Neurocase The Neural Basis of Cognition ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/nncs20 tDCS for auditory verbal hallucinations in a case of schizophrenia and left frontal lesion: efield simulation and clinical results Eva Mezger , Andre R. Brunoni , Alkomiet Hasan , Jan Häckert , Wolfgang Strube , Daniel Keeser , Frank Padberg & Ulrich Palm To cite this article: Eva Mezger , Andre R. Brunoni , Alkomiet Hasan , Jan Häckert , Wolfgang Strube , Daniel Keeser , Frank Padberg & Ulrich Palm (2020): tDCS for auditory verbal hallucinations in a case of schizophrenia and left frontal lesion: efield simulation and clinical results, Neurocase, DOI: 10.1080/13554794.2020.1776334 To link to this article: https://doi.org/10.1080/13554794.2020.1776334 Published online: 12 Jun 2020. Submit your article to this journal Article views: 4 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=nncs20 NEUROCASE https://doi.org/10.1080/13554794.2020.1776334 CASE REPORT tDCS for auditory verbal hallucinations in a case of schizophrenia and left frontal lesion: efield simulation and clinical results Eva Mezgera, Andre R. Brunoni a,b, Alkomiet Hasana,c,d, Jan Häckerta, Wolfgang Strubea,c,d, Daniel Keesera,e, Frank Padberga and Ulrich Palm a,f a Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Munich, Germany; bDepartment and Institute of Psychiatry, Laboratory of Neurosciences (LIM-27), University of Sao Paulo, São Paulo, Brazil; cPsychotherapy and Psychosomatics of the University of Augsburg, Bezirkskrankenhaus Augsburg, Augsburg, Germany; dMedizinische Fakultät, Universität Augsburg, Augsburg, Germany; eInstitute for Clinical Radiology, Klinikum der Universität München, Munich, Germany; fHospital for Psychosomatics, Medical Park Chiemseeblick, Bernau-Felden, Germany ABSTRACT ARTICLE HISTORY Transcranial direct current stimulation (tDCS) has been explored for treatment of several neuropsychiatric disorders. For tDCS use in structural brain lesions there is some evidence from motor stroke rehabilitation and post-stroke depression. Here we report the application of tDCS in a woman previously diagnosed with schizophrenia presenting refractory auditory verbal hallucinations and left prefrontal tissue lesion. Treatment with 20 left fronto-temporal tDCS had no effect on psychiatric symptoms and neuropsycholo­ gical evaluation. An ex-post electric field simulation and calculation of dorsolateral prefrontal cortex activation showed lower activation in this patient compared to a matched non-lesioned schizophrenia, and healthy control brain. Received 11 March 2020 Accepted 25 May 2020 Introduction Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique that consists in the application of weak currents through electrodes placed over the head, has gained growing importance in the treatment of neuropsychia­ tric disorders in the last years. There is a bottom of evidence for its efficacy in depressive disorders (Brunoni et al., 2016), schizophrenia (Mondino, Brunelin, et al., 2015), substancerelated disorders (Lupi et al., 2017), pain syndromes (Lefaucheur et al., 2017) and stroke rehabilitation (Grefkes & Fink, 2016). However, mixed results were also observed for tDCS use in most disorders (Lefaucheur et al., 2017), pointing out the need for sufficiently powered studies, but also symptom heteroge­ neity, e.g., after motor stroke, could attribute to divergent results (Grefkes & Fink, 2016). Inconsistent results are also seen in the neurophysiological and neuropsychological reha­ bilitation of traumatic brain injury with tDCS. Evidence for improvement of cognitive dysfunction and altered states of consciousness in these patients is sparse (Dhaliwal et al., 2015; Li et al., 2015), and especially in severely ill patients, tDCS had no sustained impact on the improvement of attention, mem­ ory, and cognitive flexibility (Lesniak et al., 2014). In psychiatric patients with concomitant structural or func­ tional brain alterations, the evidence of tDCS-driven allevia­ tion of psychiatric symptoms is also sparse. A recent case report on tDCS treatment in a patient with bipolar depression and concomitant posterior reversible encephalopathy syn­ drome (PRES) showed modest mood improvement, and safety of tDCS intervention in a patient with altered brain morphol­ ogy was proven (Palm, Padberg, et al., 2015). In a randomized CONTACT Ulrich Palm tDCS2012@googlemail.com © 2020 Informa UK Limited, trading as Taylor & Francis Group KEYWORDS tDCS; hemangioma; current distribution clinical trial evaluating the efficacy of tDCS for post-stroke depression, tDCS was found to be more active than sham and the location of the lesion did not influence the results (Valiengo et al., 2016). Here, we report for the first time a case of schizophrenia with left prefrontal brain tissue lesion, trea­ ted with left-hemispheric tDCS for refractory auditory verbal hallucinations. In addition, a simulation of the electric field (efield) was performed and compared to another matched schizophrenia patient and a healthy control. Case report Upon admittance to our tertiary care hospital, the 57-year-old woman was suffering from treatment-resistant auditory verbal hallucinations (commanding and insulting character). She was diagnosed with paranoid schizophrenia 20 years ago and had been stable over 14 years with pimozide 2 mg after the first episode. Re-exacerbation started 3 years ago and was initially treated with olanzapine and amisulpride. Initial improvement was followed by a phase of deterioration with two suicide attempts due to the commanding voices. She was then trea­ ted with clozapine which had to be stopped due to recurrent leukopenia; haloperidol led to adynamia. The following elec­ troconvulsive therapy (ECT) had to be discontinued after car­ diac deterioration and a seizure related to ECT, leading to prevention treatment with lamotrigine. Before actual admis­ sion to our hospital, she was treated in another psychiatric university hospital as an inpatient for several months with various psychopharmacological regimens. The first, consisting of amisulpride 800 mg and olanzapine 25 mg, brought no relief of hallucinations, lamotrigine 200 mg for seizure 2 E. MEZGER ET AL. Figure 1. (a) T1 anatomical scans in coronal, sagittal, and transversal projection showing a 2.8 × 1.9 cm tissue lesion in the left frontal cortex; (b) Freesurfer 3D reconstruction of the T1 anatomical scans – red circle marks the lesion; (c) electrode placement: anode over F3, cathode over left TPJ (Tp3). prevention was continued. A change of regimen to olanza­ pine/perphenazine/lamotrigine led to cognitive deficits, a new combination consisting of olanzapine/asenapine/ser­ traline/lamotrigine and intensive cognitive-behavioral psy­ chotherapy did not change symptoms. Upon admittance, she was receiving olanzapine 20 mg, asenapine 10 mg, lamo­ trigine 275 mg, sertraline 25 mg, and lorazepam 0.5 mg for at least 4 weeks. Her medical history comprised arterial hypertension and the resection of hemangioma in the left frontal cortex 2 years ago and a re-resection 1 year ago, resulting in a ­ 2.8 × 1.9 cm tissue lesion in the left frontal cortex (Figure 1 (a-c)). Surgery did not change the intensity and frequency of auditory verbal hallucinations, volition, and impetus. Laboratory workup and cerebrospinal fluid did not reveal pathologies. FDG-PET did not show a neurodegenerative pattern, EEG was normal without epileptiform discharges under lamotrigine. Methods Transcranial direct current stimulation Decision for a compassionate treatment with noninvasive brain stimulation was made after receiving written and oral informed consent from the patient and her custodian. ECT and repetitive transcranial magnetic stimulation (rTMS) were excluded for safety reasons (intracranial pressure) after brain surgery and seizure history, therefore tDCS was considered. Medication was kept stable and a series of 20 tDCS within 10 days sparing the week-end was performed following a recent report on the safety and efficacy of twice-daily tDCS (Palm, Leitner, et al., 2015). For stimulations, a neuroConn Eldith DC-stimulator was used. Saline-soaked sponge electrodes (35 cm2) were mounted over the head and fixed with rubber bands. The anode was placed left dorsolateral prefrontal cortex (DLPFC, F3 position according to the international 10–20 system with standard EEG cap), the cathode was placed over the left temporoparietal NEUROCASE 3 Figure 2. (a) Electrical field modeling in the lesioned brain of the schizophrenia patient; (b) electrical field modeling in an age- and gender-matched healthy control brain; (c) electrical field modeling in an age- and gender-matched schizophrenia patient. junction (TPJ, T3-P3 position). This montage was previously reported to be effective for auditory hallucinations (Mondino, Brunelin, et al., 2015). Left-hemispheric electrode placement was chosen on the salience of auditory verbal hallucinations in this right-handed patient (Edinburgh Handedness Test: 92%). Current intensity was set to 2 mA, duration of each single session was 30 minutes with 15-second fade-in and fade-out, separated by an interval of approximately 3 hours in the morn­ ing (e.g., 8:00, 11:00). Clinical measures Clinical (Positive and Negative Symptom Scale, PANSS; Psychotic Symptom Rating Scale, PSYRATS auditory hallucination subscale; Calgary Depression Scale in Schizophrenia, CDSS) and neuropsy­ chological (Letter-Number-Span, LNS; Thesaurus Test, WST1; Repeatable Battery for the Assessment of Neuropsychological Status, RBANS) measures were assessed before and 1 week after the end of stimulation series (4 weeks after baseline) to give enough time for neuroplasticity changes. Electrical field simulation Electrical field (efield) simulations were conducted after the treatment for an exploratory clarification of the clinical null result. Major steps for efield modeling are the segmentation of MRI anatomical pictures into different tissue types, applying conduc­ tivities to each tissue, placing the electrodes, and solving the finite element model (FEM) equation for voltage distribution. We used SimNIBS 2.0.1. (Windhoff et al., 2013) to model efield distribution and efield strength. SimNIBS relies on open-source packages such as FreeSurfer (http://surfer.nmr.mgh.harvard.edu/ 4 E. MEZGER ET AL. ), FMRIB FSL, MeshFix, Gmsh, and python. FreeSurfer uses a surface-based approach (SBA) for analyzing brain morphome­ try. The brain reconstruction is based on geometric models of the cortical surface, where highly detailed models of gray and white matter surfaces are constructed (Veldsman & Michele, 2017). After segmentation, meshing of the individual brain is conducted by Gmsh, and FEM is solved by getDP (http://getdp. info/). Using an in-house python script, surface-based data files of the efield simulation were converted to volumetric space to calculate voxel intensities and number of activated voxels of the efield. The DLPFC ROI was selected using the Sallet et al. dorsal PFC parcellation atlas (Sallet et al., 2013), as this atlas is highly eligible for volumetric data. Mean intensity and number of activated voxels were extracted using FSL. A Matlab script, kindly provided by the SimNIBS developers, was used to calcu­ late peak field strength and percentiles of efield strength. Efield results of the schizophrenia patient presented here were contrasted to a non-lesioned, age- and gender-matched brain of a schizophrenia patient as well as a non-lesioned, ageand gender-matched healthy participant. Results Twenty sessions of tDCS using a left-hemispheric frontotemporal electrode montage did not result in clinically meaningful changes of the PANSS (−3.8%) or PSYRATS auditory hallucination subscale (±0%) (Table 1). PANSS subscales showed a reduction in the positive scale from 17 to 13, and an increase in the cognition scale from 20 to 23. CDSS increased from 3 to 5 points, however still below the cutoff for a relevant depression (Mucci et al., 2017). RBANS categories revealed deficits in immediate memory, visuospatial/constructional, attention, and delayed memory before stimulation; only in language and picture naming, an above-average score was reached. Also, in WST, the patient had Table 1. Psychometric results before and after intervention. PANSS sum score Subscales Positive Negative Cognition Excitement/Hostility Depression/Anxiety PSYRATS auditory hallucination subscale CDSS sum score LNSb WSTc RBANSd Immediate memory words Immediate memory story Delayed recall words Delayed recall story Visuospatial figure Attention words Attention digit-span Language semantic fluency Language naming a Baseline 74 1 week after 72 Changes in Percent −3.8%a 17 20 20 7 10 30 13 20 23 6 10 30 ±0% 3 4 139 5 4 136 +60% ±0% −2.1% 65 63 70 <48 64 83 51 59 >106 65 61 70 <48 103 90 <40 48 >106 ±0% −3.2% ±0% ±0% +60.9% +8.4% −21.6% −18.6% ±0% Calculation based on (PANSSBaseline – PANSSEnd) x 100/(PANSSEnd – 30); b Letter Number Span. c Wortschatztest (thesaurus test): percentage score is reported; d Repeatable Battery for the Assessment of Neuropsychological Status: normalized total scores are reported. an above-average result (139%) whereas LNS was below average. After stimulation, a relevant improvement was found for RBANS visuospatial, figure copy (+60%), a deterioration was found for RBANS attention, digit span (−21%), and semantic language fluency (−18%). WST after intervention was 136%. Overall, there is no relevant or clear direction of changes in neuropsychological results (Table 1). tDCS was well tolerated; there was no side effect from the stimulation itself, discomfort was not spontaneously reported. Efield simulation With SimNIBS 2.0.1, using surface-based morphometry, the brain lesion of the patient was sufficiently reconstructed as can be seen when comparing the 3D mesh of the brain to the actual T1 anatomical scan (Figure 1(a,b)). The peak electric field strength in the lesioned brain was 0.942 V/m. As the highest peak could be driven by just one single activated voxel, percentiles are suitable for reliability. 0.5% of the highest efield values were calculated at 0.53 V/m, 1% at 0.47 V/m, and 5% at 0.34 V/m. Compared to the brain of the Schizophrenia patient with morphological abnormalities, the age- and gender-matched healthy brain showed a peak efield strength of 1.114 V/m, 0.5% of the highest efield values was calculated at 0.7 V/m, 1% at 0.65 V/m, and 5% at 0.5 V/m. An age- and gender-matched schizophrenia patient (no mor­ phological abnormalities) showed a peak efield strength of 0.76 V/m, 0.5% of the highest efield values calculated at 0.46 V/m, 1% at 0.41 V/m, and 5% at 0.31 V/m (Table 2). Using FSL, mean efield intensity and number of activated voxels were calculated from the transformed data into volu­ metric space. A mean efield intensity of 0.004 V/m emerged in the here specified Schizophrenia patient. The brain of the schizophrenia patient without morphological abnormalities showed 0.003 V/m and the brain of the healthy control 0.006 V/m, respectively. In total, 34,007.02 voxels were activated in our patient, 21,002.00 voxels in the brain of the schizophrenia patient with­ out morphological abnormalities, and 97,656.02 voxels in the healthy brain. Mean voxel intensity within the DLPFC was found to be 0.002 V/m in the Schizophrenia patient with morphological changes, 0.051 V/m in the Schizophrenia patient without mor­ phological changes, and 0.052 V/m in the healthy control. Forty-three voxels were activated within the DLPFC in the Schizophrenia patient, 1104 in the Schizophrenia match with­ out morphological changes, and 1344 in the healthy control. Discussion A tDCS series over 10 days with twice-daily stimulation exerted no clinical and neuropsychological improvement in a patient with treatment-refractory auditory verbal hallucinations and a left prefrontal brain tissue lesion. This contrasts with previous findings observed in other neuropsychiatric disorders; how­ ever, there is effectiveness of 50–60% to treat auditory verbal hallucinations in the non-lesioned schizophrenia brain by tDCS. We discuss possible reasons for the absence of meaningful effects in our case. NEUROCASE 5 Table 2. Electrical field modeling parameters. Peak electrical field (V/m) 99.5 Percentile (V/m) 99 Percentile (V/m) 95 Percentile (V/m) Number of activated voxels Intensity of activated Voxels (V/m) Number of activated voxels (DLPFC) Intensity of activated Voxels (V/m; DLPFC) Schizophrenia patient (morphological abnormalities) 0.942 0.53 0.47 0.34 34,007.02 Schizophrenia patient (non-lesioned brain) 0.76 0.46 0.41 0.31 21,002.00 Healthy control 1.114 0.7 0.65 0.5 97,656.02 0.004 43 0.002 0.003 1104 0.051 0.006 1344 0.052 One possible reason is the severe morphological abnormality observed in this patient. Neuronal networks between prefrontal cortex and temporoparietal junction (Van den Heuvel et al., 2009) may be affected by the tissue lesion. These networks have been identified in several studies to account for auditory verbal hallu­ cinations (Hoffman & Hampson, 2012). A restoration of disturbed network connections is attributed to clinical improvement of auditory hallucinations (Mondino, Jardri, et al., 2015). The tissue lesion, thus, might represent disrupted frontoparietal network connectivity, undermining tDCS effects. The morphological abnormalities might have also affected the electric current distribution in the brain. In a computer modeling study, the montage used here (anode: prefrontal cortex, cathode: temporoparietal junction) was found to induce a spread of electrical current in brain areas associated with schizophrenia pathophysiology, such as the cingulate cortex, basal ganglia, and insula (A. R. Brunoni et al., 2015). Whereas the direct stimulation of the temporoparietal junction and prefron­ tal cortex might induce symptom improvement, current flow between these regions might be important for long-term tDCS effects. In this context, a computer modeling study has shown that stroke lesions (Datta et al., 2011) affect both peak current density under the electrodes and brain electric current distribu­ tion. On the other hand, contralateral electrode montage (i.e., left TPJ cathodal stimulation and right DLPFC anodal stimula­ tion) might bring more benefit when considering that the current is spreading through deeper brain structures. Clinical issues might also explain the poor tDCS response. For instance, lamotrigine might have attenuated tDCS effects due to its effects on voltage-gated sodium channels (Nitsche et al., 2012). Nonetheless, medication was kept stable to avoid the destabilization of psychiatric symptoms and risk of seizure. In addition, the patient presented a refractory, chronic schizo­ phrenia course, in which poor results are observed despite less of the proposed intervention. Finally, the optimal protocol for tDCS schizophrenia treatment is still under dispute. For instance, Brunelin et al. (Brunelin et al., 2012) showed clinical results on auditory verbal hallucinations using 10 tDCS sessions (5 days, twice daily), whereas a longer treatment and higher total current dosage in our case had no effect. Electrical field simulation We exploratory used the simulation software SimNIBS 2.0.1 to investigate simulation effects in a morphological abnormal brain and to find possible explanations for treatment outcomes. Compared to an age- and gender-matched healthy brain, efield strength was attenuated in the morphological abnormal brain. We hypothesize this may be due to an interruption of continuous current flow and radial spread of current through the lesion filled with corticospinal fluid (CSF) (see Figure 1(a)). CSF has a very high conductance for electrical current, inducing a fast current spread losing strength and direction, resulting in a loss of focality (Reinhart et al., 2017). The current does not spread with a normal radiation through the cortex (Thair et al., 2017). This is corroborated by percentiles showing lower efield strengths. Similar results of reduced mean voxel intensity and activated voxels were seen within the DLPFC ROI. The non-lesioned schizophrenia brain does not show a relevant difference in the efield strength compared to the lesioned brain. Shown in the 3D reconstruction, ventricles are larger compared to the healthy brain. As ventricles are filled with CSF presenting a high conductance for electrical current leading to a greater spread of efield and faster loss of efield strength, this could be an explanation for lower efield strength in patients with larger ventricles. Within the DLPFC, ROI efield represented by number of activated voxels and mean intensity of voxels does not show relevant differences between healthy control and non-lesioned schizophrenia patient. However, patients react individually to stimulation and show different current spread according to anatomical differences (Kim et al., 2014). Clinical trials reported on tDCS responders ranging from 40% to 80%, amongst others because of anato­ mical differences (A. Brunoni et al., 2016). A review of Brunoni and colleagues in 2014 reported efield strengths up to 0.77 V/m in schizophrenia patients. It is still unclear if low efield strength results from a lesioned brain, overall individual anatomy, or functional connectivity changes in psychiatric disorder. In our case study, possible explanations for the low efield would be (1) both patients (lesioned and non-lesioned brain) are probably non-responders to tDCS, or (2) the patient without lesion is a non-responder while the here specified patient does not respond because of the lesion. However, this dichotomy omits the influence of other factors weakening tDCS efficacy, i.e., the overall moderate efficacy of tDCS as mentioned above. Efield modeling was exploratively and ex-post conducted for this single case study, wherefore we compared the patient to only one matched schizophrenia patient and healthy control. Comparisons to larger cohorts of controls will add meaningful 6 E. MEZGER ET AL. data to this field and should be addressed in future studies. It, therefore, remains elusive if lower DLPFC activation in this patient, which is probably due to the lesion, is the reason for the non-response to a neuromodulation approach, but the plenty of confounding factors and the single case data do not allow a further conclusion. Another limitation to this exploratory finding is the absence of electrical simulation software available for injured/lesioned brains, and reconstruction procedures of T1 anatomical images are still under discussion for lesioned brains. Our results demonstrate the need for further investigation and improve­ ment of reconstruction methods and efield models especially for pathological brain structures in the field of psychiatric and neurologic disorders, e.g., stroke rehabilitation. Conclusion In this case report, we showed that frontotemporal tDCS in a patient with prefrontal brain tissue lesion was safe. Efield simulation showed similar current distribution compared to a non-lesioned schizophrenia patient, but lower peak densities compared to a healthy control. The lack of clinical efficacy might be explained by the chronicity of the disorder, the concomitant medication, the inter-individual variability in tDCS treatment response, and the structural damage of frontotemporal neuronal networks. The structural damage could point to the inability to restore neuronal network imbalances in auditory verbal halluci­ nations by tDCS. Processing efield simulations before tDCS treat­ ment could be an interesting approach to individualize treatment strategies. By gaining more knowledge about this method and its improvement, efield simulations could serve as a potential predictor for the grade of responsiveness of a patient to tDCS. Although the result of this case report suffers from many limitations and should not be overestimated, it could serve as a template for further research investigating the impact of tDCS in structurally altered neuronal networks, e.g., by precising cur­ rent distribution with efield simulation. Note 1. Wortschatztest (German Version, Schmidt & Metzler, 1994). This paper-pencil test presents 40 cycles of six words each. Five words are distractors and one word is correct. It measures verbal and premorbid intelligence in patients with organic brain disorders. Acknowledgments This work was funded by the German Federal Ministry of Education and Research (BMBF), grant code 01EE1403E (German Center for Brain Stimulation, http://gcbs.network/gcbs). Disclosure statement UP and FP received paid speakership from Neurocare Group, Munich, Germany. FP received grants from neuroConn, Ilmenau, Germany, and Brainsway Inc., Jerusalem, Israel. UP has a private practice with Neurocare Group. 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