|
 
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| REVIEW |
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| Year : 2023 | Volume
: 2
| Issue : 2 | Page : 28-35 |
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Deep brain stimulation for obsessive-compulsive disorder: current situation
Patricia Gonzalez-Tarno1, Marta Navas-García1, Iosune Torio2, Jose A Fernández-Alén1, Cristina V Torres1
1 Department of Neurosurgery, University Hospital of La Princesa, Madrid, Spain
2 Department of Psychiatry, University Hospital of La Princesa, Madrid, Spain
| Date of Submission | 29-Mar-2023 |
| Date of Decision | 30-May-2023 |
| Date of Acceptance | 15-Jun-2023 |
| Date of Web Publication | 28-Jun-2023 |
Correspondence Address:
Cristina V Torres
Department of Neurosurgery, University Hospital of La Princesa, Madrid
Spain
Patricia Gonzalez-Tarno
Department of Neurosurgery, University Hospital of La Princesa, Madrid
Spain
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2773-2398.379338
Obsessive-compulsive disorder is a chronic and severe psychiatric disorder with a high prevalence (2–3%) worldwide, of which 30% will be refractory to conventional treatment. Surgical treatment with deep brain stimulation, approved by the U.S. Food and Drug Administration in 2009, seems to be effective in symptomatic control, with response rates exceeding 50% in severely affected patients. However, despite the efficacy indicated in the different studies, surgical treatments for psychiatric disorders are still controversial, and deep brain stimulation for obsessive-compulsive disorder is not yet considered a standard therapy. Since 2009, a wide variety of targets have been suggested for the treatment of obsessive-compulsive disorder; however, to date, there is still no consensus on which target might be optimal for the treatment of obsessive-compulsive disorder. On one hand, authors are trying to find the best target based on each patient and the variability of their symptoms, in an attempt to personalize the treatment. In parallel, there has been a shift in the paradigm of functional neurosurgery from the belief in stimulation focusing on a single target to the modulation of brain circuits or connectomes. With this in mind, it may be possible that many of the targets used in obsessive-compulsive disorder could modulate the same brain network and thus produce an improvement in patients' symptomatology. This study aims to review the evolution of this treatment up to the present time; as well as to make a comparison between these two lines of thought, thus exposing the current state of deep brain stimulation for obsessive-compulsive disorder.
Keywords: connectomes; deep brain stimulation; obsessive-compulsive disorder; target
How to cite this article:
Gonzalez-Tarno P, Navas-García M, Torio I, Fernández-Alén JA, Torres CV. Deep brain stimulation for obsessive-compulsive disorder: current situation. Brain Netw Modulation 2023;2:28-35 |
How to cite this URL:
Gonzalez-Tarno P, Navas-García M, Torio I, Fernández-Alén JA, Torres CV. Deep brain stimulation for obsessive-compulsive disorder: current situation. Brain Netw Modulation [serial online] 2023 [cited 2023 Sep 22];2:28-35. Available from: http://www.bnmjournal.com/text.asp?2023/2/2/28/379338 |
| Introduction | |  |
Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder that affects millions of people worldwide. It is characterized by chronic intrusive thoughts (obsessions) and repetitive, ritualistic behaviors or compulsions (Simón-Martínez et al., 2021). It has a lifetime prevalence of up to 2–3% of the population (Sasson et al., 1997) and is associated with important morbidity and a high risk of mortality (Meier et al., 2016; Carmi et al., 2022).
The pathophysiology of OCD is related to an excessive activity in the cortico-striatal-thalamo-cortical loops and is linked to abnormal structure and function within a frontostriatal network (Karas et al., 2018; Treu et al., 2021). An imbalance in favor of the limbic loop over the associative loop could produce an inadequate activity of the anterodorsal cingulate cortex (area 24), as well as the prefrontal area (area 46) and the amygdala (Martínez-Álvarez and Torres-Diaz, 2022b), producing pathological signals that could lead to a hyper direct input on the subthalamic nucleus and produced OCD symptoms (Li et al., 2021).
Although pharmacological and psychotherapeutic treatment is available and shows good results in many of these patients, it is known that up to 30% of them will be refractory to treatment (Lozano et al., 2019). There are a high percentage of patients, practically helpless of treatment, with a very impaired quality of life, practically unable to leave their homes and lead a normal life.
The great variability in symptomatology as well as in the heterogeneity of the disease corresponds to the response of patients to conventional treatments. It is in these patients that surgical options are being considered, among which deep brain stimulation (DBS) stands out (Lipsman et al., 2012). DBS for OCD is effective in improving their symptoms and also offers an improvement in their quality of life, which has been greatly diminished by their situation. Literature reports indicate that, to date, more than 300 OCD patients worldwide have benefited from this treatment (Mar-Barrutia et al., 2021). However, surgical treatments for psychiatric disorders are still controversial, and DBS for OCD is not yet considered a standard therapy.
DBS is a neurosurgical treatment that involves the placement of electrodes in the brain, stimulating specific targets and neuromodulating the circuits in which they participate and that, due to a dysfunction in them, cause the disease (Harmsen et al., 2020). It is a safe, effective, reversible, and individualized treatment, which is why it is currently considered one of the workhorse treatments in movement disorders. In 2009, the U.S. Food and Drug Administration approved DBS for treatment-refractory OCD, being the only Food and Drug Administration-approved psychiatric indication for DBS to date. In 2014, consensus guidelines for the use of DBS in the treatment of refractory psychiatric disorders were published by the Neurosurgery Committee for Psychiatric Disorders for the World Society for Stereotactic and Functional Neurosurgery (WSSFN) (Nuttin et al., 2014). Although there are many studies on the subject, the WSSFN stated that to consider this surgical treatment as an “approved therapy,” a minimum of two randomized, blinded controlled clinical trials conducted by two different groups of investigators, both demonstrating an acceptable risk-benefit ratio, at least comparable with existing therapies, had to be reported. The interventions should target the same brain area for the same psychiatric indication (Nuttin et al., 2014). At present, these requirements have not yet been met; there are small and few studies on the subject, in comparison with other diseases, but they do not reach the required standards, taking into account the difficulty involved in demonstrating evidence and performing randomized studies in cranial surgery. More than a decade after its approval, DBS is still considered an emerging therapy for OCD (Yan et al., 2022).
Since 2009, a wide variety of targets have been proposed for the treatment of OCD, as components of the reward and motivation system, such as the ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAc), anterior limb of the internal capsule (ALIC), subthalamic nucleus (STN), bed nucleus of the stria terminalis (BNST), and inferior thalamic peduncle (ITP) (Lee et al., 2019a). However, to date, there is no agreement on what the optimal target for OCD might be (Borders et al., 2018). Recent studies are trying to identify the best target based on each patient and the variability of their symptoms, in an attempt to personalize the treatment (Barcia et al., 2019; Li et al., 2020).
In parallel, there has been a shift in the paradigm of functional neurosurgery from the belief in stimulation focused on a single target to the modulation of brain circuits or connectomes. Although the hypothesis of modulating white-matter tracts, rather than gray matter nuclei, is not new, advances in magnetic resonance imaging sequences, such as diffusion-weighted imaging-based tractography, are now increasingly used in functional neurosurgery in order to more deliberately target white-matter tracts (Li et al., 2020). With this in mind, it may be possible that many of the targets used in OCD, and other psychiatric as well as movement disorders, could modulate the same brain network and thus produce an improvement in patients’ symptomatology; therefore, considering the tract as the therapeutic target (van der Vlis et al., 2021; Wu et al., 2021; Gadot et al., 2022).
In addition to continuing to show data on the efficacy of the therapy, the current controversy focuses on whether the target chosen should be personalized for each patient, taking into account the wide heterogeneity of this disease in terms of severity and symptomatology, or whether the target should be considered within a single tract.
This review addresses the past and the current status of DBS for the treatment of OCD, providing an overview of the different options available and showing lines of research being carried out in this field. For this purpose, a computerized PubMed search of the literature on deep brain stimulation in the treatment of OCD was conducted to collect articles addressing the heterogeneity of this disorder and its treatment. PubMed search terms included “obsessive-compulsive disorder,” “deep brain stimulation,” “target,” “nucleus accumbens,” “subthalamic nucleus,” “ventral striatum,” “internal capsule” and “connectome.”
| PERSONALIZED TARGETS VERSUS MODULATION OF BRAIN NETWORKS | | |
To this date, there is no sufficient evidence to consider one target better than any other target individually, while the optimal site for long-term DBS in OCD remains unclear. Overall, outcome measures across targets demonstrate a rate of improvement of 50% (Haber et al., 2021; Gadot et al., 2022).
Nuttin et al. (1999, 2003) reported the first series of OCD, DBS based on the authors’ previous experiences with anterior capsulotomies [Table 1]. They showed a beneficial effect in 3 out of 4 patients by stimulating the ALIC after 21 months of follow-up with a > 35% rate of Yale-Brown Obsessive Compulsive Scale (Y-BOCS) reduction (Nuttin et al., 1999, 2003). Later, Greenberg et al. (2006) conducted the first multicenter study. 10 adult OCD patients had quadripolar stimulating leads implanted bilaterally in the VC/VS. Four out of 8 patients were responders to the treatment (50%), comparable to the previous series (Greenberg et al., 2006).
The NAc, located immediately below the ALIC, is the most ventral extension of the striatum and it becomes actively involved during reward learning, emotional processing, decision making or inhibitory control behaviors (Lopez-Sosa et al., 2021). In fact, the terms VS and NAc are often used interchangeably to refer to the confluence of putamen and caudate. Based on clinical and anatomical observations, Sturm et al. (2003) proposed the NAc as the target for patients with OCD, finding a significant reduction in 3 out of 4 patients treated.
To our knowledge, there are two main double-blind randomized studies published to date. Denys et al. (2010) showed, in a randomized controlled trial conducted in 2010 with an 8-month follow-up, 16 patients with severe OCD received DBS in the NAc, with a mean decrease of 46% in the Y-BOCS score. However, during the active stimulation phase, the Y-BOCS dropped 25%, finding a less than optimal effect (25%) and not achieving the minimum of 35% required (Denys et al., 2010). On the other hand, Luyten et al. (2016) reported a response rate of 53% among 17 patients during the cross-over trial. At the last follow-up, the response rate increased to 67%, and there was a notable improvement of 37% in Y-BOCS scores, with the BNST being the targeted region
The consideration of DBS for OCD as an approved therapy required the existence of two double blind randomized studies on the same target, with positive results. As we can see, despite both studies showed efficacy, the problem was that Denys et al.’s initial requirements (Denys et al., 2010) were not met.
The BNST is positioned a few millimeters behind the NAc, located posteriorly to the ALIC. The therapeutic benefits were supported by a double-blind, randomized crossover phase. When considering the area of primary stimulation, only 25% of patients with ALIC stimulation showed notable improvement, while 80% of individuals stimulated in the BNST achieved a satisfactory response (Luyten et al., 2016; Raviv et al., 2020).
DBS targeting the ITP has been shown to alleviate symptoms in OCD. Lee et al. (2019b) reported five patients who had undergone ITP-DBS and showed that all patients were responders. With this cohort of patients, Germann et al. (2022) studied the brain network involved in the improvement following the stimulation of this target and found that the amygdala played a key role in treatment success. The results of the present study suggest that a dysfunctional connectome involving the amygdala and dorsal anterior cingulate and prefrontal area is engaged in ameliorating OCD symptoms after ITP-DBS.
In the search for other possible targets to obtain better results in terms of effectiveness, the use of STN as a target was proposed. This nucleus has been widely studied given its recognized usefulness in movement disorders such as Parkinson’s disease. It has been in these patients where behavioral side effects induced by changes in stimulation have been observed which has led to believe that this target could induce limbic side effects. In addition, it is known that the anteroventral region of the STN receives information from the dorsolateral and orbitobasal frontal cortex, the cingulate gyrus, and the lateral temporal neocortex (Temel et al., 2005). It has the advantage of being a very well-known and well-worked nucleus in functional neurosurgery, which facilitates its localization, and the nonmotor part can be easily determined on magnetic resonance imaging. Chabardès et al. (2013) showed a 78% improvement in OCD patients who underwent STN stimulation. In addition, they reported that the voltage required is lower than that used in ALIC or VS, which could extend the average life of the batteries and therefore be more efficient (Chabardès et al., 2013). Mallet et al. (2008) also reported a double-blind, multicenter crossover trial evaluating anteromedial STN DBS. 75% patients showed improvement in OCD symptoms during active vs. off stimulation (Mallet et al., 2008).
In order to enhance patient outcomes and enhance the number of individuals experiencing positive effects, our team devised an anatomical pathway in which the implanted electrodes would traverse three specific nuclei: IC, VS, and Nac (Torres Díaz et al., 2021). Contacts and stimulation settings were tailored individually, continuously adjusted until the optimal combination was identified to achieve maximum effectiveness. Out of the 14 patients involved, 11 (79%) demonstrated significant improvements due to the stimulation, evidenced by a reduction of over 35% in Y-BOCS scores, surpassing the results of most previously documented studies.
With these results, we can extrapolate that the abnormal functioning of the different limbic circuit structures will respond to brain stimulation to different degrees and may also depend on the patient's specific symptomatology. Following this theory and comparing it with the response rate of around 50%, in contrast to the results obtained in DBS for movement disorders, Barcia et al. (2019) hypothesized that this could be related to treating all patients with the same target without taking into account the predominant symptomatology in each of them. They advocate that the optimal striatal target would be located along the dorsoventral axis of the striatum, not limited to the NAc or the VC/VS, and that it will therefore depend on the patient's symptomatology as well as the pre-operative magnetic resonance imaging index to predict and locate the optimal stimulation site. With this, they reported an 86% of response rate, a higher rate than studies with specific targets for all the patients. Barcia et al. (2014) also observed that there is evidence for an asymmetrical involvement of brain regions in OCD in 2-[F18] fluoro-2-deoxy-D-glucose-positron emission tomography studies with different metabolic rates between each hemisphere and also in quantitative electroencephalogram and volumetric studies (Barcia et al., 2014). There is controversy regarding these results, since other studies have obtained completely opposite results in reference to lateralization (Baxter et al., 1987; Tot et al., 2002; Christian et al., 2008; Wobrock et al., 2010). However, this only reinforces the idea that the site of preferential activation may be an individual characteristic, which would support the theory of advocating a personalized treatment both on the target and on the stimulation side itself.
On the other hand, other groups are working on the hypothesis that different targets lead to the modulation of the same brain circuits or connectomes. Knowing the implication of the cortico-striatal-thalamo-cortical loops and the frontostriatal network in the pathophysiology of OCD, Li et al. (2020) conducted an analysis on data from four groups of patients (n = 50) who underwent DBS targeting the ALIC, NAc, or STN. They observed that the same tract was activated by stimulating any of the nuclei and that it was associated with optimal clinical outcomes. This tract connected frontal regions to the STN. They observed that the results obtained by stimulating the targeted tract in one of the cohorts could predict the results obtained in the others.
Denys et al. (2010) also proposed that there were various neural circuits that may mediate OCD. They reported that stimulation of VC/VS may enhance mood, meanwhile, anteromedial STN DBS would modulate compulsive behavior. Following this hypothesis, Tyagi et al. (2019) compared for the first time, in the same patients DBS of 2 brain targets. They reported that stimulation of the VC/VS and the anteromedial STN have similar results in terms of the magnitude of the reduction of OCD symptoms, measured with Y-BOCS. However, they found different effects on mood and cognition. Stimulation of anteromedial STN improved cognitive symptoms, meanwhile VC/VS improved mood. These dissociated effects can be seen to be reflected in tractography studies performed in these patients, where distinct brain networks would be activated.
| Discussion | | |
DBS to treat OCD obtained Food and Drug Administration approval in 2009. Prior to neuromodulation, neurosurgical interventions for drug-resistant patients with OCD consisted of ablative lesions such as anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and limbic leucotomy (Raviv et al., 2020; Martínez-Álvarez and Torres-Diaz, 2022a). These procedures would succeed in interrupting a dysfunctional cortico-striatal-thalamo-cortical circuit which, as previously referenced, underlies the pathophysiology of OCD.
The use of DBS for OCD has been increasing over the years due to its efficacy in severe patients refractory to conventional treatments. It is very important to take into account the high percentage of refractory patients (30%) since OCD is a devastating disorder that has a massive impact not only on the patient but also on their family and society, with important morbidity, often associated with other psychiatric disorders such as depression and anxiety, and a high risk of mortality, with an also high risk of suicide (Meier et al., 2016).
The most commonly used scale for the assessment of OCD severity and to measure therapeutic efficacy is the Y-BOCS score (Goodman et al., 1989). We should bear in mind that this is a subjective scale, not based on objective or measurable parameters, and, on occasions, the scores obtained in the post-surgical evaluation could be influenced by the interviewer’s interpretation. According to these results, patients will be classified into responders (≥ 35% improvement), partial responders (25–34% improvement), or non-responders (< 25%). To ensure that the results do not depend only on one scale, the use of other scales is recommended, such as the Global Assessment of Functioning to measure social functioning, the Hamilton Depression Rating Scale to assess the severity of depressive symptoms, and the quality of life scale (Torres Díaz et al., 2021).
For ensuring a more objective assessment, recent studies are looking for diagnostic biomarkers of OCD that could be used to monitor response to treatment with DBS. Fullana et al. (2020) conducted a meta-analysis studying different biomarkers (clinical, biochemical, neurophysiological, neuroimaging) and their implication in OCD. Neurocognitive variables emerged as the biomarkers with the most robust evidence, according to their findings. However, to date, no combinations of biomarkers and/or clinical data have demonstrated adequate specificity to accurately classify or diagnose any psychiatric disorder. Arumugham et al. (2021) designed a prospective open-label study to determine potential biomarkers that may help us in the future to predict the effectiveness and follow up the treatment of these patients. Currently, there remains a lack of biological or genetic indicators that can reliably predict treatment responses. However, in an ideal scenario, it is conceivable that in the future, a mere blood test may allow for the diagnosis or monitoring of OCD or other mental disorders (Bandelow et al., 2017).
DBS is a safe treatment but carries risks inherent to surgery and may be associated with stimulation-related complications (Hariz, 2002). The most frequent complication is cerebral hemorrhage, the risk of which is 1–2%, including minor hemorrhages. The incidence of seizures is less than 1% and the mortality risk is approximately 0.4% (Nuttin et al., 2014). Concerning the stimulation device, the risk of intracranial migration or fracture of the device is 3–4% (Fernández et al., 2010), and that of infection is 5–10% according to the latest series (Borders et al., 2018; Krauss et al., 2021). Regarding stimulation, side effects can be observed depending on the anatomical location of the contacts, such as the appearance of neurological or psychiatric symptoms; however, these can be avoided by changing the stimulation parameters (Zarzycki and Domitrz, 2020).
Following its approval, DBS has been employed in various regions, including VC/VS, NAc, ALIC, STN, BNST, and ITP. Furthermore, experimental evaluations have explored its application in the anterior cingulate cortex, medial dorsal and ventral anterior nuclei, anterior nucleus of the thalamus, and superolateral branch of the medial forebrain bundle. The efficacy results can be generalized to both targets, with an approximate effectiveness rate of 50%. Numerous studies have substantiated the effectiveness of this treatment approach (Nuttin et al., 1999, 2003, 2014; Greenberg et al., 2006; Denys et al., 2010; Luyten et al., 2016; Lee et al., 2019b; Raviv et al., 2020; Haber et al., 2021; Lopez-Sosa et al., 2021; Germann et al., 2022).
As previously mentioned, in 2014, the Neurosurgery Committee for Psychiatric Disorders of the World Society for Stereotactic and Functional Neurosurgery released consensus guidelines regarding this treatment. According to their guidelines, in order to qualify as an "approved therapy," at least two randomized, double-blind controlled clinical trials conducted by separate research teams focusing on the same brain region must be documented. As of now, two studies (Denys et al., 2010; Luyten et al., 2016), have come close to meeting these criteria; however, one of them fell short of achieving the minimum response rate of a 35% decrease in Y-BOCS score. Additionally, these studies targeted slightly different brain locations, with Denys et al. (2010) focusing on the NAc and Luyten concentrating on the BNST, and therefore would not strictly meet the criteria established to consider DBS an “approved therapy” for OCD. Hence the importance of recruiting new OCD patients for this treatment to perform standardized multicenter studies that will allow us to establish this therapy. This, however, is a vicious circle since if the therapy is not standard, and the referral of patients for surgical evaluation decreases.
This review demonstrates the efficacy of common targets with a 50–75% response rate, which far exceeds the placebo effect. However, most studies consist of small sample sizes and, given the heterogeneity of the disease, very heterogeneous casuistry, diverse symptoms, and follow-up periods. The majority of studies used striatal areas - ALIC, VC/VS, NAc - with similar results and a median response rate of 50%. Other targets like STN and BNST DBS have reported responder rates up to 75%. ITP, on the other hand, has shown very promising results, requiring further studies to establish them.
Despite the recognized therapeutic effectiveness and widespread utilization of DBS, certain controversies persist regarding its mechanisms of action, particularly concerning psychiatric disorders. It has been suggested that dysfunctions within various neurocircuits modulated by DBS contribute to the pathophysiology of OCD. The clinical outcomes of DBS may arise from the activation of axonal fibers spanning the cortico-striato-thalamo-cortical circuits, modification of oscillatory activity within this neural network, and/or release of essential neurotransmitters. Ultimately, the therapeutic effects of DBS in OCD are likely to stem from a combination of these effects, forming the underlying mechanism of action (Bourne et al., 2012; Senova et al., 2019).
This is the reason why many authors advocate the hypothesis of the modulation of common brain circuits or connectomes, rather than of a specific nucleus/target. Despite being a relatively new and experimental treatment in many centers, there has been a growing number of functional imaging studies utilizing magnetic resonance imaging and tractography to investigate the functional changes underlying the therapeutic effects of DBS (Baldermann et al., 2021). Recently, diffusion tensor imaging has emerged as a quantitative tool for exploring white matter tracts in OCD (Torres et al., 2014). In our research, we observed that diffusion tensor imaging could be employed to identify axonal pathways activated by stimulation, establish a correlation with individual clinical outcomes, and aid in clarifying relevant aspects in target selection for stimulation. Oh et al. (2012) reported decreased global and local fractional anisotropy in OCD compared to normal controls, particularly within callosal fibers passing through the dorsolateral prefrontal cortex or the orbitofrontal cortex. Li et al. (2020) demonstrated that the fibers projecting from the dorsal cingulate cortex to the STN (the limbic hyperdirect pathway) and the mediodorsal nucleus of the thalamus were associated with improved treatment outcomes.
In parallel, recent studies are betting on creating a trajectory in which several targets can be covered in the same electrode, given the proximity between them, thus trying to better adjust the stimulation and providing a personalized treatment for each patient (Torres Díaz et al., 2021; Naesström et al., 2022). It has been observed that variability of symptom types in OCD (checking, contamination) would carry associated activation patterns of different areas of the prefrontal cortex (Vieira et al., 2021). With this in mind, Barcia et al. (2019) reported that the most effective contacts were those that showed the strongest connectivity with those specific areas of the prefrontal cortex that were activated during the presentation of images to the patient that represented their symptomatology. This was enough to justify the 50% response rates obtained so far and to contribute to the idea of more personalized treatment for each patient according to their symptomatology. However, in a recent study, Graat et al. (2022) wanted to compare whether the performance of tractography-guided surgery would achieve better results in terms of effectiveness than surgery based on anatomical landmarks. They found no difference in Y-BOCS decrease between patients with anatomical landmark-based and tractography-based DBS.
| Conclusion | | |
The studies conducted thus far have indicated that DBS is an effective treatment for patients with refractory OCD. However, it is still considered an emerging therapy given the lack of evidence to be considered a standard therapy, according to the criteria established in psychosurgery.
Despite this, research is progressing slowly, so attempts are being made to individualize targets for specific symptoms or to try to stimulate white matter tracts, in an attempt to unify targets and improve efficacy.
It is important to continue advancing and generating evidence of the efficacy of the therapy, probably carrying out multicenter studies and advancing in the use of biomarkers that objectify the results.
It would be important in the future to establish optimal patient selection criteria, determine the ideal stimulation parameters, which at the moment remain uncertain, and elucidate whether it is better to personalize the treatment according to the OCD symptomatology or to stimulate common pathways.
| Limitations | | |
This study has several limitations, such as the small number of patients evaluated, which limits the potential scope of our conclusions. Given the variety of targets studied at the present time and taking into account that this is an emerging therapy, the number of patients in each group is small so making inferences in this regard is still limited. Further research using larger sample sizes is needed to elucidate the hypotheses stated in this review.
Author contributions
PGT and CVT conducted research work. CVT had made a substantial contribution to the design of the article. PGT wrote the manuscript. CVT, MNG, IT and JAFA revised the article critically for important intellectual content. PGT and CVT made the final editing. All authors reviewed and approved the final version of the manuscript.
Conflicts of interest
The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data availability statement
No additional data are available.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[59]
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