. Brain stimulation is achieved through the application of electric currents using non‐invasive as well as invasive techniques. Recent technological advancements have evolved into the development of precise devices with capacity to produce well‐controlled and effective brain stimulation. Currently, most used non‐invasive techniques are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), whereas the most common invasive technique is deep brain stimulation (DBS). In last decade, application of these brain stimulation techniques has not only exploded but also expanded to wide variety of neurological disorders. Therefore, in the current review, we will provide an overview of the potential of both non‐invasive (rTMS and tDCS) and invasive (DBS) brain stimulation techniques in the treatment of such brain diseases.

Administration (FDA). On the other hand, invasive technique, DBS, is also an FDA-approved treatment and, in the late 1980s, it began to emerge as a life-changing therapy for patients with involuntary movement disorders.

| Transcranial magnetic stimulation
TMS is a neuromodulation technique that uses large transient magnetic fields to induce focal electrical fields in a specific brain area, and the availability of sophisticated equipment has made it possible to employ repetitive TMS (rTMS). The effects of rTMS vary depending on the shape of the coil (figure of eight, H coil, double cone coil), 2 pacing pattern (high frequency, low frequency, theta-burst), and stimulation site.
In fact, TMS is considered as a tool with great therapeutic potential because it is safe and the risk of severe negative side effects upon application is very low.

| Mechanism of action
TMS induces short pulses of intracranial electrical current and is applied in several ways: as single pulse, as paired pulse to the same or different brain areas, or as rTMS. Single-pulse stimulus depolarizes neurons 3 ; however, rTMS can induce changes in excitability of the cerebral cortex, locally as well as in neurons at areas far from the stimulation site, along functional anatomical connections. 3,4 Although underlying mechanisms of the therapeutic outcomes of rTMS application have not been fully elucidated, rTMS can induce changes in cerebral blood flow, 5 oxygen consumption, cortical activity, 6 and release of neurotransmitters. 7,8 Therefore, it has been argued that these functional changes might be associated with positive clinical results. BOX 1 Various types of brain stimulation techniques 1. Non-invasive brain stimulation techniques modulate brain excitability by the application of either magnetic fields over the head or electrical currents directly through electrodes placed on the scalp. There are several modalities of use in both the techniques.

Transcranial magnetic stimulation (TMS)
In TMS, short electromagnetic pulses are administered through a magnetic coil. In repetitive TMS (rTMS), a figure-of-eight coil is used to stimulate precise but relatively superficial locations on the cortex, whereas in deep TMS (dTMS) a H-coil targets broader but deeper brain areas.
Magnetic seizure therapy (MST) involves the induction of a seizure by applying high-intensity magnetic field pulses through a magnetic coil placed on the head. The stimulation is limited to a focused area in the brain, and therefore, it produces minimal effect in surrounding tissues.

Transcranial electrical stimulation (tES)
The most modern and used version of tES is transcranial direct current stimulation (tDCS). In tDCS, continuous but low-intensity current is applied through electrodes (anode and cathode) placed on the scalp. High-definition tDCS (HD-tDCS) is a variant of this technique and in contrast to tDCS where distribution of electrical current in a target area is relatively diffused; HD-tDCS devices are used for increased focal stimulation of a target area.

Cranial electrotherapy stimulation (CES)
is a form of neurostimulation that applies pulsed, low-intensity current through electrodes placed on anatomical positions around the head, such as earlobes and temples.
Transcranial random noise stimulation (tRNS) is achieved by applying an alternating current which varies in frequency and amplitude (within a certain range) throughout the stimulation period. However, transcranial alternating current stimulation (tACS) is frequency specific stimulation, and therefore, current is applied at a fixed frequency rather than randomly acquired range of frequencies as in case of tRNS.
Electroconvulsive therapy (ECT) involves a brief electrical stimulation of the brain while the patient is under anesthesia. Electrodes are placed at specific sites on the scalp and electrical currents are passed through the brain to produce a brief seizure.
2. Invasive brain stimulation techniques generally involve surgery to implant an electrode deep in the brain to deliver electrical pulses at a high frequency. The intensity and frequency of electrical currents are controlled by a generator implanted under the skin of chest. Deep brain stimulation (DBS) involves application of continuous stimulation through a pair of electrodes implanted in a specific area of brain. However, vagus nerve stimulation (VNS) implicates the delivery of electrical pulses to the left vagus nerve through a device implanted under the skin.
2.1.2 | TMS application to alleviate the symptoms of neurological disorders For effective rTMS application, adjustments in both spatial and temporal parameters are essential. In literature, for the determination of spatial location of a target in brain, 52% of the studies have used magnetic resonance imaging, 27% scalp measurement, 15% functional magnetic resonance imaging, and 6% hotspot targeting. 9 Similarly, temporal parameters, which include stimulation frequency, number of pulses per trial, and interval duration between each stimulus, are also diverse. For stimulation frequency, few studies have used low-frequency stimulation of 1 Hz and most studies have applied a high-frequency stimulation ranging from 5 Hz (in 14%), [10][11][12][13][14][15][16][17][18][19] Hz (in 67%), to more than 20 Hz (in 20%). The stimulus interval time varied from 300 ms to 37,400 ms, and the number of pulses administered in each trial was <10; however, some studies applied more than 20 pulses. Additionally, combining rTMS with concurrent behavioral interventions in some neurological disorders has turned out to be more effective. 10 Therapeutic benefits of rTMS are summarized in Table 1.

Parkinson's disease
A progressive degeneration of dopaminergic neurons in the basal ganglia leads to severe impairment in motor functions of patients with Parkinson´s disease (PD). The application of rTMS by several clinical groups found that PD patients improved motor functions upon application of high-frequency (10 Hz) rTMS in M1 area of motor cortex and most patients showed improvements in bradykinesia. [11][12][13][14][15] The motor improvements in PD patients were associated with changes in neuronal activity. 16 Furthermore, a meta-analysis of 23 studies with total of 646 patients found that the application of rTMS to the motor cortex area of brain produces a significant long-term improvement in motor functions. 14

Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive deficits and is the most common form of dementia. The application of rTMS in AD patients has been shown to improve motor 17,18 and cognitive functions. 19,20 The cognitive improvement was observed immediately and one month after the treatment but not after 6 months. 21,22 Furthermore, the application of high-frequency (10 Hz) TMS significantly improved cognitive performance in AD patients with mild deterioration, 23,24 and similarly, meta-analysis studies found that rTMS is effective in treating cognitive dysfunctions in AD patients. 25,26 Vascular dementia Vascular dementia is the second most common form of dementia after AD, and it accounts for at least 20% of dementia cases. A study in rats with vascular dementia showed that application of TMS was able to improve spatial learning and memory, 27 protect pyramidal cells from apoptosis, and promote synaptic plasticity in the CA1 area of the hippocampus. 28,29 However, the studies in humans are scarce.
Nevertheless, a randomized controlled pilot study in 7 patients with vascular disease and mild cognitive deficits without vascular dementia showed that one session of high-frequency rTMS applied to the left DLPFC improved executive functioning, whereas no effects on any other cognitive functions were observed. 30 Another study in patients with vascular disease and vascular cognitive impairments but without dementia found that the stimulation of left DLPFC and not left M1 area with 4 sessions of rTMS significantly improved the cognitive ability. 31

Attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is primarily associated with deficits in attention and executive functions. A pilot study in 9 adolescents and young adults with ADHD found significant improvement after the treatment with high-frequency (10 Hz) rTMS. 32 Another pilot study in 43 adult ADHD patients showed that the application of high-frequency (18 Hz) rTMS for 3 weeks caused significant improvement in ADHD symptoms. 33 In contrast, a study in adult ADHD patients reported no effect after application of deep TMS (dTMS). 34 The effect of standard rTMS is more focal and reaches a depth of 0.7 cm, while the effect of dTMS is broader and reaches a significant depth of 3.2 cm. Therefore, it seems that a focal treatment with rTMS is more effective in the treatment of ADHD.

Dyslexia
Dyslexia affects at least 5% of school-aged children and is characterized by difficulty in learning to read and spelling of written texts.
Most dyslexics have difficulties in relating alphabet letters to the sounds they symbolize. So far, there is no study with larger number of dyslexia patients. In a study with 10 dyslexics, treatment with high-frequency (5 Hz) rTMS to areas that are not very active in dyslexics during reading, such as the left superior temporal gyrus and the left inferior parietal lobe, improved both precision and reading speed of the dyslexic adults. 35

Autism spectrum disorder
Autism spectrum disorder (ASD) is a developmental disorder and is characterized by the difficulty in social interaction and emotional recognition, repetitive behaviors, and lack of interest. The prevalence of ASD is estimated at 1 every 110 births with a higher incidence in children. [36][37][38] In a study, application of low-frequency (1 Hz) rTMS on DLPFC area of autistic patients caused significant improvements in the process of goal recognition, reduction of motor errors to specific stimuli, and reduction of repetitive and stereotactic behaviors. 39 Another study showed that autistic youths as well as adults improved their executive functions after the application of high-frequency (20 Hz) rTMS on the DLPFC. 40 In the same line, a review of 24 studies with 317 ASD patients and a meta-analysis of 23 studies with 339 ASD patients found that the application of rTMS improved the ASD symptoms in patients. 41,42

Down syndrome
Down syndrome is a genetic disorder; however, patients with Down syndrome show various neurological symptoms, such as neuromotor abnormalities, reduced learning capacity, cognitive and language alterations, and hampered reading skills. [43][44][45] The first study with TMS on the motor cortex showed that young people with Down syndrome have normal cortical excitability, but altered cortical synaptic plasticity. 46 So far, there is no study of TMS application to improve the language and cognitive alterations in Down syndrome.

Chronic pain
Chronic pain is a disorder associated with various pathologies and is thought to develop from CNS nerves damage. It has been shown that a single stimulation with high-frequency TMS produced small (12%) but short-term reduction in pain intensity, which was not considered as clinically meaningful. 47 However, a systematic review of 12 randomized clinical trials involving 350 patients with focal or generalized chronic pain found that low-frequency rTMS stimulation produced no effect, whereas high-frequency stimulation induced long-lasting analgesic effect and meaningful relief from chronic pain. 48 Similarly, other systematic reviews and meta-analysis have identified that rTMS 49,50 as well as rTMS combined with exercise 51 has beneficial effect on relieving patients from chronic pain.

| Transcranial direct current stimulation
tDCS is the most used form of electrical stimulation. In comparison with rTMS, tDCS is not as powerful and generates weak stimulus; however, it is relatively easy to use and transport, lot less expensive, and it has low incidence of side effects. The effect of tDCS varies according to the type of current (direct, alternating, pulsed, random noise), polarity (anodal or cathodal), current intensity, and stimulation site. 52  Table 2.

Alzheimer's disease
Studies have shown that tDCS can stabilize verbal memory in patients with AD dementia 62 and enhance the listening comprehension. 63 The stimulation of left DLPFC with tDCS for 5 days produced significant improvement in immediate and delayed recall performance of a picture memory and that this improvement persisted for one month. 64 In addition, a meta-analysis of 7 studies with a total of 146 mild-to-moderate AD patients showed that tDCS stimula-

TA B L E 2 (Continued)
stimulation combined with training for reading in children and adolescents with dyslexia produced long-lasting improvement in reading. 85 Application of tDCS also improved reading speed and fluency in dyslexic adults. 86

Attention deficit hyperactivity disorder
Several meta-analysis and other studies in ADHD patients have shown that the tDCS treatment increases brain connectivity and improves behavior, attention, working memory, inhibitory control, and cognitive flexibility. [87][88][89][90][91] In addition, a study in 37 ADHD patients showed that tDCS causes an improvement in impulsivity symptoms. 92

Epilepsy
Studies in children and adults with focal as well as refractory focal epilepsy have shown that a stimulation with cathodal tDCS decreases epileptiform discharges. [93][94][95][96] Similarly, several meta-analysis and systematic reviews found that cathodal tDCS application in epileptic patients with either focal epilepsy or refractory focal epilepsy successfully restrained epileptiform activity and reduced seizure frequency. 97-100

Cerebral palsy
Cerebral palsy is a permanent movement disorder that is caused by abnormal motor development or damage to the parts of brain that control movement, balance, and posture. Recent studies in children and adolescents with cerebral palsy have shown that tDCS stimulation combined with physiotherapeutic training improves body roll speed, balance, mobility, and walking distance and decreases spasticity and gait. [101][102][103][104] These studies showed that single tDCS session caused improvement for a short period; however, tDCS treatment sessions ranging from several weeks to few months produced more sustained effect. A treatment with tDCS alone also improved mobility, gait, and balance in pediatric cerebral palsy patients. [105][106][107] Chronic pain Studies have shown that a treatment with tDCS on the M1 area causes long-lasting relief in medication-resistant patients with chronic pain syndrome such as trigeminal neuralgia, post-stroke pain, back pain, and fibromyalgia. 108,109 The efficacy of tDCS in alleviating pain has also been shown in patients with multiple sclerosis joint pain, 110 neuropathic pain, 111 spinal cord injury, 112 fibromyalgia, 113 chronic migraine, 114 foot pain, 115 and intra-abdominal pain. 116 A meta-analysis studies further found that a treatment with tDCS reduces chronic pain intensity. 47

| Deep brain stimulation
DBS treatment implies passing electric current into the subcortical nuclei of the brain through surgically implanted electrodes. In contrast to rTMS and tDCS, DBS treatment in some of the brain nuclei has been shown to produce severe side effects.

| Mechanism of action
Although how DBS produces improvements remains not well understood, it has been shown that DBS treatment changes brain activity in a controlled way. The effects of DBS tend to cause excitation in neighboring axons, improvement in microvascular integrity, increase in local cerebral blood flow, and stimulation in astrocytes to release calcium, which can further lead to the release of glutamate and adenosine. 117 In addition, there is evidence that DBS can induce local and possibly distal proliferation of neurons. 118 Nevertheless, from a neurophysiological point of view, the "disruption hypothesis" appears to be increasingly accepted.
According to this hypothesis, DBS dissociates the input and output signals and causes a disruption in the anomalous flow of information. 119

| DBS application to alleviate the symptoms of neurological disorders
Therapeutic benefits of DBS are summarized in Table 3.

Alzheimer's disease
A case study found that the forniceal DBS in a patient with severe AD symptoms improved the activities of daily living but had no effect on cognition 120 and a phase II and two-year follow-up study in 42 patients with more than 65 years of age and mild AD showed that the application of Essential tremor DBS is considered as an effective and safe therapy for essential tremor.
Several meta-analysis studies in essential tremor patients found significant improvement after DBS treatment. 130,131 Autism spectrum disorder In a case report, application of DBS in basolateral amygdala caused improvement in the core symptoms of ASD and the related selfinjurious behavior in a patient of 13 years of age. 132 Similarly, in

Tourette syndrome
Tourette syndrome is a neurodevelopmental disorder characterized by the appearance of involuntary repetitive motor and vocal tics.
High percentage of patients also present other brain disorders, such as attention deficit hyperactivity disorder (ADHD) and obsessivecompulsive disorder (OCD). A meta-analysis study found that DBSmediated stimulation of both the GPi and the thalamic nucleus improved tics and decreased OCD in patients, 145 and a review of 48 studies in 120 patients with Tourette syndrome found substantial improvement in the severity of tics. 146 Similarly, other reviews and meta-analysis studies identified that the stimulation of thalamus, globus pallidus, or nucleus accumbens produced overall improvement in the symptoms of Tourette syndrome. 147-149

| CON CLUDING REMARK S
The success of brain stimulation treatment lies in the availability of an effective tool and the most desirable device would be the one which not only can penetrate deep into the brain and focally modulate a specific region and only that region but also is cheap, portable, and painless, and can be applied in awake, alert humans.
However, currently available devices fall short of such expectations.
Considering that brain stimulation technologies continue to evolve and advancing rapidly, more versatile tools are expected to develop in near future. Nonetheless, within the currently available noninvasive devices, tDCS involves passing relatively weak direct current in the brain and is inexpensive and relatively safe. While TMS is more expensive and might occasionally cause a seizure (<1%), it is powerful. In contrast, tDCS cannot cause a seizure and is weak.
DBS, which is an invasive technique, is often used as a last resort for treating patients who have shown no relief after other viable therapies, and compared to tDCS and TMS, DBS produces serious side effects. For example, there is high rate of suicide in patients treated with DBS, particularly with stimulation in STN and GPi areas of brain. 150

CO N FLI C T O F I NTE R E S T
Authors declare no conflict of interest.