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Transcranial Direct Current Stimulation Targeting the Ventromedial Prefrontal Cortex Reduces Reactive Aggression and Modulates Electrophysiological Responses in a Forensic Population

Open AccessPublished:June 01, 2021DOI:https://doi.org/10.1016/j.bpsc.2021.05.007

      Abstract

      Background

      Studies have shown that impairments in the ventromedial prefrontal cortex play a crucial role in violent behavior in forensic patients who also abuse cocaine and alcohol. Moreover, interventions that aimed to reduce violence risk in those patients are found not to be optimal. A promising intervention might be to modulate the ventromedial prefrontal cortex by high-definition (HD) transcranial direct current stimulation (tDCS). The current study aimed to examine HD-tDCS as an intervention to increase empathic abilities and reduce violent behavior in forensic substance dependent offenders. In addition, using electroencephalography, we examined the effects on the P3 and the late positive potential of the event-related potentials in reaction to situations that depict victims of aggression.

      Methods

      Fifty male forensic patients with a substance dependence were tested in a double-blind, placebo-controlled randomized study. The patients received HD-tDCS 2 times a day for 20 minutes for 5 consecutive days. Before and after the intervention, the patients completed self-reports and performed the Point Subtraction Aggression Paradigm, and electroencephalography was recorded while patients performed an empathy task.

      Results

      Results showed a decrease in aggressive responses on the Point Subtraction Aggression Paradigm and in self-reported reactive aggression in the active tDCS group. Additionally, we found a general increase in late positive potential amplitude after active tDCS. No effects on trait empathy and the P3 were found.

      Conclusions

      Current findings are the first to find positive effects of HD-tDCS in reducing aggression and modulating electrophysiological responses in forensic patients, showing the potential of using tDCS as an intervention to reduce aggression in forensic mental health care.

      Keywords

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      • Eroh J.
      • Hart J.
      • Vanneste S.
      Exploring the effects of anodal and cathodal high definition transcranial direct current stimulation targeting the dorsal anterior cingulate cortex.
      ). Therefore, in the present study we used a protocol using HD-tDCS targeting the vmPFC, with multiple sessions and with enhancing the brain state during modulation to maximize the effect (
      • Buch E.R.
      • Santarnecchi E.
      • Antal A.
      • Born J.
      • Celnik P.A.
      • Classen J.
      • et al.
      Effects of tDCS on motor learning and memory formation: A consensus and critical position paper.
      ,
      • Fisher D.B.
      • Fried P.
      • Ruffini G.
      • Ripolles O.
      • Ketchabaw T.
      • Santarnecchi E.
      • et al.
      Network-targeted non-invasive brain stimulation with multifocal tDCS.
      ,
      • Fox M.D.
      • Buckner R.L.
      • Liu H.
      • Chakravarty M.M.
      • Lozano A.M.
      • Pascual-Leone A.
      Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases.
      ,
      • Baxter B.S.
      • Edelman B.J.
      • Sohrabpour A.
      • He B.
      Anodal transcranial direct current stimulation increases bilateral directed brain connectivity during motor-imagery based brain-computer interface control.
      ).
      To study the effect of tDCS on brain functioning, the temporal dynamics could be studied using electroencephalography (EEG) (
      • Cheng Y.
      • Hung A.Y.
      • Decety J.
      Dissociation between affective sharing and emotion understanding in juvenile psychopaths.
      ,
      • Decety J.
      • Chen C.
      • Harenski C.L.
      • Kiehl K.A.
      Socioemotional processing of morally-laden behavior and their consequences on others in forensic psychopaths.
      ,
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ). The event-related potential (ERP) technique has mostly been used to investigate empathy by measuring brain responses to pictures. Studies have shown that both early and late ERP components are related to perceived pain in others (
      • Cheng Y.
      • Hung A.Y.
      • Decety J.
      Dissociation between affective sharing and emotion understanding in juvenile psychopaths.
      ,
      • Decety J.
      • Yang C.Y.
      • Cheng Y.
      Physicians down-regulate their pain empathy response: An event-related brain potential study.
      ,
      • Meng J.
      • Meriño L.M.
      • Bigdely Shamlo N.
      • Makeig S.
      • Robbins K.
      • Huang Y.
      Characterization and robust classification of EEG signal from image RSVP events with independent time-frequency features.
      ) and in reaction to self-reported trait empathy (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ,
      • Corbera S.
      • Cook K.
      • Brocke S.
      • Dunn S.
      • Wexler B.E.
      • Assaf M.
      The relationship between social competence deficits and empathy for emotional pain in schizophrenia.
      ,
      • Fabi S.
      • Leuthold H.
      Empathy for pain influences perceptual and motor processing: Evidence from response force, ERPs, and EEG oscillations.
      ,
      • Vaes J.
      • Meconi F.
      • Sessa P.
      • Olechowski M.
      Minimal humanity cues induce neural empathic reactions towards non-human entities.
      ). Two ERPs that have been studied extensively are the P3 and late positive potential (LPP).
      The P3 is an ERP that has a positive voltage in the latency of 300–650 ms (
      • Hajcak G.
      • MacNamara A.
      • Olvet D.M.
      Event-related potentials, emotion, and emotion regulation: An integrative review.
      ). The P3 is typically associated with controlling sustained attention toward salient stimuli (
      • Hajcak G.
      • MacNamara A.
      • Olvet D.M.
      Event-related potentials, emotion, and emotion regulation: An integrative review.
      ) and has been linked to empathy for pain (
      • Cheng Y.
      • Hung A.Y.
      • Decety J.
      Dissociation between affective sharing and emotion understanding in juvenile psychopaths.
      ,
      • Decety J.
      • Yang C.Y.
      • Cheng Y.
      Physicians down-regulate their pain empathy response: An event-related brain potential study.
      ,
      • Cuthbert B.N.
      • Schupp H.T.
      • Bradley M.M.
      • Birbaumer N.
      • Lang P.J.
      Brain potentials in affective picture processing: Covariation with autonomic arousal and affective report.
      ,
      • Fan Y.
      • Han S.
      Temporal dynamic of neural mechanisms involved in empathy for pain: An event-related brain potential study.
      ,
      • Ibáñez A.
      • Hurtado E.
      • Lobos A.
      • Escobar J.
      • Trujillo N.
      • Baez S.
      • et al.
      Subliminal presentation of other faces (but not own face) primes behavioral and evoked cortical processing of empathy for pain.
      ,
      • Li W.
      • Han S.
      Perspective taking modulates event-related potentials to perceived pain.
      ,
      • Coll M.P.
      Meta-analysis of ERP investigations of pain empathy underlines methodological issues in ERP research.
      ). The LPP is a positively sustained ERP that occurs around 400–1000 ms, is located at the parietal locations and the central midline (
      • Hajcak G.
      • Weinberg A.
      • MacNamara A.
      • Foti D.
      ERPs and the study of emotion.
      ), and is associated with empathy and emotional cues. A study of Cuthbert et al. (
      • Cuthbert B.N.
      • Schupp H.T.
      • Bradley M.M.
      • Birbaumer N.
      • Lang P.J.
      Brain potentials in affective picture processing: Covariation with autonomic arousal and affective report.
      ) demonstrated that the LPP indicates an increase in amplitude toward emotional stimuli, arousal, regulation, facial expressions, and affective experience regulation, and the study of Van Dongen et al. (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ) found reduced P3 and LPP in individuals with decreased empathic abilities. Therefore, studying these positive potentials contributes to the understanding of emotional regulation (
      • Cheng Y.
      • Hung A.Y.
      • Decety J.
      Dissociation between affective sharing and emotion understanding in juvenile psychopaths.
      ,
      • Cuthbert B.N.
      • Schupp H.T.
      • Bradley M.M.
      • Birbaumer N.
      • Lang P.J.
      Brain potentials in affective picture processing: Covariation with autonomic arousal and affective report.
      ,
      • Lang P.J.
      • Bradley M.M.
      Emotion and the motivational brain.
      ,
      • Fan Y.
      • Duncan N.W.
      • de Greck M.
      • Northoff G.
      Is there a core neural network in empathy? An fMRI based quantitative meta-analysis.
      ) and serves as an indication that the temporal dynamics of empathic processing in the brain can be studied using late ERPs in the EEG.
      The main aim of the current study was to examine whether modulating activity in the vmPFC using HD-tDCS would increase empathic abilities and reduce aggressive behavior in forensic patients with substance dependence. In addition, in this study we investigated the effects of the HD-tDCS intervention on electrophysiological responses (P3 and LPP) to situations that depict victims of aggression (i.e., empathy). Based on prior literature, it was expected that after active tDCS, compared with sham, empathic abilities would increase and aggression would decrease. Additionally, it was expected that the P3 and LPP amplitude after viewing pictures that depict victims of aggression would be increased after active tDCS compared with sham tDCS.
      Knowledge gained from the current study will give insight in the casual relation among activity in the vmPFC, empathy, and aggression and can inform in the development of new neuromodulation (e.g., tDCS) protocols for treatment interventions in violent forensic populations.

      Methods and Materials

      Participants

      Fifty male participants (mean age = 37.40 years, SD = 9.19 years, range: 22–62 years) were recruited from two departments of the division for forensic addiction mental health care in Antes, Poortugaal, the Netherlands, between February and October 2019. Twenty-one participants were recruited at the Forensic Addiction Clinic and 29 from the Department of Forensic Care. The patients were randomly assigned to one of the conditions and participated in a double-blind, placebo-controlled study with two conditions. Twenty-five participants received treatment as usual (TAU) + active stimulation, and 25 participants received TAU + sham (placebo). For an overview of the demographic characteristics of the sample, see Table 1. Inclusion and exclusion criteria are presented in the Supplement.
      Table 1Demographic Characteristics
      CharacteristictDCS GroupSham Group
      n%n%
      Caucasian251002392
      Non-Caucasian028
      Primary Education936832
      High School728624
      Secondary Education (VET)9361144
      DSM-5 Axis I7281040
      DSM-5 Axis II8321040
      Mono Substance Use832936
      Poly Substance Use17681664
      Characteristics are displayed in percentage of participants per group, N = 50 (n = 25 for each condition). Participants were on average 36.4 years old (SD = 8.88) in the tDCS group and on average 38.4 years old in the sham group (SD = 9.56), and participant age did not differ by condition.
      VET, Vocational Education and Training.
      The participant flow and recruitment according to CONSORT (Consolidated Standards of Reporting Trials) can be found in Figure S1.

      Procedure and Design

      The study consisted of a double-blind, placebo-controlled, randomized trial comparing a group that received active HD-tDCS intervention with a sham control group. Baseline assessments including self-report questionnaires, a resting-state EEG task, passive viewing task (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ), rating empathy task (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ), and the PSAP (
      • Cherek D.R.
      Point Subtraction Aggression Paradigm (PSAP).
      ) were conducted during the preintervention. During the following week, the participants received two 20-minute sessions of HD-tDCS stimulation or sham intervention targeting the vmPFC for 5 consecutive days (see Figure S2 for a flowchart of the procedure). There were approximately 3–4 hours between the two sessions, depending on the patients’ schedule and TAU. Outcome measurements were conducted 1 week later during the postintervention. Self-report questionnaires and tasks were conducted in a fixed order.
      A study by Nissim et al. (
      • Samani M.M.
      • Agboada D.
      • Jamil A.
      • Kuo M.F.
      • Nitsche M.A.
      Titrating the neuroplastic effects of cathodal transcranial direct current stimulation (tDCS) over the primary motor cortex.
      ) using functional magnetic resonance imaging demonstrated that the optimal gains from using tDCS could be realized by increasing the activity of the brain area of interest (i.e., the brain state). Therefore, to optimize our intervention, we increased the activity of the vmPFC while triggering these brain states by showing the subjects two empathic movies [Wonder (
      • Chbosky Stephen
      Wonder [DVD].
      ) and I am Sam (
      • Nelson Jessie
      I am Sam [DVD].
      )] and using the Reading the Mind in the Eyes task (
      • Baron-Cohen S.
      • Wheelwright S.
      • Hill J.
      • Raste Y.
      • Plumb I.
      The “Reading the Mind in the Eyes” Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism.
      ). Patients and investigators were blinded to the tDCS allocation. The principal investigator of the project, who was not involved in data collection and initial statistical analysis, preprogrammed the tDCS device in active condition or sham condition matched with a number.
      The study was conducted in accordance with the ethical standard of the Declaration of Helsinki (
      General Assembly of the World Medical Association
      World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects.
      ) and was approved by Medical and Ethical Review Board of the Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands. The trial protocol was registered at the Dutch Trial Register (NTR7701). See also Sergiou et al. (
      • Sergiou C.S.
      • Woods A.J.
      • Franken I.H.A.
      • van Dongen J.D.M.
      Transcranial direct current stimulation (tDCS) as an intervention to improve empathic abilities and reduce violent behavior in forensic offenders: Study protocol for a randomized controlled trial.
      ) for the complete published study protocol.

      High-Definition tDCS Intervention

      HD-tDCS was administered with the European Conformity–certified Neuroelectrics Starstim8 (Neuroelectrics Barcelona, SLU), operating according to the evidence-based guidelines of LeFaucheur et al. (
      • Lefaucheur J.P.
      • Antal A.
      • Ayache S.S.
      • Benninger D.H.
      • Brunelin J.
      • Cogiamanian F.
      • et al.
      Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS).
      ). Before commencement of the study, the HD-tDCS montage optimization was based on the current-flow modeling of the NIC software of the tDCS Starstim8 system [see the protocol (
      • Sergiou C.S.
      • Woods A.J.
      • Franken I.H.A.
      • van Dongen J.D.M.
      Transcranial direct current stimulation (tDCS) as an intervention to improve empathic abilities and reduce violent behavior in forensic offenders: Study protocol for a randomized controlled trial.
      ) for detailed description]. In addition, the induced E-field of the HD-tDCS montage was computed in SimNibs (version 3.2) (
      • Thielscher A.
      • Antunes A.
      • Saturnino G.B.
      Field modeling for transcranial magnetic stimulation: A useful tool to understand the physiological effects of TMS?.
      ). Detailed description on biophysical modeling can be found in the Supplement.
      The currents were transmitted through six circular Ag/AgCl PiStim high-definition electrodes (1 cm radius, π cm2) that were applied with conductive gel (Figure 1). The resulting Norm-E field and Normal E-field distribution is created in Gmsh (version 4.7.1) (
      • Geuzaine C.
      • Remacle J.-F.
      Gmsh: A 3-D finite element mesh generator with built-in pre- and post-processing facilities.
      ) with an output range from 0 to 0.25 V/m. The HD-tDCS device was programed for stimulation with 2 mA tDCS during 20 minutes for modulating the vmPFC of the participants in the active condition. The sham condition followed the same procedure, with a 30-second ramping-up and down the tDCS currents at the beginning and end of the protocol, based on earlier research indicating this method being effective for blinding (
      • Gandiga P.C.
      • Hummel F.C.
      • Cohen L.G.
      Transcranial DC Stimulation (tDCS): A tool for double-blind sham-controlled clinical studies in brain stimulation.
      ). The anodal electrode was placed on the Fpz location, and the five return or cathodal electrodes were placed on AF3, AF4, F3, Fz, and F4 (see Figure 1 for the electrical field model and the Supplement for detailed description of the biophysical modeling).
      Figure thumbnail gr1
      Figure 1(A) Placement of the electrodes at 32 standard 10–20 electroencephalography system on the scalp with anodal high-definition transcranial direct current stimulation (HD-tDCS) with 6 × 1-cm radius (π cm2) electrodes over the Fpz (2 mA) and cathodal tDCS over AF3, AF4, F3, F4, and Fz (−0.4 mA each). (B) Different views and slices of the map of electrical field induced by HD-tDCS montage as expressed in normE (V/m). This measure allows us to see the intensity of the stimulation independently by the polarity. (C) Views of the map of the electrical field expressed in normalE (E_normal) (V/m) showing the polarity (anodal/cathodal) of the stimulation.

      Electrophysiological Measurement Empathy

      To assess EEG measuring empathy, the patients had to perform a passive viewing empathy task (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ). This task was designed to measure empathic abilities through EEG. This task consists of 95 pictures displaying scenes for 6000 ms with an aggressive interaction (40), a neutral interaction (40), or a neutral object (i.e., fillers; 15). The aggressive pictures consisted of either a sexual, verbal, or physical interaction. Participants were instructed to view all the pictures passively; in this way, the automatic neural responding in the brain could be determined in the most optimal way (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ).

      State Empathy

      To assess state empathy, the patients had to perform a rating empathy task (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ). Following the passive viewing empathy task, the 95 pictures were presented another time to the patients. In this task, they were instructed to rate the pictures by answering four questions regarding arousal, emotional valence, and empathy for victim and perpetrator.

      Aggression Task

      To assess aggression, we used the PSAP (
      • Cherek D.R.
      Point Subtraction Aggression Paradigm (PSAP).
      ). The PSAP is one of the best-validated paradigms to measure aggression in a lab environment (
      • Geniole S.N.
      • MacDonell E.T.
      • McCormick C.M.
      The Point Subtraction Paradigm as a laboratory tool for investigating the neuroendocrinology of competition.
      ).
      A detailed description of the tasks used in this study included in the Supplement.

      Self-report Questionnaires

      For a complete overview of the self-report questionnaires used in the overall study, see Sergiou et al. (
      • Sergiou C.S.
      • Woods A.J.
      • Franken I.H.A.
      • van Dongen J.D.M.
      Transcranial direct current stimulation (tDCS) as an intervention to improve empathic abilities and reduce violent behavior in forensic offenders: Study protocol for a randomized controlled trial.
      ). The questionnaires used in the analysis of this paper mentioned below and described in more detail in the Supplement.

      Reactive and Proactive Aggression Questionnaire

      In order to index aggression over a week-long period, we used the Dutch translation of the Reactive and Proactive Aggression Questionnaire (RPQ) (
      • Raine A.
      • Dodge K.
      • Loeber R.
      • Gatzke-Kopp L.
      • Lynam D.
      • Reynolds C.
      • et al.
      The reactive–proactive aggression questionnaire: Differential correlates of reactive and proactive aggression in adolescent boys.
      ,
      • Cima M.
      • Raine A.
      • Meesters C.
      • Popma A.
      Validation of the Dutch Reactive Proactive Questionnaire (RPQ): Differential correlates of reactive and proactive aggression from childhood to adulthood.
      ).

      Interpersonal Reactivity Index

      In order to assess trait empathy, we used the Dutch translation of the Interpersonal Reactivity Index (
      • Davis M.H.
      A multidimensional approach to individual differences in empathy.
      ,
      • de Corte K.
      • Buysse A.
      • Verhofstadt L.L.
      • Roeyers H.
      • Ponnet K.
      • Davis M.H.
      Measuring empathic tendencies: Reliability and validity of the Dutch version of the Interpersonal Reactivity Index.
      ); this is a commonly used self-report instrument designed to assess empathic tendencies.

      The Alcohol Use Disorders Identification Test

      In order to assess alcohol use, we used the Dutch translation of the Alcohol Use Disorders Identification Test (
      • Babor T.F.
      • Higgins-Biddle J.C.
      • Saunders J.B.
      • Monteiro M.G.
      The Alcohol Use Disorders Identification Test: Guidelines for Use in Primary Care World Health Organization.
      ,
      • Allen J.P.
      • Litten R.Z.
      • Fertig J.B.
      • Babor T.
      A review of research on the Alcohol Use Disorders Identification Test (AUDIT).
      ). The ten-item Alcohol Use Disorders Identification Test includes questions to assess alcohol, intake, alcohol dependence, and alcohol-related problems.

      The Drug Use Disorders Identification Test

      In order to assess drug use, we used the Dutch translation of the Drug Use Disorders Identification Test (
      • Berman A.H.
      • Bergman H.
      • Palmstierna T.
      • Schlyter F.
      Evaluation of the Drug Use Disorders Identification Test (DUDIT) in criminal justice and detoxification settings and in a Swedish population sample.
      ,
      • Berman A.H.
      • Palmstierna T.
      • Källmén H.
      • Bergman H.
      The self-report drug use disorders identification test: Extended (DUDIT-E): Reliability, validity, and motivational index.
      ). The Drug Use Disorders Identification Test is an eleven-item screening instrument to assess nonalcohol drug use patterns and various drug-related problems.

      EEG Recording

      EEG was recorded using a mobile version of the Brain Products Active-Two System amplifier (Brain Products GmbH). Thirty-two electrodes were placed on the scalp of each participant following the international 10–20 EEG-system. Two other additional electrodes were placed vertically above and beneath the left eye (electro-oculogram); the electrodes for the left and right mastoid placement were incorporated in the EEG cap. The EEG and electro-oculogram signals were digitized with a sampling rate of 500 Hz and 24-bit analog-to-digital conversion with offline filtering.

      EEG Data Preprocessing

      Data were preprocessed offline using Brain Vision Analyzer (Brain Products GmbH). Segmentation was done per condition (neutral vs. aggression) for both P3 and LPP at pretest and posttest, in an interval of 1200 ms (−200 to 1000 ms) [see Van Dongen et al. (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      )] relative to stimulus presentation. Next, the data were filtered using a bandpass filter ranging from 0.01 to 30 Hz (phase shift-free Butterworth filters; 24 dB/octave slope), the signal was corrected for ocular artifacts using the Gratton and Coles algorithm (
      • Gratton G.
      • Coles M.G.
      • Donchin E.
      A new method for off-line removal of ocular artifact.
      ), trials with remaining artifacts (i.e., segments with an EEG signal exceeding an amplitude of 100 μV) were excluded from further analysis (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ), and data were baseline-corrected (200 ms preresponse or prestimulus period served as baseline). Nine participants had to be removed from the analyses owing to excessive amounts of artifacts in the data (i.e., <15 artifact-free segments). Bad channels with too many artifacts were corrected with topographical interpolation. This resulted in a set of EEG data of 41 participants, 21 in the sham condition and 20 in the active tDCS condition.
      Because the highest amplitude of P3 and LPP typically is seen at Pz (
      • Ikezawa S.
      • Corbera S.
      • Wexler B.E.
      Emotion self-regulation and empathy depend upon longer stimulus exposure.
      ,
      • Polich J.
      Updating P300: An integrative theory of P3a and P3b.
      ), inspection of the grand average ERPs demonstrated a maximal amplitude for aggressive pictures around 400 ms after stimulus onset (P3) and followed by the slow wave activity of the LPP, which returned to baseline after 6000 ms. For analyzing the ERPs, the P3 amplitude was defined as the mean amplitude of the Pz between 350 and 450 ms after stimulus onset (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ,
      • Decety J.
      • Yang C.Y.
      • Cheng Y.
      Physicians down-regulate their pain empathy response: An event-related brain potential study.
      ). The LPP was analyzed at the mean amplitude of the Pz between 500 and 1000 ms after stimulus onset (
      • Van Dongen J.D.M.
      • Brazil I.A.
      • Van Der Veen F.M.
      • Franken I.H.A.
      Electrophysiological correlates of empathic processing and its relation to psychopathic meanness.
      ,
      • Hajcak G.
      • Dunning J.P.
      • Foti D.
      Motivated and controlled attention to emotion: Time-course of the late positive potential.
      ). The average signal per condition was then used for determining the characteristics of the ERP.

      Statistical Analyses

      Self-report and the electrophysiological outcomes were analyzed using SPSS 25 (IBM Corp.). To test the differences between the active and the sham group from pre- to posttest on the state empathy following the aggression versus the neutral condition, four 2 (time; pre vs. post) × 2 (group; active tDCS vs. sham) analyses of variance were conducted for the scoring on arousal, emotional valence, victim, and perpetrator. Similarly, to test the differences between the active and the sham group from pre- to posttest on state aggression (PSAP), a repeated measures analysis of variance was performed. Aggression was indicated by the proportion of aggressive responses, that is, the number 2 (aggressive response option) presses divided by the total amount of presses (i.e., [no. option 2]/[no. of total button presses]).
      To investigate the electrophysiological outcomes of the P3 and LPP, two 2 (time; pre vs. post) × 2 (emotion; aggressive vs. neutral) × 2 (group; active tDCS vs. sham) repeated measures analyses of variance were conducted. For all statistical tests, the level of significance was set at p < .05.

      Results

      The result from the HD-tDCS simulation (Figure 1B) demonstrates that the vmPFC was reached with intensity sufficient to induce effect of the stimulation (0.11–0.2 V/m) (see the Supplement for details).
      See Table S1 for a report on adverse effects. Descriptive statistics for all the measures used in this study, including all the self-report questionnaires, can be found in Table 2. Results showed no significant difference between medication use and the two conditions (tDCS and sham), χ23 (N = 50) = 3.1, p = .378 (Table S2).
      Table 2Descriptive Statistics for Self-report Questionnaires, Rating Task, PSAP, P3, and LPP Amplitudes
      VariabletDCS GroupSham Group
      MeanSDRangeMeanSDRange
      Time 1 (Pretest)
      DIFF_Arousal2.522.14−0.40 to 7.283.992.490.08 to 7.47
      DIFF_Emotion−1.152.34−4.15 to 4.63−2.182.35−6.95 to 3.3
      DIFF_Victim1.761.89−3.07 to 5.052.112.60−3.42 to 6.65
      DIFF_Perpetrator−1.221.99−3.75 to 4.00−2.332.056.80 to 1.60
      PSAP0.120.090.0 to 0.470.090.100.00 to 0.37
      RPQ Total21.088.146 to 4317.688.616 to 39
      RPQ Reactive12.484.013 to 2211.404.374 to 22
      RPQ Proactive8.604.692 to 216.284.820 to 17
      IRI Total55.0014.7326 to 8456.6014.6033 to 88
      SRP-SF Total78.5614.2854 to 9872.8820.5443 to 133
      AUDIT12.3512.610 to 3711.4112.760 to 40
      DUDIT22.4412.510 to 4018.7413.630 to 40
      P3 Amplitude NEU2.415.23−7.91 to 11.592.934.25−4.87 to 11.89
      P3 Amplitude AGG3.344.38−5.56 to 14.143.214.97−8.74 to 12.82
      LPP Amplitude NEU1.296.86−18.21 to 15.191.764.85−9.92 to 11.52
      LPP Amplitude AGG2.425.48−13.43 to 10.233.275.85−10.13 to 13.13
      Time 2 (Posttest)
      DIFF_Arousal2.782.44−1.05 to 7.553.292.61−0.23 to 7.60
      DIFF_Emotion−1.382.33−5.72 to 3.45−1.732.17−7.25 to 1.90
      DIFF_Victim1.452.24−4.00 to 3.781.272.86−3.75 to 7.60
      DIFF_Perpetrator−1.743.773.95 to 3.77−1.672.34−7.60 to 2.60
      PSAP0.070.070.0 to 0.330.150.190 to 66
      RPQ Total18.589.668 to 4516.368.532 to 36
      RPQ Reactive11.204.713 to 2210.324.252 to 20
      RPQ Proactive7.375.540 to 236.044.750 to 16
      IRI Total56.3010.4539 to 7556.4512.6637 to 80
      SRP-SF Total74.9618.0937 to 11365.3215.8528 to 99
      AUDIT13.7613.030 to 378.369.180 to 33
      DUDIT19.9511.590 to 3814.4712.200 to 38
      P3 Amplitude NEU3.132.99−1.87 to 8.650.513.96−8.14 to 8.89
      P3 Amplitude AGG4.183.85−1.87 to 13.591.796.12−12.57 to 14.73
      LPP Amplitude NEU2.155.87−19.45 to 10.44−0.113.79−12.88 to 5.68
      LPP Amplitude AGG5.203.65−0.89 to 13.092.826.04−17.48 to 12.18
      AGG, aggression condition; AUDIT, Alcohol Use Disorder Identification Test; DIFF, difference score; DUDIT, Drug Use Disorder Identification Test; IRI, Interpersonal Reactivity Index; LPP, late positive potential; NEU, neutral condition; PSAP, Point Subtraction Aggression Paradigm; RPQ, Reactive Proactive Aggression Questionnaire; SRP-SF, Self-Report Psychopathy Short Form.

      State Empathy Outcomes

      Concerning state empathy, there were no significant main effects for arousal, emotional valence, empathy for victim, or empathy for perpetrator between the tDCS group and the sham group from pre- to posttest. Furthermore, we did not find any significant interaction effects.

      Aggression Outcomes

      Regarding the PSAP task, there were no significant main effects for time or group.
      We did find a significant time × group interaction effect (Figure 2) , with F1,48 = 5.87, p < .019, ηp2 = 0.11. Post hoc tests revealed that the effect is significant (p = .027) for the tDCS group and not significant for the sham group (p = .192). These results imply that the decrease in aggression from pre- to posttest was significantly stronger in the tDCS group than in the control group, with a moderate to large effect (
      • Cohen J.
      Statistical Power Analysis for the Behavioral Science.
      ).
      Figure thumbnail gr2
      Figure 2Proportion of aggressive responses on the Point Subtraction Aggression Paradigm (PSAP) for the sham group and active transcranial direct current stimulation (tDCS) group from pre- to posttest. ∗Significant effect at p ≤ .05.

      Self-report Questionnaires

      Regarding the RPQ, we found a significant effect of time on the RPQ total score F1,47 = 9.51, p = .003, ηp2 = 0.25) and RPQ reactive aggression subscale (F1,48 = 10.68, p = .002, ηp2 = 0.19) over the two groups. There were no main effects of group. These results indicate a significant reduction in self-reported reactive aggression after the intervention as compared with the pretest across both groups. There were no significant findings for the Self-Report Psychopathy Short Form, Interpersonal Reactivity Index, Alcohol Use Disorders Identification Test, or Drug Use Disorders Identification Test.

      P3 and LPP

      See Figure 3 for an overview of the grand average of P3 and LPP in the active tDCS and sham group from pre- to posttest.
      Figure thumbnail gr3
      Figure 3(A) Event-related potentials grand mean recorded at Pz during the passive empathy task for the active high-definition–transcranial direct current stimulation condition. (B) Event-related potentials grand mean recorded at Pz during the passive empathy task for sham condition.
      Analyses of the P3 amplitude showed no significant main effect for time, group, or emotion. The results indicated a significant interaction effect between time and group (F1,39 = 4.52, p = .040, ηp2 = 0.10) but not for emotion. Follow-up t tests revealed that the sham group showed a significant (t20 = 3.07, p < .01) decrease in P3 amplitude from pretest (mean = 3.07, SD = 3.82) to posttest (mean = 1.47, SD = 4.76). Graphs are displayed in Figure 4.
      Figure thumbnail gr4
      Figure 4(A) Intervention effects on the P3 amplitude (μV) for the active transcranial direct current stimulation (tDCS) group on emotion from pre- to posttest. (B) Intervention effects on the P3 for the sham group on emotion from pre- to posttest. (C) Intervention effects on the P3 post hoc between the active tDCS group and the sham group from pre- to posttest.
      Analyses of the LPP amplitude resulted in a significant main effect for emotion (F1,39 = 5.62, p = .023, ηp2 = 0.13), meaning that aggression pictures led to higher LPP amplitudes compared with the neutral pictures in both groups. There were no main effects for time or group. In addition, we found a significant interaction effect between time and group (F1,39 = 5.66, p = .022, ηp2 = 0.009). Follow-up t tests revealed that the tDCS group showed a significant (t19 = −2.29, p = .03) increase in LPP amplitude compared with the sham group, from pre- to posttest, independent of emotion, meaning an overall increase in amplitude after the intervention for the tDCS group. Graphs are displayed in Figure 5.
      Figure thumbnail gr5
      Figure 5(A) Intervention effects on the late positive potential (LPP) amplitude (μV) for the active transcranial direct current stimulation (tDCS) group on emotion from pre- to posttest. (B) Intervention effects on the LPP for the sham group on emotion from pre- to posttest. (C) Intervention effects on the LPP post hoc between the active tDCS group and the sham group from pre- to posttest.
      To check whether the increase in LPP amplitude from pre- to posttest for both aggression and neutral pictures was also present in the filler pictures, an additional analysis was performed (see the Supplement). Results showed no significant effects on time, group, or emotion.

      Discussion

      The aim of this study was twofold. First, we examined HD-tDCS as an intervention to increase empathic abilities and reduce violent behavior in forensic patients with a substance dependence. Second, we examined the HD-tDCS effects on the electrophysiological responses (P3 and LPP) to situations depicting victims of aggression. Because the intervention was the tDCS treatment in addition to TAU, all the found effects are a product of the interaction between the intervention (or placebo) and the TAU.
      Results showed no effects of tDCS on state empathy. Although this is not what we had expected, it can be explained by the fact that the vmPFC may not be directly related to empathic abilities. As shown in the model of Blair (
      • Blair R.J.R.
      Applying a cognitive neuroscience perspective to the disorder of psychopathy.
      ), decreased activity in the vmPFC is linked to impaired social and affective decision making, and the vmPFC is found to be involved in perspective-taking and regulating emotions (
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      Consistent with our hypothesis, we found a reduction in reactive aggression on the aggression task from pre-to posttest in the active tDCS group compared with the sham group. Additionally, we found the same effect for self-reported reactive aggression and the total aggression score as measured with the RPQ. The reduction of reactive aggression is consistent with previous findings on the associating between the vmPFC and aggressive behavior (
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      ), which demonstrates that diminished activity in the vmPFC leads to frustration-based reactive aggression. Consequently, the present study provides insight into the functional role of the vmPFC in reactive aggression and how modulating activity in the vmPFC can reduce aggressive responses in the laboratory setting. Future research has to show the generalizability of these results to violent behavior outside the laboratory.
      With respect to the electrophysiological measures (P3 and LPP), we expected that after a week of tDCS intervention, aggressive pictures would result in larger ERP amplitudes (more arousal, more empathy) compared with neutral pictures. This hypothesis was partly confirmed. Regarding the P3, only an interaction effect was found between time and group, showing that the P3 amplitude decreased from pre- to posttest in the sham group. One of the reasons could be that the inhibitory effect was caused by a learning effect. Studies (
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      Results for the LPP showed an increase in amplitude for the active tDCS group in both emotion conditions; although active tDCS did increase LPP amplitudes as expected, we did not expect that the LPP amplitude would also increase for neutral pictures. An explanation for this finding would be that modulating activity in the vmPFC resulted in a modulation effect in social interactions generally, regardless of the emotions displayed in the pictures. To test this hypothesis, we performed an additional analysis on the filler pictures (i.e., neutral objects) and indeed found no significant effects of tDCS on either the P3 or LPP after viewing filler pictures. Thus, even though the results did not differentiate between neutral or aggressive pictures as proposed, the current results are in line with previous research (
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      ), indicating that the positive slow potentials indicate an increased emotional regulation and affective experience (see the Supplement for detailed description of the additional analysis).
      Our model of current flow indicated that the HD-tDCS stimulation reached the vmPFC with intensity sufficient to induce an effect of the stimulation as also described in earlier studies (
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      ). We do acknowledge that a factor of interindividual variability should also be taking in consideration. Future studies could implement specific algorithms or potential biophysical modeling to individualize montage and take into account the potentially influencing factors contributing to the direction of current flow (
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      ).
      This paper has several strengths. First, this study is the first to find a decrease in aggression in forensic patients using an EEG-tDCS design. Other studies (
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      ) that have shown reduced aggression with tDCS did not include EEG in their protocol, although of significant importance for monitoring the activity of the brain region of interest. Second, we used a design that was double blinded and with multiple sessions of tDCS. It has been demonstrated in several studies (
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      ). Third, in the current study the current flow montage sufficiently reached the vmPFC. We used HD-tDCS, which is found to have a better focality (
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      • Tanaka T.
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      ,
      • Faria P.
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      A finite element analysis of the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in tDCS.
      ), we optimized the intervention by enhancing the brain state of interest during the tDCS sessions (
      • Samani M.M.
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      Titrating the neuroplastic effects of cathodal transcranial direct current stimulation (tDCS) over the primary motor cortex.
      ).
      Albeit promising, our findings should be interpreted in the context of limitations that are important to consider in future studies investigating this matter. First, we found a significant decrease in the P3 amplitude for the sham condition. Future studies should try to correct for learning effects on the P3 by implementing slightly different pictures in the viewing task or have a longer period from pre- to posttest. Second, it might not just be the impairments of the PFC that influence aggression and antisocial behavior but also neural network disruptions associated with that behavior (
      • Raine A.
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      ). Therefore, it would be relevant to investigate neural networks and functional connectivity in understanding aggressive behavior in future studies. Third, future studies should highlight the role of tDCS as a modulator, the effects of tDCS on synaptic activity as according to the Bienenstock-Cooper-Munroe rule (
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      ), and using potential biophysical modeling to individualize montage. Finally, in this study, no long-term effects of the tDCS intervention were examined, nor were effects on violence in real life. Future studies should address these issues to further support the effectiveness of this tDCS intervention.

      Conclusions

      The development of successful evidence-based therapeutic interventions in forensic mental health is crucial for reducing violence risk. To our knowledge, this is the first study investigating HD-tDCS as an intervention to increase empathic abilities and reduce violent behavior in a forensic sample and that also examined the effects on electrophysiology. Our results showed that multiple sessions of HD-tDCS targeting the vmPFC resulted in reduced aggression. In addition, this modulation also resulted in increased LPP amplitudes after viewing aggressive pictures, indicating an increase in attention to, and emotional evaluation of, scenes depicting victims of aggression. Hence, our results significantly improved our understanding of the neural correlates of aggression posed by violent individuals, and although they must be interpreted with caution when implicating in a real-life setting, they support the effectiveness of tDCS as treatment intervention in forensic patients.

      Acknowledgments and Disclosures

      CSS received a grant from the Prins Bernhard Cultuurfonds (Grant No. 40032672/MAK/ILE) and a grant from the ZonMw (Grant No. 446001064), both located in the Netherlands; ES is supported by the Beth Israel Deaconess Medical Center via the Chief Academic Officer Award 2017; and JDMvD was sponsored by the program Kwaliteit Forensische Zorg of the Expertise Center Forensic Psychiatry (Grant No. 2017-68), Stiching Koningsheide, and Stichting Volksbond Rotterdam in the Netherlands. ES is partially supported by Office of the Director of National Intelligence, Intelligence Advanced Research Projects Activity (Grant No. 2014-13121700007); the Defense Advanced Research Projects Agency (Grant No. HR001117S0030); and the National Institutes of Health (Grant Nos. P01 AG031720-06A1, R01 MH117063-01, and R01 AG060981-01). The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Office of the Director of National Intelligence, Intelligence Advanced Research Projects Activity, or the U.S. Government. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University and its affiliated academic health care centers, or the National Institutes of Health.
      We thank Nico van Beveren for the supervision of the project at the forensic clinics and the departments Forensic Addiction Clinic and Department of Forensic Care and staff for their cooperation. Furthermore, we thank Alix Weidema, Celine de Reus, Thijs Vlak, Jitse Holl, Rozemarijn Pons, and Aylin Dasdemir for their contribution in collecting the data.
      A previous version of this article was published as a preprint on PsyArXiv: https://doi.org/10.31234/osf.io/cjgdt.
      The authors report no biomedical financial interests or potential conflicts of interest.
      Dutch Trial Register: Trial NL7459; https://www.trialregister.nl/trial/7459; NTR7701.

      Supplementary Material

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