Targeting the prefrontal-supplementary motor network in obsessive-compulsive disorder with intensified electrical stimulation in two dosages: a randomized, controlled trial

ABSTRACT Obsessive-compulsive disorder (OCD) is associated with a high disease burden, and treatment options are limited. We used intensified electrical stimulation in two dosages to target

a main circuitry associated with the pathophysiology of OCD, left dorsolateral prefrontal cortex (l-DLPFC), and pre-supplementary motor area (pre-SMA) and assessed clinical outcomes,

neuropsychological performance, and brain physiology. In a double-blind, randomized controlled trial, thirty-nine patients with OCD were randomly assigned to three groups of sham, 2-mA, or

1-mA transcranial direct current stimulation (tDCS) targeting the l-DLPFC (F3) and pre-SMA (FC2) with anodal and cathodal stimulation respectively. The treatment included 10 sessions of

20-minute stimulation delivered twice per day with 20-min between-session intervals. Outcome measures were reduction in OCD symptoms, anxiety, and depressive states, performance on a

neuropsychological test battery (response inhibition, working memory, attention), oscillatory brain activities, and functional connectivity. All outcome measures except EEG were examined at

pre-intervention, post-intervention, and 1-month follow-up times. The 2-mA protocol significantly reduced OCD symptoms, anxiety, and depression states and improved quality of life after the

intervention up to 1-month follow-up compared to the sham group, while the 1-mA protocol reduced OCD symptoms only in the follow-up and depressive state immediately after and 1-month

following the intervention. Both protocols partially improved response inhibition, and the 2-mA protocol reduced attention bias to OCD-related stimuli and improved reaction time in working

memory performance. Both protocols increased alpha oscillatory power, and the 2-mA protocol decreased delta power as well. Both protocols increased connectivity in higher frequency bands at

frontal-central areas compared to the sham. Modulation of the prefrontal-supplementary motor network with intensified tDCS ameliorates OCD clinical symptoms and results in beneficial

cognitive effects. The 2-mA intensified stimulation resulted in larger symptom reduction and improved more converging outcome variables related to therapeutic efficacy. These results support

applying the intensified prefrontal-SMA tDCS in larger trials. SIMILAR CONTENT BEING VIEWED BY OTHERS EFFICACY AND SAFETY OF TRANSCRANIAL DIRECT CURRENT STIMULATION AS AN ADD-ON TREATMENT

FOR OBSESSIVE-COMPULSIVE DISORDER: A RANDOMIZED, SHAM-CONTROLLED TRIAL Article 15 January 2021 INVESTIGATING THE EFFECTS OF BRAIN STIMULATION ON THE NEURAL SUBSTRATES OF INHIBITION IN

PATIENTS WITH OCD: A SIMULTANEOUS TDCS – FMRI STUDY Article Open access 19 May 2025 EFFICACY AND TOLERABILITY OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION FOR THE TREATMENT OF

OBSESSIVE-COMPULSIVE DISORDER IN ADULTS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS Article Open access 28 May 2021 INTRODUCTION With a lifetime prevalence of 2–3%, Obsessive-compulsive

disorder (OCD) is one of the most disabling psychiatric disorders [1], with substantial functional impairment and increased risk of early mortality [2, 3]. Individuals with OCD have unwanted

and distressing thoughts (obsessions) and repetitive behaviors that the individual feels driven to perform (compulsions) [4]. While cognitive-behavioral therapy with exposure/response

prevention and serotonin reuptake inhibitor medication are considered first-line treatments for OCD, up to 40% of patients fail to respond to these treatments [5]. Non-invasive brain

stimulation techniques provide unique opportunities to not only study brain functions but also to modify core physiological parameters of human behavior and cognition (e.g., neuroplasticity)

in both healthy and clinical populations [6, 7]. Some non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), are Food and Drug

Administration (FDA)-approved for the treatment of several major neuropsychiatric disorders, including OCD [8], suggesting that other forms of techniques may be considered as a potential

intervention for patients with OCD. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that uses a weak direct electrical current to modulate brain

activity and excitability [9]. The exact mechanisms by which tDCS works are not fully understood, but its primary mechanism of action, which emerges immediately during stimulation, involves

subthreshold de- or hyperpolarization of neuronal membrane potentials, resulting in excitability-enhancing effects by anodal and excitability-reducing effects by cathodal stimulation in

conventional protocols [10, 11]. In neuropsychiatric disorders that are characterized by functional brain abnormalities (i.e., hyper- or hypoactivity of specific brain region/s and

network/s), it is possible to modify altered brain functions with tDCS and affect target behavior or cognition [12,13,14,15,16]. In OCD, results of tDCS studies have been mixed so far, and

knowledge is still limited about optimal stimulation parameters and efficacy of interventions, such as in other clinical non-invasive brain stimulation scenarios [12, 17,18,19,20].

Functional abnormalities of the dorsolateral prefrontal cortex (DLPFC) are documented in OCD [21]. Specifically, response inhibition, a core cognitive ability that is severely impaired in

OCD is linked to several regions of the prefrontal cortex, including the DLPFC and inferior frontal gyrus [22,23,24]. Another cortical region that is consistently shown to be involved in the

pathophysiology of OCD is the pre-supplementary Motor Area (pre-SMA), which is important for inhibitory control, especially of ongoing actions [25,26,27]. In OCD patients, the pre-SMA is

hyperactive, especially during cognitive task performance that requires attentional and inhibitory control [28, 29], and is, therefore, a major target of non-invasive brain stimulation

treatment [17, 30, 31]. Although the left DLPFC and pre-SMA have been targeted in previous tDCS studies, targeting both regions with anodal and cathodal stimulation respectively has not been

reported so far [19, 32]. Applying a protocol that can modulate the prefrontal-SMA network and presumably restore physiological abnormalities can have therapeutic effects. Beyond the choice

of the target region, stimulation parameters (e.g., stimulation intensity and repetition) are critical for the efficacy of the neurostimulation intervention, and recent work stress on

optimizing and/or individualizing the intervention [33, 34]. Physiological findings in healthy humans have shown that repeated stimulation with a short interval (e.g., two consecutive

stimulation sessions with a 20 min interval) can induce long-lasting LTP-like plasticity in the brain [35]. This has implications for the clinical application of tDCS. We recently showed

that such a stimulation protocol, which we refer to as “intensified” protocol, has stronger and longer therapeutic effects on social anxiety disorder [36]. In the present study, we adopted

the same stimulation protocol and furthermore, included different outcome variables to evaluate treatment efficacy. In addition to primary clinical symptoms, we assessed core cognitive

deficits in OCD patients (e.g., response inhibition, working memory) [37] and monitored changes in the oscillatory power spectrum and functional connectivity of the brain, which are

abnormally changed in OCD, such as reduced and raised alpha and delta power respectively and reduced functional connectivity [38,39,40,41]. Accordingly, in this registered, randomized,

double-blind, sham-controlled clinical trial we aimed to (1) investigate the effect of intensified stimulation over prefrontal and pre-SMA regions on primary and secondary clinical variables

in patients with OCD, (2) explore the stimulation dosage-dependency (1-mA vs 2-mA) of treatment efficacy, (3) and examine the effects of these interventions on cognitive (response

inhibition, attention bias) and electrophysiological (oscillatory power, functional connectivity) correlates of the psychopathology of OCD. This is the first tDCS RCT in OCD to explore the

effects of a novel intensified tDCS intervention at two different stimulation intensities on symptom reduction and neurocognitive correlates of OCD. METHODS PARTICIPANTS This study had a

randomized, double-blind, parallel-group design to prevent blinding failure and carry-over effects. Thirty-nine individuals diagnosed with OCD (mean age = 31.59, SD = 8.24, 26 females) were

recruited from several neuropsychiatric clinics in Ardabil, Iran from August 2020 to January 2022. Patients were randomly assigned to the active and sham stimulation groups by the block

randomization method (supplementary content). The sample size was calculated a priori based on a medium effect size suggested for tDCS studies [42] (_f_ = 0.30, _α_ = 0.05, power = 0.95, _N_

 = 39, mixed-model ANOVA with 3 measurements). Two patients from the 1-mA and sham groups did not complete the whole treatment, and final analysis was conducted on 37 participants (1 mA tDCS

_N_ = 12, 2 mA tDCS _N_ = 13, sham tDCS _N_ = 12) (Fig. 1). The inclusion criteria were: (1) diagnosis of OCD according to DSM-5, (2) being 18–50 years old, (3) being non-smoker, (4) no

previous history of neurological diseases, brain surgery, epilepsy, seizures, brain damage, head injury, or metal brain implants, and (5) absence of other psychiatric disorders. Those

patients taking anxiolytic (_N_ = _6_) and/or SSRI (_N_ = 22) medication were receiving stable doses for 6 weeks before the experiment up to the follow-up. All participants were native

speakers and had normal or corrected-to-normal vision. This was a registered clinical trial (ClinicalTrials.gov Identifier: NCT05501132) approved by the Ethics Committee of the Ardabil

University of Medical Science (Ethics code: IR.ARUMS.REC.1399.102). Participants gave their written informed consent before participation (see Table 1 for demographics). OUTCOME MEASURES

(PRIMARY AND SECONDARY CLINICAL MEASURES, COGNITIVE DEFICITS, AND BRAIN PHYSIOLOGY) PRIMARY AND SECONDARY CLINICAL MEASURES The primary outcome measure to examine the effects of the

intervention on OCD symptoms was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [43]. Additionally, anxiety and depressive states were tested by the Beck Anxiety Inventory (BAI) [44] and

the Beck Depression Inventory (BDI-II) [45], respectively, and quality of life was assessed with the WHO Quality of Life Questionnaire (WHOQUL) [46]. These measures were used to evaluate

the clinical efficacy of the intervention. The Y-BOCS is the most widely used clinician-rated interview for assessing OCD symptom severity and is a reliable measure of treatment-based

reduction of symptoms [47]. The BAI is also well suited to monitor treatment outcomes [48], and the evaluated anxiety state is correlated with OCD symptoms [49, 50]. Similarly, BDI-II scores

are associated with OCD symptoms [50], in line with the fact that around one-third of OCD patients suffer from comorbid depression [51]. A detailed description of these measures can be

found in the supplementary information. COGNITIVE ASSESSMENT AND BRAIN PHYSIOLOGY We used a battery of neuropsychological tests that are sensitive to the cognitive deficit profile of OCD

affected by interventions. Deficits of inhibitory control, working memory performance, and attention (e.g., sustained attention, set-shifting) are among the most well-documented cognitive

deficits in OCD [37, 52, 53]. Importantly, these cognitive deficits are associated with frontal–striatal and frontal dysfunctions [29, 54,55,56], which are targeted by the intervention in

this experiment. We examined response inhibition with the Go/No-Go task and Flanker test, working memory with the n-back task, and attention bias to OCD-related stimuli with an adapted

dot-probe task. A detailed description of these measures is provided in the supplementary information. Finally, we monitored resting EEG to see how power spectrum and functional connectivity

change after the intervention, specifically in frequency bands of interest (e.g., alpha, delta, gamma) [38,39,40,41]. A detailed description of the measures and EEG data preprocessing and

analysis are in the supplementary content. TDCS Direct currents were generated by an electrical stimulator (Oasis Pro, Mind Alive, Canada), and applied through a pair of saline-soaked sponge

electrodes (7 × 5 cm) for two periods of 20 min and 20 min intervals between each stimulation period [36]. Stimulation was delivered on 5 consecutive days (two stimulations per day). In

both active (1-mA, 2-mA) and sham conditions, anodal and cathodal electrodes were placed over the left DLPFC (F3), and right pre-SMA (FC2), respectively, to keep a minimum 6 cm distance

between the edges of the electrodes [57]. To localize the right pre-SMA first, the pre-SMA was identified using the EEG 10–20 system for electrode positioning (i.e., 15% cm anterior to Cz)

[17, 58]. In sham stimulation, the electrical current was ramped up and down for 30 seconds to generate the same sensation as in the active condition and then turned off [59]. To guarantee

blinding, tDCS was applied by independent investigators who were not involved in outcome measures rating [60]. A side-effect survey was done after each tDCS session. Blinding efficacy was

not explored among patients and experimenters. A 3D model of the current flow in the head was created to determine induced electrical fields in the brain for the above-mentioned tDCS

protocol (Fig. 2). PROCEDURE Prior to the experiment, participants completed a brief questionnaire to evaluate their suitability for brain stimulation. All participants received 10 sessions

of stimulation (2 sessions daily, 5 days in total) with 20-minute intervals between the sessions. To avoid confounding effects of the intervention at circadian non-preferred time, which can

significantly affect neuroplasticity induction [61], all stimulation sessions took place between 11:00–14:00, and participants were not under sleep pressure [62]. Clinical cognitive measures

were evaluated before the first intervention (pre-intervention), right after the end of the last intervention (post-intervention), and 1-month following the last stimulation session

(follow-up). EEG measurements took place only before and after the intervention. Patients were instructed about the tasks before the beginning of the experiment. None of the patients

received any kind of psychotherapy during the study. Participants were blind to the study hypotheses and stimulation conditions. The experimenter who conducted the outcome measures was

blinded to the tDCS conditions (Fig. 2). STATISTICAL ANALYSIS Data analyses were conducted with the statistical package SPSS, version 26.0 (IBM, SPSS, Inc., Chicago, IL), and the GraphPad

Prism 8.2.1 (GraphPad Software, San Diego, California). The normality and homogeneity of data distribution, and variance were confirmed by Shapiro-Wilk and Levin tests, respectively.

Between-group differences in demographic variables were explored by Chi-square tests or Fisher’s exact test for categorical variables and F-tests for continuous variables. A multivariate

Analysis of Variance (MANOVA) was first performed on the post-intervention and follow-up means of all outcome variables with group as the fixed factor and pre-intervention measures as

covariates. This was to help protect against inflating the Type 1 error rate in the follow-up ANOVAs and post-hoc comparisons. A series of one-way ANOVA’s on each dependent variable was

conducted as follow-up tests to the MANOVA. Finally, a series of post-hoc analyses were calculated using Dunnett’s multiple comparisons to examine individual mean difference comparisons

across groups (active 1 mA, active 2 mA, sham) and time points (pre-intervention, post-intervention, follow-up). The critical level of significance was 0.05 for all statistical analyses.

RESULTS SIDE EFFECTS AND BASELINE ASSESSMENT Participants tolerated the stimulation well, and no adverse effects were reported during and after stimulation, replicating the safety of the

intervention [63, 64]. No significant difference was found between the group ratings of tDCS side effects (Supplementary Table S1). No significant between-group differences emerged in the

pre-intervention measurements (Supplementary Table S2). PRIMARY CLINICAL OUTCOME: REDUCTION OF OCD SYMPTOMS AND ANXIETY A statistically significant MANOVA effect was seen for both

post-intervention (Pillais’ Trace = 1.64, _F_(24, 24) = 4.63, _p_ < 0.001) and follow-up measurements (Pillais’ Trace = 2.98, _F_(24, 24) = 4.63, _p_ = 0.005). The results of the

follow-up ANOVAs revealed a significant main effect of group on both Y-BOCS scores (post-intervention: _F_(2, 22) = 7.14, _p_ = 0.004, _ηp__2_ = 0.394; follow-up: _F_(2, 22) = 13.54, _p_ 

< 0.004, _ηp__2_ = 0.552) and BAI scores (post-intervention_: F_(2, 22) = 8.78, _p_ = 0.002, _ηp__2_ = 0.423; follow-up: _F_(2, 22) = 5.78, _p_ = 0.010, _ηp__2_ = 0.345). Next, Dunnett’s

multiple comparisons were performed on individual mean difference and showed a significant decrease in Y-BOCS scores at the post-intervention time in the 2-mA group (_p_ = 0.021, _d_ = 

0.98), at the 1-month follow-up in both the 2-mA (_p_ = 0.004, _d_ = 1.01) and 1-mA (_p_ = 0.013, _d_ = 1.23) groups as compared to pre-intervention time, but no significant changes were

seen in the sham group (Fig. 3A). When compared to the sham group, reduced Y-BOCS scores were significant in both active groups only at the follow-up (1-mA: _p_ = 0.044, _d_ = 1.16; 2-mA:

_p_ = 0.045, _d_ = 0.82) (Fig. 3B). For the BAI scores, Dunnett’s multiple comparisons showed a significant decrease in BAI scores from pre-intervention to both post-intervention (_p_ = 

0.025, _d_ = 0.85) and 1-month follow-up (_p_ = 0.009, _d_ = 0.97) only in the 2-mA group (Fig. 3C). When compared to the sham group, both active groups showed a non-significant trendwise

reduction of BAI scores at the post-intervention assessment (1-mA: _p_ = 0.074; 2-mA: _p_ = 0.083) (Fig. 3D). SECONDARY CLINICAL OUTCOMES: MOOD AND QUALITY OF LIFE The results of the

follow-up ANOVAs revealed a significant main effect of group on BDI-II scores (post-intervention: _F_(2, 22) = 7.13, _p_ = 0.004, _ηp__2_ = 0.394; follow-up: _F_(2, 22) = 10.47, _p_ < 

0.001, _ηp__2_ = 0.488) and quality of life (post-intervention: _F_(2, 22) = 3.58, _p_ = 0.045, _ηp__2_ = 0.246; follow-up: _F_(2, 22) = 7.33, _p_ = 0.004, _ηp__2_ = 0.400). Dunnett’s post

hoc tests showed that BDI-II scores were reduced from the pre-intervention to both post-intervention and 1-month follow-up assessment in both, 2-mA (post-intervention: _p_ = 0.002, _d_ = 

1.15; follow-up: _p_ < 0.001, _d_ = 1.34) and 1-mA (post-intervention: _p_ < 0.001, _d_ = 1.65; follow-up: _p_ = 0.001, _d_ = 1.49) groups, but not in the sham group, and reduced

depressive state at each time point was significant in both active groups vs. the sham group (Fig. 3E, F). No significant individual mean differences were found across groups in

quality-of-life scores (Fig. 3G). However, we calculated the changes in quality of life scores from the baseline to post-intervention and follow-up. Dunnett’s post hoc test of score changes

across groups showed that quality of life scores significantly improved after the intervention only in the 2 mA group (_p_ = 0.025) (Fig. 3H). COGNITIVE FUNCTIONS: IMPROVED INHIBITORY

CONTROL IN BOTH ACTIVE TDCS GROUPS In the Flanker test, the follow-up ANOVAs revealed a significant main effect of group on both, congruent (post-intervention: _F_(2, 22) = 10.08, _p_ < 

0.001, _ηp__2_ = 0.478; follow-up: _p_ = 0.901) and incongruent trials (post-intervention: _F_(2, 22) = 8.01, _p_ = 0.002, _ηp__2_ = 0.422; follow-up: _p_ = 0.445) only after the

intervention and not follow-up. Dunnett’s multiple-test comparisons revealed a significant _pre_ vs _post_-intervention RT reduction of incongruent stimuli (_p_ = 0.015, _d_ = 1.35) only in

the 1-mA group, which, however, was not significant vs the sham (Fig. 4A, B). In the Go/No-Go task, the results of the follow-up ANOVAs revealed a significant main effect of group for No-Go

trials reaction time (post-intervention: _F_(2, 22) = 7.11, _p_ = 0.004, _ηp__2_ = 0.393; follow-up: _F_(2, 22) = 4.34, _p_ = 0.026, _ηp__2_ = 0.283) and a marginally significant effect on

No-Go trials accuracy at the post-intervention measurement (_F_(2, 22) = 3.39, _p_follow-up = 0.054, _ηp__2_ = 0.233). Dunnett’s multiple-test comparisons showed increased accuracy from the

pre-intervention to the follow-up measurement in 2-mA (_p_ = 0.022, _d_ = 0.87) and 1-mA (_p_ = 0.032, _d_ = 0.27) groups (Fig. 4C). The 2-mA protocol significantly reduced RT from pre vs

post-intervention (_p_ = 0.027, _d_ = 1.92) and pre vs follow-up (_p_ = 0.037, _d_ = 1.95) as well (Fig. 4E) and here the performance speed on the No-Go trials was significantly faster in

the 2-mA group vs the sham after the intervention (_p_ = 0.014, _d_ = 1.73) (Fig. 4F). COGNITIVE FUNCTIONS: WORKING MEMORY AND ATTENTION BIAS In working memory performance, the follow-up

ANOVAs revealed a significant main effect of group only on performance speed after the intervention (_F_(2, 22) = 16.76, _p_ < 0.001, _ηp__2_ = 0.604) and 1-month follow-up (_F_(2, 22) = 

13.87, _p_ < 0.001, _ηp__2_ = 0.558). Dunnett’s multiple comparisons showed a significantly faster pre- vs post-intervention RT (_p_ < 0.001, _d_ = 1.92) and pre vs follow-up RT (_p_ 

< 0.001, _d_ = 1.95) in the 2-mA and a significant pre vs follow-up RT reduction (_p_ = 0.003, _d_ = 1.01) in the 1-mA group. In the 2-mA group, this RT reduction was furthermore larger

than that of the sham group at post-intervention (_p_ = 0.007, _d_ = 1.73) and follow-up (_p_ = 0.002, _d_ = 1.91) measurements (Fig. 4G, H). Finally, in the attention bias of patients to

OCD-related stimuli, the follow-up ANOVAs showed a significant main effect of group for both, OCD-related (post-intervention: _F_(2, 22) = 8.82, _p_ = 0.002, _ηp__2_ = 0.445; follow-up:

_F_(2, 22) = 5.53, _p_ = 0.011, _ηp__2_ = 0.335) and unrelated stimuli (post-intervention: _F_(2, 22) = 5.82, _p_ = 0.009, _ηp__2_ = 0.346; follow-up: _F_(2, 22) = 9.45, _p_ = 0.001, _ηp__2_

 = 0.462). Dunnett’s multiple-test comparisons showed a significantly faster pre- vs post-intervention RT for both, OCD-related (_p_ < 0.026, _d_ = 0.70) and unrelated (_p_ < 0.007,

_d_ = 0.93) stimuli in the 2-mA group (Fig. 4I, K). No significant between-group RT differences were, however found for the post-intervention and follow-up measurements. INTERVENTION-RELATED

CHANGES IN EEG POWER SPECTRUM DENSITY AND FUNCTIONAL CONNECTIVITY PSD Analysis with a cluster-based permutation test (post vs pre) revealed a significant increase in relative alpha power in

the left frontal region (cluster-level statistic = 16, _p_ < 0.01) and the occipital region (cluster-level statistic = 11, _p_ < 0.05) in the 2-mA group compared to the sham group.

Additionally, a significant decrease in relative delta power was observed in a cluster located in the occipital region (cluster-level statistic = −11, _p_ < 0.05) in the 2-mA group

compared to the sham group. In the 1-mA group, a significant increase in relative alpha power was observed in the right frontal region (cluster-level statistic = 11, _p_ < 0.001) (Fig.

5C). Topographical plots of the relative power changes (post power – pre power) in all frequency bands after each intervention are in supplementary information (Fig. S1). Regarding

functional connectivity, comparative analysis of post-intervention Phase Locking Value (PLV) matrices showed a general trend of increased connectivity in higher frequency bands in both

active groups as compared to the sham group (Fig. 5A, B and Fig. S2). When we compared both groups with each other, the 2-mA group generally decreased functional connectivity across most

frequency bands (EEG connectivity results are fully described in the supplementary information). We did not see any relevant correlation between EEG parameters and clinical/cognitive

measures. DISCUSSION In this randomized, double-blind, sham-controlled, parallel-group clinical trial, we investigated the impact of an intensified tDCS protocol (stimulation twice per day

with 20-min intervals) over the prefrontal-supplementary motor network, in two dosages (1-mA vs. 2-mA) on primary clinical symptoms, neuropsychological performance, and electrophysiological

correlates in patients with OCD. The 2-mA stimulation dosage significantly reduced OCD symptoms and anxiety after the intervention and in the follow-up. Both active stimulation protocols

significantly reduced depressive symptoms. At the neuropsychological level, both active protocols partially improved response inhibition, and the 2-mA protocol reduced attention bias to

threat-related stimuli and improved working memory performance as well. Both protocols increased alpha, and the 2-mA protocol decreased delta oscillatory power too. Both protocols increased

connectivity in higher frequency bands at frontal-central areas compared to the sham. No significant changes were observed in the sham group for any outcome measures. These findings can be

explained from neurophysiological and neuropsychological perspectives. The hallmark finding of neuroimaging studies refers to lateral hypoconnectivity (including the DLPFC) and medial

hyperconnectivity (including the pre-SMA) in OCD [37, 65], which was the rationale for applying our stimulation protocol and is in line with findings from rTMS studies [66]. We applied

anodal stimulation over the left DLPFC to increase the activity of this region and cathodal stimulation of the pre-SMA to downregulate activity. With causal modulation of cerebral

excitability with tDCS [6], we expected to restore functional abnormalities in the OCD-relevant brain circuitry, and in principal accordance, this intervention was associated with behavioral

and clinical improvement in this study. In further accordance, the intervention, especially after 2-mA stimulation, restored altered alpha and delta oscillatory power in patients [38], and

both protocols increased connectivity in the prefrontal regions, which is reduced in OCD patients, that can be likely an appropriate treatment cortical target [21, 66]. In addition to

neurophysiological changes, neuropsychological accounts could also explain our findings. The most well-known psychological mechanisms underlying OCD psychopathology include impaired

cognitive control (the inability to regulate compulsive behavior) [67], impaired cognitive flexibility (the inability to regulate thinking) [68], and impaired balance between goal-directed

behavior and more automatic habit learning [69, 70]. Importantly, these cognitive abilities are related to lateral and medial prefrontal cortices [23, 37, 71]. The behavioral tasks we used

are primarily related to cognitive control and cognitive flexibility (e.g., response inhibition, working memory), and the performance of these tasks was significantly improved after

intervention, more obviously in the 2-mA group. Here, it should however be noted that the effects of both protocols on response inhibition were smaller than expected, which could be due to

the higher relevance of the right prefrontal region in cognitive inhibition [72]. That said, anodal stimulation of the left DLPFC was also shown to improve executive functions in

neuropsychiatric patients in previous studies [13, 36, 73, 74], and might explain treatment effects in OCD patients. One major rationale of this study was to identify the effect of different

stimulation dosages on treatment efficacy, specifically in the intensified protocol, which we had already applied in another study with promising results [36]. This protocol has not been

applied in OCD to the best of our knowledge. Our results in this study show that the 2-mA intensified tDCS protocol was overall more effective than both, sham stimulation and the 1-mA

stimulation, especially for the clinical variables, and it improved more outcome measures including measures of behavioral performance, compared to the 1-mA protocol (e.g., working memory,

attention bias). The rationale behind the protocol comes from a study showing that twice-stimulation with 20-minute intervals leads to longer aftereffects on cortical excitability compared

to non-repeated stimulation or stimulation with long intervals and resembles features of late-phase LTP [35, 75]. This finding has at least two important clinical implications. First, the

2-mA stimulation is associated with higher clinical efficacy in OCD, and probably in other anxiety disorders, as shown in our previous work in patients with social anxiety disorder [36].

Second, the intensified stimulation (twice per day with a 20 min interval), has significant clinical efficacy for treatment-related variables. This is in line with physiological studies that

have shown that repeated tDCS sessions induce larger increases in excitability [76] and more importantly suggest that the intensified protocol (repetition of two 20-minute stimulation with

a 20-minute interval between) can be promising for clinical application in other neuropsychiatric diosders. Our protocol was different from other commonly applied protocols in other aspects.

First and to the best of our knowledge, none of the previous tDCS randomized trials targeted the prefrontal-SMA network by stimulating both left DLPFC and pre-SMA [77, 78]. Additionally,

this is also the first randomized-controlled trial that compared the efficacy of two stimulation dosages which is typically needed for establishing clinical efficacy of an intervention.

Finally, in comparison to other protocols used in previous studies, a recent metanalysis of tDCS RCTs in OCD showed that protocols that applied cathodal stimulation over the pre-SMA with an

extracephalic return electrode delivered stronger electric fields to the circuity involved in OCD in comparison to the other montages [19]. None of these tDCS studies targeted the left DLPFC

with anodal tDCS. This metanalysis, however, did not find significant differences between active vs sham tDCS in contrast to our study. Our study had several limitations. First, the

intrinsically limited focality of tDCS can result in a relatively diffuse stimulation. Neuroimaging methods can help to more accurately identify the regions directly affected by tDCS in

future studies. Furthermore, we did not examine blinding efficacy in patients and could not measure EEG in the follow-up due to COVID-19-related restrictions. With respect to blinding

efficacy, the 2-mA intensity typically results in more sensations over the skin as compared to the sham and 1-mA protocol, which may affect patients’ blinding. However, there was no

significant difference in reported ratings of tDCS side effects between groups (see supplementary information, Table S1). Taken together, our findings suggest that the intensified

prefrontal-supplementary motor cortex tDCS protocol introduced for the treatment of OCD is promising and might be effective in other neuropsychiatric disorders. Both primary OCD symptoms and

secondary treatment-related variables (anxiety, depressive state, quality of life) and cognitive functions (response inhibition, working memory, and attentional bias) improved after the

intervention, especially in the 2-mA group. Partial effects of the intervention on response inhibition might suggest further optimizing the protocol by targeting the right prefrontal cortex,

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Berlin, Heidelberg. Download references ACKNOWLEDGEMENTS Michael Nitsche is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project Number 316803389—SFB

1280, project A6, and by the German Centre of Mental Health (Project Number 01EE2302D). The datasets generated and/or analyzed during the current study are publicly available at

https://osf.io/dfm2j/ and in the supplementary content. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Psychology, Faculty of Humanities, University of Zanjan, Zanjan, Iran

Jaber Alizadehgoradel * Department of Psychiatry and Psychology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Behnam Molaei * Department of Psychiatry, School of

Medicine, Hacettepe University, Ankara, Turkey Khandan Barzegar Jalali * Department of Family Health, Social Determinants of Health Research Center, Ardabil University of Medical Sciences,

Ardabil, Iran Asghar Pouresmali * Sharif Brain Center, Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran Kiomars Sharifi * School of Cognitive Sciences,

Institute for Research in Fundamental Sciences, Tehran, Iran Kiomars Sharifi & Mohammad Ali Salehinejad * Department of Psychology and Educational Sciences, University of Tehran, Tehran,

Iran Amir-Homayun Hallajian * Department of Psychology, Shahid Beheshti University, Tehran, Iran Vahid Nejati * Department of Psychology and Neurosciences, Leibniz Research Centre for

Working Environment and Human Factors, Dortmund, Germany Benedikt Glinski, Michael A. Nitsche & Mohammad Ali Salehinejad * Dipartimento di Scienze Cognitive, Psicologiche, Pedagogiche e

degli studi culturali, Università di Messina, Messina, Italy Carmelo M. Vicario * Bielefeld University, University Hospital OWL, Protestant Hospital of Bethel Foundation, University Clinic

of Psychiatry and Psychotherapy and University Clinic of Child and Adolescent Psychiatry and Psychotherapy, Bielefeld, Germany Michael A. Nitsche * German Centre for Mental Health (DZPG),

Bochum, Germany Michael A. Nitsche Authors * Jaber Alizadehgoradel View author publications You can also search for this author inPubMed Google Scholar * Behnam Molaei View author

publications You can also search for this author inPubMed Google Scholar * Khandan Barzegar Jalali View author publications You can also search for this author inPubMed Google Scholar *

Asghar Pouresmali View author publications You can also search for this author inPubMed Google Scholar * Kiomars Sharifi View author publications You can also search for this author inPubMed

 Google Scholar * Amir-Homayun Hallajian View author publications You can also search for this author inPubMed Google Scholar * Vahid Nejati View author publications You can also search for

this author inPubMed Google Scholar * Benedikt Glinski View author publications You can also search for this author inPubMed Google Scholar * Carmelo M. Vicario View author publications You

can also search for this author inPubMed Google Scholar * Michael A. Nitsche View author publications You can also search for this author inPubMed Google Scholar * Mohammad Ali Salehinejad

View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS JA: conceptualization, investigation, data curation, validation. BM: resources, project

administration, data curation. KBJ & AP: investigation, data curation. A-HH & KS: EEG analysis, 3D modeling, visualization, writing—original draft (EEG part). VN: software. BG: data

analysis. CMV: writing—review & editing. MAN: supervision, methodology, writing—review & editing. MAS: conceptualization, methodology, supervision, writing—original draft,

writing—review & editing, visualization, formal analysis (clinical/behavioral part). CORRESPONDING AUTHORS Correspondence to Behnam Molaei or Mohammad Ali Salehinejad. ETHICS

DECLARATIONS COMPETING INTERESTS Michael Nitsche is a member of the Scientific Advisory Boards of Neuroelectrics and NeuroDevice. All other authors declare no competing interests. ADDITIONAL

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THIS ARTICLE CITE THIS ARTICLE Alizadehgoradel, J., Molaei, B., Barzegar Jalali, K. _et al._ Targeting the prefrontal-supplementary motor network in obsessive-compulsive disorder with

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28 July 2023 * Revised: 04 January 2024 * Accepted: 05 January 2024 * Published: 05 February 2024 * DOI: https://doi.org/10.1038/s41398-024-02736-y SHARE THIS ARTICLE Anyone you share the

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