Non-invasive brain stimulation to enhance the effects of behavioral interventions and psychotherapy

Non-invasive brain stimulation to enhance the effects of behavioral interventions and psychotherapy

Non-invasive brain stimulation techniques have gained increasing popularity and have been complemented by other psychotherapeutic interventions in order to induce changes in brain activity and modify behavioral responses.

Alessia Gallucci and Alessandra Vergallito – OPEN SCHOOL Cognitive Psychotherapy and Research Milan


Advertising message Non-invasive brain stimulation techniques are increasingly used not only for research purposes, but also to enhance the effects of behavioral treatments with patients with neuropsychological disorders (Buch et al., 2017; Wessel et al., 2015) and psychiatric (Brunelin et al. 2018; Palm et al., 2017; Jahshan et al., 2017).

The results, however, are to be considered partial and need more experimental evidence to reach a clinical recommendation with respect to the effectiveness of these treatments (Vicario et al., 2019).

This article aims to illustrate the state of the art with respect to the use of brain stimulation techniques in the psychiatric field, accompanied by pharmacological and psychotherapy interventions.

Non-invasive brain stimulation (NIBS) techniques have gained increasing popularity among researchers and clinicians in order to induce changes in brain activity and modify the behavioral responses of participants.

NIBS include transcranial magnetic stimulation (TMS) and electrical stimulation (tES), which is further divided according to the way in which the current is administered, i.e. continuous (transcranial direct current stimulation, tDCS), alternating (transcranial stimulation at alternating current, tACS) or random (transcranicarandomnoise stimulation, tRNS). For the purposes of this article only TMS and tDCS will be treated, which have had greater application in both clinical and research fields.

TMS and tDCS influence cortical excitability by using different mechanisms. The TMS consists of a coil connected to a capacitor; the instrument is able to release a magnetic field of strong intensity (up to 4T) and short duration (280μs). The impulse induces an over-threshold depolarization in the cell membrane in the underlying neurons, generating an action potential (Barker et al., 1985, 1987), followed by a depolarization or hyperpolarization of the interconnected neurons. The spatial resolution of the TMS varies according to the shape of the coil, for example an 8-shaped coil (or butterfly coil) allows a focal stimulation, allowing to stimulate small portions of bark (0.5-2 cm2).

TMS can be administered in single impulse mode, in which the impulses are released with a time interval such as not to induce long-term modifications in the underlying cerebral cortex, or repetitive (rTMS), which has the aim of causing plastic changes in the stimulated areas . In particular, we speak of low frequency rTMS (low frequency, lf-rTMS) when the pulses are released with a frequency lower than 1 Hz for a few minutes (effect of reducing the excitability of the area) vs high frequency rTMS (high -frequency, hf-rTMS), in which the pulses are released with a frequency greater than 3 HZ (increase of the excitability of the stimulated area).

The tDCS instead acts through the application of a weak electric current (~ 1-2 mA) for a variable time (10-20 minutes, Nitsche et al., 2008), using a pair of electrodes positioned on the scalp (Nitsche & Paulus, 2000 ; Priori et al., 1998). One of the electrodes has a positive charge (anode), while the other has a negative charge (cathode). The two poles differently influence the underlying cerebral cortex, in fact the positive pole depolarizes the neuronal membrane, while the negative pole hyperpolarizes it. Unlike TMS, the polarization induced by tDCS is sub-threshold, that is, too weak to generate an action potential; however, it is capable of inducing changes in resting membrane potential, making the neuronal response to stimuli more or less probable (Bindman et al., 1964).

In addition to the difference in the type of effect induced at the brain level, the two techniques have peculiarities and limitations that make them more or less usable in certain contexts. The TMS, unlike the tDCS, is an expensive and difficult to transport instrument. Furthermore, the administration of TMS can be distracting / annoying in somato-sensorial terms: the impulses in fact generate sound “clicks” and facial muscle contractions, which can make it difficult to use while the participant is performing a task.

The tDCS, on the other hand, does not generate particular sensory sensations except a slight tingling / itching under the electrodes at the time of the start of the stimulation (eg Poreisz et al., 2007), for this reason it is particularly suitable to be used during the performance of tasks and in cases where a control condition with sham / placebo stimulation is required (Gandiga et al., 2006).

NIBS are widely used in research, in order to investigate the functional state of brain systems, trace a causal relationship between a certain neural area / network and perform a task, deepen the functional connectivity between brain areas and induce / map changes in neural plasticity.

At a diagnostic level, TMS is used in evaluating the functionality of the motor system in various pathologies, such as multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders affecting the spine, cranial and facial nerves (Rossini and Rossi, 2007; Groppa et al., 2012; Rossini et al., 2015; Menon et al., 2015). Numerous studies, however, suggest that the technique may be useful in the differential diagnosis of different forms of dementia (eg Benussi et al., 2017; Pierantozzi et al., 2004), to identify specific treatment markers (Canali et al., 2014 ) and monitor rehabilitation treatment (Cipollari et al., 2015).

As for indications for treatment, apart from a few exceptions (e.g. depression, see the next paragraph), NIBS are currently used in the neuropsychological and psychiatric rehabilitation field at an experimental level only. Although considered to be potentially useful for the treatment of a variety of ailments, researchers agree that more empirical evidence is needed to establish their clinical effectiveness and track specific rehabilitation protocols. To this end, panels of world experts periodically deal with evaluating the state of the art on the subject and drawing guidelines for the use of techniques in clinical practice.

For the purposes of this article we will describe the state of the art of using NIBS as an intervention in psychiatric disorders.

To date, psychiatric disorders are among the most common diseases worldwide, with an extremely negative impact on quality of life and socio-working functioning, connected to high mortality rates and high costs for health services (Wittchen et al ., 2011). Despite the majority of patients accessing standard psychotherapeutic and pharmacological treatments, the data show that 20-30% of patients with major depressive disorder, 40-60% of patients with obsessive-compulsive disorder and up to 50% of patients with schizophrenia do not respond to traditional treatments (Bloch et al., 2006; Rush et., 2006; Scholten et al., 2013; Yamanaka et al., 2010).

These data, together with the evidence about the involvement of specific neural networks in psychiatric disorders, have made research necessary on alternative forms of treatment such as NIBS which, alongside traditional therapies, can enhance their effects, allowing to develop interventions as possible specific and effective.

In particular, with respect to the possibility of combining psychotherapy with the use of NIBS, the protocols provide for intermittent treatment, in order to induce changes in neural function and behavioral outcome. Furthermore, studies show that the neurobiological effects of psychotherapy do not depend only on the anotomo-functional anomalies that characterize the various disorders, but also on the specific effects consequent to the application of NIBS on the cortex. Similarly, in line with studies on the effectiveness of motor and cognitive rehabilitation treatments (Buch et al., 2017; Jahshan et al., 2017), the effects of psychotherapeutic interventions on learning and top control mechanisms- down, can favor the long-term maintenance of NIBS outcomes (Bajbouj & Padberg, 2014). From a practical point of view, NIBS are cheap and generally well tolerated by patients, favoring their application also in public health contexts. Compared with pharmacotherapy, NIBS have fewer side effects, increasing the possibility of patient compliance.

In the following paragraphs the state of the art of the application of NIBS in psychiatric disorders will be described.

DDM is the disorder against which the effectiveness of NIBS has been most demonstrated. The rationale for the development and application of NIBS protocols for the treatment of DDM derives from the evidence of structural and functional abnormalities involving the dorsolateral (DLPFC) and ventromedial prefrontal cortex (VMPFC), the amygdala and the hippocampus (Campbell et al., 2004; Grimm et al., 2009). In particular, research shows a hyperexcitability of the left DLPFC and a hyperexcitability of the right DLPFC (Debener et al., 2000). Rehabilitation protocols with NIBS therefore aim to restore interhemispheric imbalance, using the hf-rTMS on the left DLPFC and lf-rTMS on the right DLPFC (Lefaucheur et al., 2014), or tDCS with anodic stimulation on the left DLPFC with contralateral supraorbital cathode, although several authors are suggesting the use of a bi-hemispherical anode assembly on the left DLPFC and cathode on the homologous right region (e.g. Brunoni et al., 2012). The efficacy of rTMS in DDM is confirmed by its approval in the treatment of drug resistant depression by the FDA (Food and Drug Administration, 2008). With regard to rTMS, several studies have shown significant improvements even three months after the end of treatment when stimulation was associated with CBT (e.g. Donse et al., 2018). Crucially, the improvements observed shortly after starting treatment were predictive of outcomes at the end of treatment,

Compared to rTMS, a single case study (Vedeniapin et al., 2010) showed a significant improvement in depressive symptoms after 39 sessions of high frequency rTMS on the left DLPFC, 14 of which in combination with cognitive behavioral therapy (CBT) standard. The effects of the combined intervention were also observed at follow-up after three months. A more recent study (Donse et al., 2018) subjected 196 patients to 10 CBT sessions in which rTMS was applied at high frequency on the left DLPFC or at low frequency on the right DLPFC. In line with the previous study, the results showed significant remission of symptoms even three months after the end of treatment, with no particular differences between the two rTMS stimulation protocols. crucially,

The efficacy of tDCS in DDM is still a matter of debate, although the most recent guidelines (Lefaucheur et al., 2017) suggest an indication of level B treatment (probable efficacy). A single case study has shown its effectiveness when applied together with CBT (D’Urso et al., 2013), not replicated by Welch and collaborators (2018), who recorded improvements in both real and placebo stimulation. The combination of tDCS and Cognitive Control Therapy, which consists of a series of exercises to enhance the working memory to be performed on the computer, has also been studied, showing effects if the two were combined. The effects were stronger after some time compared to those detected immediately at the end of the treatment (Segrave et al.,

Advertising message Neuroimaging studies have reported in the case of phobic patients functional anomalies affecting neural structures such as the amygdala, hippocampus, insula and prefrontal cortex, which together with the anterior cingulate cortex and the striated body make up the circuit. fear (Davis, 2006), particularly involved in anxiety disorders in general (Shin & Liberzon, 2010). In particular, a reduced ability of the frontal structures to inhibit responses to fear of subcortical structures, especially of the amygdala, was observed in patients (Deppermann et al., 2016). Most of the studies investigated the effects of CBT and stimulation.

At the moment there are no indications on the effectiveness of the treatment of phobias with NIBS, however some studies have used TMS protocols (Intermittent Theta-burst or iTBS) combined with CBT showing that, although there are no significant clinical improvements, the protocol of real stimulation compared to that of placebo is able to activate the cortex that was hypofunctioned at the baseline (Deppermann et al., 2016). However, these results have not been replicated by another study by the same research group in which iTBS has been applied together with psychoeducation (Deppermann et al., 2014).

Particularly useful in the treatment of phobias could be the combination of NIBS and virtual reality, in order to associate stimulation with exposure techniques. Some studies have shown positive beneficial effects, particularly of rTMS, especially in accelerating the appearance of the benefits of CBT (Guhn et al., 2014). A study by Notzon et al. (2015) instead showed that the use of iTBS, followed by exposure through virtual reality, did not affect the electrophysiological parameters of patients with arachnophobia (skin conductance, heart beat) during the presentation of phobic stimuli. The protocol, however, consisted of a single stimulation session, not sufficient to measure treatment efficacy. Moreover,

Numerous studies have highlighted a functional imbalance between the two neural pathways that connect the cortex to the basal ganglia and the thalamus in patients with obsessive-compusive disorder (DOC). In particular, there is an over-activation of the direct excitatory pathway, responsible for the initiation and continuation of a certain behavior, and a hypo-activation of the indirect inhibitory pathway, which allows the interruption of the behavior and the possibility of passing from one behavior to the other. other (Cummings, 1993; Groenewegen & Uylings 2000; Saxena & Rauch 2000). Most of the tDCS studies have been performed without coupling neuro stimulation to standard treatments and considering individual cases or small groups of patients. In these cases, a significant reduction in symptoms was observed following the cathodic stimulation of the left DLPFC (Volpato et al., 2013). Other areas considered as effective targets of stimulation protocols are the frontal orbital cortex (Mondino et al., 2015) and the left supplementary motor cortex (D’urso et al., 2016).

Studies with TMS, for the most part on individual cases, have observed the combined effects of rTMS and CBT. In particular, one study showed clinically significant improvements in a patient with drug resistant DOC after 16 CBT sessions, 10 of which in combination with high frequencyrTMS applied on the left DLPFC. The results were encouraging, as the effects of the combined treatment were long-term, with a positive impact on the general functioning level (Grassi et al., 2015). Although the results of this first study have also been replicated by another research (Tan et al, 2015), the methodology used does not allow to draw firm conclusions on the effectiveness of the treatment. In fact, these studies lack the placebo condition, they expect patients to be aware of the treatment they receive and disregard ongoing drug therapies. Further methodologically more rigorous studies and on a larger number of patients may in the future clarify the effects of NIBS and psychotherapy in patients with DOC.

Compared to behavioral interventions, however, a double-blind study reported improvements in symptoms immediately following exposure exercises followed by high-frequency rTMS stimulation of the medial prefrontal cortex and of the anterior cingulate cortex (Carmi et al., 2018)

As with phobias, also in the case of PTSD, many studies have investigated the effects of combined treatment of NIBS with exposure therapy. In fact, neuroimaging data have shown that patients with PTSD generally show hyperactivation of the right prefrontal cortex during exposure to trigger stimuli (Rauch et al., 1996). Therefore, stimulation can target this area (cathodic lf-rTMS / tDCS) or the contralateral homologue (anodic hf_rTMS / tDCS) in order to rebalance brain activation. Two studies where the target area was DLPFC did not show significant results (Fryml et al., 2019; Osuch et al., 2009), while a study by Isserles et al. (2013) showed a reduction in symptoms after real rTMS stimulation preceded by exposure to traumatic stimuli, compared to control conditions (placebo rTMS preceded by exposure to traumatic stimuli; real rTMS preceded by exposure to non-traumatic stimuli). The increased sample size, the clinical characteristics of the patients, the target area and the stimulation parameters could justify the positive results of the study by Isserles and collaborators (2013).

In schizophrenia, NIBS have been predominantly used to treat auditory hallucinations and negative symptoms, on which drug treatment has less effective effects (Lefaucheur et al., 2017). Neuropsychological and neuroimaging studies have shown that this symptomatology is attributable to a disconnection between frontal and temporal areas. In particular, auditory hallucinations seem to be attributable to an increase in brain activation in the left hemisphere, in particular at the level of the upper temporal gyrus (Homan et al., 2013). The studies therefore focused on the use of low frequency rTMS or cathodic tDCS on this region, in order to reduce cortical activity (Lefaucheur et al., 2017).

The neural correlates of the negative symptomatology, on the other hand, consist of a hypofunctionality of the prefrontal areas (eg Hill et al., 2004), therefore the high frequency rTMS and the tDCS in anodic mode have been applied in order to increase cortical excitability . The studies, conducted on small patient samples, have shown improvements in negative symptoms, associated with an increase in connectivity between DLPFC and the left temporal cortex (Brunelin et al., 2012; Mondino et al., 2015; Lefaucheur et al., 2017).

At the neural level, addiction patients show functional anomalies at the level of DLPFC, which plays a particularly important role in inhibitory control and reward mechanisms (Goldstein and Volkow, 2002; Wilson et al., 2004). The researchers therefore focused on stimulating this neural network for both high frequency rTMS, which showed a possible efficacy for nicotine addiction, and for tDCS, which received a level B evaluation (probable efficacy) instead. for the treatment of addictions (Lefaucheur et al., 2017). In the studies, the researchers opted for a bi-hemispherical assembly, with anode positioned on the right DLPFC and cathode on the left, which proved effective for nicotine dependence (Boggio et al., 2009; Fecteau et al., 2014 )

As evidenced by recent reviews and guidelines (Lefaucheur et al., 2017), NIBS techniques and traditional treatments, such as psychotherapy and cognitive interventions, have so far shown promising results for the treatment of neurological and psychiatric disorders. Furthermore, NIBS have long been used effectively in the clinical setting, also in the diagnostic phase, and in the research setting, where an increasing number of studies are working to clarify their effects. However, it is still unclear what the role of the different neural areas considered as the target of stimulation is and how stimulation combined with traditional therapies can act on the symptoms, cognitive mechanisms and behavioral outcome of different disorders. This short article was intended to describe the state of the art regarding the characteristics of NIBS and the efficacy data with respect to the use of these techniques combined with standard psychotherapeutic and cognitive interventions, which so far have shown partial efficacy. Future studies are however necessary to develop treatment protocols with NIBS combined with traditional treatments, identifying more effectively the target neural areas and the cognitive mechanisms that influence the pathological behaviors and experiences of patients.