A systematic review on the therapeutic effectiveness of non-invasive brain stimulation for the treatment of anxiety disorders
Introduction
Exploring new avenues for the treatment of mental disorders through non-pharmacological and/or non-invasive intervention approaches is of growing interest in the neuroscience community. This interest is motivated by the hope to deal with drug-treatment resistant disorders, to provide effective treatments in case of concurrent medical conditions that prevent standard treatments and to enhance efficacy of therapies by combining standard treatment approaches with non-invasive brain stimulation. One goal of research endeavours is to identify methodologies for the management of neuropsychiatric disorders that combine both therapeutic efficacy and tolerability. Since pathologically altered neural plasticity is an important component of many neurological and psychiatric diseases, non-invasive stimulation of the brain is an potential treatment option, as it is able to modulate neural activity (e.g., Kronberg et al., 2017; Ziemann,2017) by acting on synaptic plasticity (Fritsch et al., 2010; Kronberg et al., 2017; Nitsche et al., 2012b). The precise underlying mechanisms of non-invasive brain stimulation-induced synaptic plasticity have still to be clarified. Yet, evidence suggests that respective plasticity is linked to long-term potentiation (LTP) and long-term depression (LTD) (e.g., Monte-Silva et al., 2013; Nitsche et al., 2003; see also Bliss and Cooke, 2011).
Several review articles suggest therapeutic efficacy of non-invasive brain stimulation for the treatment of a wide range of neurological and psychiatric disorders, such as depression (Mutz et al., 2018), addiction (Feil and Zangen, 2010) and epilepsy (Cooper et al., 2018) in both pediatric and adult populations. For more extensive reviews in the field see also (Flöel, 2014; Kuo et al., 2014; Martin et al., 2017; Rivera-Urbina Guadalupe et al., 2017;Vicario and Nitsche, 2013a, Vicario and Nitsche, 2013bb). In the current article, we aim to provide a systematic review on therapeutic effects of non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), on anxiety disorders in adult populations, such as specific phobias (SP), social anxiety disorder (SAD), panic disorder (PD), agoraphobia, and generalized anxiety disorder (GAD). In the context of this review, it is worthwhile noting that post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) are no longer listed under the anxiety disorders category by the Diagnostic and Statistical Manual of Mental Disorders (DSM) Fifth Edition (Association, A.P., 2014, 2014; see also (Craske et al., 2017). We did not examine the effects of non-invasive brain stimulation on these syndromes because these disorders have been comprehensively addressed in several recent systematic reviews and/or meta-analyses (e.g., Berlim et al., 2013; Brunelin et al., 2018; Yan et al., 2017; Zhou et al., 2017).
We provide a brief introduction concerning the basic physiological principles underlying the effects of the mentioned non-invasive brain stimulation techniques. However, is not an aim of this review to address this aspect in detail. More exhaustive/detailed overviews are provided by several specialized reviews in the field (Klomjai et al., 2015a, b; Polanía et al., 2018; Valero-Cabré et al., 2017; Woods et al., 2016; Yavari et al., 2018).
tDCS is a well-established neurostimulation technique that allows stimulation of the cerebral cortex in a safe and non-invasive way. Stimulation is conducted via two or more electrodes with opposite polarities (i.e., anodal and cathodal) placed on the scalp and connected with a battery-driven constant current stimulator with a maximum output in the milliampere (mA) range. A relatively weak electrical direct current (usually 1 ∼ 2 mA) is applied via the electrodes, and a proportion of it enters the brain (Nitsche et al., 2008, 2003; Nitsche and Paulus, 2000). At the macroscopic level, anodal (A) stimulation increases cortical excitability, whereas cathodal (C) stimulation decreases it (Stagg and Nitsche, 2011). However, the impact and directionality of the effects of tDCS on cortical excitability are also influenced by stimulation intensity, as suggested by the study by Batsikadze et al. (2013) where both anodal and cathodal tDCS at 2 mA increased corticospinal excitability, whereas 1 mA cathodal tDCS decreased it. The effects on cortical excitability can last for up to 90 min after a single stimulation session of 13 ∼ 20 min duration (Nitsche and Paulus, 2000), and can be further extended by repeated stimulation (i.e., cumulative effects) (Monte-Silva et al., 2013). The physiological aftereffects of prolonged (i.e., application for several minutes) anodal and cathodal tDCS are dependent on synaptic modulation. This assumption is supported by pharmacological studies in humans (Nitsche et al., 2012a) and animal models (Fritsch et al., 2010; Kronberg et al., 2017). For example, enhanced long-term potentiation (LTP) in basal dendrites of rat hippocampal slices has been documented in response to anodal stimulation (Kronberg et al., 2017). Anodal stimulation increases intracortical facilitation (ICF), and its after-effects are prevented by NMDA receptor blockade, but enhanced by respective receptor agonists (Liebetanz et al., 2002; Nitsche et al., 2003, 2004; Nitsche et al., 2005). NMDA receptor block can also prevent cathodal tDCS-generated after-effects (Nitsche et al., 2003). Given the role of the glutamatergic receptor on ICF (Keller, 1993), it can, therefore, be assumed that glutamatergic neurons are crucial for the induction of plasticity by tDCS. Moreover, tDCS-induced glutamatergic plasticity might be prompted by tDCS-generated alterations of GABA activity. This is suggested by a magnetic resonance spectroscopy (MRS) study documenting a reduction of GABA content of the motor cortex (Stagg et al., 2009) following both anodal and cathodal tDCS.
rTMS is another non-invasive and safe brain stimulation technique based on the application of trains of magnetic pulses over a target cortical region, through the use of a copper coil placed over the scalp, which induces electrical pulses at the brain level. The application of trains of multiple pulses of TMS with a short inter-stimulus interval induces a long-lasting change on cortical excitability (Pascual-Leone et al., 1994). In this regard, it is important to distinguish between low and high-frequency rTMS. Generally speaking, appropriate intensity of low frequency (1–5 Hz) rTMS decreases cortical excitability, while an appropriate intensity of high-frequency rTMS (> 5 Hz) increases cortical excitability (Pell et al., 2011). Theta Burst stimulation (TBS) is another rTMS protocol, which induces similar effects as conventional rTMS, but requires less time. Generally speaking, Intermittent TBS (iTBS) produces excitatory effects, whereas continuous TBS (cTBS) produces a reduction of cortical excitability (Li et al., 2014). LTP- and LTD-like mechanisms seem to be involved also in rTMS-induced after-effects (Ziemann et al., 2008. See also Müller-Dahlhaus and Vlachos, 2013 for a review). Vlachos et al. (2012) reported functional and structural changes of CA1 pyramidal neurons of entorhino-hippocampal slice cultures following repetitive magnetic stimulation. Research in rodent models provides relevant insights in the molecular mechanisms associated with rTMS. Wang et al. (2011) have documented an increment of brain-derived neurotrophic factor (BDNF) binding affinity with NMDA receptors in the rat prefrontal cortex (PFC) in response to 5 days of rTMS. Importantly, BDNF plays a key role in the regulation of synaptic strength and mediation of neural plasticity (Bramham and Messaoudi, 2005).
The main goal of this article is to provide a state-of-the-art review on the therapeutic benefits of non-invasive brain stimulation in anxiety disorders. According to recent suggestions (e.g., Månsson et al., 2016), one important pathological mechanism in anxiety disorders is maladaptive structural and functional neuroplasticity of prefrontal and limbic regions. It is suggested that anxiety is associated with a hypoactivation of the left DLPFC (e.g., Amit Etkin and Wager, 2007; Nishimura et al., 2007), which inhibits the amygdala, a neural structure involved in threat detection and processing, which is elevated across most anxiety disorders (Notzon et al., 2015). On the other hand, there is evidence for higher activation of the right DLPFC in Aanxiety disorders, such as panic disorder (Nordahl et al., 1998; Prasko et al., 2004). These atypical functional activation patterns might be also associated with respective structural abnormalities of these neural regions, which might contribute to the emergence and chronicity of cognitive/emotional deficits (i.e., exaggerated fear response/threat perception). For instance, it was provided evidence of amygdalar and volume alterations in social anxiety, possibly associated with symptom severity (Machado-de-Sousa et al., 2014). In line with these premises, non-invasive brain stimulation might be a helpful treatment approach, via counteracting respective dysregulated activity and maladaptive neuroplasticity by modulating pathological hypo-/hyper-activation patterns of the DLPFC in respective clinical populations, as described above. In the discussion section of this review, we also outline a treatment model for anxiety disorders via non-invasive brain stimulation, which is conceptually based on up-/downregulation mechanisms and might serve as guide for future systematic investigations in the field.
This review will help to clarify i) whether and to what extent non-invasive brain stimulation is an effective treatment of different anxiety disorders, and ii) which combination in terms of stimulation type (i.e., inhibitory vs. excitatory) and cortical target is suited for the therapy of anxiety disorders. Moreover, it will provide information about relevant stimulation parameters as a starting point for systematic optimization, as well as generate hypotheses how non-invasive brain stimulation might be combined with other interventions to obtain improved therapeutic benefits.
Section snippets
Methods
Data for this systematic review were collected in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) (Moher et al., 2010). The PRISMA consists of a checklist intended to facilitate preparation and reporting review/meta-analysis studies by identifying, selecting, and critically appraising relevant research, and collecting and analyzing data from the studies that are included in the review.
Anxiety disorders
In the next paragraphs, we address the therapeutic effects of non-invasive brain stimulation on anxiety disorders. According to the DSM-5 (Association, A.P., 2014), anxiety disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia and generalized anxiety disorder. We did not consider separation anxiety disorder and selective mutism, as these are specific childhood syndromes.
Discussion
We systematically reviewed 27 published reports of studies in which non-invasive brain stimulation was administered to test effects on anxiety symptoms in patients affected by different anxiety disorders. Overall, the studies examined in this review support the concept that non-invasive brain stimulation represents a promising therapeutic approach for the treatment of anxiety disorders.
In most studies, an improvement of anxiety symptoms was associated with stimulation of the PFC, which
Declaration of interests
This work was supported by grants from the (i) Alexander von Humboldt Foundation, Germany; ii) The SFB 1280 – Extinction learning; iii) The BMBF GCBS project (grant 01EE1403C). All authors declare no competing interests.
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