Transcranial magnetic stimulation for the treatment of anxiety disorder

Introduction

Individuals may experience anxiety as a warning sign in unknown situations, especially in response to fear and anticipation of danger.¹ However, it is considered pathological when it directly affects the individual’s quality of life, affecting social relations, cognitive function, and the wake–sleep cycle.^2–4 Anxiety disorders represent one of the major psychiatric disorders today that can impair the quality of life of adults.^2–4

The Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-5) defines the presence of an anxiety disorder when some criteria are met, for example: symptoms occurring more than six months, excessive anxiety and worry, panic attacks, restlessness or feeling nervous, fatigue, irritability, sleep and eating disorder. Based on the symptomatology, anxiety disorders can be classified in: Generalized Anxiety Disorder (GAD), Social Anxiety Disorder, Panic Disorder (PD), Agoraphobia, Separation Anxiety Disorder, Selective Mutism and Specific Phobias. In addition to anxiety disorders, anxiety can be a symptom or comorbidity in several other pathologies, such as Major Depression,⁵ Obsessive Compulsive Disorder,⁶ TBI,⁷ among others.

Neuromodulation minimizes the impact of mood changes^8–11 and repetitive transcranial magnetic stimulation (rTMS) is receiving attention in the last decade.^12,17 TMS is a non-invasive method of stimulating the motor cortex neurons through the scalp and skull based on the principle of electromagnetic induction.^18,19 TMS was approved by the Food and Drug Administration (FDA) in 2008 as an alternative treatment for Major Depression Disorder,²⁰ and has been shown to decrease the symptoms of Post Traumatic Stress Disorder (PTSD),²¹ Obsessive Compulsive Disorder (OCD),²² and Anxiety Disorders.¹⁴

Non-invasive brain stimulation techniques allow researchers to study in real-time the human brain activity, characterize the balance of excitation and cortical inhibition, and help guide plastic changes.⁸ With TMS, you can apply repetitive induced current pulses that can increase or decrease cortical excitability and stimulate the process of neuronal plasticity.^9,23,24 A coil of wire is placed on the scalp generating an electric current that flows through the target area, inducing neuronal depolarization. Possible effects are depended on subject’s age, pharmacological treatment, number of technical parameters, including the intensity and number of stimulations (ie, frequency), coil orientation, focus, and depth of stimulation.^9,25,26

Although TMS pulses (simple and repetitive) are considered safe, it is contraindicated for people who use a pacemaker or other implantable electronic devices.^21,27 Patients with bone defects and craniotomy pose another concern, because the conductance of the structures would be modified.^21,24 Some adverse effects might occur, such as headache and minor muscle spasms at the stimulation site.^21,25,28,29

Recent literature reviews discussed the use of TMS as an intervention strategy for anxiety. Vicario et al's³⁰ study addressed the use of TMS and transcranial direct current stimulation (tDCS) and other studies portray its efficacy for other psychiatric disorders, without major insights.^14,30–32 However, there is a gap in the literature regarding rTMS efficacy in anxiety symptoms (primary and secondary outcomes) in clinical trials. Our study focused on the effectiveness of TMS for Anxiety Disorders and as an intervention for Anxiety Symptoms arising from other pathologies. We make the division between anxiety arising from Neurological Disorders and Psychiatric Disorders. Our hypothesis was that high-frequency rTMS on the dorsolateral prefrontal cortex (DLPFC) will decrease anxiety symptoms in patients with anxiety disorders, considering anxiety as the primary outcome.

Methods

We conducted a literature online search including Web of Science Medline/PubMed MEDLINE databases. We have included publications from any time until March 2019. We included clinical trial and open-label using the keywords: “TMS”, “transcranial magnetic stimulation”, “noninvasive brain stimulation”, and “anxiety”. The first exclusion was by title and followed by abstracts and full texts. Abstracts and full text, and studies were included if fulfilled, the inclusion criteria: (a) use of rTMS as intervention; (b) anxiety was assessed as primary or secondary outcome; (c) sample was adults; (d) published in peer-review journals; (e) full text written in English. The exclusion criteria: (a) animal studies; (b) case report; (c) systematic review or meta-analysis; (d) paper not written in English; (e) study with healthy; and (f) studies that did not report the use of rTMS in anxiety symptoms. Searching and data analysis were performed by Rodrigues PA and Zaninotto AL. This method follows PRISMA guidelines.

Results

Figure 1 shows the systematic review that initially 358 papers were found (Pubmed =172; Web of Science =186). We found 32 studies that fulfilled our eligibility criteria.

Figure 1 Flow diagram of the papers selected in our study, following PRISMA statement guidelines.

For a better understanding of the results, we divided the target population of the trials in two categories: Category 1) patients with Anxiety Disorders, according to DSM-5 (Table 1); Category 2) Anxiety symptoms, from neurological and psychiatric disorders that also evaluated anxiety symptoms as comorbidity (Table 2).

Table 1 Patients with anxiety disorders, according to DSM 5

Table 2 Anxiety symptoms, from neurological and psychiatric disorders

Treatment for anxiety disorders

In our search, five studies were randomized double-blind clinical trial (RCT) and two studies were open-label. Seven papers described Anxiety Disorders as the main outcome for rTMS,^5,33–38 one was related to Anxiety Disorders, two were Panic Disorder (PD), and the other four were GAD (Table 1). The sample size of these studies ranged from 13 to 25 patients.

The right dorsolateral prefrontal cortex (DLPFC) was the most frequent stimulation region and in one study they stimulated the left region of the DLPFC. The predominant frequency used was 1 Hz, although one study compared the use of 1 hz and 10 hz and another used only 20 Hz.

The number of sessions ranged between 10 and 30 and the number of pulses per stimulation ranged from 750 to 3600. Most papers used an intensity of 110% of the rest motor threshold (RMT), one used 80% and other used 90% of RMT and one study did not specify.

Treatment for other psychiatric neurological diseases

We found 23 studies reporting rTMS as an alternative for the treatment of neurological or psychiatric disorders and as secondary intervention to anxiety symptoms (Table 2).^6,21,39–61

Papers that cited symptoms of anxiety as comorbidity were grouped in Neurological Disorders (Table 3)^{40,45,47,51,54,55,59} and Psychiatric Disorders (Table 4).^{6,21,39,41–44,46,48–50,52,53,56–58,60,61} We found that MDD is the psychiatric disorder with the highest occurrence appearing in seven papers while pain is the highest Neurological Disorders occurrence appearing in three papers.

Table 3 Symptoms of anxiety present in neurological disorders

Fourteen papers reported the stimulation in the left DLPFC, three papers both left and right DLPFC and in one study the left auditory cortex was stimulated. Two papers focused the stimulation in the left temporoparietal region and left primary motor cortex. The stimulation target of right DLPFC appeared in three papers, in addition to those already mentioned. These regions were stimulated in one paper each: primary motor cortex contralateral to the amputated leg, motor cortex area of the frontal lobe, and the epileptogenic focus. Two studies described stimulation in the left temporoparietal region and left primary motor cortex.

High pulse frequency (>5 Hz) used in rTMS protocols can have an excitatory effect while a low frequency (1 Hz) has an inhibitory effect. These effects are not limited to the target of stimulation, favoring the improvement of mood symptoms since there is complex connectivity of the cerebral cortex with other deep brain regions, favoring, ultimately, the improvement of mood symptoms. Most studies analyzed in this review used 10 stimulation sessions and half used excitatory stimulation for all subjects with rTMS frequency range between 5 Hz and 20 Hz. In the treatment of anxious symptoms, studies reported using between 4 and 31 sessions with 200–5000 pulses per stimulation and an intensity of 20–130% of the RMT.

Measures of anxiety symptoms

One of the criteria used to include the paper in our systematic review was to contain measures to assess the symptoms of anxiety pre and post rTMS sessions. The Hamilton Rating Scale for Anxiety (HRSA) was the main scale found in this review; overall, this scale appeared in 14 papers; secondly the Beck Anxiety Inventory (BAI) and the State-Trait Anxiety Inventory (STAI), both appearing in four papers. In Table 5, we observe the other scales of assessment of the symptoms of anxiety found and their frequency in the papers.

Table 4 Symptoms of anxiety present in psychiatric disorders

Table 5 Anxiety scales found in papers

Clinical findings

We observed, in general, that most of the studies found satisfactory results with the use of rTMS in Anxiety Disorders and Anxiety as comorbidity.

In the studies on Anxiety Disorders, it was observed that three papers reported a sustained effect of response on the improvement of anxious symptoms, one paper reported improvement of symptoms, although this response did not sustain in the long term and one paper reported that there was no significant improvement.

The papers on Anxious Symptoms showed that most of the studies obtained the sustained effect of response on the anxiety symptoms observed in 21 studies. Two studies showed improvement but not sustained over time and one of them did not find a positive response to the improvement in anxiety symptoms.

Tolerability and safety

Adverse effects were minimal, showing that there is safety in the application of rTMS in anxious symptoms independent of the primary outcome.

In the papers on Anxiety Disorders, only one study reported that one participant in the active group had seizures and three participants reported transient dizziness; in the other papers, no adverse effects were reported.

In the papers on Anxious Symptoms, mild side effects were observed. The most frequent effect was a headache that appeared in 12 studies. In two studies, some patients were withdrawn because of side effects or treatment intolerance. Table 6 has the description and frequency of other side effects found in the papers on Anxious Symptoms.

Table 6 Side effects of rTMS found in papers

Discussion

The rTMS is already established as a non-invasive valid alternative to measure plastic alterations of the cerebral cortex for the treatment of depression,² borderlines,⁴¹ OCD,⁶ among other pathologies. We observed in this review that anxiety is one of the main symptoms related to current mood disorders, with a direct impact on individuals’ quality of life.⁷

TMS have a direct correlation between the parameters associated with cortical excitability and plasticity, suggesting the existence of mechanisms that partially overlap and probably act in the same neurophysiological framework.⁶²

Pennisi et al suggest that lesion in the ischemic subcortical and prefrontal region might have implications in cognition and mood and may result in functional changes of the intracortical system, in addition to associating an increase in global cortical excitability, together with a significant worsening of frontal lobe abilities, but without substantial functional impairment.⁶²

Cortical plasticity plays a clear and fundamental role in patients with depression, while this still seems to be firmly established in anxiety disorders.⁶³

Studies observed that impaired brain plasticity may be one of the pathophysiological mechanisms underlying cognitive decline and major depression.⁶³ Some degree of cognitive impairment is often observed across the clinical spectrum of mood disorders, and between depression and cognition often bidirectional.⁶³ Depressed patients have significant differences between the brain hemispheres, the intracortical neurochemical circuit (inhibitory or excitatory) might be unbalanced, the excitability of the motor cortex and TMS may indicate a disruption of plasticity.⁶³ The data suggest that the motor cortex is more refractory to modulatory inputs from other non-motor areas within the CNS in depressed individuals.⁶³ In addition, several studies have shown that functional abnormalities in cortical connections may play crucial roles in patients with depression and other mood disorders.⁶³

Studies with depressive disorder usually predict anxiety symptoms as a secondary outcome. It is possible to observe how this mechanism occurs in cases of anxiety disorders, since it is directly related to the functioning of neurotransmitters and to the cerebral circuits. TMS may interfere directly in this functioning and may influence the regulation of anxiety as a symptom arising from another psychopathology or as an anxiety disorder.⁶³

Other studies^14,30,32 have found that TMS have promising results as a treatment for anxiety disorders; we observed comparable results, showing TMS intervention having positive effects on anxiety symptoms. However, there is still no standard intervention protocol for the use of TMS, neither for anxiety or depression disorders, as a comorbidity of psychiatric and neurological disorders.^14,30,32

A few studies describe protocols for TMS application on anxiety disorders, Dilkov et al³³ evidenced the effects of rTMS on participants with GAD. Most participants who received treatment from 25 rTMS sessions had a clinically significant decrease in anxiety symptoms as identified by the efficacy symptom scale.³³

Another study also observed positive results in subjects with GAD after 30 rTMS sessions according to pre- and post-treatment comparative assessment scales.³⁵ However, the Sham coil group also had reduced anxiety symptoms; they had a limited sample size and further assessment is necessary.³⁵

The authors used 2 sessions of rTMS in the prefrontal ventromedial cortex region for the treatment of Acrophobia and fear of irrational stature.⁶⁴ Their study used virtual reality technology to assist in the therapy and they observed a better response for fear and symptoms.⁶⁴

There is no clear pattern for using high or low frequencies of TMS stimulation in which regions of the brain. One review study cited the use of both high- and low-frequency TMS stimulation under the right and left stimulation target DLPFC.³⁰ Iannone et al¹⁴ cited papers that used both high and low frequencies of TMS on anxiety disorders. Another review study found that the right and left DLPFC were targets for TMS stimulation in most papers.³¹ However, when searching for anxiety as a secondary outcome, the stimulation region was dependable on the primary outcome of the TMS intervention. TMS stimulation for pathologies involving motor aspects poses another difficulty.⁶⁵ In these cases, the stimulation target was primarily in specific regions of the motor cortex.⁶⁵

Patients with Restless Legs Syndrome (RLS) who receive TMS intervention had improvements on anxiety symptoms with the improvement of the RLS symptoms.⁴⁷ A similar study found that using TMS to stimulate the motor cortex area alleviated motor sensory complaints of RLS patients. TMS excitation and inhibition rates indicate intracortical injury and corticospinal imbalance, involving GABAergic and glutamatergic circuits, as well as impairment of the short-term mechanisms of plasticity.⁶⁵ The activation induced by rTMS with the consequent increase in dopamine release may have contributed to the clinical and neurophysiological outcome in those patients.⁶⁵ The occurrence of anxiety in patients with RLS is related to an abnormal sensorimotor integration, suggesting an interrupted connectivity in the RLS.⁶⁶ Using TMS in the sensory cortex motor region may promote improvements of physical symptoms and therefore reduction in anxiety.⁶⁶

TMS has also been shown to be effective as a sustained response effect compared to drug intervention. It is observed that drug-resistant patients on MDD treatment achieved improvement of symptoms with the use of TMS after a period of six months post-intervention, while this period is reduced when only medication is used.⁶⁷

Although there is no consensus in the TMS intervention parameters for anxiety disorders and symptoms due to neurological or psychiatric disorders, we observed that the DLPFC region is preferred among researcher’s stimulation target. TMS have promising results in high frequency, promoting excitatory stimulation, and low frequency, promoting inhibitory stimulation. The number of sessions should range from 10 to 20 sessions so that the sustained response effect is possible. The stimulation of the motor cortex, especially in the sensorimotor region, also shows promising results in the stimulation of anxiety symptoms due to neurological disorders, mainly focusing on motor aspects.

Conclusion

We observed in this review that TMS might be a satisfactory intervention measure to improve anxiety, although there are a limited number of reports on the use of this intervention. In addition, satisfactory results have also noted that TMS is a safe treatment strategy with low side effect. Further studies using TMS could direct the treatment with psychological or psychiatric intervention.